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WO2025155561A1 - Methods of treating long covid - Google Patents

Methods of treating long covid

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Publication number
WO2025155561A1
WO2025155561A1 PCT/US2025/011583 US2025011583W WO2025155561A1 WO 2025155561 A1 WO2025155561 A1 WO 2025155561A1 US 2025011583 W US2025011583 W US 2025011583W WO 2025155561 A1 WO2025155561 A1 WO 2025155561A1
Authority
WO
WIPO (PCT)
Prior art keywords
coronavirus
triol
ene
ethynylandrost
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/011583
Other languages
French (fr)
Inventor
Penelope N. Markham
Christopher L. Reading
Clarence Nathaniel Ahlem
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biovie Inc
Original Assignee
Biovie Inc
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Filing date
Publication date
Application filed by Biovie Inc filed Critical Biovie Inc
Publication of WO2025155561A1 publication Critical patent/WO2025155561A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Long COVID also known as long-haul COVID, post-COVID syndrome, and post-acute sequelae of COVID- 19, refers to a range of symptoms that persist for months beyond the initial phase of COVID- 19 infection. These symptoms can vary widely in severity and type, affecting different systems of the body, such as the lungs, heart, brain, and immune system. Some common symptoms include fatigue, brain fog, altered sense of taste and smell, difficulty in sleeping, and anxiety or depression. Although the exact cause of Long COVID remains unclear, factors such as persistent inflammation, tiny blood clots, autoimmune responses, viral and spike protein persistence, reactivation of dormant viruses like Epstein- Barr, and psychological impacts from severe illness are believed to play a role.
  • aspects of the disclosure relate to a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus.
  • the method includes administering to the subject 17a-ethynylandrost- 5-ene-3P,7P,17
  • the SARS-CoV-2 variant is at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.V 1 Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS- CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.1 , and XEC.
  • a B.1.1.7 variant of SARS-CoV-2 a.k.a. 201/501 Y.V 1 Variant of Concern (VOC) 202012/01
  • a B.1.351 variant of SARS-CoV-2 a.k.a. 20H/501Y.V2
  • the subject has post viral fatigue symptoms.
  • the post viral fatigue symptom is Long COVID.
  • the subject exhibits Long CO VID symptoms comprising at least one symptom selected from the group consisting of fatigue including severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, CO VID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twit
  • the subject did not have post-viral fatigue symptoms before being infected with the virus. In some embodiments, the subject develops the symptoms of post viral fatigue during or after being infected with the virus. In some embodiments, the subject experiences between about a 5% to about 100% improvement in conditions related to the virus. In some embodiments, the subject experiences between about a 5% to about 100% reduction in conditions related to the virus. In some embodiments, the 17a-ethynylandrost-5- ene-3P,7P,17P-triol is administered orally. In some embodiments, the 17a-ethynylandrost-5- ene-3P,7P,17P-triol is administered intravenously.
  • the at least one sign, condition, or symptom of Long COVID is selected from the group consisting of: fatigue include severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry
  • the subject did not have at least one sign, condition, or symptom of Long COVID prior to infection with COVID. In some embodiments, the subject develops the at least one sign, condition, or symptom of Long COVID after three weeks from initial infection with COVID. In some embodiments, the subject experiences between about a 5% to about 100% improvement in at least one sign, condition, or symptom of Long COVID. In some embodiments, the subject experiences between about a 5% to about 100% reduction in at least one sign, condition, or symptom of Long CO VID. In some embodiments, the further includes monitoring the subject for a reduction in symptoms of Long COVID following the administration of 17a- ethynylandrost-5-ene-3P,7P,17P-triol.
  • the patient has been diagnosed with Long Covid for a duration selected from the group consisting of 1 month, 3 months, 6 months, and 1 year.
  • 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered to subjects who have a confirmed diagnosis of Long COVID through a positive COVID-19 antibody test.
  • 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered in combination with a second therapeutic agent selected from the group consisting of anti-inflammatory agents, antiviral agents, and immune modulators.
  • the subject is concurrently receiving physical therapy or cognitive behavioral therapy for symptoms of Long COVID.
  • the at least one sign, condition, or symptom of Long COVID includes neurological symptoms, and the 17a-ethynylandrost-5- ene-3p,7p,17p-triol is specifically administered to treat or alleviate the neurological symptoms.
  • the at least one sign, condition, or symptom of Long COVID are ameliorated or treated within a time period following administration of 17a-ethynylandrost-5- ene-3P,7P,17P-triol, the time period being selected from the group consisting of 2 weeks, 1 month, 3 months, and 6 months.
  • the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered orally.
  • the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered intravenously.
  • the 17oc-ethynylandrost- 5-ene-3p,7p,17P-triol is a solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol.
  • the solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol is crystalline solvate of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol.
  • FIG. 1 illustrates three graphs representing CDR-SB from baseline with NE3107 correlated with changes from baseline in TNFa, phospho-Tau, and AP42/AP40.
  • FIG. 2 illustrates a graph showing the correlation of change of age deceleration of NE3107 versus placebo.
  • FIG. 3 illustrates a double-blind, placebo-controlled, 12-week study design schema.
  • a “formulation” or the like means a composition that one can administer to a subject, e.g., human or animal.
  • Formulations are suitable for human or veterinary applications and would typically have expected characteristics for the formulation, e.g., parenteral formulations for human use would usually be sterile solutions or suspensions.
  • an “excipient”, “carrier”, “pharmaceutically acceptable carrier” or similar terms mean one or more component(s) or ingredient(s) that is acceptable in the sense of being compatible with the other ingredients in the disclosed compositions or formulations and not overly deleterious to the patient, animal, tissues or cells to which the formulation is to be administered.
  • Effective amount refers to the amount required to produce a desired effect (e.g., enhancing the half-life, bioavailability or efficacy of a compound described herein, treating biological aging in a subject, reducing DNA methylation in a subject, etc.
  • subject As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given their ordinary meaning in the art and shall also refer to an organism that has cancer and/or leukemia. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.
  • Preventing in reference to a disease, disorder or condition refers to preventing a disease, disorder or condition, e.g., causing the clinical symptoms of the disease, disorder or condition not to develop.
  • the term “prevent,” “prevents,” or “prevention” may also refer to a delay in the onset of a disease or disorder or the lessening of symptoms upon onset of the disease or disorder. The terms are not meant to imply complete abolition of disease and encompass any type of prophylactic treatment that reduces the incidence of the condition or delays the onset and/or progression of the condition.
  • therapeutically effective amount and “effective amount” refer to the amount of active pharmaceutical ingredient necessary to provide the desired pharmacologic result. In practice, the therapeutically effective amount will vary widely depending on the severity of the disease condition, age of the subject, and the desired therapeutic effect.
  • treatment shall be given their ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
  • VOC VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC.
  • the disease or condition in the subject associated with the virus is post- viral fatigue syndrome.
  • the disease or condition in the subject associated with the virus is post- viral fatigue.
  • the subject exhibits post- viral long-term symptoms.
  • the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63).
  • the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl).
  • the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV.
  • the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV.
  • the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19.
  • the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV).
  • the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov).
  • the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.
  • VOC VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC.
  • the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue.
  • the subject exhibits post-viral long-term symptoms.
  • the disease or condition in the subject associated with the virus is Long COVID.
  • the disease or condition in the subject associated with the virus is chronic Covid.
  • the disease or condition in the subject associated with the virus is long-haul Covid.
  • the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses.
  • the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections.
  • the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection.
  • the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex.
  • the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection.
  • the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia.
  • the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance.
  • the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization.
  • the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia.
  • POTS postural orthostatic tachycardia syndrome
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia.
  • the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects.
  • the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism).
  • the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease.
  • the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
  • methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure: or a pharmaceutical composition comprising the compound.
  • the virus is a coronavirus.
  • the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63(HCoV-NL63).
  • the coronavirus is a beta coronavirus, for example but not limited to, OC43(HCoV-OC43) or HKU1 (HCoV-HKUl).
  • the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV.
  • the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV.
  • the coronavirus is SARS-CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid-19.
  • the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV).
  • the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov).
  • the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a.
  • the disease or condition in the subject associated with the virus is post- viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long CO VID.
  • the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long- haul Covid.
  • the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection.
  • the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'COVID toes', as part of the symptom complex.
  • the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection.
  • the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia.
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia.
  • the virus is a coronavirus.
  • the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63).
  • the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl).
  • the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV.
  • the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV.
  • the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19.
  • the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV).
  • the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov).
  • the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.
  • VOC VI Variant of Concern (VOC) 202012/01), aB.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC.
  • the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia.
  • the virus is a coronavirus.
  • the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63).
  • the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl).
  • the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV.
  • the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV.
  • VOC VI Variant of Concern ( VOC) 202012/01 ), a B .1.351 variant of SARS-CoV-2 (a. k. a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.l.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN. l.1.18, LB. l, and XEC.
  • the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue.
  • the subject exhibits post-viral long-term symptoms.
  • the disease or condition in the subject associated with the virus is Long COVID.
  • the disease or condition in the subject associated with the virus is chronic Covid.
  • the disease or condition in the subject associated with the virus is long-haul Covid.
  • the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses.
  • the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections.
  • the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection.
  • the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'COVID toes', as part of the symptom complex.
  • the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection.
  • methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure:
  • the virus is a coronavirus.
  • the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63).
  • the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl).
  • the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV.
  • the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV.
  • the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19.
  • the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV).
  • the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov).
  • the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.
  • the subject exhibits post-viral long-term symptoms.
  • the disease or condition in the subject associated with the virus is Long COVID.
  • the disease or condition in the subject associated with the virus is chronic Covid.
  • the disease or condition in the subject associated with the virus is long-haul Covid.
  • the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses.
  • the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections.
  • the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection.
  • the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex.
  • the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection.
  • the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia.
  • the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance.
  • the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization.
  • the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia.
  • POTS postural orthostatic tachycardia syndrome
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia.
  • methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of 17-ethynyl- 10/ , 13 -di methyl 2, 3, 4, 7, 8/?, 95, 10, 11, 12, 13, 14S, 15, 16, 17-hexadecahydro-lH-cyclopenta[a]phenanthrene-37?, 7R, 175-triol, which is represented by Formula 1, or a pharmaceutical composition comprising Formula 1.
  • the compound of Formula 1 may also be referred to as Compound 1 or 17oc-ethynylandrost- 5-ene-3p,7p,17P-triol and is represented by the structure below.
  • the coronavirus is SARS- CoV-2 or Covid-19.
  • the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV).
  • the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov).
  • SARS-CoV-2 is at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.
  • VOC VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB. l, and XEC.
  • the disease or condition in the subject associated with the virus is post- viral fatigue syndrome.
  • the disease or condition in the subject associated with the virus is post- viral fatigue.
  • the subject exhibits post-viral long-term symptoms.
  • the disease or condition in the subject associated with the virus is Long CO VID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long- haul Covid.
  • the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance.
  • the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post- traumatic stress disorder (PTSD) due to severe illness or hospitalization.
  • PTSD post- traumatic stress disorder
  • the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia.
  • POTS postural orthostatic tachycardia syndrome
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia.
  • the virus is a coronavirus.
  • the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63).
  • the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl).
  • the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV.
  • the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV.
  • the coronavirus is SARS-CoV-2, a SARS-CoV-2 variant, a SARS-CoV- 2 mutant, or Covid- 19.
  • the coronavirus is a gamma coronavirus (y- CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV).
  • the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov).
  • the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.
  • VOC VI Variant of Concern ( VOC) 202012/01 ), a B .1.351 variant of SARS-CoV-2 (a. k. a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.l.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN. l.1.18, LB. l, and XEC.
  • the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue.
  • the subject exhibits post- viral long-term symptoms.
  • the disease or condition in the subject associated with the virus is Long COVID.
  • the disease or condition in the subject associated with the virus is chronic Covid.
  • the disease or condition in the subject associated with the virus is long-haul Covid.
  • the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses.
  • the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections.
  • the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments.
  • the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis.
  • the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis.
  • the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection.
  • the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously.
  • the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance.
  • the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization.
  • the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia.
  • POTS postural orthostatic tachycardia syndrome
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia.
  • the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects.
  • the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism).
  • the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease.
  • the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS-C) as a distinct post-COVID condition.
  • MISIS-C multisystem inflammatory syndrome in children
  • the subject experiences significant fluctuations in body temperature, not necessarily classified as fever, but noticeable enough to cause discomfort.
  • the subject displays signs of chronic fatigue syndrome, characterized by prolonged and severe tiredness not alleviated by rest.
  • the subject suffers from sporadic episodes of intense migraine-like headaches, different in intensity and pattern from their usual headaches.
  • the subject develops sensitivity to light or sound, which was not present before the viral infection.
  • the subject experiences psychological effects, such as unexplained mood swings, depression, or anxiety, which may be linked to the physiological impacts of the virus.
  • the subject has difficulty regulating their body temperature, leading to episodes of excessive sweating or cold chills without fever.
  • cardiovascular symptoms manifest as coronary microvascular dysfunction, persistent fluctuations in blood pressure, or the onset of arrhythmias and tachycardia.
  • the subject develops autonomic dysfunction, including symptoms consistent with Postural Orthostatic Tachycardia Syndrome (POTS) or other forms of dysautonomia.
  • POTS Postural Orthostatic Tachycardia Syndrome
  • Neurological symptoms such as chronic tingling sensations, paresthesia, or light sensitivity (photophobia) may also emerge.
  • the subject experiences endocrine dysregulation, including new-onset diabetes, thyroid abnormalities, or hormonal imbalances, which may result in changes in menstrual cycles or menopause-like symptoms.
  • a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus includes administering to the subject 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
  • the virus is Covid- 19.
  • the subject meets the Diagnosis of Chronic Fatigue Syndrome (CFS).
  • CFS Chronic Fatigue Syndrome
  • the subject has concurrent occurrence of at least one or more of Long COVID symptoms which persisted or recurred during 3 or more consecutive months of illness.
  • the Long COVID symptoms are not known to be preceded by the infection of Covid- 19.
  • the Long COVID symptoms include, but are not limited to, fatigue, post-exertional malaise, headache, sleep disturbance, memory problems, problems with concentration, brain fog, fever, chills, cough, shortness of breath, difficulty breathing, loss of taste, loss of smell, and chest pain.
  • the method may further include diagnosing the subject for the presence of Covid- 19 or a Covid- 19 antibody.
  • the method includes administering a combination of 17a-ethynylandrost-5-ene-3P,7P,17P-triol and an anti-inflammatory agent to reduce systemic inflammation associated with Long COVID.
  • the method incorporates a regimen of physical therapy designed to gradually improve exercise tolerance and manage post-exertional malaise in subjects meeting the Diagnosis of Chronic Fatigue Syndrome (CFS).
  • CFS Diagnosis of Chronic Fatigue Syndrome
  • the method involves psychological or cognitive behavioral therapy to address memory problems, concentration difficulties, and brain fog in subjects with Long COVID symptoms.
  • the treatment includes supplemental oxygen therapy or respiratory exercises for subjects experiencing persistent shortness of breath or difficulty breathing.
  • the method includes administering a course of vitamins and nutritional supplements aimed at boosting the immune system and alleviating fatigue and weakness.
  • the method involves the use of telemedicine for ongoing monitoring and management of Long COVID symptoms, especially for subjects with limited mobility or access to healthcare facilities.
  • the method includes a holistic approach, integrating lifestyle modifications such as diet changes, stress management techniques, and sleep hygiene practices to improve overall well-being and mitigate symptoms like sleep disturbance and fatigue.
  • the method further includes administering neuroprotective agents to treat neurological symptoms such as loss of taste, loss of smell, and neuropathic pain.
  • the method further includes the use of antiviral medications in combination with 17a- ethynylandrost-5-ene-3P,7P,17P-triol to target any residual viral activity that may be contributing to ongoing symptoms.
  • the method further includes periodic screening for secondary infections or complications that could exacerbate Long COVID symptoms, ensuring comprehensive care of the subject.
  • a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject afflicted with a post- viral illness includes administering to the subject 17a-ethynylandrost-5-ene-3P,7P,17P-triol, wherein the post-viral illness is caused by or associated with the viral disease or infection in the subject.
  • the post-viral illness is caused by the viral disease in the subject.
  • 17a-ethynylandrost-5-ene-3P,7P,17P-triol treats symptoms associated with recovery from the viral disease in the subject.
  • the symptoms include fatigue, post-exertional malaise (PEM), problems with memory or concentration, sore throat, headache, muscle or joint pain, dizziness, brain fog, shortness of breath, and/or unrefreshing sleep.
  • the post-viral illness is Long COVID.
  • the method further includes administering 17a-ethynylandrost-5-ene-3P,7P,17P-triol in conjunction with an anticoagulant or blood thinner to treat or prevent blood clotting issues commonly seen in post-viral illnesses like Long COVID.
  • the method includes the use of supplemental oxygen or respiratory support devices for subjects experiencing persistent respiratory difficulties as a result of the post-viral illness.
  • the method includes cognitive rehabilitation therapies to specifically address and ameliorate problems with memory and concentration associated with brain fog in Long COVID patients.
  • the method involves administering a tailored regimen of gentle physical exercises and physiotherapy to help subjects manage muscle or joint pain and gradually improve their physical function.
  • the method incorporates psychological counseling or therapy to help subjects cope with the mental health impacts, such as anxiety or depression, that often accompany prolonged illnesses like Long COVID.
  • the method includes the use of nutritional supplements or dietary adjustments to support overall health and mitigate symptoms like fatigue and unrefreshing sleep.
  • the method includes the administration of immune modulators or supplements to balance the immune response and reduce systemic inflammation characteristic of post-viral syndromes.
  • the method includes regular monitoring and assessment of cardiovascular health, given the increased risk of heart-related issues in post-viral illness scenarios.
  • the method includes using hydration therapy, either orally or intravenously, to alleviate symptoms of dizziness and improve overall energy levels in subjects.
  • the method further includes the use of non- pharmacological interventions such as acupuncture or massage therapy to provide relief from symptoms like muscle pain and headache.
  • the subject may experience an improvement or amelioration in one or more symptoms associated with a previous viral infection after administration of a compound or composition as described herein.
  • the subject may experience an improvement or amelioration in one or more symptoms associated with Long COVID after administration of a compound or composition as described herein.
  • the prevention or reduction in symptoms related to Long COVID may be reduced by an amount equal to or greater than approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 99%, 100%, or ranges including and/or spanning the aforementioned values after administration of the compound or composition as described herein.
  • subjects may experience improvement or amelioration in one or more symptoms of Long COVID from approximately 5% to 100% after administration of the compound or composition as described herein and at least one pharmaceutically acceptable excipient.
  • the post-viral long-term symptoms may have lasted from the time of infection to the administering step, for a time selected from the group consisting of: one week, two weeks, three weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, and more than 2 years.
  • the administering is performed after the subject was infected for at least a time selected from the group consisting of 30 days, 50 days, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, and more than 2 years.
  • the method includes administering to the subject a dose of a compound or composition as described herein.
  • the dose includes from about 1 mg to about 100 mg of a compound or composition as described herein.
  • the dose includes about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg of a compound or composition as described herein, or ranges including and/or spanning the aforementioned values.
  • the method includes administering from about 2 mg to about 5 mg of a compound or composition as described herein. In some embodiments, the method includes administering from about 10 mg to about 40 mg of a compound or composition as described herein. In some embodiments, the method includes administering from about 20 mg to about 40 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 2 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 5 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 10 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 20 mg of a compound or composition as described herein.
  • the method includes, for example, administering about 40 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 50 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 80 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 100 mg of a compound or composition as described herein.
  • the method includes administering to the subject a dose of 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
  • the dose includes from about 1 mg to about 100 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
  • the dose includes about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, or ranges including and/or spanning the aforementioned values.
  • the method includes administering from about 2 mg to about 5 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
  • the method includes administering from about 10 mg to about 40 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering from about 20 mg to about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 2 mg 17a-ethynylandrost-5-ene- 3P,7P,17P-triol. In some embodiments, the method includes administering about 5 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol.
  • the method includes administering about 10 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 20 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes, for example, administering about 40 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 80 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
  • the method includes administering a compound or composition as described herein once a day. In some embodiments, the method includes administering a compound or composition as described herein twice a day. In some embodiments, the method includes administering the compound or composition as described herein three times a day. In some embodiments, the method includes administering a compound or composition as described herein once a week. In some embodiments, the method includes administering the compound or composition as described herein once a month. In some embodiments, the method includes administering the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol once a day.
  • the method includes administering the 17a- ethynylandrost-5-ene-3P,7P,17P-triol twice a day. In some embodiments, the method includes administering the 17a-ethynylandrost-5-ene-3P,7P,17P-triol three times a day. In some embodiments, the method includes administering the 17a-ethynylandrost-5-ene-3P,7P,17P- triol once a week. In some embodiments, the method includes administering the 17a- ethynylandrost-5-ene-3P,7P,17P-triol once a month.
  • the administrating step may be performed after the primary COVID-19 symptoms of acute illness have been resolved.
  • the administering step may be performed when the post-viral long-term symptoms persist beyond the typical recovery period for acute viral illnesses, which is often considered to be about two weeks.
  • the treatment may be initiated at a specific time point after the onset of long-term symptoms, such as within the first three weeks, to potentially prevent the progression or worsening of these symptoms.
