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WO2022061171A1 - Polythérapies comprenant du disulfiram - Google Patents

Polythérapies comprenant du disulfiram Download PDF

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Publication number
WO2022061171A1
WO2022061171A1 PCT/US2021/050961 US2021050961W WO2022061171A1 WO 2022061171 A1 WO2022061171 A1 WO 2022061171A1 US 2021050961 W US2021050961 W US 2021050961W WO 2022061171 A1 WO2022061171 A1 WO 2022061171A1
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WIPO (PCT)
Prior art keywords
disulfiram
tbhq
amount
composition
cell
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.)
Ceased
Application number
PCT/US2021/050961
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English (en)
Inventor
Rachel JACOBSON
Wendy COUSIN
An Nguyen
Tempest Plott
William Van Trump
Dat Nguyen
Daniel Chen
Jarred Heinrich
Ben KOMALO
Lauren NICOLAISEN
Christian Elabd
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.)
Spring Discovery Inc
Original Assignee
Spring Discovery Inc
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Filing date
Publication date
Priority claimed from US17/149,557 external-priority patent/US11065214B1/en
Application filed by Spring Discovery Inc filed Critical Spring Discovery Inc
Publication of WO2022061171A1 publication Critical patent/WO2022061171A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
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    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/11—Orthomyxoviridae, e.g. influenza virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/165—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy

Definitions

  • Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening critical illnesses with substantial morbidity and mortality.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Age is a critical risk factor in progression of ARDS, where incidence increases to 306 cases per 100,000 person years in patients 75 to 84 years of age and mortality increases to 60% in patients 85 years of age and older.
  • ARDS The precipitating conditions associated with the development of ARDS can be classified as direct injury to the lung, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, pneumonia, and pulmonary contusion and indirect injury to the lung, including sepsis, pancreatitis, and multiple blood transfusions.
  • SARS-CoV2 severe acute respiratory syndrome coronavirus 2
  • ARDS represents a stereotypic response to these various etiologies that is characterized by exaggerated pulmonary inflammation, infiltration of activated neutrophils, accumulation of alveolar interstitial fluid, and hypoxemia.
  • the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal.
  • the present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.
  • An aspect of the present disclosure is a composition for inhibiting and/or reducing pyroptotic cell death in a cell.
  • the composition comprises disulfiram as an active agent and tert-Butylhydroquinone (TBHQ) as a potentiating ingredient, wherein the amount of disulfiram is from about 5 mg to about 500 mg and the amount of TBHQ is from about 0.02% to about 56% by weight of disulfiram
  • the amount of TBHQ is from about 15 mg to about 40 mg.
  • the amounts of disulfiram and TBHQ treats acute lung injury (ALI), acute respiratory distress syndrome (ARDS), actinic keratosis, alopecia, chronic obstructive pulmonary disease, Cryopyrin- Associated Periodic Syndrome (CAPS), dry eye, gout or gouty arthritis, idiopathic pulmonary fibrosis ⁇ Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), liver conditions (including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis), macular degeneration, multiple sclerosis, psoriasis, skin cancer, and/or uveitis.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • CAPS Cryopyrin- Associated Periodic Syndrome
  • dry eye gout or gouty arthritis
  • idiopathic pulmonary fibrosis ⁇ Inflammatory Bowel Diseases including Crohn’s disease, Ulcer
  • the amounts of disulfiram and TBHQ limit the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • the composition is formulated for oral administration as a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule or the composition is formulated for parenteral administration as a solution, suspension, dispersion, or emulsion.
  • the amounts of disulfiram and TBHQ provide a synergistic effect, e. g. , characterized using a Synergy Fold Ratio and/or using the Loewe Additivity Model.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg.
  • the amount of disulfiram is about 250 mg and the amount of TBHQ is about 18.5 mg or the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • composition comprising from about 5 mg to about 500 mg of disulfiram and tert-Butylhydroquinone (TBHQ) in an amount from about 0.02% to about 56% by weight of disulfiram.
  • TBHQ tert-Butylhydroquinone
  • the amounts of disulfiram and TBHQ limit the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • the amount of TBHQ is from about 15 mg to about 40 mg.
  • the amount of disulfiram is about 250 mg or about 500 mg and the amount of TBHQ is about 7.4% of the amount of disulfiram.
  • the composition is formulated for oral administration as a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule or the composition is formulated for parenteral administration as a solution, suspension, dispersion, or emulsion.
  • the amounts of disulfiram and TBHQ provide a synergistic effect, e. g. , characterized using a Synergy Fold Ratio and/or using the Loewe Additivity Model.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg.
  • the amount of disulfiram is about 250 mg and the amount of TBHQ is about 18.5 mg or the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • compositions comprising from about 5 mg to about 500 mg of disulfiram and tert-Butylhydroquinone (TBHQ) in an amount from about 0.02% to about 56% by weight of disulfiram.
  • TBHQ tert-Butylhydroquinone
  • the amount of TBHQ is from about 15 mg to about 40 mg.
  • the amount of disulfiram is about 250 mg or about 500 mg and the amount of TBHQ is about 7.4% of the amount of disulfiram.
  • the composition is formulated for oral administration as a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule or the composition is formulated for parenteral administration as a solution, suspension, dispersion, or emulsion.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg, e. g. , the amount of disulfiram is about 250 mg and the amount of TBHQ is about 18.5 or wherein the amount of disulfiram is from about 450 mg to about 550 mg and the amount of TBHQ is from about 30 mg and about 45 mg, e.g, the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • the composition further comprises one or more of additional ingredients listed in Table 1.
  • a further aspect of the present disclosure is a plurality of compositions comprising a first composition comprising disulfiram as an active agent in an amount from about 5 mg to about 500 mg and tert- Butylhydroquinone (TBHQ) as a potentiating ingredient in an amount from about 0.02% to about 56% by weight of disulfiram and a second composition comprising disulfiram as an active agent in an amount from about 5 mg to about 500 mg and TBHQ as a potentiating ingredient in an amount from about 0.02% to about 56% by weight of disulfiram.
  • TBHQ tert- Butylhydroquinone
  • the amount of disulfiram is about 250 mg and the amount of TBHQ is from about 15 mg to about 20 mg or the amount of disulfiram is about 500 mg and the amount of TBHQ is from about 30 mg and about 45 mg.
  • the amounts of TBHQ in the first composition and/or in the second composition is about 7.4% of the amount of disulfiram.
  • the amounts of disulfiram and TBHQ inhibit and/or reduce pyroptotic cell death in a cell and/or treat acute lung injury (ALI), acute respiratory distress syndrome (ARDS), actinic keratosis, alopecia, chronic obstructive pulmonary disease, Cryopyrin-Associated Periodic Syndrome (CAPS), dry eye, gout or gouty arthritis, idiopathic pulmonary fibrosis, Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), liver conditions (including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis), macular degeneration, multiple sclerosis, psoriasis, skin cancer, and/or uveitis. .