  • the administration of the treatment may be tailored based on the subject’s recovery trajectory, with the timing adjusted according to the persistence or severity of specific symptoms like fatigue or brain fog.
  • the treatment may be commenced after a comprehensive medical evaluation confirming that the subject’s symptoms are not attributable to other underlying medical conditions that might have emerged post-infection.
  • the treatment may be delayed until a thorough assessment of the subject’s immune response to the initial infection may be conducted, to ensure the treatment aligns with the current state of the immune system.
  • the administering step may be synchronized with the completion of a prescribed course of other medications or treatments for COVID-19, to avoid potential drug interactions and enhance treatment efficacy.
  • the treatment begins only after the subject has been symptom- free for a brief period, to distinguish between ongoing acute symptoms and emerging long-term post-viral symptoms.
  • the treatment initiation may be dependent on the subject’s return to certain baseline activities or levels of physical function, as a measure of recovery progress.
  • the treatment starts after a set period following the last positive COVID- 19 test, to ensure that the virus has been cleared and the symptoms experienced are indeed post-viral.
  • the treatment is administered in conjunction with regular health check-ups and monitoring, to track the evolution of the post-viral symptoms and adjust the treatment plan as necessary.
  • the treatment initiation may be based on specific biomarkers or laboratory results indicating one or more diseases or conditions associated with Long COVID.
  • the one or more diseases or conditions associated with Long COVID include ongoing inflammation, immune dysregulation, or tissue damage associated with long-term COVID- 19 symptoms.
  • the timing of treatment may be adjusted depending on the subject’s age, medical history, or risk factors for chronic conditions, to optimize safety and efficacy.
  • the treatment may be initiated in conjunction with physical therapy or rehabilitation programs, particularly if the subject exhibits mobility issues or physical deconditioning as part of their post-viral symptoms.
  • the treatment may be started alongside psychological counseling or mental health interventions, especially in cases where anxiety, depression, or cognitive impairments are prominent.
  • the treatment plan may include an evaluation of the subject’s nutritional status, with supplementation or dietary modifications provided concurrently to support recovery.
  • the treatment may be tailored to address specific organ systems affected, such as targeted therapies for respiratory, cardiovascular, or neurological sequelae.
  • the timing of treatment initiation may be coordinated with seasonal factors, such as avoiding administration during periods of heightened respiratory illness risk to prevent exacerbation of symptoms.
  • the treatment plan may be initiated only after the subject has undergone a structured diagnostic protocol to identify co-infections, secondary complications, or latent viral reactivations that may influence treatment outcomes.
  • the treatment may be initiated in a stepwise manner, beginning with conservative approaches and escalating to more intensive interventions based on the subject’s response and symptom persistence.
  • the solid state form is crystalline 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the solid state form is crystalline 17a-ethynylandrost-5-ene-3p,7p,17P-triol substantially free of 17a- ethynylandrost-5-ene-3p,7p,17P-triol in amorphous form.
  • the solid state form is crystalline solvate 17a- ethynylandrost-5-ene-3p,7p,17P-triol.
  • the crystalline solvate is crystalline methanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
  • the crystalline solvate is crystalline ethanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
  • the crystalline solvate is crystalline hydrate 17a-ethynylandrost-5-ene- 3p,7p,17p-triol.
  • Crystalline solvate of 17a-ethynylandrost-5-ene-3p,7p,17P-triol, crystalline methanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol, crystalline ethanoate 17a- ethynylandrost-5-ene-3p,7p,17P-triol, crystalline hydrate 17a-ethynylandrost-5-ene- 3p,7p,17p-triol are disclosed in WO 2009/124300A2, which is incorporated herein by reference in its entirety.
  • the crystalline solvate is Form III 17a- ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is Form IV 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is Form V 17a-ethynylandrost-5-ene-3p,7p,17P-triol. Crystalline solvate Form III, crystalline solvate Form IV, and crystalline solvate Form V are disclosed in WO 2009/124300A2, which is incorporated herein by reference in its entirety.
  • the solid-state form of 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is amorphous 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
  • the amorphous 17a-ethynylandrost-5-ene-3p,7p,17P-triol substantially free of 17a-ethynylandrost-5-ene-3p,7p,17P-triol in solid state form.
  • the compound or pharmaceutical composition described herein is administered orally. In some embodiments, the compound or pharmaceutical composition described herein is administered intravenously. In some embodiments, the compound or pharmaceutical composition described herein is administered topically. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered orally. In other embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered intravenously. In other embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered topically.
  • a compound as described herein is administered as a formulation or a composition with at least one pharmaceutically acceptable excipient. In some embodiments, a compound as described herein is administered as a formulation or a composition with at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier. In some embodiments, 17a-ethynylandrost-5-ene- 30,70, 17P-triol is administered as a formulation with at least one pharmaceutically acceptable excipient. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered as a formulation with at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier.
  • 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is administered as a formulation with at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable excipients suitable for use in the compositions include absorption enhancing agents, acidifying agents, agents for modified release, alkalizing agents, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying agents, flavoring agents, humectants, humidity-adjusting agents, pH-adjusting agents, preservatives, solubilizing agents, stabilizers, surface-active agents, suspending agents, sweetening agents, taste-masking agents, and wetting agents.
  • Formulations include compositions comprising 1, 2, 3, 4 or more pharmaceutically acceptable excipients or carriers.
  • the compositions are used to prepare formulations suitable for human or animal use.
  • Suitable administration routes for formulations include oral, rectal, nasal, transmucosal, topical (including buccal and sublingual), vaginal, rectal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, intraocular and epidural).
  • aqueous and non-aqueous liquid or cream formulations are delivered by a parenteral, oral or topical route.
  • 17a-ethynylandrost-5-ene-3P,7P,17P-triol may be present as an aqueous or a non-aqueous liquid formulation or a solid formulation suitable for administration by any of the routes disclosed herein, e.g., oral, topical, buccal, sublingual, parenteral, inhaled aerosol or a depot such as a subcutaneous depot or an intraperitoneal or intramuscular depot.
  • the preferred route may vary with, for example, the subject’s pathological condition or weight or the subject’s response to therapy with 17a- ethynylandrost-5-ene-3P,7P,17P-triol or other therapy that is used or that is appropriate to the circumstances.
  • excipients for formulations include emulsifying wax, propyl gallate, citric acid, lactic acid, polysorbate 80, sodium chloride, isopropyl palmitate, glycerin, white petrolatum and other excipients disclosed herein.
  • Formulations, or compositions disclosed herein for use to make formulations suitable for administration by the routes disclosed herein optionally comprise an average particle size in the range of about 0.01 to about 500 microns, about 0.1 to about 100 microns or about 0.5 to about 75 microns.
  • Average particle sizes include a range between 0.01 and 500 microns in 0.05 micron or in 0.1 micron or other increments, e.g., an average particle size of about 0.05, 0.1, 0.5, 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 85, 100, 120, etc. microns).
  • compositions that comprise 17a-ethynylandrost-5-ene-3P,7P, 17)3- triol or compositions that comprise 17a-ethynylandrost-5-ene-3P,7P,17P-triol are used as intermediates to make a formulation, they may comprise one, two, three or more of these average particle sizes, or size ranges.
  • one may optionally mill, sieve or otherwise granulate the compound or composition to obtain a desired particle size.
  • Non-limiting examples of disintegrants suitable for use in the compositions include alginic acid or alginates, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, and carboxymethyl starch.
  • Non-limiting examples of binders suitable for use in the compositions include acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, polyethylene oxides, povidone, and pregelatinized starch.
  • Non-limiting examples of antioxidants suitable for use in the compositions include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, and derivatives of tocopherol.
  • the pharmaceutical compositions include a pharmaceutically acceptable formulation of a compound, as described herein.
  • the pharmaceutical composition includes 17oc-ethynylandrost-5-ene-3p,7p,17P- triol.
  • the pharmaceutical compositions include a polymorph form of a compound as described herein.
  • the delay time is equal to or greater than about: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years, or ranges including and/or spanning the aforementioned values. In several embodiments, the delay time is equal to or greater than 2 years. In some embodiments, the delay time is zero and the additional medicament is administered concurrently with the first administration of the composition. In several embodiments, the additional medicament is administered using a dosage schedule that is daily, weekly, monthly, or any combination of the foregoing. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more daily dosages of the composition. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more weekly dosages of the composition. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more monthly dosages of the composition.
  • the neurodegenerative condition related to Long COVID includes, but is not limited to, neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia.
  • the neurodegenerative condition related to Long COVID includes, but is not limited to, mental health impacts, for example, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization.
  • the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia.
  • POTS postural orthostatic tachycardia syndrome
  • the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging.
  • the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV).
  • EBV Epstein-Barr virus
  • the dose includes about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg 100 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol, or ranges including and/or spanning the aforementioned values.
  • the method includes administering from about 10 mg to about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
  • the method includes administering from about 20 mg to about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 20 mg 17a-ethynylandrost-5- ene-3 P, 7P, 17 P-triol.
  • the one or more Long COVID symptoms is selected from the group consisting of: fatigue including severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry
  • the at least one sign, condition, or symptom of Long COVID is selected from the group consisting of: fatigue include severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, go
  • 3P,7P,17P-triol is administered at a dose from about 20 mg.
  • a composition comprising 17a-ethynylandrost-5-ene-3P,7P,17P-triol, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier for use in treating a disease or condition caused by a coronavirus.
  • 17a-ethynylandrost-5-ene-3P,7P,17P-triol is in an oral dosage of about 10 mg to about 40 mg.
  • NE3107 17a- ethynylandrost-5-ene-3P,7P,17P-triol
  • NE3107 is an orally bioavailable, blood-brain barrier-permeable, insulinsensitizer that is anti-inflammatory but not immunosuppressive, and possesses unique attributes for targeting the mechanisms underlying the neurological symptoms of Long COVID.
  • NE3107 has the potential to reduce symptoms including fatigue and cognitive dysfunction by targeting the mechanism underlying pro-inflammatory pattern recognition tolllike receptors (TLR) driven neuroinflammation.
  • TLR pro-inflammatory pattern recognition tolllike receptors
  • TPL2/ERK signaling pathway is also a central hub in obesity-associated inflammation and metabolic disorders, and required for the perpetuation and augmentation of inflammation by TNF-a, selective inhibition of this pathway could short-circuit not only the perpetuated activation of the inflammatory cascade in Long COVID but also the insulin resistance and new onset Type 2 diabetes that has been reported to develop post-infection.
  • NE3107 ameliorates inflammatory responses elicited by TLR4: Preclinical studies in macrophages have demonstrated that NE3107 inhibits LPS-stimulated (TLR4- driven) ERK phosphorylation and inhibits activation of NFKB (p65 NFKB phosphorylation and nuclear localization and KB occupancy at the IL-6 promoter). In vitro and in vivo studies have demonstrated that NE3107 decreases the expression of inflammatory cytokines and chemokines.
  • mice oral treatment with NE3107 (40 mg/kg) significantly (p ⁇ 0.05) decreased neutrophil counts and exudate volumes (-50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury.
  • NE3107 binds the MAP kinase ERK, likely in a compartmentalized spatiotemporal scaffold (TPL2/MEK/ERK) that directs pro-inflammatory signaling downstream of TLR engagement.
  • NE3107 also appears to inhibit signaling via the TNFR1 receptor, that also activates the TPL2/MEK/ERK signaling cascade and creates a feed-forward loop to sustain an inflammatory state.
  • NE3107 include: a Phase 1 safety study in normal volunteers (single weekly escalating dose up to 100 mg), a Phase 1 study in obese individuals with impaired glucose tolerance (28-day, 3 dose levels), a Phase 1/Phase 2 study in subjects with ulcerative colitis (28-day), a Phase 1 /Phase 2 study of potential methotrexate-NE3107 interactions in subjects with rheumatoid arthritis (28-day), and a Phase 2 study conducted in 2 stages: the first stage in type 2 diabetes in combination with metformin (84-day), and the second stage in type 2 diabetes in treatment naive subjects (84-day).
  • the study was designed to measure NE3107 intrinsic promotoric activity and potential enhancement of levodopa activity or decrease in levodopa side effects from use in combination with NE3107, as well as potential improvements in activities of daily living (MDS-UPDRS Part II) and nonmotor features of PD (MDS-UPDRS Part I and Non-Motor Symptom Assessment Scale for Parkinson Disease.)
  • the study also measured potential pharmacokinetics drug-drug interactions of NE3107 with levodopa and functional interactions with any PD comedications of study participants.
  • NE3107 was studied in an Investigator-sponsored, open-label study in subjects with clinically mild dementia of the Alzheimer’s type (NCT05227820).
  • NE3107 BID 20 mg NE3107 BID for 3 months.
  • NE3107 decreased plasma TNF levels and this reduction correlated significantly with improved cognition.
  • Hyperphosphorylated phospho-tau in cerebral spinal fluid was also reduced and was correlated with improvement in the Alzheimer’s Disease Composite Score.
  • Neuroimaging data indicated regiospecific blood flow improvements, reduced hippocampal compensation, and increased precuneous glutathione, which also correlated with decrease phosphor-tau.
  • Analysis of DNA methylation in whole blood collected prior to treatment and at the end of the 3 -month Treatment Period indicated a mean decrease in the biological age of 19 of 22 subjects of 4.3 years using the PhenoAge calculator and 3.3 years using the DNAm-Age Skin Blood Clock. There were no drug-related treatment-emergent adverse effects (see FIG. 2).
  • NM101 a Phase III, double-blind, randomized, placebo-controlled, parallel group, multi center study of NE3107 in subjects who have mild-to-moderate probable AD (NCT04669028). Subjects were randomized to receive 20 mg NE3107 twice daily (BID) or placebo for 26 weeks following dose titration of 5 mg BID for two weeks and 10 mg BID for two weeks. The study enrolled 439 subjects and will complete in September 2023. Due to significant deviations from protocol and GCP violations at 15 clinical sites data from 80% of patients enrolled was excluded from the final analysis which led to the study being underpowered for the primary endpoints CDR-SB and ADAS-Cogl2.
  • Intervention Period (12 weeks) will include assessments outlined in the Schedule of Assessments (SOA) (Table 2). These will consist of a review of eligibility criteria, medical history, safety evaluations, and the administration of Clinical Outcome Assessments (COA) tools in the following recommended sequence: PROMIS Cognitive Function Short Form 8a (PROMIS Cognitive Function SF8a), PROMIS Fatigue Short Form 13a (PROMIS Fatigue SF13a), Cogstate Cognition Battery, DSQ-PEM, PROMIS Sleep Disturbance Short Form 8a (PROMIS Sleep Disturbance SF8a), SF-12, Patient Global Impression of Severity (PGI-S) Overall, PGI-S Fatigue, PGI-S think Clearly, Long COVID Other Burdensome Symptoms, the Columbia- Suicide Severity Rating Scale (C-SSRS) Since the Last Visit form, and the Clinical Global Impression of Severity (CGLS).
  • SOA Schedule of Assessments
  • C-SSRS Columbia- Suicide Severity Rating Scale
  • Participants who continue to meet eligibility criteria at this visit will be randomly assigned to either the NE3107 treatment arm or the placebo treatment arm based on a central 1: 1 randomization schedule.
  • the first dose of the study intervention will be administered following the completion of all baseline assessments. Participants will initiate treatment on Day 1 (Visit 2) and will continue taking the assigned intervention for 12 weeks.
  • Safety and efficacy will be evaluated during site visits conducted every 28 ⁇ 3 days at Week 4 (Visit 3), Week 8 (Visit 4), and Week 12 (Visit 5), with assessments performed as specified in the SOA (Table 2).
  • a virtual visit will be conducted four weeks after the participant completes or discontinues the study intervention. During this virtual visit (Visit 6; Week 16), information on adverse events (AEs) and concomitant medications will be collected. If deemed necessary, the investigator may request the participant to attend an in-person visit at the study site.
  • AEs adverse events
  • concomitant medications If deemed necessary, the investigator may request the participant to attend an in-person visit at the study site.
  • EOS End of the study
  • Week 16 the date of the last visit for the final participant enrolled in the study.
  • a participant is considered to have completed the study if they have successfully completed all study periods, including the Week 16 EOS visit, as specified in the Schedule of Assessments (SOA) (Table 2).
  • a medical monitor from the contract research organization will have primary oversight of the participants enrolled in this study.
  • the sponsor’s medical monitor may also participate in safety reviews of blinded data and key study decisions, including participant withdrawal due to adverse events (AEs) and emergency unblinding.
  • AEs adverse events
  • Each participant’s medical history, SARS-CoV-2 history, and results from screening assessments, including available safety laboratory results, will be reviewed by the Enrollment Authorization Committee (EAC) to authorize participant randomization.
  • the EAC comprising relevant medical experts selected by the sponsor, will assess study suitability for each participant based on the entry criteria and study objectives. When necessary, the EAC will consult with the investigator to address and resolve outstanding questions or issues before providing its decision.
  • the EAC will evaluate the participant’s screening assessments and document its decision regarding eligibility. If a participant is deemed ineligible for randomization, this decision, along with a rationale, will be recorded in the electronic data capture (EDC) system. Participants not approved by the EAC will be classified as screen failures. To ensure the integrity of the study, a dedicated charter will be developed to guide the EAC’s operations. The EAC approval form will serve as documentation for each participant’s inclusion in the study and must be stored in the site study file.
  • EDC electronic data capture
  • the study may be discontinued at the discretion of the Applicant and the Applicant’s medical monitor for reasons such as increased frequency, severity, or duration of known AEs; medical or ethical concerns affecting the study’s continuation; difficulties in participant recruitment; or cancellation of drug development.
  • Participants must be adults aged 18 to 64 years at the time of screening and have Long CO VID, defined as the presence of at least fatigue and neurocognitive impairment attributed to a SARS-CoV-2 infection that occurred at least three months prior to screening.
  • the index SARS-CoV-2 infection must be confirmed by a positive nucleic acid or antigen test during the acute illness (as documented in the medical record) or a clinical diagnosis of COVID- 19 by the participant’s physician. Symptoms must not be attributable to an alternative diagnosis, as determined by the investigator, and must have persisted for a duration of at least three months but no longer than 24 months from the index infection.
  • Participants must meet specific criteria on standardized assessments, including a PROMIS Cognitive Function SF8a T-score ⁇ 40 (> 1 standard deviation below the normative mean), a Cogstate Cognition battery score > 1 standard deviation below the normative mean for at least two of the five tests in the battery, and a PROMIS Fatigue SF13a T-score > 60 (> 1 standard deviation above the normative mean). Additionally, participants must have a plasma high-sensitivity C-reactive protein (hs-CRP) level > 3.0 mg/L.
  • hs-CRP plasma high-sensitivity C-reactive protein
  • Participants with prior or active unstable or progressive major psychiatric or neurological conditions unrelated to SARS-CoV-2 infection that may impact the ability to evaluate the treatment effect are not eligible.
  • Premenstrual dysphoric disorder is also exclusionary.
  • Participants with physical, cognitive, or language impairments sufficient to interfere with cognitive assessments, diagnosed reading disabilities, dyslexia, or clinically significant learning disorders are ineligible. Those with documented ADHD prior to the index COVID- 19 infection will also be excluded. Additionally, participants with known active bacterial, fungal, viral, or other infections requiring treatment within 30 days prior to randomization, which meet criteria for systemic involvement (as determined by the investigator), are not eligible. However, mild or localized infections, such as uncomplicated urinary tract infections, yeast infections, sexually transmitted infections, or mild dermatophyte infections, may not be exclusionary upon review by the study investigator.
  • Other exclusion criteria include a diagnosis of narcolepsy or excessive daytime sleepiness, an Epworth Sleepiness Scale Score of 18 or greater (indicating severe sleepiness), and a history of cardiovascular conditions such as congestive heart failure, suspected or known dissecting aneurysm, recent systemic or pulmonary embolism, recent myocardial infarction (within six months), severe valvular heart disease, ventricular aneurysm, active or suspected myocarditis or pericarditis, or thrombophlebitis or intracardiac thrombi.
  • Study personnel are responsible for maintaining the integrity of the study blind to minimize bias during the study. All participants and study personnel will remain blinded to the assigned treatment throughout the study period.
  • a specific participant's treatment assignment may be identified only if urgently needed for their clinical management or welfare.
  • the investigator should consult the medical monitor before unblinding, although participant safety and clinical management take priority. If necessary, the treatment assignment will be accessed through the IWRS. Unblinding of treatment assignments is discouraged if the knowledge will not materially alter the management of the medical emergency. Participant safety must always be the foremost consideration in such decisions.
  • any medication or vaccine including over-the-counter or prescription medicines, recreational drugs, vitamins, and herbal supplements, that a participant is receiving at the time of enrollment or during the study must be recorded.
  • the documentation should include the reason for use, dates of administration (start and end), and dosage details (dose and frequency). If questions arise regarding prior or concomitant therapy, the medical monitor should be consulted. Participants may continue pretrial medications during the study if the dose has been stable for at least three months prior to screening (Visit 1) and no dosage changes are planned during the study without prior investigator approval.
  • the Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are reliable, widely used, publicly available tools designed to measure patient-reported health symptoms and health-related quality of life across a variety of diseases, including chronic conditions. These instruments are accessible through the HealthMeasures website and are extensively utilized in both clinical research and patient care.