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • CAPS Cryopyrin-Associated Periodic Syndrome
  • dry eye gout or gouty arthritis
  • the amounts of disulfiram and TBHQ limit the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • one or both composition is formulated for oral administration as a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule and/or one or both compositions are formulated for parenteral administration as a solution, suspension, dispersion, or emulsion.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount ofTBHQ is from about 16 mg and about 20 mg, e.g, about 250 mg and the amount of TBHQ is about 18.5 or wherein the amount of disulfiram is from about 450 mg to about 550 mg and the amount of TBHQ is from about 30 mg and about 45 mg, e. g. , the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • the plurality of compositions further comprises and one or more of additional ingredients listed in Table 1.
  • Yet a further aspect of the present disclosure is a method for limiting the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • the method comprises administrating a composition comprising from about 5 mg to about 500 mg of disulfiram and tert- Butylhydroquinone (TBHQ) in an amount from about 0.02% to about 56% by weight of disulfiram.
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • the composition is formulated for oral administration as a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule or the composition is formulated for parenteral administration as a solution, suspension, dispersion, or emulsion.
  • the amount of disulfiram is about 250 mg or about 50 mg and the amount of TBHQ is about 7.4% of the amount of disulfiram.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg, e.g., .
  • the amount of disulfiram is about 250 mg and the amount ofTBHQ is about 18.5 or the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • the present disclosure provides a method for inhibiting and/or reducing pyroptotic cell death in a cell, the method comprising contacting the cell with an active agent that is disulfiram and a potentiating ingredient that is tert-Butylhydroquinone (TBHQ), thereby inhibiting and/or reducing pyroptotic cell death.
  • an active agent that is disulfiram and a potentiating ingredient that is tert-Butylhydroquinone (TBHQ)
  • TBHQ tert-Butylhydroquinone
  • the amount of disulfiram is from about 5 mg to about 500 mg and the amount of TBHQ is from about 0.02% to about 56% by weight of disulfiram and a combination of disulfiram and TBHQ provides a synergistic effect.
  • the disulfiram and the TBHQ are included in one composition and the composition consists essentially of disulfiram and TBHQ.
  • the method comprises contacting the cell with a first composition consisting essentially of disulfiram and contacting the cell with a second composition consisting essentially TBHQ.
  • inhibiting and/or reducing pyroptotic cell death in the cell increases the lifespan of the cell.
  • the synergistic effect is characterized using a Synergy Fold Ratio and/or using the Loewe Additivity Model.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg.
  • the amount of disulfiram is about 250 mg and the amount ofTBHQ is about 18.5 or the amount of disulfiram is about 250 mg and the amount of TBHQ is about 37 mg.
  • An aspect of the present disclosure is a method for inhibiting and/or reducing pyroptotic cell death in a cell.
  • the method comprises contacting the cell with an active agent that is disulfiram and a potentiating ingredient that is tert-Butylhydroquinone (TBHQ), thereby inhibiting and/or reducing pyroptotic cell death, wherein the amount of disulfiram is from about 5 mg to about 500 mg and the amount of TBHQ is from about 0.02% to about 56% by weight of disulfiram and a combination of disulfiram and TBHQ provides a synergistic effect, wherein the combination of disulfiram and TBHQ treats acute lung injury (ALI), acute respiratory distress syndrome (ARDS), actinic keratosis, alopecia, chronic obstructive pulmonary disease, Cryopyrin- Associated Periodic Syndrome (CAPS), dry eye, gout or gouty arthritis, idiopathic pulmonary fibrosis, Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), liver conditions (including nonalcoholic fatty
  • the combination of disulfiram and TBHQ inhibits and/or reduces a pathological inflammatory response, alters a T-cell’ s age, and/or alters mitochondrial function in the cell.
  • the disulfiram and the TBHQ are included in one composition and the composition consists essentially of disulfiram and TBHQ.
  • the method comprises contacting the cell with a first composition consisting essentially of disulfiram and contacting the cell with a second composition consisting essentially TBHQ.
  • inhibiting and/or reducing pyroptotic cell death in the cell increases the lifespan of the cell.
  • the synergistic effect is characterized using a Synergy Fold Ratio and/or using the Loewe Additivity Model.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg.
  • the amount of disulfiram is about 250 mg and the amount of TBHQ is about 18.5 or the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • An aspect of the present disclosure is a method for boosting activity of an immune cell.
  • the method comprises contacting the immune cell with an active agent that is disulfiram and a potentiating ingredient that is tert-Butylhydroquinone (TBHQ), thereby boosting activity of the immune cell, wherein the amount of disulfiram is from about 5 mg to about 500 mg and the amount of TBHQ is from about 0.02% to about 56% by weight of disulfiram and a combination of disulfiram and TBHQ provides a synergistic effect.
  • an active agent that is disulfiram and a potentiating ingredient that is tert-Butylhydroquinone (TBHQ)
  • TBHQ tert-Butylhydroquinone
  • the disulfiram and the TBHQ are included in one composition and the composition consists essentially of disulfiram and TBHQ.
  • the method comprises contacting the immune cell with a first composition consisting essentially of disulfiram and contactingthe cell withan at least second composition consisting essentially TBHQ.
  • boosting activity of the immune cell increases an effective immune response against an infectious agent and/or an atypical cell.
  • boosting activity of the immune cell improves the immune cell’s response against a component contained in a vaccine, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • boosting activity of the immune cell comprises inhibiting a pathological immune response.
  • boosting activity of the immune cell minimizes overactive immune cell activity.
  • the synergistic effect is characterized using a Synergy Fold Ratio and/or using the Loewe Additivity Model.
  • the amount of disulfiram is from about 225 mg to about 275 mg and the amount of TBHQ is from about 16 mg and about 20 mg.
  • the amount of disulfiram is about 250 mg and the amount of TBHQ is about 18.5 or the amount of disulfiram is about 500 mg and the amount of TBHQ is about 37 mg.
  • composition or an at least third composition comprises one or more of additional ingredients listed in Table 1.
  • the cell is a human cell or the patient is a human patient.
  • the disulfiram is a variant of disulfiram and having the structure of Formula (II).
  • the disulfiram may be a variant of disulfiram and may have the structure of F ormula (II) .
  • the disulfiram is a variant of disulfiram and having the structure of Formula (II).
  • the present disclosure provides a composition or a plurality of compositions for use in any herein disclosed method.
  • the present disclosure provides use of any herein-disclosed composition or any herein- disclosed plurality of compositions in a method for limiting the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • the present disclosure provides use of any herein-disclosed composition or any herein- disclosed plurality of compositions in a method for inhibiting and/ or reducing pyroptotic cell death in a cell. In yet a further aspect, the present disclosure provides use of any herein -disclosed composition or any herein- disclosed plurality of compositions in a method for boosting activity of an immune cell.
  • the present disclosure provides a method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorderin amammal, for reducing a symptomof aging in amammal, and/or boosting an immune system in a mammal comprising.
  • the method comprises administering to the mammal a therapeutically effective amount of disulfiram and one or more of the additional ingredients listed in Table 1.
  • Also provided herein is an in vivo, in vi fro, or ex vivo method for increasing lifespan of a cell and/ or boosting activity of an immune cell.
  • the method comprising contacting the cell or the immune cell with disulfiram and one or more of the additional ingredients listed in Table 1.
  • the present disclosure provides a method for improving effectiveness of a vaccine in a mammal in need thereof.
  • the method comprises administering a therapeutically effective amount of disulfiram and one or more of the additional ingredients listed in Table 1.
  • the mammal contemporaneously and/or subsequently will be administered a vaccine.
  • Another aspect of the present disclosure is a method for reducing a predicted biological age of a cell.
  • the method comprises contacting the cell with a therapeutically effective amount of disulfiram and one or more additional ingredients listed in Table 1.
  • the present disclosure provides a composition comprising disulfiram and one or more of the additional ingredients listed in Table 1.
  • the present disclosure also provides a plurality of compositions comprising a first composition comprising disulfiram and a second composition comprising one or more of the additional ingredients listed in Table 1.
  • disulfiram may be replaced with a herein-disclosed aldehyde dehydrogenase (ALDH) modulator (e.g, NCT-501, 4-Diethylaminobenzaldehyde, Daidzin, CM10, EN40, 4-Hydroxynonenal, RV01, CVT-10216, 3-Hydroxybenzaldehyde, or ANS-66372) or with a herein- disclosed gasdermin D inhibitor (e.g, aloe emodin, 2-iodomelatonin, LDC7559, necrosulfonamide, tasimelteon, ramelteon, melatonin, emodin, or BAY 11-7082).
  • ALDH aldehyde dehydrogenase
  • FIG. 1A to FIG. ID show data obtained when virally -infected cells were treated with a disulfiram.
  • FIG. 1A shows cytokine levels from the supernatant of vesicular stomatitis virus encoding a red fluorescent protein (rVSV- AG- mCherry)- infected cells (infected at lOx MOI); asterisks indicate statistical significance relative to untreated control cells. Data is normalized by total cell count.
  • FIG. IB and FIG. 1C respectively, show reticularity measurements of mitochondria and aging scores in T cells.
  • 1C horizontal bars represent the distribution of untreated controls from younger and older donors; the solid line represents the median and the lower and upper dashed lines represent the 25 th and 75 th quartile ⁇ respectively.
  • the line graph represents the median and 95% CI fortreated cells, with statistical significance relative to untreated control cells indicated by asterisks.
  • IL interleukin
  • MCP1 monocyte chemoattractant protein 1
  • MOI multiplicity of infection
  • PBMC peripheral blood mononuclear cell
  • TNF tumor necrosis factor.
  • FIG. 2 shows a pyroptosis assay illustrating inhibition of pyroptosis by disulfiram and copper treatment. Effect of disulfiram on pyroptosis was measured across a range of doses from 0.002 to 125 pM. Effect of disulfiram in the presence of 10 mM Copper (II) Gluconate on pyroptosis was also measured. In the presence of Copper (II) Gluconate, disulfiram’s IC50 based on pyroptosis was reduced 3.4-fold.
  • FIG. 3 shows the effect of cells treated with disulfiram alone, tert-Butylhydroquinone (TBHQ) alone, or disulfiram and TBHQ in combination at different concentrations.
  • FIG. 4 shows the effect of cells treated with TBHQ and different concentrations of disulfiram.
  • FIG. 5A to FIG. 5C show synergistic effects of TBHQ on disulfiram activity.
  • FIG. 5A is atable of synergy ratio of actual/ expected effect at each concentration of TBHQ and disulfiram; cells in grey indicate positive synergy.
  • FIG. 5B and FIG. 5C show average synergy at different concentrations of TBHQ and disulfiram
  • FIG. 6 is atable showing the percent difference in IC50 between disulfiram alone vs. disulfiram and TBHQ at various concentrations or constant ratio (last column).
  • TBHQ combined with disulfiram shifts the IC50 to the left relative to disulfiram alone in a dose-dependent manner.
  • TBHQ has no effect on pyroptosis inhibition or a clear IC50, indicating effects on early inhibition and shifted IC50 is synergistic.
  • FIG. 7 shows the effect of cells treated with disulfiram alone, cinnamaldehyde alone, or disulfiram and cinnamaldehyde in combination at different concentrations.
  • FIG. 8 shows the effect of cells treated with cinnamaldehyde and different concentrations of disulfiram.
  • FIG. 9A to 9C show synergistic effects of cinnamaldehyde on disulfiram activity.
  • FIG. 9A is a table of synergy ratio of actual/expected effect at each concentration of cinnamaldehyde and disulfiram; cells in grey indicate positive synergy.
  • FIG. 9B and FIG. 9C are graphs showing average synergy at different concentrations of cinnamaldehyde and disulfiram.
  • FIG. 10 is a table showing the percent difference in IC50 between disulfiram alone vs. disulfiram and cinnamaldehyde at various concentrations or constant ratio (last column). Cinnamaldehyde combined with disulfiram shifts the IC50 to the left relative to disulfiram alone in a dose-dependent manner, cinnamaldehyde has no effect on pyroptosis inhibition or a clear IC50, indicating effects on early inhibition and shifted IC50 is synergistic.
  • FIG. 11 shows the effect of cells treated with disulfiram alone, nordihydroguaiaretic acid (NDGA) alone, or disulfiram and NDGA in combination at different concentrations.
  • FIG. 12 shows the effect of cells treated with NDGA and different concentrations of disulfiram.
  • FIG. 13A to 13C show synergistic effects of NDGA on disulfiram activity.
  • FIG. 13A is atable of synergy ratio of actual/expected effect at each concentration of NDGA and disulfiram; cells in grey indicate positive synergy.
  • FIG. 13B and FIG. 13C are graphs showing average synergy at different concentrations of NDGA and di sulfiram.
  • FIG. 14 is a table showing the percent difference in IC50 between disulfiram alone vs. disulfiram and NDGA at various concentrations or constant ratio (last column). NDGA combined with disulfiram shifts the IC50 to the left relative to disulfiram alone at the highest concentrations. NDGA alone has little to no effect on pyroptosis inhibition, so effects on Disulfiram inhibition and shifted IC50 is synergistic.
  • the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal.
  • the present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.
  • ADH Aldehyde dehydrogenase
  • Aldehyde dehydrogenases are a group of enzymes that catalyze the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The produced carboxylic acids leave the liver (where the highest concentration of the enzymes are located) and are metabolized by the body’s muscle and heart. There are three different classes of these enzymes in mammals: class 1 (ALDH1, low Km, cytosolic), class 2 (ALDH2, low Km, mitochondrial), and class 3 (ALDH3, high Km, such as those expressed in tumors, stomach, and cornea). To date, nineteen ALDH genes have been identified within the human genome. These enzymes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes, e.g, from alcohol oxidation.
  • aspects of the present disclosure relate to active ingredients, compositions, and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, boosting an immune system in a mammal, and improving effectiveness of a vaccine in a mammal.
  • the methods comprise administering to the mammal a composition comprising a therapeutically effective amount of an active ingredient that is an aldehyde dehydrogenase (ALDH) modulator.