  • the PROMIS Cognitive Function SF8a a key instrument in this study, consists of 8 items assessing patient- reported cognitive abilities such as attention, mental clarity, processing speed, problemsolving, and mental fatigue. Each item is scored on a 5-point Likert scale. This instrument will be administered on the visit days specified in the SoA (Table 2).
  • the Cogstate Cognition battery of tests will also be administered on the visit days specified in the SoA (Table 2). Training for test supervisors at each site will be provided by Cogstate through eLearning activities. Upon completing the required training, test supervisors will receive certification from the Cogstate Learning Management System (LMS) and gain access to the digital test battery. Cogstate will also brief the study’s Clinical Research Associates on the test battery, the training and certification process for test supervisors, and anticipated data monitoring activities. These activities will include verification of source data and interactions with study sites throughout the trial. All hardware and software required for administering the Cogstate Cognition battery will be pre-tested by Cogstate before being sent to each site.
  • LMS Cogstate Learning Management System
  • the International Digit Symbol Substitution Test - Symbols is a processing speed assessment based on the well-established digit symbol coding paradigm. In this test, participants are presented with a legend that defines nine symbols, each corresponding to a digit from 1 to 9. During the test, a conveyor belt appears on the screen displaying a series of empty boxes labeled with numbers. Participants must select the correct symbol that corresponds to the number in a highlighted box from a set of symbol options displayed at the bottom of the screen. The goal is to place as many correct symbols as possible into the corresponding boxes within the test duration. Performance is evaluated based on the total number of correct responses, with the test lasting approximately three minutes.
  • the Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are a set of highly reliable, widely used, and publicly available tools designed to measure patient-reported health symptoms and health-related quality of life domains across a variety of diseases, including chronic conditions. These instruments are accessible through the HealthMeasures website and are extensively utilized in clinical research and care.
  • the PROMIS Fatigue SF13a consists of 13 items that assess the severity and impact of fatigue on daily life. Each item is scored on a 5-point Likert scale. This instrument will be administered on the visit days outlined in the Schedule of Assessments (SoA) (Table 2).
  • the self-report measure PGI-S Overall assesses a participant’s perception of the overall severity of their disease symptoms on a 5-point scale. In this study, participants will rate the overall severity of their Long CO VID symptoms as "none,” “mild,” “moderate,” “severe,” or “very severe.” The PGI-S Overall will be administered on the visit days outlined in the SoA (Table 2). The related self-report measure, PGLC Overall, reflects a participant’s perception of the overall efficacy of the treatment and their status since the start of the treatment.
  • the Long COVID Other Burdensome Symptoms questionnaire consists of three items measuring the participant’s reported severity and frequency of symptoms such as headache, tinnitus, and decreased appetite. Each item is scored on a 5-point Likert scale. This questionnaire will be administered on the visit days outlined in the SoA (Table 2).
  • the Clinical Global Impression of Severity (CGI-S) reflects the clinician's assessment of the overall severity of a participant’s disease symptoms, measured on a 5-point scale.
  • An abbreviated, clinically directed physical examination will be performed during all visits in the intervention period, at the End of Study (EOS) visit (Visit 6), or as needed in response to an adverse event (AE). These abbreviated examinations will assess systems deemed appropriate by the examiner, focusing on clinical signs, symptoms, or relevant medical history. Height and weight will be measured and recorded at the screening visit (Visit 1). Hip and waist circumferences will be measured and recorded at baseline (Visit 2), Visit 4 (Day 56), and Visit 5 (Day 84). Investigators should pay close attention to clinical signs and symptoms related to any prior serious illnesses.
  • ECG parameters including heart rate, rhythm, PR interval, QRS complex, QT interval, QTc, and QTcF interval, will be assessed. All scheduled ECGs will be conducted after participants have rested quietly in a supine position for 5 minutes. Source data for ECGs will include tracing paper printouts, which will be retained. Clinical laboratory tests to be performed are listed in Table 5, with their timing and frequency outlined in the SoA (Table 2). Participants are advised to refrain from food for at least 8 hours prior to sample collection.
  • the investigator must review laboratory results, document the review, and record any clinically significant changes occurring during the study as an AE. All laboratory results must be retained as source documents. Laboratory tests with clinically significant abnormal values during the study will be repeated until the values are no longer considered clinically significant by the investigator or medical monitor. All protocol-required laboratory tests will be conducted in accordance with the laboratory manual and the SoA (Table 2). If tests performed at the site’s local laboratory yield results deemed clinically significant by the investigator, these results must also be recorded.
  • a lateral flow test for COVID- 19 will be performed at any visit where symptoms suggestive of COVID- 19 are present.
  • the Epworth Sleepiness Scale is a brief, self-administered questionnaire designed to measure daytime sleepiness. It consists of eight questions that assess the likelihood of dozing off in various situations, such as reading, watching TV, or driving. The total score ranges from 0 to 24, with higher scores indicating greater levels of sleepiness.
  • the PHQ-2 is a widely used tool for screening, diagnosing, monitoring, and measuring the severity of depression. It consists of the first two items of the PHQ-9, which inquire about the degree to which an individual has experienced depressed mood and anhedonia. The PHQ-2 is not intended to establish a definitive diagnosis or to monitor depression severity but rather to serve as a screening instrument. Its effectiveness has been validated in three studies demonstrating variability in sensitivity.
  • the Columbia-Suicide Severity Rating Scale (C-SSRS) is a widely used tool to assess the risk of suicide. This tool will be administered by a clinician or a trained designee to monitor suicidal ideation and behavior prospectively in individual participants.
  • the C-SSRS Baseline/Screening form will be used at the Screening visit to assess lifetime and past six-month suicidality risk.
  • the C-SSRS Since Last Visit form will be administered during Visits 2 through 5 to evaluate suicidality since the participant's last visit. Participants who answer "YES" to Questions 4 or 5 in the C-SSRS questionnaire indicating suicidal ideation should be referred to a mental health professional.
  • Plasma samples will be collected to assess levels of inflammatory biomarkers, that may include adiponectin, leptin, ceruloplasmin, phospho-tau (p-tau), neurofilament light (NfL), Glial fibrillary acidic proteins (GLAP), Amyloid beta42/beta40, Clq, interferon (JEN)-y, IL-1 (3, IL-6, IL-17, IL-23, TNF, RANTES, Monocyte chemoattractant protein-1 (MCP1), high sensitivity C-reactive protein (hs-CRP), fasting insulin, fasting glucose; and antinuclear antibodies (ANA).
  • inflammatory biomarkers may include adiponectin, leptin, ceruloplasmin, phospho-tau (p-tau), neurofilament light (NfL), Glial fibrillary acidic proteins (GLAP), Amyloid beta42/beta40, Clq, interferon (JEN)-y, IL
  • Blood samples will be collected to evaluate trough levels of NE3107 and dosing compliance. Participants should be instructed to note the time of the most recent NE3107 dose prior to sample collection. Timing of dose should be recorded in the eCRF.

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Abstract

Disclosed herein are compositions and methods useful for the prevention, treatment, reduction, or amelioration of various diseases, disorders, or conditions. Some aspects pertain to a pharmaceutical composition comprising 17-ethynyl-10R, 13S-dimethyl 2, 3, 4, 7, 8R, 9S, 10, 11, 12, 13, 14S, 15, 16, 17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R, 7R, 17S-triol, including solid states thereof. Also presented herein is the surprising discovery that exposing a subject to the compound and/or compositions disclosed herein can prevent, treat, reduce, or ameliorate a condition related to a subject previously infected with a virus.

Description

METHODS OF TREATING LONG COVID
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic priority claim is identified in the PCT Request as filed with the present application are hereby incorporated by reference in their entireties.
Field of the Disclosure
[0002] The present disclosure relates to the field of chemistry and medicine. More particularly, the present disclosure relates generally to methods for the treatment of Long COVID.
BACKGROUND
[0003] Long COVID, also known as long-haul COVID, post-COVID syndrome, and post-acute sequelae of COVID- 19, refers to a range of symptoms that persist for months beyond the initial phase of COVID- 19 infection. These symptoms can vary widely in severity and type, affecting different systems of the body, such as the lungs, heart, brain, and immune system. Some common symptoms include fatigue, brain fog, altered sense of taste and smell, difficulty in sleeping, and anxiety or depression. Although the exact cause of Long COVID remains unclear, factors such as persistent inflammation, tiny blood clots, autoimmune responses, viral and spike protein persistence, reactivation of dormant viruses like Epstein- Barr, and psychological impacts from severe illness are believed to play a role.
[0004] In clinical practice, treatment for Long CO VID is highly individualized due to the diverse nature of the symptoms. There is no universal treatment approach. Depending on the symptoms, treatment options might include medications for specific symptoms like cough, headaches, anxiety, and depression, as well as interventions for underlying causes if identifiable, such as blood clots. Other treatment methods have included stellate ganglion block or olfactory retraining for sensory issues, physical therapy for pain or movement issues, pulmonary rehabilitation for breathing difficulties, and counseling to manage psychological effects of the illness. [0005] Long COVID, therefore, presents a complex clinical challenge, necessitating new therapeutics to individual patient needs.
SUMMARY OF THE DISCLOSURE
[0006] Aspects of the disclosure relate to a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus. In some embodiments, the method includes administering to the subject 17a-ethynylandrost- 5-ene-3P,7P,17|3-triol. In some embodiments, the virus is selected from the group consisting of coronavirus, human coronavirus 229E, human coronavirus OC43, human coronavirus NL63, human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus (MERS-Cov), severe acute respiratory syndrome-related coronavirus (SARS-CoV), SARS- CoV-2, a variant, a mutant, thereof, a type thereof, a subtype thereof, a lineage thereof, a clade thereof, and a subclade thereof. In some embodiments, the virus is SARS-CoV-2 or a SARS- CoV-2 variant. In some embodiments, the SARS-CoV-2 variant is at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y.V 1 Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS- CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.1 , and XEC. In some embodiments, the subject has post viral fatigue symptoms. In some embodiments, the post viral fatigue symptom is Long COVID. In some embodiments, the subject exhibits Long CO VID symptoms comprising at least one symptom selected from the group consisting of fatigue including severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, CO VID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness, joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post-exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia. In some embodiments, the subject did not have post-viral fatigue symptoms before being infected with the virus. In some embodiments, the subject develops the symptoms of post viral fatigue during or after being infected with the virus. In some embodiments, the subject experiences between about a 5% to about 100% improvement in conditions related to the virus. In some embodiments, the subject experiences between about a 5% to about 100% reduction in conditions related to the virus. In some embodiments, the 17a-ethynylandrost-5- ene-3P,7P,17P-triol is administered orally. In some embodiments, the 17a-ethynylandrost-5- ene-3P,7P,17P-triol is administered intravenously. In some embodiments, the 17a- ethynylandrost-5-ene-3p,7p,17P-triol is a solid state form of 17a-ethynylandrost-5-ene- 3p,7p,17p-triol. In some embodiments, the solid state form of 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is crystalline solvate of 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is crystalline methanolate 17a-ethynylandrost-5-ene- 3p,7p,17p-triol. In some embodiments, the crystalline solvate is crystalline ethanolate 17a- ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is crystalline hydrate 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is Form III 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is Form IV 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, crystalline solvate is Form V 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
[0007] Some aspects of the disclosure relate to a method for the treatment of Long COVID in a patient in need thereof. In some embodiments, the method includes administering to the subject 17a-ethynylandrost-5-ene-3P,7P,17P-triol, wherein, administering 17a- ethynylandrost-5-ene-3P,7P,17P-triol to the subject reduces or improves at least one sign, condition, or symptom of Long COVID. In some embodiments, the at least one sign, condition, or symptom of Long COVID is selected from the group consisting of: fatigue include severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post- exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia. In some embodiments, the subject did not have at least one sign, condition, or symptom of Long COVID prior to infection with COVID. In some embodiments, the subject develops the at least one sign, condition, or symptom of Long COVID after three weeks from initial infection with COVID. In some embodiments, the subject experiences between about a 5% to about 100% improvement in at least one sign, condition, or symptom of Long COVID. In some embodiments, the subject experiences between about a 5% to about 100% reduction in at least one sign, condition, or symptom of Long CO VID. In some embodiments, the further includes monitoring the subject for a reduction in symptoms of Long COVID following the administration of 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the patient has been diagnosed with Long Covid for a duration selected from the group consisting of 1 month, 3 months, 6 months, and 1 year. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered to subjects who have a confirmed diagnosis of Long COVID through a positive COVID-19 antibody test. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered in combination with a second therapeutic agent selected from the group consisting of anti-inflammatory agents, antiviral agents, and immune modulators. In some embodiments, the subject is concurrently receiving physical therapy or cognitive behavioral therapy for symptoms of Long COVID. In some embodiments, the at least one sign, condition, or symptom of Long COVID includes neurological symptoms, and the 17a-ethynylandrost-5- ene-3p,7p,17p-triol is specifically administered to treat or alleviate the neurological symptoms. In some embodiments, the at least one sign, condition, or symptom of Long COVID are ameliorated or treated within a time period following administration of 17a-ethynylandrost-5- ene-3P,7P,17P-triol, the time period being selected from the group consisting of 2 weeks, 1 month, 3 months, and 6 months. In some embodiments, the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered orally. In some embodiments, the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered intravenously. In some embodiments, the 17oc-ethynylandrost- 5-ene-3p,7p,17P-triol is a solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol is crystalline solvate of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is crystalline methanolate 17oc-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is crystalline ethanolate 17oc-ethynylandrost-5-ene- 3p,7p,17p-triol. In some embodiments, the crystalline solvate is crystalline hydrate 17a- ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is Form III 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, the crystalline solvate is Form IV 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In some embodiments, crystalline solvate is Form V 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIG. 1 illustrates three graphs representing CDR-SB from baseline with NE3107 correlated with changes from baseline in TNFa, phospho-Tau, and AP42/AP40.
[0009] FIG. 2 illustrates a graph showing the correlation of change of age deceleration of NE3107 versus placebo.
[0010] FIG. 3 illustrates a double-blind, placebo-controlled, 12-week study design schema.
DETAILED DESCRIPTION
[0011] The following description provides context and examples, but should not be interpreted to limit the scope of the disclosure covered by the claims that follow in this specification or in any other application that claims priority to this specification. No single component or collection of components is essential or indispensable. For example, in some embodiments one or more variables, such as Y or Y and Q may be omitted. Any feature, structure, component, material, step, or method that is described and/or illustrated in any embodiment in this specification can be used with or instead of any feature, structure, component, material, step, or method that is described and/or illustrated in any other embodiment in this specification.
Definitions
[0012] As used herein and unless otherwise stated or implied by context, terms that are used herein have the meanings that are defined here. The descriptions of embodiments and examples that are described illustrate the disclosure and they are not intended to limit it in any way. Unless otherwise contraindicated or implied, e.g., by including mutually exclusive elements or options, in these definitions and throughout this specification, the terms “a” and “an” mean one or more and the term “or” means and/or.
[0013] A “formulation” or the like means a composition that one can administer to a subject, e.g., human or animal. Formulations are suitable for human or veterinary applications and would typically have expected characteristics for the formulation, e.g., parenteral formulations for human use would usually be sterile solutions or suspensions.
[0014] An “excipient”, “carrier”, “pharmaceutically acceptable carrier” or similar terms mean one or more component(s) or ingredient(s) that is acceptable in the sense of being compatible with the other ingredients in the disclosed compositions or formulations and not overly deleterious to the patient, animal, tissues or cells to which the formulation is to be administered.
[0015] ‘Effective amount” refers to the amount required to produce a desired effect (e.g., enhancing the half-life, bioavailability or efficacy of a compound described herein, treating biological aging in a subject, reducing DNA methylation in a subject, etc.
[0016] As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given their ordinary meaning in the art and shall also refer to an organism that has cancer and/or leukemia. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.
[0017] “Preventing” in reference to a disease, disorder or condition refers to preventing a disease, disorder or condition, e.g., causing the clinical symptoms of the disease, disorder or condition not to develop. As used herein, the term “prevent,” “prevents,” or “prevention” (and grammatical equivalents thereof) may also refer to a delay in the onset of a disease or disorder or the lessening of symptoms upon onset of the disease or disorder. The terms are not meant to imply complete abolition of disease and encompass any type of prophylactic treatment that reduces the incidence of the condition or delays the onset and/or progression of the condition.
[0018] The terms “therapeutically effective amount” and “effective amount” refer to the amount of active pharmaceutical ingredient necessary to provide the desired pharmacologic result. In practice, the therapeutically effective amount will vary widely depending on the severity of the disease condition, age of the subject, and the desired therapeutic effect.
[0019] The terms “treatment,” “treating,” “treat,” and the like shall be given their ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. The terms “treatment,” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and/or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.
[0020] The term “Long COVID” refers to a condition characterized by long-term consequences persisting after the typical convalescence period following an acute COVID-19 infection. It is also known as post-COVID-19 syndrome, post-COVID-19 condition, post-acute sequelae of COVID-19 (PASC), long haul COVID, or chronic COVID syndrome (CCS). Long COVID can affect individuals of any age, including those with mild infections, and is typically defined as the persistence or emergence of symptoms for two or more weeks after the acute phase of illness. Long COVID may involve nearly every organ system, with documented sequelae including, but not limited to: respiratory system disorders, nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, musculoskeletal pain, and anemia.
[0021] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, and up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5- fold, and within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.
[0022] All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless specifically stated otherwise. Also, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the general description and the following detailed description are exemplary and explanatory only and are not restrictive. The term “and/or” denotes that the provided possibilities can be used together or be used in the alternative. Thus, the term “and/or” denotes that both options exist for that set of possibilities.
[0023] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the disclosure. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as “and/or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should be read as “and/or” unless expressly stated otherwise. [0024] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.
Methods of Treatment
[0025] Aspects of the present disclosure relate to methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure: wherein, one of R5 and R6 is — OH and the other R5 and R6 is — H, one of R12 and R13 is — OH and the other R12 and R13 is — H, R14 and R15 are — H, R16 is — H, R17 is — H or — OH, R18 is — OH, R19 is ethynyl, and R24 and R25 are — CH3, or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS- CoV. In some embodiments, the coronavirus is SARS-CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid-19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue. In some embodiments, the subject exhibits post- viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long COVID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
[0026] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure: wherein, R1 is — OH or an ester, R2 is — OH or an ester, R3 is — OH, =0, a halogen, an ester or =CH2, and R4 is an optionally substituted amine, an amide, an N-linked amino acid, =N0H or — NHOH, or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long COVID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition. [0027] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure: or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63(HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43(HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS-CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid-19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB. l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long CO VID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long- haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'COVID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS-C) as a distinct post-COVID condition.
[0028] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure:
virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), aB.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long COVID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
[0029] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure.
or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), aB.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long CO VID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
[0030] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure.
or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2 or Covid-19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern ( VOC) 202012/01 ), a B .1.351 variant of SARS-CoV-2 (a. k. a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.l.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN. l.1.18, LB. l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long COVID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'COVID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection.
[0031] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure:
or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), aB.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long CO VID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
[0032] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure:
or a pharmaceutical composition comprising the compound. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid- 19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), aB.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long CO VID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
[0033] In some embodiments methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of a compound having the structure:
or a pharmaceutical composition comprising Formula 1. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2, a SARS-CoV-2 variant, a SARS-CoV-2 mutant, or Covid-19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), aB.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P. l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB.l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long COVID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'CO VID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS- C) as a distinct post-COVID condition.
[0034] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of 17-ethynyl- 10/ , 13 -di methyl 2, 3, 4, 7, 8/?, 95, 10, 11, 12, 13, 14S, 15, 16, 17-hexadecahydro-lH-cyclopenta[a]phenanthrene-37?, 7R, 175-triol, which is represented by Formula 1, or a pharmaceutical composition comprising Formula 1. The compound of Formula 1 may also be referred to as Compound 1 or 17oc-ethynylandrost- 5-ene-3p,7p,17P-triol and is represented by the structure below.
Formula 1 or a pharmaceutical composition comprising Formula 1. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS- CoV-2 or Covid-19. In some embodiments, the coronavirus is a gamma coronavirus (y-CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, SARS-CoV-2 is at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.1.1.18, LB. l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue. In some embodiments, the subject exhibits post-viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long CO VID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long- haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'COVID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post- traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to longterm effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS-C) as a distinct post-CO VID condition.