  • the active ingredient is combined with a potentiating ingredient, as disclosed herein.
  • the ALDH modulator is an ALDH modulator or an ALDH agonist.
  • the ALDH modulator is Disulfiram, NCT-501, 4-Diethylaminobenzaldehyde, Daidzin, CM10, EN40, 4-Hydroxynonenal, RV01, CVT-10216, 3-Hydroxybenzaldehyde, or ANS-66372.
  • Disulfiram is a specific inhibitor of an aldehy de-dehydrogenase (ALDH1). Disulfiram was approved by the US Food and Drug Administration in 1951 for alcohol aversion therapy after researchers observed that it induced the effects of a hangover after alcohol consumption. Disulfiram blocks the maj or metabolic reaction that converts alcohol into acetaldehyde.
  • ADH1 aldehy de-dehydrogenase
  • Disulfiram also known as Tetraethylthiuram disulfide, Antabuse, Antabus, diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate, and 1 -(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide; CAS Reference Number: 97-77-8
  • Disulfiram also known as Tetraethylthiuram disulfide, Antabuse, Antabus, diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate, and 1 -(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide; CAS Reference Number: 97-77-8
  • disulfiram includes disulfiram itself and any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • disulfiram includes disulfiram itself and any of its metabolites and/or their derivatives and variants thereof.
  • metabolites include diethyldithiocarbamate, methyl diethyldithiocarbamate, dithiomethylcarbamate, S -Methyl N,N-Diethylthiocarbamate, diethyl -amine, and carbon disulfide.
  • the ALDH modulator is an ALDH agonist.
  • the ALDH agonist is Alda-1.
  • Alda-1 is an activator of aldehyde dehydrogenase 2 (ALDH2).
  • Alda- 1 increases activity of wild-type ALDH2* 1 and variant ALDH2*2 (by ⁇ 2-fold and 11 -foldrespectively). It is capable of partly restoring mutant ALDH2*2 activity, and protective against cardiac ischemia.
  • the pore-forming protein gasdermin (such as gasdermin D) is the final pyroptosis executioner downstream of inflammasome activation.
  • Gasdermin D inhibitor compounds of the present disclosure inhibit gasdermin pore formation and subsequent secretion of inflammatory mediators such as IE- lb.
  • aspects of the present disclosure relate to active ingredients, compositions, and methods for increasing lifespan, for preventing or treating a disease including an aging -related disorder, for reducing a symptom of aging, boosting an immune system in a mammal, and improving effectiveness of a vaccine in a mammal.
  • the methods comprise administering to the mammal a composition comprising a therapeutically effective amount of an active ingredient that is a gasdermin D inhibitor.
  • Gasdermin D (GSDMD or DFNA5L) is a recently -identified pore-forming protein.
  • the active ingredient is combined with a potentiating ingredient, as disclosed herein.
  • the gasdermin D inhibitor is disulfiram, aloe emodin, 2-iodomelatonin, LDC7559, necrosulfonamide, tasimelteon, ramelteon, melatonin, emodin, or BAY 11-7082.
  • Disulfiram also known as Tetraethylthiuram disulfide, Antabuse, Antabus, diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate, and 1 -(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide; CAS Reference Number: 97-77-8
  • Disulfiram also known as Tetraethylthiuram disulfide, Antabuse, Antabus, diethylcarbamothioylsulfanyl N,N-diethylcarbamodithioate, and 1 -(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide; CAS Reference Number: 97-77-8
  • disulfiram includes disulfiram itself and any pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • disulfiram includes disulfiram itself and any of its metabolites and/or their derivatives and variants thereof.
  • metabolites include diethyldithiocarbamate, methyl diethyldithiocarbamate, dithiomethylcarbamate, S-Methyl N,N-Diethylthiocarbamate, diethyl -amine, and carbon disulfide.
  • disulfiram includes disulfiram itself and any of its metabolites and/or their derivatives and variants thereof.
  • disulfiram includes variants of disulfiram, which, as used herein is, a compound having the structure of Formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
  • Xi and X2 are each independently O or S; p is 1 or 2;
  • Ri, R2, Rs, and R4 are each independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C5 alkynyl, Cs-Cs cycloalkyl, 4-10 membered heterocycloalkyl, C(O)OR la , or C(O)NR la R lb ; wherein each is optionally substituted with 1, 2, or 3 R 5 ; or R 1 and R 2 together with theN atom to which they are attached from a 4- 10 membered ring, which is optionally substituted with 1, 2, 3, or 4 R 6 .
  • each R 5 , R 6 , and R 7 is independently selected from halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, CN, NO2, OR la , C(O)R lb , C(O)NR la R 1 b, C(O)OR la , NR la R lb , S(O)2R lb and S(O)2NR la R lb ; each R la and R lb is independently selected from H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
  • the compound of Formula (II) has the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
  • the compound of Formula (I) is l-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methaneihioamide, also known as Di sulfiram.
  • an active ingredient of the present disclosure i.e. , an ALDH modulator or gasdermin D inhibitor (c.g. disulfiram or a variant thereof and having the structure of Formula (II)) may be combined (in a composition and/or in a method) with a potentiating ingredient (e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • a potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic add (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic add
  • Table 1 The potentiating ingredient
  • a composition comprising the active ingredient alone will be less effective, for example, than a composition comprising the active ingredient and its potentiating ingredient (e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)).
  • a method in which the active ingredient is administered alone is less effective than a method in which the active ingredient is administered with a potentiating agent (either as a single composition or as distinct compositions that are administered contemporaneously or sequentially).
  • An increased and/or improved effectiveness may be determined by any assay, phenotype, marker, or indicator demonstrating a desired outcome from a treatment or administration of a composition.
  • effectiveness may be shown as a reduction in markers/indicators of an aging cell, an increase in markers/indicators of a healthy cell, an extension of the active life of a cell, a reduction in apoptosis, increased longevity of a mammal, a reduction in the predicted biological age of a cell, increased titer of antibodies in response to a vaccine, inhibition of pyroptosis in an in vitro assay, an immune profile, and phenotypic changes in a cell that report health and/or activity.
  • Increased and/or improved effectiveness may be objective (e.g. , quantifiable) or subjective (e.g. , qualifiable).
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • GRAS tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • Table 1 The potentiating ingredient
  • GRAS tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • Table 1 is a compound that is generally recognized as safe (GRAS; e.g , by the FDA)
  • IID see, the World Wide Web at accessdata.fda.gov/ scripts/cder/iig/index.cfm
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • the potentiating ingredient is considered an “inactive ingredient”.
  • an inactive ingredient is any component of a drug product other than the active ingredient (see, the World Wide Web at fda.gov/drugs/drug-approvals-and-databases/ inactive-ingredients-approved-drug-products-search- frequently- asked- questions, the contents of which is incorporated by reference in its entirety).
  • the active ingredient is an ALDH modulator or gasdermin D inhibitor (e.g , disulfiram or a variant thereof and having the structure of Formula (II)).
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • Table 1 another additional ingredient (as disclosed in Table 1)) is any substance that can intentionally be added to a food as a food additive and which is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use.
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • FDCA Federal Food, Drug, and Cosmetic Act
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • Table 1 The potentiating ingredient
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic add
  • Non-limiting examples of a metabolite includes a salt and ester of the potentiating ingredient (e.g., tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)).
  • the potentiating ingredient e.g., tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • a metabolite or a derivative of a potentiating ingredient e.g, tert- Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert- Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • Table 1 The usefulness of a metabolite or a derivative of a potentiating ingredient (e.g, tert- Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)) is useful, e.g. , in the compositions and methods of the present disclosure.
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • Table 1 another additional ingredient
  • the enhanced, increased, and/or improved effectiveness and/or activity of the active ingredient may be any amount between about 1.1-fold and about 3-fold, e.g, about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2. 8, 2.9, or 3 -fold, and any fold therebetween; as examples, any fold amount between about 1.1 to about 1.3, about 1.1 to about 1.5, about 1. 1 to about 1.7, about 1. 1 to about 1.9, about 1.
  • 1 to about 2. 1, about 1. 1 to about 2.3, about 1. 1 to about 2.5, about 1. 1 to about 2.7, about 1. 1 to about 2.9, about 1. 1 to about 3, about 1.3 to about 1.5, about 1.3 to about 1.7, about 1.3 to about 1.9, about 1.3 to about 2.
  • the enhanced, increased, and/or improved effectiveness and/or activity of the active ingredient may be any amount between about 3-fold and about 5-fold, e.g, about 3, 3.
  • the enhanced, increased, and/or improved effectiveness and/or activity of the active ingredient may be any amount between about 5-fold and about 15-fold. As examples, the effectiveness may be increased about 5,
  • the enhanced, increased and/or improved effectiveness and/or activity of the active ingredient is greater than about 15-fold.
  • the increased and/or improved effectiveness may begreater than about 1%, e.g, about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 100%, and any percentage therebetween.
  • an enhanced, increased, and/or improved effectiveness and/or activity of the active ingredient i.e. , an ALDH modulator or gasdermin D inhibitor (e. g., disulfiram or a variant thereof and having the structure of Formula (II))
  • an ALDH modulator or gasdermin D inhibitor e. g., disulfiram or a variant thereof and having the structure of Formula (II)
  • an ALDH modulator or gasdermin D inhibitor e. g., disulfiram or a variant thereof and having the structure of Formula (II)
  • effectiveness and/or activity may be shown as a reduction in markers/indicators of an aging cell, an increase in markers/indicators of a healthy cell, an extension of the active life of a cell, a reduction in apoptosis, increased longevity of a mammal, a reduction in the predicted biological age of a cell, increased titer of antibodies in response to a vaccine, inhibition of pyroptosis in an in vitro assay, an immune profile, and phenotypic changes in a cell that report health and/or activity.
  • Increased and/or improved effectiveness may be objective (e.g, quantifiable) or subjective (e.g, qualifiable).
  • the potentiating ingredient e.g, tert-Butylhydroquinone (TBHQ), cinnamaldehyde, nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1)
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • enhance ⁇ increases, and/or improve the active ingredient’s effectiveness and/or activity e.g, in pyroptosis inhibition
  • lower doses of the active ingredient may be administered to amammal while still providing a desired outcome. This lower dose may minimize adverse effects resulting from the active ingredient administration, if any.
  • the additional ingredients used in the present disclosure increase and/or improve the effectiveness of disulfiram.
  • a composition comprising disulfiram alone will be less effective than a composition comprising disulfiram and one or more additional ingredients.
  • a method in which disulfiram is administered alone is less effective than a method in which disulfiram is administered with one or more additional ingredients (either as a single composition or as distinct compositions that are administered contemporaneously).
  • the additional ingredients, as disclosed herein enhance disulfiram’s ability to inhibit pyroptosis.
  • the present disclosure provides methods that comprise administering a therapeutically effective amount of ALDH modulator or gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1, contacting a cell or immune cell with disulfiram and one or more of the additional ingredients listed in Table 1, a composition comprising ALDH modulator or gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1, and a plurality of compositions comprising a first composition comprising ALDH modulator or gasdermin D inhibitor and a second composition comprising one or more of the additional ingredients listed in Table 1.
  • the ALDH modulator or gasdermin D inhibitor is disulfiram.
  • Additional information about the additional ingredients listedin Table 1 can be determined from publicly available databases and websites.
  • the American Chemical Society’s website see, the Worldwide Web at cas.org
  • the Chemical Book at the World Wide Web chemicalbook.com
  • Med Chem Express see, the World Wide Web at medchemexpress. com
  • compositions Comprising Disulfiram and tert-Butylhydroquinone (TBHQ)
  • the methods of the present disclosure comprise administeringto amammal atherapeutically effective amount of disulfiram and a potentiating ingredient that is tert-Butylhydroquinone (TBHQ).
  • the method may comprise contacting a cell (in vivo, in vitro, or ex vivo) with disulfiram and tert-Butylhydroquinone (TBHQ).
  • disulfiram includes disulfiram itself and any of its metabolites and/or their derivatives. Examples of metabolites include diethyldithiocarbamate, diethyl -amine, and carbon disulfide. Disulfiram also includes a variant of disulfiram and having the structure of F ormula (II)).
  • the active agent is disulfiram and the potentiating ingredient is TBHQ.
  • TBHQ has the following chemical identifiers: CAS 1948-33-0, DrugBank DB07726, MedChem HY-100489, and SelleckChem S4990.
  • TBHQ protects against Doxorubicin (DOX)-induced cardiotoxicity through activation of nuclear factor erythroid 2-related factor 2 (NrF2).
  • NrF2 nuclear factor erythroid 2-related factor 2
  • TBHQ is also an ERK activator, and rescues Dehydrocorydaline (DHC) -induced cell proliferation inhibition in melanoma.
  • DHC Dehydrocorydaline
  • the term TBHQ includes TBHQ itself and any of its metabolites, derivatives, and/or precursors. Examples of TBHQ metabolites include TBHQ -glucuronide and TBHQ-sulfate.
  • An example of a TBHQ precursor is butylated hydroxyanisole (
  • a composition of the present disclosure comprises an active agent that is disulfiram and a potentiating ingredient that is TBHQ.
  • a plurality of compositions of the present disclosure may comprise a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is TBHQ.
  • the present disclosure provides methods that comprise administering atherapeutically effective amount of an active agent that is disulfiram and a potentiating ingredient that is TBHQ, contacting a cell or immune cell with an active agent that is disulfiram and a potentiating ingredient that is TBHQ, a composition comprising an active agent that is disulfiram and a potentiating ingredient that is TBHQ, and a plurality of compositions comprising a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is TBHQ.
  • a potentiating ingredient i.e., TBHQ, enhances, increases, and/or improves the desirable activity of the active ingredient, i.e., disulfiram.
  • the potentiating ingredient enhances pyroptosis activity of disulfiram.