[0035] In some embodiments, methods to prevent, treat, reduce, or ameliorate a disease or condition in a subject associated with a virus by administering to the subject a pharmaceutically effective amount of (3S,5R,7S,8R,9S,10S,13S,14S,17R)-17-ethynyl-10,13- dimethylhexadecahydro-lH-cyclopenta[a]phenanthrene-3,7,17-triol, which is represented by Formula 2, or a pharmaceutical composition comprising Formula 2. The compound of Formula 2 may also be referred to as Compound 2, and is represented by the structure below. Formula 2
In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is an alpha coronavirus, for example but not limited to, 229E (HCoV-229E) or NL63 (HCoV-NL63). In some embodiments, the coronavirus is a beta coronavirus, for example but not limited to, OC43 (HCoV-OC43) or HKU1 (HCoV-HKUl). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome or MERS-CoV. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome or SARS-CoV. In some embodiments, the coronavirus is SARS-CoV-2, a SARS-CoV-2 variant, a SARS-CoV- 2 mutant, or Covid- 19. In some embodiments, the coronavirus is a gamma coronavirus (y- CoV), for example but not limited to, an avian coronavirus (infectious bronchitis virus, IBV). In some embodiments, the coronavirus is a delta coronavirus, for example but not limited to, porcine delta coronavirus (PDCov). In some embodiments, the SARS-CoV-2 variant is a member of at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern ( VOC) 202012/01 ), a B .1.351 variant of SARS-CoV-2 (a. k. a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.l.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN. l.1.18, LB. l, and XEC. In some embodiments, the disease or condition in the subject associated with the virus is post-viral fatigue syndrome. In some embodiments, the disease or condition in the subject associated with the virus is post- viral fatigue. In some embodiments, the subject exhibits post- viral long-term symptoms. In some embodiments, the disease or condition in the subject associated with the virus is Long COVID. In some embodiments, the disease or condition in the subject associated with the virus is chronic Covid. In some embodiments, the disease or condition in the subject associated with the virus is long-haul Covid. In some embodiments, the coronavirus is a novel strain not previously identified in humans, exhibiting unique genetic markers distinct from known coronaviruses. In some embodiments, the disease or condition in the subject associated with the virus manifests as an atypical respiratory syndrome, differing in symptomatology from traditional respiratory infections. In some embodiments, the coronavirus causes neurological symptoms in the subject, such as loss of smell and taste, headaches, or cognitive impairments. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular complications, including myocarditis, arrhythmias, or increased risk of thrombosis. In some embodiments, the coronavirus triggers an overactive immune response in the subject, leading to conditions such as cytokine release syndrome or secondary hemophagocytic lymphohistiocytosis. In some embodiments, the subject with coronavirus infection experiences gastrointestinal symptoms, such as nausea, vomiting, or diarrhea, as primary manifestations of the infection. In some embodiments, the coronavirus infection in the subject leads to a multisystem inflammatory syndrome, affecting multiple organ systems simultaneously. In some embodiments, the disease or condition in the subject associated with the coronavirus is characterized by a prolonged recovery phase, with symptoms persisting for months beyond the acute phase of the infection. In some embodiments, the subject infected with the coronavirus exhibits skin manifestations, such as rashes or 'COVID toes', as part of the symptom complex. In some embodiments, the subject shows a higher susceptibility to secondary bacterial or fungal infections following a coronavirus infection. In some embodiments, the subject infected with the coronavirus exhibits neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments, the subject infected with the coronavirus exhibits musculoskeletal issues, for example but not limited to, chronic muscle pain (myalgia) or joint pain (arthralgia), weakness, or fatigue affecting physical performance. In some embodiments, the subject infected with the coronavirus exhibits mental health impacts, for example but not limited to, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS-C) as a distinct post-COVID condition.
[0036] In some embodiments, the subject previously infected with a virus exhibits at least one symptom. In some embodiments, the at least one symptom is select from, but not limited to, fatigue, inability to exercise or be active because of fatigue, and low exercise tolerance because of fatigue, shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post- exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia. In some embodiments, the subject experiences significant fluctuations in body temperature, not necessarily classified as fever, but noticeable enough to cause discomfort. In some embodiments, the subject displays signs of chronic fatigue syndrome, characterized by prolonged and severe tiredness not alleviated by rest. In some embodiments, the subject suffers from sporadic episodes of intense migraine-like headaches, different in intensity and pattern from their usual headaches. In some embodiments, the subject develops sensitivity to light or sound, which was not present before the viral infection. In some embodiments, the subject experiences psychological effects, such as unexplained mood swings, depression, or anxiety, which may be linked to the physiological impacts of the virus. In some embodiments, the subject has difficulty regulating their body temperature, leading to episodes of excessive sweating or cold chills without fever. In some embodiments, the subject reports changes in their menstrual cycle or hormonal imbalances post- viral infection. In some embodiments, the subject notices a decrease in libido or other changes in sexual health that correlate with the timeline of the viral infection. In some embodiments, the subject develops new allergies or sensitivities to foods or environmental factors that were not problematic before the infection. In some embodiments, the subject experiences unexplained changes in weight, either weight loss or gain, that cannot be attributed to changes in diet or exercise habits. In some embodiments, the subject experiences immune dysregulation, which may include the development of autoimmune conditions or the reactivation of latent viral infections, such as Epstein-Barr Virus. In some embodiments, cardiovascular symptoms manifest as coronary microvascular dysfunction, persistent fluctuations in blood pressure, or the onset of arrhythmias and tachycardia. In some embodiments, the subject develops autonomic dysfunction, including symptoms consistent with Postural Orthostatic Tachycardia Syndrome (POTS) or other forms of dysautonomia. Neurological symptoms, such as chronic tingling sensations, paresthesia, or light sensitivity (photophobia), may also emerge. In some embodiments, the subject experiences endocrine dysregulation, including new-onset diabetes, thyroid abnormalities, or hormonal imbalances, which may result in changes in menstrual cycles or menopause-like symptoms. In some embodiments, visual and auditory symptoms, such as photophobia, difficulty focusing vision, worsening tinnitus, or eye strain, become apparent. In some embodiments, the subject develops sleep disturbances, including insomnia, hypersomnia, or fragmented sleep patterns, distinct from general fatigue. In some embodiments, the subject reports widespread chronic pain resembling fibromyalgia or musculoskeletal discomfort beyond typical muscle and joint pain. In some embodiments, mental health effects, such as the development of mood swings, anxiety, depression, obsessive-compulsive tendencies, or unexplained sadness, occur as a result of post- viral impacts. In some embodiments, the subject notices unexplained changes in weight, either gain or loss, that cannot be linked to changes in diet or exercise, as well as fluctuations in libido or other changes in sexual health. In some embodiments, the subject develops new allergies or sensitivity to foods or environmental factors that were previously non-problematic. In some embodiments, gastrointestinal discomfort such as persistent bloating or irritable bowel syndrome-like symptoms is observed. In some embodiments, the subject experiences sharp or sudden chest pain, vertigo, or dizziness as distinct post-viral symptoms.
[0037] In some embodiments, a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus includes administering to the subject 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the virus is Covid- 19. In some embodiments, the subject meets the Diagnosis of Chronic Fatigue Syndrome (CFS). In some embodiments, the subject has concurrent occurrence of at least one or more of Long COVID symptoms which persisted or recurred during 3 or more consecutive months of illness. In some embodiments, the Long COVID symptoms are not known to be preceded by the infection of Covid- 19. In some embodiments, the Long COVID symptoms include, but are not limited to, fatigue, post-exertional malaise, headache, sleep disturbance, memory problems, problems with concentration, brain fog, fever, chills, cough, shortness of breath, difficulty breathing, loss of taste, loss of smell, and chest pain. In some embodiments, the method may further include diagnosing the subject for the presence of Covid- 19 or a Covid- 19 antibody. In some embodiments, the method includes administering a combination of 17a-ethynylandrost-5-ene-3P,7P,17P-triol and an anti-inflammatory agent to reduce systemic inflammation associated with Long COVID. In some embodiments, the method incorporates a regimen of physical therapy designed to gradually improve exercise tolerance and manage post-exertional malaise in subjects meeting the Diagnosis of Chronic Fatigue Syndrome (CFS). In some embodiments, the method involves psychological or cognitive behavioral therapy to address memory problems, concentration difficulties, and brain fog in subjects with Long COVID symptoms. In some embodiments, the treatment includes supplemental oxygen therapy or respiratory exercises for subjects experiencing persistent shortness of breath or difficulty breathing. In some embodiments, the method includes administering a course of vitamins and nutritional supplements aimed at boosting the immune system and alleviating fatigue and weakness. In some embodiments, the method involves the use of telemedicine for ongoing monitoring and management of Long COVID symptoms, especially for subjects with limited mobility or access to healthcare facilities. In some embodiments, the method includes a holistic approach, integrating lifestyle modifications such as diet changes, stress management techniques, and sleep hygiene practices to improve overall well-being and mitigate symptoms like sleep disturbance and fatigue. In some embodiments, the method further includes administering neuroprotective agents to treat neurological symptoms such as loss of taste, loss of smell, and neuropathic pain. In some embodiments, the method further includes the use of antiviral medications in combination with 17a- ethynylandrost-5-ene-3P,7P,17P-triol to target any residual viral activity that may be contributing to ongoing symptoms. In some embodiments, the method further includes periodic screening for secondary infections or complications that could exacerbate Long COVID symptoms, ensuring comprehensive care of the subject. [0038] In some embodiments, a method for preventing, treating, reducing, or ameliorating a disease or condition in a subject afflicted with a post- viral illness includes administering to the subject 17a-ethynylandrost-5-ene-3P,7P,17P-triol, wherein the post-viral illness is caused by or associated with the viral disease or infection in the subject. In some embodiments, the post-viral illness is caused by the viral disease in the subject. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol treats symptoms associated with recovery from the viral disease in the subject. In some embodiments, the symptoms include fatigue, post-exertional malaise (PEM), problems with memory or concentration, sore throat, headache, muscle or joint pain, dizziness, brain fog, shortness of breath, and/or unrefreshing sleep. In some embodiments, the post-viral illness is Long COVID. In some embodiments, the method further includes administering 17a-ethynylandrost-5-ene-3P,7P,17P-triol in conjunction with an anticoagulant or blood thinner to treat or prevent blood clotting issues commonly seen in post-viral illnesses like Long COVID. In some embodiments, the method includes the use of supplemental oxygen or respiratory support devices for subjects experiencing persistent respiratory difficulties as a result of the post-viral illness. In some embodiments, the method includes cognitive rehabilitation therapies to specifically address and ameliorate problems with memory and concentration associated with brain fog in Long COVID patients. In some embodiments, the method involves administering a tailored regimen of gentle physical exercises and physiotherapy to help subjects manage muscle or joint pain and gradually improve their physical function. In some embodiments, the method incorporates psychological counseling or therapy to help subjects cope with the mental health impacts, such as anxiety or depression, that often accompany prolonged illnesses like Long COVID. In some embodiments, the method includes the use of nutritional supplements or dietary adjustments to support overall health and mitigate symptoms like fatigue and unrefreshing sleep. In some embodiments, the method includes the administration of immune modulators or supplements to balance the immune response and reduce systemic inflammation characteristic of post-viral syndromes. In some embodiments, the method includes regular monitoring and assessment of cardiovascular health, given the increased risk of heart-related issues in post-viral illness scenarios. In some embodiments, the method includes using hydration therapy, either orally or intravenously, to alleviate symptoms of dizziness and improve overall energy levels in subjects. In some embodiments, the method further includes the use of non- pharmacological interventions such as acupuncture or massage therapy to provide relief from symptoms like muscle pain and headache.
[0039] In some embodiments, the subject may experience prevention or reduction in one or more symptoms associated with a previous viral infection after administration of a compound or composition as described herein. In some embodiments, the subject may experience prevention or reduction in one or more symptoms associated with Long COVID after administration of a compound or composition as described herein. In some embodiments, the prevention or reduction in symptoms related to Long COVID may be reduced by an amount equal to or greater than approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 99%, 100%, or ranges including and/or spanning the aforementioned values after administration of the compound or composition as described herein. For example, subjects may experience prevention or reduction in one or more symptoms of Long COVID from approximately 5% to 100% after administration of the compound or composition as described herein and at least one pharmaceutically acceptable excipient.
[0040] In some embodiments, the subject may experience an improvement or amelioration in one or more symptoms associated with a previous viral infection after administration of a compound or composition as described herein. In some embodiments, the subject may experience an improvement or amelioration in one or more symptoms associated with Long COVID after administration of a compound or composition as described herein. In some embodiments, the prevention or reduction in symptoms related to Long COVID may be reduced by an amount equal to or greater than approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 99%, 100%, or ranges including and/or spanning the aforementioned values after administration of the compound or composition as described herein. For example, subjects may experience improvement or amelioration in one or more symptoms of Long COVID from approximately 5% to 100% after administration of the compound or composition as described herein and at least one pharmaceutically acceptable excipient.
[0041] In some embodiments, the post-viral long-term symptoms may have lasted from the time of infection to the administering step, for a time selected from the group consisting of: one week, two weeks, three weeks, 1 month, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, and more than 2 years. In some embodiments, the administering is performed after the subject was infected for at least a time selected from the group consisting of 30 days, 50 days, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, and more than 2 years.
[0042] In some embodiments, the method includes administering to the subject a dose of a compound or composition as described herein. In some embodiments, the dose includes from about 1 mg to about 100 mg of a compound or composition as described herein. In some embodiments, the dose includes about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg of a compound or composition as described herein, or ranges including and/or spanning the aforementioned values. In some embodiments, the method includes administering from about 2 mg to about 5 mg of a compound or composition as described herein. In some embodiments, the method includes administering from about 10 mg to about 40 mg of a compound or composition as described herein. In some embodiments, the method includes administering from about 20 mg to about 40 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 2 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 5 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 10 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 20 mg of a compound or composition as described herein. In some embodiments, the method includes, for example, administering about 40 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 50 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 80 mg of a compound or composition as described herein. In some embodiments, the method includes administering about 100 mg of a compound or composition as described herein.
[0043] In some embodiments, the method includes administering to the subject a dose of 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the dose includes from about 1 mg to about 100 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the dose includes about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, or ranges including and/or spanning the aforementioned values. In some embodiments, the method includes administering from about 2 mg to about 5 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering from about 10 mg to about 40 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering from about 20 mg to about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 2 mg 17a-ethynylandrost-5-ene- 3P,7P,17P-triol. In some embodiments, the method includes administering about 5 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 10 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 20 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes, for example, administering about 40 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 80 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
[0044] In some embodiments, the method includes administering a compound or composition as described herein once a day. In some embodiments, the method includes administering a compound or composition as described herein twice a day. In some embodiments, the method includes administering the compound or composition as described herein three times a day. In some embodiments, the method includes administering a compound or composition as described herein once a week. In some embodiments, the method includes administering the compound or composition as described herein once a month. In some embodiments, the method includes administering the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol once a day. In some embodiments, the method includes administering the 17a- ethynylandrost-5-ene-3P,7P,17P-triol twice a day. In some embodiments, the method includes administering the 17a-ethynylandrost-5-ene-3P,7P,17P-triol three times a day. In some embodiments, the method includes administering the 17a-ethynylandrost-5-ene-3P,7P,17P- triol once a week. In some embodiments, the method includes administering the 17a- ethynylandrost-5-ene-3P,7P,17P-triol once a month. [0045] In some embodiments, the administrating step may be performed after the primary COVID-19 symptoms of acute illness have been resolved. In some embodiments, the administering step may be performed when the post-viral long-term symptoms persist beyond the typical recovery period for acute viral illnesses, which is often considered to be about two weeks. In some embodiments, the treatment may be initiated at a specific time point after the onset of long-term symptoms, such as within the first three weeks, to potentially prevent the progression or worsening of these symptoms. In some embodiments, the administration of the treatment may be tailored based on the subject’s recovery trajectory, with the timing adjusted according to the persistence or severity of specific symptoms like fatigue or brain fog. In some embodiments, the treatment may be commenced after a comprehensive medical evaluation confirming that the subject’s symptoms are not attributable to other underlying medical conditions that might have emerged post-infection. In some embodiments, the treatment may be delayed until a thorough assessment of the subject’s immune response to the initial infection may be conducted, to ensure the treatment aligns with the current state of the immune system. In some embodiments, the administering step may be synchronized with the completion of a prescribed course of other medications or treatments for COVID-19, to avoid potential drug interactions and enhance treatment efficacy. In some embodiments, the treatment begins only after the subject has been symptom- free for a brief period, to distinguish between ongoing acute symptoms and emerging long-term post-viral symptoms. In some embodiments, the treatment initiation may be dependent on the subject’s return to certain baseline activities or levels of physical function, as a measure of recovery progress. In some embodiments, the treatment starts after a set period following the last positive COVID- 19 test, to ensure that the virus has been cleared and the symptoms experienced are indeed post-viral. In some embodiments, the treatment is administered in conjunction with regular health check-ups and monitoring, to track the evolution of the post-viral symptoms and adjust the treatment plan as necessary. In some embodiments, the treatment initiation may be based on specific biomarkers or laboratory results indicating one or more diseases or conditions associated with Long COVID. In some embodiments, the one or more diseases or conditions associated with Long COVID include ongoing inflammation, immune dysregulation, or tissue damage associated with long-term COVID- 19 symptoms. In some embodiments, the timing of treatment may be adjusted depending on the subject’s age, medical history, or risk factors for chronic conditions, to optimize safety and efficacy. In some embodiments, the treatment may be initiated in conjunction with physical therapy or rehabilitation programs, particularly if the subject exhibits mobility issues or physical deconditioning as part of their post-viral symptoms. In some embodiments, the treatment may be started alongside psychological counseling or mental health interventions, especially in cases where anxiety, depression, or cognitive impairments are prominent. In some embodiments, the treatment plan may include an evaluation of the subject’s nutritional status, with supplementation or dietary modifications provided concurrently to support recovery. In some embodiments, the treatment may be tailored to address specific organ systems affected, such as targeted therapies for respiratory, cardiovascular, or neurological sequelae. In some embodiments, the timing of treatment initiation may be coordinated with seasonal factors, such as avoiding administration during periods of heightened respiratory illness risk to prevent exacerbation of symptoms. In some embodiments, the treatment plan may be initiated only after the subject has undergone a structured diagnostic protocol to identify co-infections, secondary complications, or latent viral reactivations that may influence treatment outcomes. In some embodiments, the treatment may be initiated in a stepwise manner, beginning with conservative approaches and escalating to more intensive interventions based on the subject’s response and symptom persistence.
[0046] In several embodiments, the pharmaceutical composition includes a solid state form of a compound as described herein. In several embodiments, the pharmaceutical compositions include a solid state form of at least one compound as described herein. In several embodiments, the solid state form is of at least one compound as described herein. In several embodiments, the solid state form is a crystalline form of at least one of the compounds as described herein substantially free of 17a-ethynylandrost-5-ene-3p,7p,17P-triol in amorphous form. In several embodiments, the pharmaceutical compositions include a solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the solid state form is crystalline 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the solid state form is crystalline 17a-ethynylandrost-5-ene-3p,7p,17P-triol substantially free of 17a- ethynylandrost-5-ene-3p,7p,17P-triol in amorphous form.
[0047] In several embodiments, the solid state form is crystalline solvate 17a- ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is crystalline methanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is crystalline ethanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is crystalline hydrate 17a-ethynylandrost-5-ene- 3p,7p,17p-triol. Crystalline solvate of 17a-ethynylandrost-5-ene-3p,7p,17P-triol, crystalline methanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol, crystalline ethanoate 17a- ethynylandrost-5-ene-3p,7p,17P-triol, crystalline hydrate 17a-ethynylandrost-5-ene- 3p,7p,17p-triol are disclosed in WO 2009/124300A2, which is incorporated herein by reference in its entirety.
[0048] In several embodiments, the crystalline solvate is Form III 17a- ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is Form IV 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the crystalline solvate is Form V 17a-ethynylandrost-5-ene-3p,7p,17P-triol. Crystalline solvate Form III, crystalline solvate Form IV, and crystalline solvate Form V are disclosed in WO 2009/124300A2, which is incorporated herein by reference in its entirety.
[0049] In several embodiments, the solid-state form of 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is amorphous 17a-ethynylandrost-5-ene-3p,7p,17P-triol. In several embodiments, the amorphous 17a-ethynylandrost-5-ene-3p,7p,17P-triol substantially free of 17a-ethynylandrost-5-ene-3p,7p,17P-triol in solid state form.
[0050] In some embodiments, the compound or pharmaceutical composition described herein is administered orally. In some embodiments, the compound or pharmaceutical composition described herein is administered intravenously. In some embodiments, the compound or pharmaceutical composition described herein is administered topically. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered orally. In other embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered intravenously. In other embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered topically.
[0051] In some embodiments, a compound as described herein is administered as a formulation or a composition with at least one pharmaceutically acceptable excipient. In some embodiments, a compound as described herein is administered as a formulation or a composition with at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier. In some embodiments, 17a-ethynylandrost-5-ene- 30,70, 17P-triol is administered as a formulation with at least one pharmaceutically acceptable excipient. In some embodiments, 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered as a formulation with at least one pharmaceutically acceptable excipient and at least one pharmaceutically acceptable carrier. In some embodiments, 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is administered as a formulation with at least one pharmaceutically acceptable carrier. Other pharmaceutically acceptable excipients suitable for use in the compositions include absorption enhancing agents, acidifying agents, agents for modified release, alkalizing agents, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying agents, flavoring agents, humectants, humidity-adjusting agents, pH-adjusting agents, preservatives, solubilizing agents, stabilizers, surface-active agents, suspending agents, sweetening agents, taste-masking agents, and wetting agents.
[0052] Formulations include compositions comprising 1, 2, 3, 4 or more pharmaceutically acceptable excipients or carriers. The compositions are used to prepare formulations suitable for human or animal use. Suitable administration routes for formulations include oral, rectal, nasal, transmucosal, topical (including buccal and sublingual), vaginal, rectal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, intraocular and epidural). In general, aqueous and non-aqueous liquid or cream formulations are delivered by a parenteral, oral or topical route. In other embodiments, such as the disclosure intermittent dosing methods, 17a-ethynylandrost-5-ene-3P,7P,17P-triol may be present as an aqueous or a non-aqueous liquid formulation or a solid formulation suitable for administration by any of the routes disclosed herein, e.g., oral, topical, buccal, sublingual, parenteral, inhaled aerosol or a depot such as a subcutaneous depot or an intraperitoneal or intramuscular depot. It will be appreciated that the preferred route may vary with, for example, the subject’s pathological condition or weight or the subject’s response to therapy with 17a- ethynylandrost-5-ene-3P,7P,17P-triol or other therapy that is used or that is appropriate to the circumstances.