  • the potentiating ingredient, i. e. , TBHQ, used in the present disclosure enhances, increases, and/ or improves the effectiveness and/or desirable activity of the active ingredient, i.e., disulfiram.
  • a composition comprising disulfiram alone will be less effective, for example, than a composition comprising disulfiram and its potentiating ingredient TBHQ.
  • a method in which disulfiram is administered alone is less effective than a method in which disulfiram is administered with TBHQ (either as a single composition or as distinct compositions that are administered contemporaneously or sequentially).
  • the potentiating ingredient, as disclosed herein enhances disulfiram’s ability to inhibit pyroptosis.
  • disulfiram may be administered to a mammal while still providing a desired outcome. This lower dose may minimize adverse effects resulting from disulfiram administration.
  • disulfiram is administered at a daily dosage or as a single dosage of about 5 mg to about 750 mg per day.
  • disulfiram is administered at atotal daily dosage or as a single dosage of about 5, 6, 7, 8, 9, 10, 15, 18, 18.5, 19, 20, 25, 30, 45, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 240, 250, 260, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 700 mg per day, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage may be 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg, 75-80 mg, 80-85 mg, 85-90 mg, 90-95 mg, 95-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 230-260 mg, 240-270 mg, 250-275 mg, 275-300 mg, 300-325 mg, 325-350 mg, 350-375 mg, 375-400 mg, 400-425 mg, 425-450 mg, 450-475 mg, 475-500 mg, 500-525 mg, 525-550 mg, 550-575 mg, 575-600 mg, 600-625 mg, 625-650 mg, 630-660 mg, 640-670 mg, 650-675 mg, or 675-700 mg
  • the total daily dosage or the single dosage may be 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is between 230 mg and 260 mg, e.g, 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, or 260 mg, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is 250 mg.
  • the total daily dosage or the single dosage may be 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg,
  • the total daily dosage or the single dosage is 500 mg.
  • the total daily dosage or the single dosage may be 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg,
  • the total daily dosage or the single dosage of disulfiram is 250 mg.
  • the disulfiram may be administered lx, 2x, or 3x per day to achieve the daily dosage.
  • a daily dose of 250 mg with a once per day administration only a single administration of 250 mg will be given; for a daily dose of 500 mg with a twice per day administration, two administrations of about 250 mg will be given; and for a daily dose of 750 mg with a thrice per day administration, three administrations of about 250 mg will be given.
  • TBHQ is administered at a daily dosage or as a single dosage from about 1 mg to about 100 mg.
  • the daily dosage or the single dosage of TBHQ may be about 1-3 mg, 2-5 mg, 3-6 mg, 4-7 mg, 5-8 mg, 6-9 mg, 7-10 mg, 8-11 mg, 9-12 mg, 10-13 mg, 11-14 mg, 12-15 mg, 13-16 mg, 14-17 mg, 15-18 mg, 16-19 mg, 17 - 20 mg, 20-25 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg, and any total daily dosage or single dosage therebetween.
  • the TBHQ may be administered at a total daily dosage or as a single dosage of about 1 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, or 100 mg, and any daily dosage or single dosage therebetween.
  • the TBHQ may be administered at a total daily dosage or as a single dosage of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, and any daily dosage or single dosage therebetween.
  • the daily dosage or the single dosage of TBHQ may be about 1 -2 mg, 2-3 mg, 3-4 mg, 4-5 mg, 5-6 mg, 6-7 mg, 7-8 mg, 8-9 mg, or 9-10 mg.
  • the TBHQ may be administered at a total daily dosage or as a single dosage of about 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg, and any daily dosage or single dosage therebetween.
  • the TBHQ may be administered at a total daily dosage or as a single dosage of about 18.0 mg, 18.1 mg, 18.2 mg, 18.3 mg, 18.4 mg, 18.5 mg, 18.6mg, 18.7 mg, 18.8 mg, 18.9 mg, or 19.0 mg, and any daily dosage or single dosage therebetween.
  • the TBHQ may be administered at a total daily dosage or as a single dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, and any daily dosage or single dosage therebetween.
  • the daily dosage or the single dosage of TBHQ may be about 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg and any daily dosage or single dosage therebetween.
  • the potentiating ingredient, i. e., TBHQ may be administered lx, 2x, or 3x per day to achieve the daily dosage.
  • the potentiating ingredient, i. e., TBHQ, and the disulfiram are administered in two separate formulations.
  • the TBHQ and the disulfiram are administered in a single formulation.
  • the amount of TBHQ is about 0.02% to about 56% of the amount of disulfiram (by weight).
  • the amount of TBHQ may be about 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.
  • the amount of TBHQ may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the disulfiram, and any percentage therebetween.
  • the percentage may be about 1 %- 1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or9.5%-10%oftheweightofthe disulfiram.
  • the amount of TBHQ may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, or 56% of the weight of the disulfiram, and any percentage therebetween.
  • the percentage may be about 10%- 15%, 15%- 20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, 45%-50%, or 50%-56% of the weight of the disulfiram.
  • disulfiram is administered at a daily dosage or as a single dosage of about 5 mg to about 750 mg per day and TBHQ is administered at a daily dosage or as a single dosage from about 1 mg to about 100 mg.
  • disulfiram is administered at a total daily dosage or as a single dosage of about 5, 6, 7, 8, 9, 10, 15, 18, 18.5, 19, 20, 25, 30, 45, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 240, 250, 260, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 700 mg per day, and any total daily dosage or single dosage therebetween and TBHQ is administered at a total daily dosage or as a single dosage of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg,
  • the total daily dosage or the single dosage of disulfiram may be 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg, 75-80 mg, 80-85 mg, 85-90 mg, 90-95 mg, 95-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 230-260 mg, 240-270 mg, 250-275 mg, 275-300 mg, 300-325 mg, 325-350 mg, 350-375 mg, 375-400 mg, 400-425 mg, 425-450 mg, 450-475 mg, 475-500 mg, 500-525 mg, 525-550 mg, 550-575 mg, 575-600 mg, 600-625 mg, 625-650 mg, 630-660 mg, 640-670 mg, 650-675 mg, or
  • the total daily dosage or the single dosage of disulfiram may be 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg, and any total daily dosage or single dosage therebetween and TBHQ may be administered at a total daily dosage or as a single dosage of about 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg, and any daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage of disulfiram is between 230 mg and 260 mg, e.g., 230 mg, 231 mg, 232 mg, 233 mg, 234 mg, 235 mg, 236 mg, 237 mg, 238 mg, 239 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 251 mg, 252 mg, 253 mg, 254 mg, 255 mg, 256 mg, 257 mg, 258 mg, 259 mg, or 260 mg, and any total daily dosage or single dosage therebetween (as examples, about 230 mg to about 235 mg, about 230 mg to about 240 mg, about 230 mg to about 245 mg, about 230 mg to about 250 mg, about 230 mg to about 255 mg, about 230 mg to about 260 mg, about 235 mg to about 240 mg, about 235 mg to about 245 mg, about 235
  • the total daily dosage or the single dosage of disulfiram is 250 mg and the total daily dosage or the single dosage of TBHQ is 18.5 mg.
  • the total daily dosage or the single dosage of disulfiram may be 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, or 500 mg, and any total daily dosage or single dosage therebetween and TBHQ may be administered at a total daily dosage or as a single dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg, and any daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage of disulfiram is 500 mg and the total daily dosage or the single dosage of TBHQ is 37 mg.
  • the total daily dosage or the single dosage of disulfiram may be 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, or 750 mg, and any total daily dosage or single dosage therebetween and TBHQ may be administered at a total daily dosage or as a single dosage of about 20 mg, 30 mg
  • Compositions and methods of the present disclosure may further comprise one or more additional ingredients as disclosed in Table 1.
  • the additional ingredients may also potentiate the activity of the active agent, i. e. , disulfiram.
  • the additional ingredient may be considered a second potentiating ingredient.
  • the additional ingredient may also assist in the potentiating activity of TBHQ.
  • the additional ingredient may be generally activity inert and, instead, provide other favorable properties to a composition, e.g., acting as abinder, abuffer, a solute, an excipient, andso forth.
  • acompositionofthe present disclosure may comprise disulfiram and TBHQ and one or more additional ingredients.
  • a first composition may comprise disulfiram
  • a second composition may comprise TBHQ
  • an at least third composition may comprise one or more additional ingredients.
  • a subj ect may be administered a composition comprising disulfiram, TBHQ, and one or more additional potentiating ingredients.
  • a subject may be administered a first composition comprising disulfiram, a second composition comprising TBHQ, and an at least third composition comprising one or more additional ingredients.
  • the one or more additional ingredients are listed herein in Table 1
  • compositions Comprising Disulfiram and Cinnamaldehyde
  • the methods of the present disclosure comprise administering to a mammal a therapeutically effective amount of an active ingredient that is disulfiram and a potentiating ingredient that is cinnamaldehyde
  • the method may comprise contacting a cell (in vivo, in vitro, or ex vivo) with an active ingredient that is disulfiram and a potentiating ingredient that is cinnamaldehyde.
  • disulfiram includes disulfiram itself and any of its metabolites and/or their derivatives.
  • metabolites include di ethyldithiocarbamate, diethyl -amine, and carbon disulfide.
  • Disulfiram also includes a variant of disulfiram and having the structure of F ormula (II)).
  • the active agent is disulfiram and the potentiating ingredient is cinnamaldehyde.
  • Cinnamaldehyde has the following chemical identifiers: CAS: 14371 -10-9, 104-55-2; DrugBank: DB14184; MedChem: HY-N0609; and SelleckChem: S3763.
  • Cinnamaldehyde is the aldehyde that gives cinnamon its flavor and odor. Cinnamaldehyde occurs naturally in the bark of cinnamon trees and other species of the genus Cinnamomum like camphor and cassia. These trees are the natural source of cinnamon, and the essential oil of cinnamon bark is about 90% cinnamaldehyde. Cinnamaldehyde is also used as a fungicide.
  • cinnamaldehyde Proven effective on over 40 different crops, cinnamaldehyde is typically applied to the root systems of plants. Its lowtoxicity and well-known properties make it ideal for agriculture. To a lesser extent, cinnamaldehyde is an effective insecticide, and its scent is also known to repel animals like cats and dogs. Cinnamaldehyde is also known as a corrosion inhibitor for steel and other ferrous alloys in corrosive fluids. It can be used in combination with additional components such as dispersing agents, solvents and other surfactants. Concentrated cinnamaldehyde is a skin irritant, and the chemical is toxic in large doses, but no agencies suspect the compound is a carcinogen or poses a long-term health hazard. Most cinnamaldehyde is excreted in urine as cinnamic acid, an oxidized form of cinnamaldehyde.
  • cinnamaldehyde examples include (2E)-3-Phenyl-2-propenal, (2E)-3-Phenylacrylaldehyde, (e)- 3-Phenyl-2-propenal, (e)-3-Phenylpropenal, (e)-3-Phenyl-propenal, (e)-Cinnamaldehyde, (e)-Cinnamic aldehyde, (e)-Phenylvinyl aldehyde, 3-Fenylpropenal, 3-Phenyl-2-propen-l-al, 3-Phenyl-2- propenaldehyde, 3 -Phenylacrolein, 3-Phenylacrylaldehyde, 3-Phenylprop-2-enal, 3-Phenylprop-2- enaldehyde, 3-Phenylpropenal, Benzylideneacetaldehyde, beta-Phenylacrolein, beta-Phenyl
  • IID see, the World Wide Web at accessdata.fda.gov/ scripts/cder/iig/index.cfm
  • cinnamaldehyde includes cinnamaldehyde itself and any of its metabolites, derivatives, relatives, and/or precursors.
  • An example of a cinnamaldehyde metabolite includes cinnamic acid.
  • An example of a cinnamaldehyde precursor includes cinnamyl alcohol.
  • Examples of other cinnamaldehyde relatives include benzyl cinnamate (which is an ester of cinnamaldehyde), methyl cinnamate (which is an ester of cinnamic acid), and hydrocinnamic acid (which results from hydrogenation of cinnamic acid).
  • a composition of the present disclosure may comprise an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde.
  • a plurality of compositions of the present disclosure may comprise a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is cinnamaldehyde.
  • the present disclosure provides methods that comprise administering a therapeutically effective amount of an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, contacting a cell or immune cell with an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, a composition comprising an active agent that is disulfiram and a potentiating ingredient that is cinnamaldehyde, and a plurality of compositions comprising a first composition comprising an active agait that is disulfiram and a second composition comprising a potentiating ingredient that is cinnamaldehyde.
  • a potentiating ingredient i. e., cinnamaldehyde, enhances, increases, and/or improves the desirable activity of the active ingredient, i. e., disulfiram.
  • the potentiating ingredient enhances pyroptosis activity of disulfiram.
  • the potentiating ingredient i.e., cinnamaldehyde
  • the disulfiram are administered in two separate formulations.
  • the cinnamaldehyde and the disulfiram are administered in a single formulation.
  • disulfiram is administered at a daily dosage or as a single dosage of about 5 mg to about 750 mg per day.
  • disulfiram is administered at a total daily dosage or as a single dosage of about 5, 6, 7, 8, 9, 10, 15, 18, 18.5, 19, 20, 25, 30, 45, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 240, 250, 260, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 700 mg per day, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage may be 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg, 75-80 mg, 80-85 mg, 85-90 mg, 90-95 mg, 95-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 230-260 mg, 240-270 mg, 250-275 mg, 275-300 mg,
  • the total daily dosage or the single dosage may be 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is between 230 mg and 260 mg, e.g.
  • the total daily dosage or the single dosage is 250 mg.
  • the total daily dosage or the single dosage may be 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, or 500 mg, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is 500 mg.
  • the total daily dosage or the single dosage may be 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, or 750 mg, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is 750 mg. In some embodiments, the total daily dosage or the single dosage of disulfiram is 250 mg. And, the amount of cinnamaldehyde is about 0.01% to about 45% of the amount of disulfiram (by weight). The amount of cinnamaldehyde may be about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0. 1%, 0. 11%, 0. 12%, 0. 13%, 0. 14%, 0.15%, 0. 16%, 0. 17%, 0. 18%, 0.