[0053] The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. Techniques, excipients and formulations generally are found in, e.g., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 2022, 23rd edition, Adeboye et al., PDA J. Pharm. Sci. Tech. 1997 51: 166-171, G. Cole, et al., editors, Pharmaceutical Coating Technology, 1995, Taylor & Francis, ISBN 0 136628915, H. A. Lieberman, et al., editors, Pharmaceutical Dosage Forms, 1992 2ndrevised edition, volumes 1 and 2, Marcel Dekker, ISBN 0824793870, J. T. Carstensen. Pharmaceutical Preformulation, 1998, pages 1-306, Technomic Publishing Co. ISBN 1566766907. Exemplary excipients for formulations include emulsifying wax, propyl gallate, citric acid, lactic acid, polysorbate 80, sodium chloride, isopropyl palmitate, glycerin, white petrolatum and other excipients disclosed herein.
[0054] Formulations, or compositions disclosed herein for use to make formulations suitable for administration by the routes disclosed herein optionally comprise an average particle size in the range of about 0.01 to about 500 microns, about 0.1 to about 100 microns or about 0.5 to about 75 microns. Average particle sizes include a range between 0.01 and 500 microns in 0.05 micron or in 0.1 micron or other increments, e.g., an average particle size of about 0.05, 0.1, 0.5, 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50, 60, 75, 85, 100, 120, etc. microns). When 17a-ethynylandrost-5-ene-3P,7P, 17)3- triol or compositions that comprise 17a-ethynylandrost-5-ene-3P,7P,17P-triol are used as intermediates to make a formulation, they may comprise one, two, three or more of these average particle sizes, or size ranges. In preparing any of the compositions or formulations that are disclosed herein and that comprise 17a-ethynylandrost-5-ene-3P,7P,17P-triol (and optionally one or more excipients and/or one or more carriers), one may optionally mill, sieve or otherwise granulate the compound or composition to obtain a desired particle size.
[0055] Non-limiting examples of fillers suitable for use in the compositions include lactose, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, and collagen.
[0056] Non-limiting examples of diluents suitable for use in the compositions include e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, and sugar.
[0057] Non-limiting examples of disintegrants suitable for use in the compositions include alginic acid or alginates, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, and carboxymethyl starch.
[0058] Non-limiting examples of binders suitable for use in the compositions include acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, polyethylene oxides, povidone, and pregelatinized starch.
[0059] Non-limiting examples of glidants and/or lubricants suitable for use in the compositions include stearic acid, magnesium stearate, calcium stearate or other metallic stearates, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, and sodium acetate.
[0060] Non-limiting examples of antioxidants suitable for use in the compositions include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, and derivatives of tocopherol.
[0061] In several embodiments, the pharmaceutically acceptable excipient is selected from sodium dodecyl sulfate, microcrystalline cellulose, magnesium stearate, and any combination of the foregoing. In several embodiments, the pharmaceutically acceptable excipient is sodium dodecyl sulfate.
[0062] In several embodiments, the pharmaceutical compositions are formulated into oral dosage forms. In several embodiments, the dosage forms can include capsules and tablets. In some embodiments, the dosage forms can include one or more different types of delayed release layers selected from sealant and/or enteric layers. For example, delayed release layers having different release rate characteristics can provide the dosage form with different overall drug release characteristics. In some such embodiments, the pharmaceutically acceptable excipient is a surface active agent. In several embodiments, the surface active agent is present in an amount sufficient to provide 90% dissolution of the pharmaceutical composition in water at ambient temperature after 30 min. In several embodiments, the surface active agent is sodium lauryl sulfate. In several embodiments, the pharmaceutical composition is a capsule or a tablet.
[0063] In several embodiments, the pharmaceutical compositions contain less than about 5% by weight of 3 P-hydroxy-androst-5-ene-7, 17-dione. In several embodiments, the pharmaceutical compositions contain less than about 3% by weight of impurities.
[0064] In several embodiments, the pharmaceutical compositions include a pharmaceutically acceptable formulation of a compound, as described herein. In some embodiments, the pharmaceutical composition includes 17oc-ethynylandrost-5-ene-3p,7p,17P- triol. In some embodiments, the pharmaceutical compositions include a polymorph form of a compound as described herein.
[0065] In several embodiments, the use is concurrent with a use of at least one additional medicament. In several embodiments, the additional medicament is administered at a delay time after a first administration of the composition. In several embodiments, the first administration may occur using a dosage schedule that is daily, weekly, monthly, or any combination of the foregoing. In several embodiments, the dosage schedule of the first administration may include one, two, three or more daily dosages of the composition. In several embodiments, the dosage schedule of the first administration may include one, two, three or more weekly dosages of the composition. In several embodiments, the dosage schedule of the first administration may include one, two, three or more monthly dosages of the composition. In several embodiments, the delay time is equal to or greater than about: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years, or ranges including and/or spanning the aforementioned values. In several embodiments, the delay time is equal to or greater than 2 years. In some embodiments, the delay time is zero and the additional medicament is administered concurrently with the first administration of the composition. In several embodiments, the additional medicament is administered using a dosage schedule that is daily, weekly, monthly, or any combination of the foregoing. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more daily dosages of the composition. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more weekly dosages of the composition. In several embodiments, the dosage schedule of the additional medicament may include one, two, three or more monthly dosages of the composition.
[0066] Several embodiments of the present disclosure relate to the use of 17a- ethynylandrost-5-ene-3p,7p,17P-triol in the manufacture of a medicament for treating a neurodegenerative condition related to Long COVID. In some embodiments, the neurodegenerative condition related to Long COVID includes, but is not limited to, neurological and cognitive symptoms, for example but not limited to, brain fog, memory loss, or difficulty concentrating, sleep disturbances, insomnia, or hypersomnia. In some embodiments the neurodegenerative condition related to Long COVID includes, but is not limited to, mental health impacts, for example, depression or anxiety as direct or secondary consequences of the infection or post-traumatic stress disorder (PTSD) due to severe illness or hospitalization. In some embodiments, the subject infected with the coronavirus exhibits autonomic dysregulation, for example but not limited to, postural orthostatic tachycardia syndrome (POTS) or other forms of dysautonomia. In some embodiments, the subject infected with the coronavirus exhibits pulmonary and respiratory sequelae, for example but not limited to, persistent dyspnea (shortness of breath) or reduced lung capacity or fibrosis or scarring in lung tissues visible through imaging. In some embodiments, the subject infected with the coronavirus exhibits immune dysregulation, for example but not limited to, long-term autoimmunity or chronic inflammatory states or reactivation of latent viral infections, such as Epstein-Barr virus (EBV). In some embodiments, the subject infected with the coronavirus exhibits Chronic Pain Syndromes, for example but not limited to, new-onset chronic pain conditions, such as fibromyalgia. In some embodiments, the subject infected with the coronavirus exhibits cardiovascular effects, for example but not limited to, persistent hypertension or hypotension unrelated to acute illness or microvascular dysfunction or endothelial injury leading to long-term effects. In some embodiments, the subject infected with the coronavirus exhibits endocrine and metabolic effects, for example but not limited to, development of new or worsened diabetes mellitus or thyroid dysfunction (e.g., thyroiditis or hypothyroidism). In some embodiments, the subject infected with the coronavirus exhibits kidney and renal effects, for example but not limited to, long-term decline in kidney function or increased risk of chronic kidney disease. In some embodiments, the subject infected with the coronavirus exhibits pediatric manifestations, for example but not limited to, inclusion of multisystem inflammatory syndrome in children (MIS-C) as a distinct post-COVID condition. In some embodiments, the method includes administering to the subject a dose of 17a- ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the dose includes from about 10 mg to about 100 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the dose includes about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg 100 mg 17a- ethynylandrost-5-ene-3P,7P,17P-triol, or ranges including and/or spanning the aforementioned values. In some embodiments, the method includes administering from about 10 mg to about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering from about 20 mg to about 40 mg 17a-ethynylandrost-5-ene-3P,7P,17P-triol. In some embodiments, the method includes administering about 20 mg 17a-ethynylandrost-5- ene-3 P, 7P, 17 P-triol.
[0067] Accordingly, the present disclosure thus includes the following numbered alternatives:
[0068] 1. A method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus, the method comprising administering to the subject a therapeutically effective amount of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, optionally in a pharmaceutically acceptable carrier.
[0069] 2. The method of alternative 1, wherein the virus is selected from the group consisting of coronavirus, human coronavirus 229E, human coronavirus OC43, human coronavirus NL63, human coronavirus HKU1, Middle East respiratory syndrome- related coronavirus (MERS-Cov), severe acute respiratory syndrome-related coronavirus (SARS- CoV), SARS-CoV-2, SARS-CoV-2 variant, SARS-CoV-2 mutation, influenza virus, adenovirus, herpes virus, rhinovirus, respiratory syncytial virus, Ebola Virus, West Niles Virus, Zika Virus, H5 influenza, H7 influenza, H5N1 influenza, WestNiles Virus, St. Louis encephalitis, Japanese encephalitis, Eastern equine encephalitis, Western equine encephalitis, Zika Virus, MERS-CoV, HCoV-EMC, Influenz A, Influenza B, H1N1 influenza, H3N2 influenza, H7N9 influenza, H5N6 influenza, H10N8 influenza, H9N2 influenza, H6N1 influenza, a mutant, thereof, a type thereof, a subtype thereof, a lineage thereof, a clade thereof, and a subclade thereof. [0070] 3. The method of alternative 2, wherein the virus is SARS-CoV-2 or a
SARS-CoV-2 variant.
[0071] 4. The method of alternative 2, wherein the SARS-CoV-2 variant is at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 20I/501Y.V1 Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.1.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN.l.1.18, LB.1, and XEC.
[0072] 5. The method of any one of alternatives 1 to 4, wherein the subject has post viral fatigue symptoms or is afflicted with post viral fatigue symptoms.
[0073] 6. The method of alternative 5, wherein the post viral fatigue symptom is one or more Long CO VID symptoms.
[0074] 7. The method of alternative 6, wherein the one or more Long COVID symptoms is selected from the group consisting of: fatigue including severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post-exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia.
[0075] 8. The method of any one of alternatives 1 to 7, wherein the subject did not have post-viral fatigue symptoms before being infected with the virus.
[0076] 9. The method of any one of alternatives 1 to 8, wherein the subject develops the symptoms of post viral fatigue during or after being infected with the virus.
[0077] 10. The method of any one of alternatives 1 to 9, wherein the subject experiences between about a 5% to about 100% improvement in the condition in the subject previously infected with the virus.
[0078] 11. The method of any one of alternatives 1 to 10, wherein the subject experiences between about 5% to about 100% improvement to the disease in the subject previously infected with the virus. [0078] 12. The method of any one of alternatives 1 to 11, wherein the 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered at a dose from about 10 mg to about 40 mg. [0079] 13. The method of alternative 12, wherein the 17a-ethynylandrost-5-ene-
30,70, 17P-triol is administered at a dose from about 20 mg.
[0080] 14. The method of any one of alternatives 1 to 13, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered once a day.
[0081] 15. The method of any one of alternatives 1 to 13, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered twice a day.
[0082] 16. The method of any one of alternatives 1 to 15, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered orally.
[0083] 17. The method of any one of alternatives 1 to 17, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered in a solid dosage form.
[0084] 18. The method of any one of alternatives 1 to 16, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered intravenously.
[0085] 19. The method of any one of Alternatives 1 to 17, wherein the 17a- ethynylandrost-5-ene-3p,7p,17P-triol is a solid state form of 17a-ethynylandrost-5-ene-
3p,7p,17p-tnol.
[0086] 20. The method of Alternative 18, wherein the solid state form of 17a- ethynylandrost-5-ene-3p,7p,17P-triol is crystalline solvate of 17a-ethynylandrost-5-ene- 3p,7p,17p-tnol.
[0087] 21. The method of Alternative 19, wherein the crystalline solvate is crystalline methanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
[0088] 22. The method of Alternative 20, wherein the crystalline solvate is crystalline ethanolate 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
[0089] 23. The method of Alternative 21, wherein the crystalline solvate is crystalline hydrate 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
[0090] 24. The method of Alternative 21, wherein the crystalline solvate is Form
III 17a-ethynylandrost-5-ene-3p,7p,17P-triol.
[0091] 25. The method of Alternative 21, wherein the crystalline solvate is Form
IV 17a-ethynylandrost-5-ene-3 P,7P, 17 P-triol.
[0092] 26. The method of Alternative 21, wherein the crystalline solvate is Form
V 17a-ethynylandrost-5-ene-3 P,7P, 17 P-triol. [0093] 27. A method for the treatment of Long CO VID in a patient in need thereof, the method comprising: administering to the subject a therapeutically effective amount of 17a- ethynylandrost-5-ene-3P,7P,17P-triol, optionally in a pharmaceutically acceptable carrier, wherein, administering 17a-ethynylandrost-5-ene-3P,7P,17P-triol to the subject reduces or improves at least one sign, condition, or symptom of Long CO VID.
[0094] 28. The method of alternative 27, wherein the at least one sign, condition, or symptom of Long COVID is selected from the group consisting of: fatigue include severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post-exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia.
[0095] 29. The method of alternative 27 or 28, wherein the subject did not have at least one sign, condition, or symptom of Long COVID prior to infection with COVID.
[0096] 30. The method of alternative 27 or 28, wherein the subject develops the at least one sign, condition, or symptom of Long CO VID after three weeks from initial infection with CO VID.
[0097] 31. The method of any one of alternatives 27 to 30, wherein the subject experiences between about a 5% to about 100% improvement in at least one sign, condition, or symptom of Long CO VID.
[0098] 32. The method of any one of alternatives 27 to 31, wherein the subject experiences between about a 5% to about 100% reduction in at least one sign, condition, or symptom of Long CO VID.
[0099] 33. The method of any one of alternatives 27 to 32, further comprising monitoring the subject for a reduction in symptoms of Long COVID following the administration of 17a-ethynylandrost-5-ene-3P,7P,17P-triol.
[0100] 34. The method of any one of alternatives 27 to 33, wherein the patient has been diagnosed with Long Covid for a duration selected from the group consisting of 1 month, 3 months, 6 months, and 1 year. [0101] 35. The method of any one of alternatives 27 to 34, wherein 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered to subjects who have a confirmed diagnosis of Long COVID through a positive COVID-19 antibody test.
[0102] 36. The method of any one of alternatives 27 to 35, wherein 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered in combination with a second therapeutic agent selected from the group consisting of anti-inflammatory agents, antiviral agents, and immune modulators.
[0103] 37. The method of any one of alternatives 27 to 36, wherein the subject is concurrently receiving physical therapy or cognitive behavioral therapy for symptoms of Long COVID.
[0104] 38. The method of any one of alternatives 27 to 37, wherein the at least one sign, condition, or symptom of Long COVID includes neurological symptoms, and the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is specifically administered to treat or alleviate the neurological symptoms.
[0105] 39. The method of any one of alternatives 27 to 38, wherein the at one sign, condition, or symptom of Long COVID are ameliorated or treated within a time period following administration of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, the time period being selected from the group consisting of 2 weeks, 1 month, 3 months, and 6 months.
[0106] 40. The method of any one of alternatives 27 to 39, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered at a dose from about 10 mg to about 40 mg.
[0107] 41. The method of alternative 40, wherein the 17a-ethynylandrost-5-ene-
3P,7P,17P-triol is administered at a dose from about 20 mg.
[0108] 42. The method of any one of alternatives 27 to 41, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered once a day.
[0109] 43. The method of any one of alternatives 27 to 41, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered twice a day.
[0110] 44 The method of any one of alternatives 27 to 43, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered orally.
[0111] 45. The method of any one of alternatives 27 to 44, wherein the 17a- ethynylandrost-5-ene-3P,7P,17P-triol is administered intravenously. [0112] 46. The method of any one of Alternatives 27 to 45, wherein the 17a- ethynylandrost-5-ene-3p,7p,17P-triol is a solid state form of 17a-ethynylandrost-5-ene- 3p,7p,17p-tnol.
[0113] 47. A method for the treatment of the 2019 coronavirus disease (COVID-
19) caused by a SARS-CoV-2 virus, a SARS-CoV-2 variant, or a SARS-CoV-2 mutation in a mammal in need thereof comprising administering an effective amount of at least one of:
optionally in a pharmaceutically acceptable carrier.
[0114] 48. Use of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, or a pharmaceutically salt thereof, optionally in a pharmaceutically acceptable carrier, in the preparation of a medicament for the treatment of a disease or condition caused by a coronavirus.
[0115] 49. A composition comprising 17a-ethynylandrost-5-ene-3P,7P,17P-triol, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier for use in treating a disease or condition caused by a coronavirus.
[0116] 50. The use of alternative 48 or composition of alternative 49, wherein the
17a-ethynylandrost-5-ene-3P,7P,17P-triol is in an oral dosage of about 10 mg to about 40 mg.
[0117] 51. Use of a compound selected from
optionally in a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment, prevention, or prophylaxis of a disease or condition associated with Long COVID.
[0118] 51. The method of alternative 47 or the use of alternative 50, wherein the at least one compound is provided to prevent a disease or condition associated with Long COVID.
EXAMPLES
[0119] The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.
Example 1
[0120] The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by the recently emerged virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2). Approximately 30% of those who survive illness with COVID-19, including those who experience only a mild disease course, experience debilitating post-acute sequelae of COVID, called PASC or Long COVID, persisting 3 months after infection. Data from the CDC suggest that Long CO VID disproportionately affects women, and individuals between the ages of 40 and 59 have the highest reported rates of developing this post-acute infection syndrome. There is strong evidence that neuroinflammation contributes to at least the more common symptoms of fatigue, sleep disorders and cognitive impairment in Long COVID. [0121] This study will evaluate novel treatments, strategies, or therapeutic targets for associated neurological diseases and psychological conditions, which may include repurposing existing drugs. The goal of this study is to evaluate a novel treatment, 17a- ethynylandrost-5-ene-3P,7P,17P-triol (“NE3107”), for the associated neurological conditions of Long COVID. NE3107 is an orally bioavailable, blood-brain barrier-permeable, insulinsensitizer that is anti-inflammatory but not immunosuppressive, and possesses unique attributes for targeting the mechanisms underlying the neurological symptoms of Long COVID. NE3107 has the potential to reduce symptoms including fatigue and cognitive dysfunction by targeting the mechanism underlying pro-inflammatory pattern recognition tolllike receptors (TLR) driven neuroinflammation. Currently NE3107 is in clinical development for Alzheimer’s and Parkinson’s diseases, two neurodegenerative diseases where TLR-driven inflammation contributes to the neuropathology and cognitive decline.
[0122] The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an estimated 770 million individuals being infected and 6.99 million deaths globally. Acute infection represents a spectrum of disease severity ranging from mild cold/cough-like symptoms to severe pneumonia, acute respiratory distress syndrome (ARDS) and death. Approximately 30% of those who survive the illness, including those who experience only a mild disease course, experience post-acute sequelae of COVID, called PASC or Long CO VID, persisting 3 months after infection that include neurological, glycometabolic and physical disorders. Patients report suffering from clusters of debilitating symptoms including post-exertional malaise, fatigue, cognitive dysfunction/brain fog/ memory defects, generalized pain, shortness of breath, persisting high temperature, and psychiatric problems, with more than 50% of patients experiencing at least one symptom for at least 2 years. The prevalence and debilitating nature of these symptoms has resulted in PASC or Long COVID being recognized as a “disability” under the Americans with Disabilities Act and represents a significant burden on the healthcare system. The findings in a publication that used electronic health record data to identify patients with Long COVID, emphasized that “Long COVID will not have a single definition, and it might be better described as a set of related conditions with their own symptoms, trajectories, and treatments”. There are different clinical presentations of Long COVID (eg, neurologic, metabolic, cardiopulmonary), and intensive efforts continue to establish these clinical phenotypes and underlying pathogenic mechanisms (NIH Recover Initiative). Data from a prospective longitudinal cohort study of 9764 participants in the RECOVER adult cohort, reported that 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2-infected participants at 6 months or more after infection compared with uninfected participants. A preliminary rule for identifying PASC was derived based on a composite symptom score. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included post-exertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements and a definition of PASC as a new condition specific to SARS-CoV-2 infection has been proposed.
[0123] Hyperactivation of the pro-inflammatory transcription factor NFkB and resulting inflammation appears to be the key driver of both acute and chronic COVID. Disease severity correlates with the inflammatory response and circulating levels of chemokines and cytokines, most notably the NF-kappa-b stimulated proinflammatory cytokines IL-6 and TNFa. Long COVID is highly associated with inflammatory markers IL-6, IFNy, MCP-1 (CCL2) and VCAM-1 and with the macrophage-secreted triad IL-6, TNFa and IL-10. Substantial evidence has already accumulated that strongly suggests that persistent immune activation is associated with ongoing symptoms following COVID- 19, notably the cytokine interleukin 6 (IL-6), which is elevated among most of those with Long CO VID. Moreover, higher levels of IL-6 have been reported in women and those with a central sensitization (CS) phenotype compared with the cardiopulmonary phenotype. Symptom cluster of diarrhea (73%), high heart rates (59%), dizziness (45%), swallowing problems (45%), voice problems (45%), and low blood pressure (14%) appear to be related to inflammation of the vagus nerve post-infection.
[0124] A more recent study has identified a serum proteome signature in patients with Long COVID that identifies those with a persistent inflammatory state. In that study >50% of the patients had persistent inflammation. Moreover, the inflammatory signature pointed to cytokine blockade for the NF-icB-driven (potentially activated by TNF) inflammatory cytokines TNF and IL-6 as a potential therapeutic strategy. [0125] A persisting reservoir of SARS-CoV-2 outside of the CNS, possibly in the gastrointestinal tract or adipose tissue, may be an underlying cause of Long COVID. The SARS-CoV-2 Spike protein persists and circulates in patients with Long COVID. Spike appears to contribute to neuroinflammation and cognitive impairment since the infusion of Spike protein into the brains of rodents induces a Long COVID-like syndrome resulting in microglial activation, neuroinflammation and memory impairment Indeed Spike administered peripherally can cross the blood brain barrier and result in late impact cognitive impairment in mice after subcutaneous infusion.
[0126] Both Spike protein and/or its SI subunit, that is released into the bloodstream upon binding of Spike to the ACE2 receptor, function as a pathogen-associated molecular pattern (PAMP) and activate pro-inflammatory signaling in macrophages via engagement of pattern recognition toll-like receptors (TLR) TLR2 and TLR4. The importance of the TLR4 signaling pathway in Long CO VID is corroborated by the genetic association of TLR4 variants with Long COVID and the inhibition in vivo of neuroinflammation and cognitive impairment induced by Spike with a pharmacological inhibitor of TLR4. It is well documented that stimulation of TLR4, TLR2, the TNF receptor TNFR1 and IL- 10 receptor in macrophages results in the activation of downstream kinases TPL2/MEK/ERK and activation of NF-KB, inducing the expression of inflammatory cytokine triad IL-6, TNF and IL- 10 and chemokines. In vitro, SI increases the activation/phosphorylation of ERK in lung epithelial cells and murine macrophages and reduction of ERK phosphorylation by an inhibitor of the ERK kinase, MEK, reduces the expression of IL-6 and IL- 10. Inhibition of this TLR-driven signaling pathway has been recently proposed for the treatment of Long CO VID. Since the TPL2/ERK signaling pathway is also a central hub in obesity-associated inflammation and metabolic disorders, and required for the perpetuation and augmentation of inflammation by TNF-a, selective inhibition of this pathway could short-circuit not only the perpetuated activation of the inflammatory cascade in Long COVID but also the insulin resistance and new onset Type 2 diabetes that has been reported to develop post-infection.
[0127] NE3107, the 17-alpha-ethynyl derivative of the naturally occurring human adrenal sterol 0-androstenetriol (0-AET), is an orally available, safe, insulin-sensitizer that has shown anti-inflammatory activity in murine models of NFicB-driven inflammation including ulcerative colitis, multiple sclerosis, type 1 diabetes mellitus, and chronic obstructive pulmonary disease. NE3107 ameliorates inflammatory responses elicited by TLR4: Preclinical studies in macrophages have demonstrated that NE3107 inhibits LPS-stimulated (TLR4- driven) ERK phosphorylation and inhibits activation of NFKB (p65 NFKB phosphorylation and nuclear localization and KB occupancy at the IL-6 promoter). In vitro and in vivo studies have demonstrated that NE3107 decreases the expression of inflammatory cytokines and chemokines.
[0128] NE3107 has shown broad anti-inflammatory activity in animal models of rheumatoid arthritis, ulcerative colitis, multiple sclerosis, lung inflammation, autoimmune type 1 diabetes, and neuroinflammation. In these models, nuclear factor kappa B (NFKB) activation and proinflammatory cytokine production were consistently suppressed. Furthermore, NE3107 was not markedly immunosuppressive in rodent models of ovalbumin immunization, Klebsiella pneumoniae or Pseudomonas aeruginosa infection, Coxsackievirus B3 myocarditis, delayed-type hypersensitivity, and mitogen-induced proliferation, or in the human mixed lymphocyte reaction assay.
[0129] In the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with NE3107 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in: (1) production of TNF-alpha, IL-6, and IL- 17; and (2) decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. NE3107 was not found to be immune suppressive in any of the classical models tested, including mitogen-induced proliferation, delayed-type hypersensitivity, or mixed lymphocyte reaction.
[0130] Diabetic db/db, insulin-resistant, diet-induced obese C57BL/6J mice and genetically obese ob/ob mice treatment with NE3107 (previously HE3286) markedly improved glucose homeostasis via suppression of inflammation driving insulin resistance. Treatment with NE3107 was accompanied by suppressed expression of the prototype macrophageattracting chemokine monocyte chemoattractant protein- 1 in WAT, along with its cognate receptor C-C motif chemokine receptor-2. Exposure of mouse macrophages to NE3107 in vitro caused partial suppression of endotoxin (lipopolysaccharide)-induced NF B-sensitive reporter gene expression, NF B nuclear translocation, and NFKB/p65 serine phosphorylation. Proinflammatory kinases, including IkappaB kinase, c-Jun NH2-terminal kinase, and p38, were also inhibited by NE3107. [0131] NE3107 atenuates LPS- and TNF alpha- stimulated inflammation in primary murine macrophages, and chemokine production in adipocytes.
[0132] In mice, oral treatment with NE3107 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (-50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury.
[0133] Moreover, oral administration of NE3107 significantly decreased TNF, IL- 1P and iNOS expression and neuronal damage in the brains of mice with MPTP-induced Parkinson’s disease, a model of Parkinson’s where TLR4 contributes to neuroinflammation.
[0134] Our current understanding of the mechanism of action of NE3107 is that it binds the MAP kinase ERK, likely in a compartmentalized spatiotemporal scaffold (TPL2/MEK/ERK) that directs pro-inflammatory signaling downstream of TLR engagement. NE3107, importantly, also appears to inhibit signaling via the TNFR1 receptor, that also activates the TPL2/MEK/ERK signaling cascade and creates a feed-forward loop to sustain an inflammatory state. Given the blood brain- barrier permeability of NE3107 and its ability to inhibit the TLR4/TPL2/MEK/ERK pathway that plays a key role in amyloidp-mediated activation of microglia, neuroinflammation and insulin resistance in Alzheimer’s Disease, NE3107 is currently being developed as a treatment for AD. In a Phase 2a study in 23 subjects with mild/moderate cognitive decline due to degenerative dementia, 3 months of treatment with NE3107 resulted in: 1) an improvement in cognition, that significantly correlated with a reduction in TNF; 2) a significant improvement in depression, as evaluated by PHQ-9 scores, and 3) a reversal of biological aging as evaluated by epigenetic clocks. Recent positive findings from a 28-day randomized, placebo-controlled Phase 2b trial in PD evaluating the safety and efficacy of NE3107 in 40 carbidopa/levodopa-treated patients with PD, have shown a statistically significant improvement from baseline in the Domain 2 (sleep/fatigue) score on the NMSS compared to patients receiving placebo (unpublished data; abstract in preparation) in addition to improvements in motor function.
[0135] NE3107, by virtue of its selective inhibition of the TLP2/ERK signaling pathway downstream from IKB kinase (IKK), is also an insulin sensitizer in mouse and rat models of diabetes and human subjects with impaired glucose tolerance and type 2 diabetes mellitus. NE3107’s combination of anti-inflammatory and insulin sensitizing activity provides the foundation for the proposed clinical trial in Long COVID. Insulin resistance and underlying chronic inflammation exacerbate the course of disease and may be associated with disease severity and the risk of development of Long COVID. Moreover, SARS-CoV-2 infection can trigger insulin resistance de novo, manifesting as new onset Type 2 diabetes and it appears that infection of adipocytes and downregulation of adiponectin can further contribute to the elevated inflammatory state.
[0136] NE3107 has a number of additional attributes important for the treatment of Long COVID. Unlike other anti-inflammatory agents NE3107 is not markedly immunosuppressive in rodent models or in the human mixed lymphocyte reaction assay (reviewed in Ahlem 2011). Additionally, NE3107 has a low predicted risk for drug: drug interactions with CO VID-19 anti-viral agents. Finally, there have been no treatment related serious adverse events reported in completed or ongoing clinical studies to date.
[0137] In summary, NE3107, is an orally bioavailable, blood- brain barrier- permeable, insulin-sensitizer that is anti-inflammatory but not immunosuppressive with unique attributes for targeting the mechanisms underlying symptom clusters of Long COVID. Importantly, NE3107 has a low risk for drug: drug interactions which may be important should viral persistence prove to be a contributing factor to chronic inflammation..
[0138] NE3107 Prior Clinical Studies: The clinical trials conducted to date with
NE3107 include: a Phase 1 safety study in normal volunteers (single weekly escalating dose up to 100 mg), a Phase 1 study in obese individuals with impaired glucose tolerance (28-day, 3 dose levels), a Phase 1/Phase 2 study in subjects with ulcerative colitis (28-day), a Phase 1 /Phase 2 study of potential methotrexate-NE3107 interactions in subjects with rheumatoid arthritis (28-day), and a Phase 2 study conducted in 2 stages: the first stage in type 2 diabetes in combination with metformin (84-day), and the second stage in type 2 diabetes in treatment naive subjects (84-day). More recently a 3-month Phase 2a study was conducted in 23 patients with mild/moderate cognitive decline due to degenerative dementia, a 28-day Phase 2b in 40 patients with PD randomized 1 : 1 and a 6-month Phase 3 study in ~ 400 patients with mild/mod probable AD (ongoing, enrollment completed, topline results Q42023). To date, > 400 subjects (18 healthy volunteers, 41 obese subjects, 87 T2DM subjects, 18 ulcerative colitis patients, 14 RA patients, 23 patients with mild/mod cognitive decline due to degenerative dementia, 20 PD patients and >200 AD patients) have been exposed to at least one dose of NE3107 or placebo in these studies. More than 200 patients have been exposed to 20 mg NE3107 twice a day for 6 months.
[0139] A Double-Blind, Placebo-Controlled, Safety, Tolerability, and Pharmacokinetics Study in Parkinson’s Disease (PD) Participants Treated with Carbidopa/Levodopa and NE3107 (NCT05083260) was recently conducted. The study was designed to measure NE3107 intrinsic promotoric activity and potential enhancement of levodopa activity or decrease in levodopa side effects from use in combination with NE3107, as well as potential improvements in activities of daily living (MDS-UPDRS Part II) and nonmotor features of PD (MDS-UPDRS Part I and Non-Motor Symptom Assessment Scale for Parkinson Disease.) The study also measured potential pharmacokinetics drug-drug interactions of NE3107 with levodopa and functional interactions with any PD comedications of study participants. Forty patients ranging from 30 to 80 years of age, with a confirmed diagnosis of Parkinson’s disease taking levodopa at least three times daily (total at least 300 mg daily) and having a reliable morning off-state after withholding PD meds for eight hours, were enrolled and received 20 mg NE3107 or placebo BID for 27 days following (Day 1) baseline assessments of off-state MDS-UPDRS Part III and assessment of MDS-UPDRS Part III, time on or off and motor complications for 8 hours after taking their normal PD medications. This study was not powered for statistical significance. The motor and non-motor endpoints for the study were 1) Change in MDS-UPDRS Part III Score from baseline (practically-defined OFF) to post-dose timepoints each day; 2) total OFF time over the 8-hour assessment period, 3) Average MDS-UPDRS Part III Score when ON, 4) MDS-UPDRS Part I Score, 5) MDS-UPDRS Part II Score, 6) Total ON time with or without dyskinesia during the 8-hour study period, 7) Dyskinesia severity during the 8-hour study period (if applicable), 8) Time to onset of ON time, and 9) Non-Motor Symptom Assessment Scale for Parkinson Disease (NMSS). Although not powered for efficacy, NE3107 treatment significantly increased the frequency of subjects with morning UPDRS Part 3 scores that after withholding levodopa overnight, were less than or equal to (better than or equal to) baseline line Part 3 scores following morning levodopa administration (6 of 20 active vs 0 of 19 placebo, p=0.02, Fisher’s exact test). NE3107 also significantly improved NMSS scores for fatigue (Q4) p=0.02, urge to move legs (Q6) p=0.0036, and saliva dribbling (Q 19) p= 0.0395. [0140] NE3107 was studied in an Investigator-sponsored, open-label study in subjects with clinically mild dementia of the Alzheimer’s type (NCT05227820). A total of 23 subjects aged 53 to 87 years were treated with 20 mg NE3107 BID for 3 months. NE3107 decreased plasma TNF levels and this reduction correlated significantly with improved cognition. Hyperphosphorylated phospho-tau in cerebral spinal fluid was also reduced and was correlated with improvement in the Alzheimer’s Disease Composite Score. Neuroimaging data indicated regiospecific blood flow improvements, reduced hippocampal compensation, and increased precuneous glutathione, which also correlated with decrease phosphor-tau. Analysis of DNA methylation in whole blood collected prior to treatment and at the end of the 3 -month Treatment Period indicated a mean decrease in the biological age of 19 of 22 subjects of 4.3 years using the PhenoAge calculator and 3.3 years using the DNAm-Age Skin Blood Clock. There were no drug-related treatment-emergent adverse effects (see FIG. 2).
[0141] NE3107 Clinical Studies
[0142] NE3107 (20 mg BID for a duration of 6 months) has been evaluated in
NM101, a Phase III, double-blind, randomized, placebo-controlled, parallel group, multi center study of NE3107 in subjects who have mild-to-moderate probable AD (NCT04669028). Subjects were randomized to receive 20 mg NE3107 twice daily (BID) or placebo for 26 weeks following dose titration of 5 mg BID for two weeks and 10 mg BID for two weeks. The study enrolled 439 subjects and will complete in September 2023. Due to significant deviations from protocol and GCP violations at 15 clinical sites data from 80% of patients enrolled was excluded from the final analysis which led to the study being underpowered for the primary endpoints CDR-SB and ADAS-Cogl2. Despite this, with only 57 patients in the per protocol modified intent to treat group [placebo (n=33); NE3107 (n=24)], that had comparable baseline characteristics, there was a notable improvement in cognition with NE3107 treatment versus placebo after 6 months of treatment that appeared better than that achieved by Lecanemab after 18 months of treatment.
Table 1
* Lower is improvement
** Higher is improvement
[0143] Moreover, changes in CDR-SB from baseline with NE3107 appear correlated with changes from baseline in TNF, phospho-Tau and A042/AP4O (see FIG. 1).
[0144] The most surprising finding, however, given the small number of patients, was the impact of NE3107 on biological age. Despite biological aging data being available at this time for only half of the patients, patients treated with NE3107 for 6 months experienced a significant deceleration of aging, a difference of -4.66 years, (p = 0.02) from those treated with placebo, as measured by change from baseline in the skin blood clock. To the best of our knowledge this is the first time a therapeutic intervention has been shown to impact biological aging in a randomized, controlled clinical trial. [0145] Collectively the data show correlations of change among neuroimaging, clinical measures, and biomarkers of inflammation, AD neuropathology and aging, occurring concomitantly with the administration of NE3107, suggesting potential drug effects of NE3107 in dementia.
[0146] No drug-related deaths or drug-related serious adverse effects had been reported and 1.8% of the participants discontinued the study due to treatment emergent effects.
[0147] Clinical Trial Protocol of NE3107 to Evaluate Efficacy and Safety of NE3107 in Adults with Long COVID
[0148] Overview
[0148] NE3107 is an orally bioavailable anti-inflammatory agent with the ability to cross the blood-brain barrier and a well-characterized safety and tolerability profile, intended for outpatient treatment of neurological symptoms associated with Long COVID. The primary objective of this study is to assess the efficacy, safety, and tolerability of NE3107 oral capsules compared to a matching placebo in adults with Long COVID who exhibit cognitive impairment and fatigue. This multicenter study in the U.S. will enroll over 200 participants with neurocognitive dysfunction and self-reported fatigue attributed to Long COVID. Eligible participants will be randomized (1 :1) to receive either NE3107 20 mg twice daily (BID) or a matching placebo for 12 weeks. Blinding will be maintained throughout the study, with treatment assignments concealed from participants, investigators, assessors, and all study personnel at the CRO and sponsor organizations. The chosen dosage of 20 mg (one 20 mg capsule taken twice daily) is consistent with dosing regimens used in the Applicant's previous clinical studies for Alzheimer’s disease and Parkinson’s disease. A 12- week treatment duration has been selected as it is expected to provide sufficient time for NE3107 to influence inflammation and metabolic pathways underlying Long COVID pathophysiology. This duration aligns with evidence from other clinical trials evaluating similar endpoints in Long COVID patients. Safety data from previous studies of NE3107 at 20 mg BID in adult populations with cognitive impairment support the 12- week treatment period, with completed studies ranging from 3 to 6 months. The study will include three phases: Screening, Intervention, and Follow-up. Details on assessments and their timing can be found in the Schedule of Activities (Table 2). FIG. 3 illustrates a double-blind, placebo-controlled, 12- week study design schema. Table 2
[0149] Screening Period (up to 4 weeks)
[0150] Participants with documented Long COVID who provide written informed consent will undergo a screening process to determine eligibility. The Screening visit (Visit 1) will include evaluations specified in the Schedule of Assessments (SOA) (Table 2). These assessments will comprise a comprehensive review of the participant's medical history, laboratory testing (including high-sensitivity C-reactive protein [hs-CRP]), and an electrocardiogram (ECG) to assess cardiac function. Additionally, Clinical Outcome Assessment (COA) tools will be administered in a recommended sequence to ensure a systematic evaluation. These tools include the Epworth Sleepiness Scale to assess daytime sleepiness, the Patient Health Questionnaire-2 (PHQ-2) for initial depression screening, and the PROMIS Cognitive Function Short Form 8a (PROMIS Cognitive Function SF8a) to measure perceived cognitive abilities, along with other PROMIS assessments as needed. This comprehensive approach ensures a thorough evaluation of the participant’s health and Long COVID-related symptoms during the screening process.
[0151] Intervention Period (12 weeks) [0152] The baseline visit (Visit 2) will include assessments outlined in the Schedule of Assessments (SOA) (Table 2). These will consist of a review of eligibility criteria, medical history, safety evaluations, and the administration of Clinical Outcome Assessments (COA) tools in the following recommended sequence: PROMIS Cognitive Function Short Form 8a (PROMIS Cognitive Function SF8a), PROMIS Fatigue Short Form 13a (PROMIS Fatigue SF13a), Cogstate Cognition Battery, DSQ-PEM, PROMIS Sleep Disturbance Short Form 8a (PROMIS Sleep Disturbance SF8a), SF-12, Patient Global Impression of Severity (PGI-S) Overall, PGI-S Fatigue, PGI-S Think Clearly, Long COVID Other Burdensome Symptoms, the Columbia- Suicide Severity Rating Scale (C-SSRS) Since the Last Visit form, and the Clinical Global Impression of Severity (CGLS).
[0153] Participants who continue to meet eligibility criteria at this visit will be randomly assigned to either the NE3107 treatment arm or the placebo treatment arm based on a central 1: 1 randomization schedule. The first dose of the study intervention will be administered following the completion of all baseline assessments. Participants will initiate treatment on Day 1 (Visit 2) and will continue taking the assigned intervention for 12 weeks. Safety and efficacy will be evaluated during site visits conducted every 28 ± 3 days at Week 4 (Visit 3), Week 8 (Visit 4), and Week 12 (Visit 5), with assessments performed as specified in the SOA (Table 2).
[0154] Follow-up Period (4 weeks)
[0155] A virtual visit will be conducted four weeks after the participant completes or discontinues the study intervention. During this virtual visit (Visit 6; Week 16), information on adverse events (AEs) and concomitant medications will be collected. If deemed necessary, the investigator may request the participant to attend an in-person visit at the study site.
[0156] Additional Study Parameters
[0157] NE3107 is an orally bioavailable, blood-brain barrier-permeable insulin sensitizer that is anti-inflammatory but not immunosuppressive, making it uniquely suited to target the mechanisms underlying neurological symptoms of Long COVID. By addressing pro- inflammatory pattern recognition toll-like receptor (TLR)-driven neuroinflammation, NE3107 has the potential to alleviate symptoms such as fatigue and cognitive dysfunction. The selected dosage of 20 mg twice daily (BID) is consistent with the dosing regimen used in the Applicant’s completed studies on Parkinson’s disease (PD) (Study NM201, NCT05083260), and Alzheimer’s disease (AD) (Study NM101, NCT04669028). The treatment duration of 12 weeks was chosen as it is considered sufficient to impact the inflammatory and metabolic mechanisms underlying Long COVID pathophysiology, supported by evidence from other clinical trials evaluating similar endpoints in this patient population.
[0158] The safety of NE3107 for a 12- week treatment period is supported by data from a completed double-blind, placebo-controlled study conducted by the Applicant in participants with mild probable AD, as well as from an investigator-initiated open-label study in participants with mild cognitive impairment and AD. The end of the study (EOS) is defined as the date of the last visit (Week 16) for the final participant enrolled in the study. A participant is considered to have completed the study if they have successfully completed all study periods, including the Week 16 EOS visit, as specified in the Schedule of Assessments (SOA) (Table 2).
[0159] A medical monitor from the contract research organization (CRO) will have primary oversight of the participants enrolled in this study. The sponsor’s medical monitor may also participate in safety reviews of blinded data and key study decisions, including participant withdrawal due to adverse events (AEs) and emergency unblinding. Each participant’s medical history, SARS-CoV-2 history, and results from screening assessments, including available safety laboratory results, will be reviewed by the Enrollment Authorization Committee (EAC) to authorize participant randomization. The EAC, comprising relevant medical experts selected by the sponsor, will assess study suitability for each participant based on the entry criteria and study objectives. When necessary, the EAC will consult with the investigator to address and resolve outstanding questions or issues before providing its decision.
[0160] The EAC will evaluate the participant’s screening assessments and document its decision regarding eligibility. If a participant is deemed ineligible for randomization, this decision, along with a rationale, will be recorded in the electronic data capture (EDC) system. Participants not approved by the EAC will be classified as screen failures. To ensure the integrity of the study, a dedicated charter will be developed to guide the EAC’s operations. The EAC approval form will serve as documentation for each participant’s inclusion in the study and must be stored in the site study file. [0161] The study may be discontinued at the discretion of the Applicant and the Applicant’s medical monitor for reasons such as increased frequency, severity, or duration of known AEs; medical or ethical concerns affecting the study’s continuation; difficulties in participant recruitment; or cancellation of drug development. Investigators, in consultation with the sponsor and sponsor’s medical monitor, also have the authority to independently discontinue the study at their site if participant safety concerns arise.
[0162] Inclusion Criteria
[0163] Participants are eligible for inclusion in the study only if all of the following criteria are met:
[0164] Participants must be adults aged 18 to 64 years at the time of screening and have Long CO VID, defined as the presence of at least fatigue and neurocognitive impairment attributed to a SARS-CoV-2 infection that occurred at least three months prior to screening. The index SARS-CoV-2 infection must be confirmed by a positive nucleic acid or antigen test during the acute illness (as documented in the medical record) or a clinical diagnosis of COVID- 19 by the participant’s physician. Symptoms must not be attributable to an alternative diagnosis, as determined by the investigator, and must have persisted for a duration of at least three months but no longer than 24 months from the index infection. Participants must meet specific criteria on standardized assessments, including a PROMIS Cognitive Function SF8a T-score < 40 (> 1 standard deviation below the normative mean), a Cogstate Cognition battery score > 1 standard deviation below the normative mean for at least two of the five tests in the battery, and a PROMIS Fatigue SF13a T-score > 60 (> 1 standard deviation above the normative mean). Additionally, participants must have a plasma high-sensitivity C-reactive protein (hs-CRP) level > 3.0 mg/L.
[0165] Participants must be willing and able to provide voluntary written informed consent, complete required surveys and clinical assessments, and attend the virtual follow-up visit at the end of the 4-week follow-up period (the End of Study visit). They must agree to maintain current doses of regular medications throughout the trial, except in cases where new medications or dose changes are deemed essential by a physician. Females using hormone replacement therapy (HRT) must have been on a stable regimen for at least six months before randomization and agree to continue the regimen until the final safety assessment at Week 16. [0166] Participants must meet specific reproductive health requirements. Females must either be postmenopausal (no menstrual bleeding for over a year or confirmed via follicle- stimulating hormone [FSH] assessment), surgically sterilized for at least six months (e.g., hysterectomy, bilateral oophorectomy, or tubal ligation), or agree to use highly effective contraception, such as double-barrier methods (e.g., condom with spermicide or an intrauterine device [IUD] with spermicide). Oral contraceptives alone are not sufficient. Males who are not vasectomized must either be abstinent or agree to use double-barrier contraception and ensure their partner uses highly effective birth control until the study concludes. Participants must also agree to allow blood collection for DNA methylation analysis and demonstrate nativelevel proficiency in English.
[0167] Exclusion Criteria
[0168] Participants will be excluded from the study if any of the following criteria apply:
[0169] Participants who have tested positive for SARS-CoV-2 nucleic acid or rapid antigen tests within the past 14 days or received a COVID-19 or influenza vaccination within 30 days of randomization are ineligible. Those with a history of admission to the intensive care unit for COVID-19-related symptoms or who required mechanical ventilation (intubation) for COVID- 19 care will also be excluded.
[0170] Participants with prior or active unstable or progressive major psychiatric or neurological conditions unrelated to SARS-CoV-2 infection that may impact the ability to evaluate the treatment effect are not eligible. This includes, but is not limited to, conditions such as progressive neurodegenerative diseases (e.g., Alzheimer’s or Parkinson’s disease), past traumatic brain injuries associated with ongoing post-concussive symptoms, epilepsy or seizure disorders requiring ongoing treatment, seizures or loss of consciousness within 12 months prior to screening, post-stroke deficits interfering with assessments (e.g., aphasia), formal thought disorders (e.g., schizophrenia, psychotic bipolar disorder), uncontrolled neuropsychiatric or neurological disorders within the previous six months, functional neurological disorders, and Major Depressive Disorder not on stable treatment for at least three months or with a PHQ-2 score > 3. Premenstrual dysphoric disorder is also exclusionary.
[0171] Participants with physical, cognitive, or language impairments sufficient to interfere with cognitive assessments, diagnosed reading disabilities, dyslexia, or clinically significant learning disorders are ineligible. Those with documented ADHD prior to the index COVID- 19 infection will also be excluded. Additionally, participants with known active bacterial, fungal, viral, or other infections requiring treatment within 30 days prior to randomization, which meet criteria for systemic involvement (as determined by the investigator), are not eligible. However, mild or localized infections, such as uncomplicated urinary tract infections, yeast infections, sexually transmitted infections, or mild dermatophyte infections, may not be exclusionary upon review by the study investigator.
[0172] Other exclusion criteria include a diagnosis of narcolepsy or excessive daytime sleepiness, an Epworth Sleepiness Scale Score of 18 or greater (indicating severe sleepiness), and a history of cardiovascular conditions such as congestive heart failure, suspected or known dissecting aneurysm, recent systemic or pulmonary embolism, recent myocardial infarction (within six months), severe valvular heart disease, ventricular aneurysm, active or suspected myocarditis or pericarditis, or thrombophlebitis or intracardiac thrombi.
[0173] Participants with clinically significant findings on an electrocardiogram (ECG), as determined by the investigator, will not be eligible. Examples of such abnormalities include documented myocardial infarction or recent significant ECG changes suggesting infarction or acute cardiac events, symptoms of coronary insufficiency (e.g., angina pectoris or ST segment depression on ECG), evidence of uncontrolled atrial or ventricular ectopy or myocardial conduction defects increasing the risk of syncope (e.g., second-degree or higher A- V block), and QT prolongation (QTcF >450 msec for males or >470 msec for females).
[0174] Exclusions also include a history of moderate or severe obstructive pulmonary disease, chronic fatigue syndrome, fibromyalgia, or postural orthostatic tachycardia syndrome (POTS) prior to the index COVID-19 infection. Participants with chronic Lyme disease or tertiary syphilis with persistent symptoms or sequelae, or those requiring related therapy, are not eligible. Additional exclusions include a history of HIV (types 1 or 2), hepatitis B, or hepatitis C unless successfully treated with undetectable viral load for at least three months. Screening lab abnormalities causing fatigue or cognitive impairment, such as severe anemia, hypocalcemia, or thyroid dysfunction, will also result in exclusion.
[0175] Participants with specific abnormal lab findings at screening will be excluded. These include alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels >2 upper limit of normal (ULN), hemoglobin <10 g/dL (females) or <11.5 g/dL (males), an international normalized ratio (INR) >1.5 unless on anticoagulants with a stable dose for >4 weeks prior to screening, creatinine clearance <45 mL/min, or untreated diabetes with hemoglobin Ale >7.0.
[0176] Pregnant or lactating participants are excluded, as are participants with a history of systemic cancer therapy in the past five years (except localized basal cell carcinoma or in-situ cervical cancer successfully treated with surgical excision), or an unstable medical illness likely to interfere with study data. Participants with a history of alcohol or substance use disorder within 12 months of screening, or those at serious suicide risk based on investigator judgment or C-SSRS evaluation, are also excluded.
[0177] Lifetime history of breast cancer, unwillingness to refrain from cognitive training or cognitive-enhancing supplements during the study, or use of prohibited or restricted medications will also disqualify participants. Evidence of autoimmune diseases commonly associated with pulmonary involvement, current need for supplemental oxygen, or recent investigational agent use (within 30 days, or 90 days for biologies) are additional exclusions.
[0178] Participants who received direct-acting antiviral agents for COVID-19 infection within two weeks, TNF inhibitors within 90 days, or systemic/intra-articular steroids within 30 days prior to randomization will not be eligible. Planned medical interventions, including surgeries likely to impede study assessments, will also disqualify participants.
[0179] Relatives of sponsor representatives or study site personnel employed at the site of study conduct are ineligible. Participants currently using or recently (within 30 days) receiving naltrexone, or requiring potent CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, itraconazole) or CYP2C9/CYP2C19 inhibitors (e.g., fluoxetine, fluconazole), are excluded from participation.
[0180] Screen Failure
[0181] Screen failures are participants who provide consent to participate in the clinical trial but are not randomized due to the results of screening assessments or the review by the Enrollment Authorization Committee (EAC). To ensure transparent reporting and compliance with CONSORT publishing requirements, as well as to address potential queries from regulatory authorities, a minimal set of information must be collected for all screen failures. This information includes demographic data, details of the screen failure, the specific eligibility criteria not met, and any serious adverse events (SAEs) that may have occurred. [0182] In certain cases, participants may be allowed to undergo re-screening. Such decisions will be made on a case-by-case basis through discussion between the Investigator and the Medical Monitor.
[0183] Discontinuation of Treatment and Withdrawal of Participants
[0184] A participant may be withdrawn from the study at the investigator’s discretion or for any of the following reasons: pregnancy, significant protocol violations, or non-compliance with the study intervention. Withdrawal may also occur if the investigator determines that, based on a clinical adverse event (AE), laboratory abnormality, or other medical condition or situation, continued participation would not be in the participant's best interest. Other reasons for withdrawal include worsening of the disease, perceived lack of efficacy, or the need to initiate another Long COVID therapy (regardless of type), with the specific reason documented accordingly. Additionally, participants may be withdrawn if the sponsor or investigator terminates the study, if the participant requests discontinuation for any reason, if the participant joins another clinical trial, or if there is documented reinfection with COVID- 19.
[0185] The reason for a participant’s discontinuation or withdrawal from the study will be recorded on the electronic case report form (eCRF). Participants retain the right to withdraw from the study at any time, for any reason.
[0186] End of Treatment/Early Termination
[0187] If a randomized participant discontinues the study intervention or withdraws from the study before completing the treatment period, they will be asked to complete the Early Termination Visit (ETV), which also serves as the End of Treatment visit (EOT/Visit 5), as soon as possible, following the procedures outlined in the Schedule of Assessments (SOA) (Table 2). Participants who successfully complete the 12-week treatment period and the subsequent 4-week follow-up period will be asked to attend the End-of-Study (EOS) visit, as detailed in the SOA (Table 2).
[0188] Lost to Follow-Up
[0189] A participant will be considered lost to follow-up when these two criteria apply: Participant fails to return for 1 scheduled in person visit; and participant cannot be contacted by the study site staff. Contact is defined as three documented reasonable attempts made over a 10-day period. [0190] Study Intervention and Concomitant Therapy
[0191] NE3107 is formulated with commonly used excipients for oral products
(sodium lauryl sulfate, microcrystalline cellulose, crospovidone, magnesium stearate) and filled into gelatin capsules. NE3107 capsules and placebo capsules are identical in appearance.
[0192] Study Intervention Administered
[0193] NE3107 and the placebo will be supplied by the sponsor’s designated manufacturer in compliance with current Good Manufacturing Practices (cGMP). The investigational product will be dispensed at the clinical sites. Packages of the study intervention will have labels that meet applicable regulatory requirements and may include information such as participant identifier, study drug name, dosage strength, lot number, protocol number, caution statement, storage instructions, and sponsor identification.
[0194] The study intervention will be dispensed by the investigator or a qualified designee or, when applicable, shipped directly to the participant. The intervention is to be used exclusively within the clinical study and in accordance with the protocol instructions.
[0195] Table 3 provides details about the study interventions supplied for this study, and Table 4 outlines the two study arms. The study drug may also be shipped to participants from the site pharmacy. Study staff should consult the Pharmacy Manual for additional guidance on the dispensing and handling of the study drug.
Table 3 : Study Intervention(s) Administered
Table 4: Study Arm(s)
[0196] Assignment to Study Intervention
[0197] After completing the screening assessments and receiving approval from the Enrollment Authorization Committee (EAC), participants will be randomized in a 1 : 1 ratio to receive either NE3107 20 mg BID or a matching placebo. All participants will be centrally randomized at Visit 2 (Baseline) using an interactive web response system (IWRS). Before the study begins, each site will receive log-in information and detailed instructions for using the IWRS.
[0198] The study intervention will be dispensed during study visits as outlined in the Schedule of Assessments (SoA) (Table 2). Returned study intervention will not be redispensed to participants. Personnel involved in the study will remain blinded to the randomization schedule until the official unblinding of treatment assignments. Each participant may only be randomized once, and no participant will be randomized into the study more than one time.
[0199] Blinding and Emergency Unblinding
[0200] This is a double-blind study in which participants, investigators, outcomes assessors, and members of the study staff at the CRO or sponsor are blinded to the study intervention. The randomization codes will be managed by the interactive web response system (IWRS), which is programmed with blind-breaking instructions.
[0201] Study personnel are responsible for maintaining the integrity of the study blind to minimize bias during the study. All participants and study personnel will remain blinded to the assigned treatment throughout the study period. In the event of an emergency, a specific participant's treatment assignment may be identified only if urgently needed for their clinical management or welfare. When possible, the investigator should consult the medical monitor before unblinding, although participant safety and clinical management take priority. If necessary, the treatment assignment will be accessed through the IWRS. Unblinding of treatment assignments is discouraged if the knowledge will not materially alter the management of the medical emergency. Participant safety must always be the foremost consideration in such decisions.
[0202] If a participant’s treatment assignment is unblinded, the sponsor must be notified within 24 hours of the occurrence without revealing the specific treatment assignment. The investigator must document the date and reason for the unblinding in the appropriate source document and electronic case report form (eCRF) for the participant.
[0203] Participants will self-administer the study intervention at home, except for the first dose, which will be administered on-site during the baseline visit (Visit 2). Treatment compliance will be assessed through blood levels of NE3107. Dose modification is not anticipated during the study, and the study intervention will not be available to participants after the completion of the treatment period.
[0204] Any medication or vaccine, including over-the-counter or prescription medicines, recreational drugs, vitamins, and herbal supplements, that a participant is receiving at the time of enrollment or during the study must be recorded. The documentation should include the reason for use, dates of administration (start and end), and dosage details (dose and frequency). If questions arise regarding prior or concomitant therapy, the medical monitor should be consulted. Participants may continue pretrial medications during the study if the dose has been stable for at least three months prior to screening (Visit 1) and no dosage changes are planned during the study without prior investigator approval.
[0205] Certain medications and therapies are prohibited during the study. These include medications with D2 receptor antagonist activity, such as haloperidol or olanzapine, unless low-dose aripiprazole (< 2 mg/day) is being used for non-excluded conditions or for occasional treatment of gastric symptoms like domperidone or metoclopramide. Stimulants, including amphetamine and modafinil, are also prohibited, as are systemic or intra-articular steroids, amantadine, N-methyl-D-aspartate receptor antagonists such as memantine or ketamine, and naltrexone, including low-dose formulations. Potent CYP3A4 inhibitors, such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, and verapamil, and potent CYP2C9 and CYP2C19 inhibitors, such as amiodarone, fluconazole, miconazole, piperine, fluoxetine, fluvoxamine, and ticlopidine, are also restricted.
[0206] Participants must adhere to certain restrictions during the study. Sedating medications, including short-acting benzodiazepines like midazolam, antihistamines such as diphenhydramine, or antimuscarinic/anticholinergic medicines like tolterodine, must be withheld for at least 12 hours before assessments. Non-sedating antihistamines, such as cetirizine, fexofenadine, or loratadine, are allowed within this timeframe. Additionally, participants must refrain from consuming alcohol and cannabis-containing products for at least 12 hours before assessments.
[0207] Study Assessments and Procedures
[0208] Study procedures and their timing are summarized in the Schedule of Assessments (SoA) (Table 2). Protocol waivers or exemptions are not permitted, and copies of all evaluation and assessment tools are provided in the Study Manual. Adherence to the study design requirements, including those outlined in the SoA, is essential and mandatory for the proper conduct of the study.
[0209] All screening evaluations must be completed and reviewed to ensure potential participants meet all eligibility criteria. Randomization requires approval from the Enrollment Authorization Committee (EAC). The investigator will maintain a screening log to document details of all participants screened, including confirmation of eligibility or reasons for screening failure, as applicable.
[0210] The procedures for administering the Clinical Outcome Assessment (CO A) instruments will be emphasized during site training at each Investigator Meeting. Studyspecific COA training will be provided to all site investigators and staff to ensure consistent oversight and management of COA administration, thereby maintaining the highest data quality. It is critical that all site investigators and staff understand the rationale for including CO As in the protocol and follow the specified procedures for COA instrument collection.
[0211] Efficacy Assessments
[0212] Planned timepoints for all efficacy assessments are outlined in the Schedule of Assessments (SoA) (Table 2). Copies of all evaluation and assessment tools are provided in the Study Manual for reference.
[0213] The Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are reliable, widely used, publicly available tools designed to measure patient-reported health symptoms and health-related quality of life across a variety of diseases, including chronic conditions. These instruments are accessible through the HealthMeasures website and are extensively utilized in both clinical research and patient care. The PROMIS Cognitive Function SF8a, a key instrument in this study, consists of 8 items assessing patient- reported cognitive abilities such as attention, mental clarity, processing speed, problemsolving, and mental fatigue. Each item is scored on a 5-point Likert scale. This instrument will be administered on the visit days specified in the SoA (Table 2).
[0214] The Cogstate Cognition battery of tests will also be administered on the visit days specified in the SoA (Table 2). Training for test supervisors at each site will be provided by Cogstate through eLearning activities. Upon completing the required training, test supervisors will receive certification from the Cogstate Learning Management System (LMS) and gain access to the digital test battery. Cogstate will also brief the study’s Clinical Research Associates on the test battery, the training and certification process for test supervisors, and anticipated data monitoring activities. These activities will include verification of source data and interactions with study sites throughout the trial. All hardware and software required for administering the Cogstate Cognition battery will be pre-tested by Cogstate before being sent to each site.
[0215] Among the Cogstate tests, the Detection test measures psychomotor function using a simple reaction time paradigm with playing card stimuli. Participants view a series of identical joker cards and are asked to press the "Yes" key as soon as the card in the center of the screen turns face up. The software records the speed and accuracy of each response. The test duration is approximately 3 minutes.
[0216] The Identification test is a measure of visual attention that employs a well- validated choice reaction time paradigm using playing card stimuli. In this test, participants view cards featuring either red or black joker designs. The participant's task is to determine whether the card displayed in the center of the screen is red. They respond by pressing the "Yes" key if the card is red and the "No" key if the card is black. The software records the speed and accuracy of each response, with the test duration lasting approximately three minutes.
[0217] The International Digit Symbol Substitution Test - Symbols is a processing speed assessment based on the well-established digit symbol coding paradigm. In this test, participants are presented with a legend that defines nine symbols, each corresponding to a digit from 1 to 9. During the test, a conveyor belt appears on the screen displaying a series of empty boxes labeled with numbers. Participants must select the correct symbol that corresponds to the number in a highlighted box from a set of symbol options displayed at the bottom of the screen. The goal is to place as many correct symbols as possible into the corresponding boxes within the test duration. Performance is evaluated based on the total number of correct responses, with the test lasting approximately three minutes.
[0218] The International Shopping List test is a measure of verbal learning based on a well-validated list-learning paradigm. The test involves high-frequency, high-imagery, concrete nouns (items from a shopping list) that are read aloud to the participant by the test supervisor at a rate of one word every two seconds. After all 12 words have been read, the participant is asked to recall as many words as possible, as quickly as possible. The test supervisor records the participant's recalled words on the testing device. This process is repeated two more times, with the same list being read aloud and recalled during each trial. The software calculates the number of correct responses based on the data recorded by the test supervisor. The duration of the test is approximately five minutes.
[0219] The Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are a set of highly reliable, widely used, and publicly available tools designed to measure patient-reported health symptoms and health-related quality of life domains across a variety of diseases, including chronic conditions. These instruments are accessible through the HealthMeasures website and are extensively utilized in clinical research and care. The PROMIS Fatigue SF13a consists of 13 items that assess the severity and impact of fatigue on daily life. Each item is scored on a 5-point Likert scale. This instrument will be administered on the visit days outlined in the Schedule of Assessments (SoA) (Table 2).
[0220] The DSQ-PEM is a comprehensive self-report tool specifically developed to evaluate symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The PEM section of the DSQ contains 10 items that measure the exacerbation of symptoms following physical, cognitive, or emotional exertion. Each item is scored on a 5- point Likert scale. The DSQ-PEM will be administered on the visit days specified in the SoA (Table 2).
[0221] Another PROMIS instrument, the PROMIS Sleep Disturbance SF8a, includes 8 items that assess the quality and severity of sleep disturbances. These items evaluate aspects such as sleep quality, latency, maintenance, restorative properties, frequency of disturbance, and perceived depth of sleep, with each item scored on a 5-point Likert scale. The PROMIS Sleep Disturbance SF8a will also be administered on the visit days detailed in the SoA (Table 2).
[0222] The SF-12 is a shorter version of the SF-36 Health Survey, designed to provide an efficient yet reliable and valid measure of overall health status. Its streamlined format makes it particularly suitable for large-scale surveys and studies where minimizing respondent burden and survey length is important. Responses to the SF-12 items are scored to produce two summary measures: the Physical Component Summary and the Mental Component Summary, which offer an overview of an individual’s physical and mental health, respectively. The SF-12 will be administered on the visit days specified in the Schedule of Assessments (SoA) (Table 2).
[0223] The self-report measure PGI-S Overall assesses a participant’s perception of the overall severity of their disease symptoms on a 5-point scale. In this study, participants will rate the overall severity of their Long CO VID symptoms as "none," "mild," "moderate," "severe," or "very severe." The PGI-S Overall will be administered on the visit days outlined in the SoA (Table 2). The related self-report measure, PGLC Overall, reflects a participant’s perception of the overall efficacy of the treatment and their status since the start of the treatment. This is rated on a 7-point scale, with participants indicating their change as "very much improved," "much improved," "slightly improved," "no change," "slightly worse," "much worse," or "very much worse." The PGI-C Overall will also be administered on the visit days detailed in the SoA (Table 2).
[0224] The PGI-S Fatigue and PGI-C Fatigue are single-item questionnaires designed to assess the severity and change specifically in the participant’s fatigue symptoms. The PGI-S Think Clearly and PGI-C Think Clearly are similarly single-item questionnaires used to evaluate the severity and change in the participant’s ability to think clearly or "brain fog." These questionnaires use the same 5-point and 7-point scales as the PGI-S Overall and PGI-C Overall, respectively. Both the PGLS/C Fatigue and PGLS/C Think Clearly will be administered on the visit days specified in the SoA (Table 2).
[0225] The Long COVID Other Burdensome Symptoms questionnaire consists of three items measuring the participant’s reported severity and frequency of symptoms such as headache, tinnitus, and decreased appetite. Each item is scored on a 5-point Likert scale. This questionnaire will be administered on the visit days outlined in the SoA (Table 2). [0226] The Clinical Global Impression of Severity (CGI-S) reflects the clinician's assessment of the overall severity of a participant’s disease symptoms, measured on a 5-point scale. In this study, the CGI-S is used to evaluate the overall severity of the participant’s Long COVID symptoms, with ratings categorized as "none," "mild," "moderate," "severe," or "very severe." The CGI-S will be administered on the visit days specified in the Schedule of Assessments (SoA) (Table 2).
[0227] The Clinical Global Impression of Change (CGI-C) reflects the clinician’s assessment of the overall efficacy of the treatment since its initiation. The CGI-C uses a 7- point scale to evaluate changes in the participant’s overall health status, with ratings of "very much improved," "much improved," "slightly improved," "no change," "slightly worse," "much worse," or "very much worse." The CGI-C will also be administered on the visit days outlined in the SoA (Table 2).
[0228] Safety Assessments
[0229] Planned timepoints for all safety assessments are provided in the SOA (Table 2).
[0230] A complete physical examination will be conducted during the screening visit (Visit 1) by the site investigator or a medically qualified designee. This examination will include, at a minimum, assessments of general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, heart, lungs, abdomen, extremities, musculoskeletal system, and neurologic system, as well as any other areas deemed appropriate by the examiner.
[0231] An abbreviated, clinically directed physical examination will be performed during all visits in the intervention period, at the End of Study (EOS) visit (Visit 6), or as needed in response to an adverse event (AE). These abbreviated examinations will assess systems deemed appropriate by the examiner, focusing on clinical signs, symptoms, or relevant medical history. Height and weight will be measured and recorded at the screening visit (Visit 1). Hip and waist circumferences will be measured and recorded at baseline (Visit 2), Visit 4 (Day 56), and Visit 5 (Day 84). Investigators should pay close attention to clinical signs and symptoms related to any prior serious illnesses.
[0232] Vital signs, including temperature, respiratory rate, radial heart rate, and blood pressure, will be assessed at screening (Visit 1), during all intervention period visits, and during the follow-up visit (Visit 6/EOS). Blood pressure will be measured in a supine position after 10 minutes of rest and again after standing for 3 minutes. These measurements will be recorded in the electronic case report form (eCRF). A 12-lead electrocardiogram (ECG) with a 10-second rhythm strip will be performed locally in triplicate at time points specified in the Schedule of Assessments (SoA) (Table 2) and interpreted by the site investigator or designee. Additional ECGs may be performed at the discretion of the investigator.
[0233] ECG parameters, including heart rate, rhythm, PR interval, QRS complex, QT interval, QTc, and QTcF interval, will be assessed. All scheduled ECGs will be conducted after participants have rested quietly in a supine position for 5 minutes. Source data for ECGs will include tracing paper printouts, which will be retained. Clinical laboratory tests to be performed are listed in Table 5, with their timing and frequency outlined in the SoA (Table 2). Participants are advised to refrain from food for at least 8 hours prior to sample collection.
[0234] The investigator must review laboratory results, document the review, and record any clinically significant changes occurring during the study as an AE. All laboratory results must be retained as source documents. Laboratory tests with clinically significant abnormal values during the study will be repeated until the values are no longer considered clinically significant by the investigator or medical monitor. All protocol-required laboratory tests will be conducted in accordance with the laboratory manual and the SoA (Table 2). If tests performed at the site’s local laboratory yield results deemed clinically significant by the investigator, these results must also be recorded.
Table 5 Clinical Laboratory Tests
[0235] Other Safety and Screening Assessments
[0236] A lateral flow test for COVID- 19 will be performed at any visit where symptoms suggestive of COVID- 19 are present.
[0237] The Epworth Sleepiness Scale is a brief, self-administered questionnaire designed to measure daytime sleepiness. It consists of eight questions that assess the likelihood of dozing off in various situations, such as reading, watching TV, or driving. The total score ranges from 0 to 24, with higher scores indicating greater levels of sleepiness.
[0238] The PHQ-2 is a widely used tool for screening, diagnosing, monitoring, and measuring the severity of depression. It consists of the first two items of the PHQ-9, which inquire about the degree to which an individual has experienced depressed mood and anhedonia. The PHQ-2 is not intended to establish a definitive diagnosis or to monitor depression severity but rather to serve as a screening instrument. Its effectiveness has been validated in three studies demonstrating variability in sensitivity. [0239] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a widely used tool to assess the risk of suicide. This tool will be administered by a clinician or a trained designee to monitor suicidal ideation and behavior prospectively in individual participants. The C-SSRS Baseline/Screening form will be used at the Screening visit to assess lifetime and past six-month suicidality risk. The C-SSRS Since Last Visit form will be administered during Visits 2 through 5 to evaluate suicidality since the participant's last visit. Participants who answer "YES" to Questions 4 or 5 in the C-SSRS questionnaire indicating suicidal ideation should be referred to a mental health professional.
[0240] When multiple assessments requiring blood samples and safety laboratory evaluations occur simultaneously, a single blood sample may be collected and aliquoted appropriately to perform the required analyses. Additional details on sampling, processing, and shipping are available in the Laboratory Manual.
[0241] Whole blood samples will also be collected for DNA methylation analysis and stored frozen. Storage conditions are specified in the Laboratory Manual. No gene sequencing will be conducted as part of this study.
[0242] Plasma samples will be collected to assess levels of inflammatory biomarkers, that may include adiponectin, leptin, ceruloplasmin, phospho-tau (p-tau), neurofilament light (NfL), Glial fibrillary acidic proteins (GLAP), Amyloid beta42/beta40, Clq, interferon (JEN)-y, IL-1 (3, IL-6, IL-17, IL-23, TNF, RANTES, Monocyte chemoattractant protein-1 (MCP1), high sensitivity C-reactive protein (hs-CRP), fasting insulin, fasting glucose; and antinuclear antibodies (ANA).
[0243] Blood samples will be collected to evaluate trough levels of NE3107 and dosing compliance. Participants should be instructed to note the time of the most recent NE3107 dose prior to sample collection. Timing of dose should be recorded in the eCRF.
Table 6 - Objectives and Endpoints:
[0244] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the disclosure.

Claims

WHAT IS CLAIMED IS:
1. A method for preventing, treating, reducing, or ameliorating a disease or condition in a subject previously infected with a virus, the method comprising: administering to the subject a therapeutically effective amount of 17a- ethynylandrost-5-ene-3P,7P, 170- triol.
2. The method of claim 1, wherein the virus is selected from the group consisting of coronavirus, human coronavirus 229E, human coronavirus OC43, human coronavirus NL63, human coronavirus HKU1, Middle East respiratory syndrome- related coronavirus (MERS- Cov), severe acute respiratory syndrome-related coronavirus (SARS-CoV), SARS-CoV-2, SARS-CoV-2 variant, SARS-CoV-2 mutation, influenza virus, adenovirus, herpes virus, rhinovirus, respiratory syncytial virus, Ebola Virus, West Niles Virus, Zika Virus, H5 influenza, H7 influenza, H5N1 influenza, WestNiles Virus, St. Louis encephalitis, Japanese encephalitis, Eastern equine encephalitis, Western equine encephalitis, Zika Virus, MERS- CoV, HCoV-EMC, Influenza A, Influenza B, H1N1 influenza, H3N2 influenza, H7N9 influenza, H5N6 influenza, H10N8 influenza, H9N2 influenza, H6N1 influenza, a mutant, thereof, a type thereof, a subtype thereof, a lineage thereof, a clade thereof, and a subclade thereof.
3. The method of claim 2, wherein the virus is SARS-CoV-2, SARS-CoV-2 variant, or SARS-CoV-2 mutation.
4. The method of claim 2, wherein the SARS-CoV-2 variant is at least one of the group consisting of a B.1.1.7 variant of SARS-CoV-2 (a.k.a. 201/501 Y. VI Variant of Concern (VOC) 202012/01), a B.1.351 variant of SARS-CoV-2 (a.k.a. 20H/501Y.V2), a P.l variant of SARS-CoV-2 (a.k.a. 20J/501Y.V3), B.1.427, B.1.429, JN.l, JN.l.7, B.2.86, KP.2, KP.3, KP.3.1.1, JN. l.1.18, LB.l, and XEC.
5. The method of any one of claims 1 to 4, wherein the subject has post viral fatigue symptoms or is afflicted with post viral fatigue symptoms.
6. The method of claim 5, wherein the post viral fatigue symptoms are one or more Long COVID symptoms.
7. The method of claim 6, wherein the one or more Long COVID symptoms is selected from the group consisting of: fatigue including severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, CO VID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness, joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post-exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia.
8. The method of any one of claims 1 to 7, wherein the subject did not have post-viral fatigue symptoms before being infected with the virus.
9. The method of any one of claims 1 to 8, wherein the subject develops the symptoms of post viral fatigue during or after being infected with the virus.
10. The method of any one of claims 1 to 9, wherein the subject experiences between about a 5% to about 100% improvement in conditions related to the virus.
11. The method of any one of claims 1 to 9, wherein the subject experiences between about a 5% to about 100% reduction in conditions related to the virus.
12. The method of any one of claims 1 to 11, wherein the 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is administered at a dose from about 1 mg to about 40 mg.
13. The method of claim 12, wherein the 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered at a dose from about 20 mg.
14. The method of any one of claims 1 to 13, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered once a day.
15. The method of any one of claims 1 to 13, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered twice a day.
16. The method of any one of claims 1 to 15, wherein the 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is administered in a pharmaceutically acceptable carrier.
17. The method of any one of claims 1 to 16, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered orally.
18. The method of any one of claims 1 to 17, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered in a solid dosage form.
19. The method of any one of claims 1 to 15, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered intravenously.
20. The method of any one of Claims 1 to 19, wherein the 17oc-ethynylandrost-5-ene- 3p,7p,17p-triol is a solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol.
21. The method of Claim 20, wherein the solid state form of 17oc-ethynylandrost-5- ene-3p,7p,17p-triol is crystalline solvate of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol.
22. The method of Claim 21, wherein the crystalline solvate is crystalline methanolate 17oc-ethynylandrost-5-ene-3p,7p,17P-triol.
23. The method of Claim 22, wherein the crystalline solvate is crystalline ethanolate 17oc-ethynylandrost-5-ene-3 P,7P, 17 P-triol.
24. The method of Claim 23, wherein the crystalline solvate is crystalline hydrate 17oc-ethynylandrost-5-ene-3 P,7P, 17 P-triol.
25. The method of Claim 23, wherein the crystalline solvate is Form III 17a- ethynylandrost-5-ene-3p,7p,17P-triol.
-1 OS-
26. A method for the treatment or amelioration of Long COVID in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of 17a- ethyny landrost- 5-ene-30,70, 170- triol, wherein, administering 17a-ethynylandrost-5-ene-30,70,170-triol to the subject reduces or improves at least one sign, condition, or symptom of Long COVID.
27. The method of claim 26, wherein the at least one sign, condition, or symptom of Long COVID is selected from the group consisting of: fatigue include severe fatigue, inability to exercise or be active because of fatigue, low exercise tolerance because of fatigue shortness of breath or difficulty breathing, persistent chest pain or pressure, cough, heart palpitations, diarrhea, partial or complete loss of sense of smell, tachycardia, hair loss, blurry vision, neuropathy in feet and hands, partial or complete loss of sense of taste, nausea or vomiting, clogged ears, dry eyes, tremors or shakiness, floaters or flashes of light in vision, rash, tinnitus or humming in ears, changed sense of taste, dry or peeling skin, phantom smells, costochondritis, low blood oxygen, COVID toes, thrush, dyspnea, phlegm in back of throat, constant thirst, muscle twitching, heat intolerance, abnormally low temperature, cold burning feeling in lungs, goiter or lump in throat, dry scalp or dandruff, anemia, elevated thyroid, sicca syndrome, red eyes, dysgeusia, sputum production, lack of appetite, vertigo, muscle pain, cognitive problems, brain fog, problems with concentration, problems with thinking, chills, sweats, sleep problems, muscle or body aches, difficulty concentrating or focusing, headache, difficulty sleeping, anxiety, memory problems, dizziness joint pain, sore throat, night sweats, fever or chills, congested or runny nose, sadness, reflux or heartburn, changing symptoms, abdominal pain, lower back pain, shortness of breath or exhaustion from bending over, weight gain, calf cramps, sleeping more than normal, upper back pain, nerve sensations, sharp or sudden chest pain, confusion, feeling irritable, weight loss, post nasal drip, dry throat, high blood pressure, swollen hands or feet, mouth sores or sore tongue, neck muscle pain, hot blood rush, bone aches in extremities, feeling of burning skin, extreme pressure at base of head or occipital nerve, swollen lymph nodes, brain pressure, kidney pain, spikes in blood pressure, hand or wrist pain, bulging veins, mid-back pain at base of ribs, burning sensations, painful scalp, jaw pain, arrhythmia, cracked or dry lips, foot pain, eye stye or infection, low blood pressure, kidney issues or protein in urine, urinary tract infection, hormone imbalances, drastic personality change, gastroesophageal reflux disease with excessive salivation, herpes infection, EBV infection, trigeminal neuralgia, bilateral neck throbbing around lymph nodes, syncope, sadness, chest pain, rhinitis, hypersensitivity, post-exertional malaise (PEM), persistent fatigue after sleep, autonomic dysfunction, involuntary muscle spasms, chronic pain syndromes, digestive issues, loss of bladder control, persistent low-grade fever, sensitivity to cold or temperature extremes, difficulty swallowing, skin discoloration, depersonalization, mood swings, recurrent infections, hair thinning, new or worsening allergies, difficulty with balance, seizure-like episodes, facial pain or neuralgia, changes in menstrual cycle, swelling in joints or extremities, persistent metallic taste, sudden hearing loss, chronic sore or burning tongue, unexplained bruising, hypercoagulability, hypoglycemia-like symptoms, difficulty regulating emotions, reduced muscle tone, changes in handwriting or fine motor skills, hives, enlarged spleen visual snow or persistent visual disturbances, altered heart rate response, and myalgia.
28. The method of claim 26 or 27, wherein the subject did not have one sign, condition, or symptom of Long CO VID prior to infection with COVID.
29. The method of claim 26 or 27, wherein the subject develops the one sign, condition, or symptom of Long CO VID after three weeks from initial infection with CO VID.
30. The method of any one of claims 26 to 29, wherein the subj ect experiences between about a 5% to about 100% improvement in at least one sign or symptom of Long COVID.
31. The method of any one of claims 26 to 30, wherein the subject experiences between about a 5% to about 100% reduction in at least one sign or symptom of Long CO VID.
32. The method of any one of claims 26 to 31, further comprising monitoring the subject for a reduction in symptoms of Long COVID following the administration of 17a- ethynylandrost-5-ene-3P,7P, 17P-triol.
33. The method of any one of claims 26 to 32, wherein the patient has been diagnosed with Long Covid for a duration selected from the group consisting of 1 month, 3 months, 6 months, and 1 year.
34. The method of any one of claims 26 to 33, wherein 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered to subjects who have a confirmed diagnosis of Long COVID through a positive COVID-19 antibody test.
35. The method of any one of claims 26 to 34, wherein 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered in combination with a second therapeutic agent selected from the group consisting of anti-inflammatory agents, antiviral agents, and immune modulators.
36. The method of any one of claims 26 to 35, wherein the subject is concurrently receiving physical therapy or cognitive behavioral therapy for symptoms of Long COVID.
37. The method of any one of claims 26 to 36, wherein the at least one sign, condition, or symptom of Long COVID includes neurological symptoms, and the 17a-ethynylandrost-5- ene-3p,7p,17p-triol is specifically administered to treat or alleviate the neurological symptoms.
38. The method of any one of claims 26 to 37, wherein the at least one sign, condition, or symptom of Long COVID are ameliorated or treated within a time period following administration of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, the time period being selected from the group consisting of 2 weeks, 1 month, 3 months, and 6 months.
39. The method of any one of claims 26 to 38, wherein the 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is administered at a dose from about 1 mg to about 40 mg.
40. The method of claim 39, wherein the 17a-ethynylandrost-5-ene-3P,7P,17P-triol is administered at a dose from about 20 mg.
41. The method of any one of claims 26 to 40, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered once a day.
42. The method of any one of claims 26 to 40, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered twice a day.
43. The method of any one of claims 26 to 42, wherein the 17a-ethynylandrost-5-ene- 3p,7p,17p-triol is administered in a pharmaceutically acceptable carrier.
44. The method of any one of claims 26 to 43, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered orally.
45. The method of any one of claims 26 to 44, wherein the 17a-ethynylandrost-5-ene- 3P,7P,17P-triol is administered intravenously.
46. The method of any one of Claims 26 to 45, wherein the 17oc-ethynylandrost-5- ene-3p,7p,17p-triol is a solid state form of 17oc-ethynylandrost-5-ene-3p,7p,17P-triol.
47. A method for the treatment of the 2019 coronavirus disease (COVID-19) caused by a SARS-CoV-2 virus, a SARS-CoV-2 variant, or a SARS-CoV-2 mutant in a mammal in need thereof comprising administering an effective amount of at least one of:
optionally in a pharmaceutically acceptable carrier.
48. Use of 17a-ethynylandrost-5-ene-3P,7P,17P-triol, optionally in a pharmaceutically acceptable carrier, in the preparation of a medicament for the treatment of a disease or condition caused by a coronavirus.
49. A composition comprising 17a-ethynylandrost-5-ene-3P,7P,17P-triol, optionally in a pharmaceutically acceptable carrier for use in treating a disease or condition caused by a coronavirus.
50. The use of claim 48 or composition of claim 49, wherein the 17a-ethynylandrost- 5-ene-3p,7p,17P-triol is in an oral dosage of about 1 mg to about 40 mg.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007300404B2 (en) * 2006-04-22 2009-12-17 Neurmedix, Inc. Drugs and uses
US20210308147A1 (en) * 2012-09-24 2021-10-07 Edward M. Lichten Use of androgens for treating corona virus
WO2022245532A1 (en) * 2021-05-18 2022-11-24 Biovie Inc. Compositions for treatment of neurodegenerative conditions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007300404B2 (en) * 2006-04-22 2009-12-17 Neurmedix, Inc. Drugs and uses
US20210308147A1 (en) * 2012-09-24 2021-10-07 Edward M. Lichten Use of androgens for treating corona virus
WO2022245532A1 (en) * 2021-05-18 2022-11-24 Biovie Inc. Compositions for treatment of neurodegenerative conditions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AUCI DOMINICK L., MANGANO KATIA, DESTICHE DANIEL, WHITE STEVEN K, HUANG YUJIN, BOYLE DAVID, FRINCKE JAMES, READING CHRISTOPHER L, : "Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis", INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, SPANDIDOS PUBLICATIONS, GR, vol. 25, no. 4, 2 March 2010 (2010-03-02), GR , pages 625 - 633, XP093339232, ISSN: 1107-3756, DOI: 10.3892/ijmm_00000385 *
CHOUDHARY PRINCY, SINGH TANU, AMOD AYUSH, SINGH SANGEETA: "Evaluation of phytoconstituents of Tinospora cordifolia against K417N and N501Y mutant spike glycoprotein and main protease of SARS-CoV-2- an in silico study", JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, ADENINE PRESS, NEW YORK, NY, US, vol. 41, no. 9, 13 June 2023 (2023-06-13), US , pages 4106 - 4123, XP093339235, ISSN: 0739-1102, DOI: 10.1080/07391102.2022.2062787 *

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