  • the amount of cinnamaldehyde may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.
  • the percentage may be about 1%-1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5%-10% of the weight of the disulfiram.
  • the amount of cinnamaldehyde may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, or 45% ofthe weight of the disulfiram, and any percentage therebetween.
  • the percentage may be about 10%- 15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, or 40%-45% ofthe weight ofthe disulfiram
  • the potentiating ingredient, i.e., cinnamaldehyde, and the active agent, i.e., disulfiram are administered in two formulations
  • the amount of cinnamaldehyde is about 0.01% to about 45% of the weight of the disulfiram.
  • the amount of cinnamaldehyde may be about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.
  • the amount of cinnamaldehyde may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the disulfiram, and any percentage therebetween.
  • the percentage may be about 1%-1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5%-10% of the weight of the disulfiram.
  • the amount of cinnamaldehyde may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, or 45% of the weight of the disulfiram, and any percentage therebetween. As examples, the percentage may be about 10%- 15%, 15%-20%, 20%- 25%, 25%-30%, 30%-35%, 35%-40%, or 40%-45% of the weight of the disulfiram.
  • compositions and methods of the present disclosure may further comprise one or more additional ingredients as listed in Table 1.
  • the additional ingredients may also potentiate the activity of the active agent, i. e. , disulfiram.
  • the additional ingredient may be considered a second potentiating ingredient.
  • the additional ingredient may also assist in the potentiating activity of cinnamaldehyde.
  • the additional ingredient may be generally activity inert and, instead, provide other favorable properties to a composition, e.g., acting as a binder, a buffer, a solute, an excipient, and so forth.
  • a composition of the present disclosure may comprise disulfiram and cinnamaldehyde and one or more additional ingredients.
  • a first composition may comprise disulfiram
  • a second composition may comprise cinnamaldehyde
  • an at least third composition may comprise one or more additional ingredients.
  • a subject may be administered a composition comprising disulfiram, cinnamaldehyde, and one or more additional potentiating ingredients.
  • a subject may be administered a first composition comprising disulfiram, a second composition comprising cinnamaldehyde, and an at least third composition comprising one or more additional ingredients.
  • the one or more additional ingredients are listed herein in Table 1.
  • compositions Comprising Disulfiram and Nordihydroguaiaretic Acid (NDGA)
  • the methods of the present disclosure comprise administering to a mammal a therapeutically effective amount of an active ingredient that is disulfiram and a potentiating ingredient that is nordihydroguaiaretic acid (NDGA).
  • the method may comprise contacting a cell (in vivo, in vitro, or ex vivo) with an active ingredient that is disulfiram and a potentiating ingredient that is NDGA.
  • disulfiram includes disulfiram itself and any of its metabolites and/or their derivatives.
  • metabolites include di ethyldithiocarbamate, diethyl -amine, and carbon disulfide.
  • Disulfiram also includes a variant of disulfiram and having the structure of F ormula (II)).
  • the active agent is disulfiram and the potentiating ingredient is nordihydroguaiaretic acid (NDGA).
  • NDGA has the following chemical identifiers: CAS: 500- 38-9; DrugBank: DB00179; MedChem: HY-N0198; and SelleckChem: S3984.
  • NDGA is a tetrol that is butane which is substituted at positions 2 and 3 by 3,4-dihydroxybenzyl groups.
  • Masoprocol the mesoform found in the leaves of the creosote bush (Larrea divaricata), is a potent lipoxygenase inhibitor that interferes with arachidonic acid metabolism; also inhibits formyltetrahydrofolate synthetase, carboxyl esterase, and cyclooxygenase to a lesser extent. It has a role as an antioxidant and a plant metabolite. It is a member of catechols, a tetrol and alignan.
  • Nordihydroguaiaretic acid includes 4-[4-(3,4-dihydroxyphenyl)-2,3- dimethylbutyl]benzene-l,2-diol, Actinex, Dihydronorguaiaretic acid, Erythro-nordihydroguaiaretic acid, Masoprocol, Meso-Nordihydroguaiaretic acid, NDGA, and Nordihydroguaiaretic acid.
  • the term nordihydroguaiaretic acid (NDGA) includes NDGA itself and any of its metabolites, derivatives, and/or precursors. Examples of NDGA metabolites includes 3 -methyl NDGA.
  • a composition of the present disclosure comprises an active agent that is disulfiram and a potentiating ingredient that is NDGA.
  • a plurality of compositions of the present disclosure may comprise a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is NDGA.
  • the present disclosure provides methods that comprise administering a therapeutically effective amount of an active agent that is disulfiram and a potentiating ingredient that is NDGA, contacting a cell or immune cell with an active agent that is disulfiram and a potentiating ingredient that is NDGA, a composition comprising an active agent that is disulfiram and a potentiating ingredient that is NDGA, and a plurality of compositions comprising a first composition comprising an active agent that is disulfiram and a second composition comprising a potentiating ingredient that is NDGA.
  • a potentiating ingredient i.e., NDGA, enhances, increases, and/or improves the desirable activity of the active ingredient, i.e., disulfiram.
  • the potentiating ingredient enhances pyroptosis activity of disulfiram.
  • disulfiram is administered at a daily dosage or as a single dosage of about 5 mg to about 750 mg per day.
  • disulfiram is administered at a total daily dosage or as a single dosage of about 5, 6, 7, 8, 9, 10, 15, 18, 18.5, 19, 20, 25, 30, 45, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 240, 250, 260, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 700 mg per day, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage may be 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, 45-50 mg, 50-55 mg, 55-60 mg, 60-65 mg, 65-70 mg, 70-75 mg, 75-80 mg, 80-85 mg, 85-90 mg, 90-95 mg, 95-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 200-225 mg, 225-250 mg, 230-260 mg, 240-270 mg, 250-275 mg, 275-300 mg,
  • the total daily dosage or the single dosage may be 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg, and any total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is between 230 mg and 260 mg, e.g.
  • the total daily dosage or the single dosage is 250 mg.
  • the total daily dosage or the single dosage may be 300 mg, 305 mg,
  • the total daily dosage or the single dosage is 500 mg.
  • the total daily dosage or the single dosage may be 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, or 750 mg, and any combination of the total daily dosage or single dosage therebetween.
  • the total daily dosage or the single dosage is 500 mg.
  • the total daily dosage or the single dosage is 750 mg. In some embodiments, the total daily dosage or the single dosage of disulfiram is 250 mg.
  • the amount of NDGA is about 0.03% to about 101% of the amount of disulfiram (by weight). The amount of NDGA may be about 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% of the weight of the disulfiram.
  • the amount of NDGA may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, ofthe weight ofthe disulfiram, and any percentage therebetween.
  • the percentage may be about 1% - 1.5%, 1.5%- 2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%-5.5%, 5.5%-6%, 6%-6.5%, 6.5%- 7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5 %- 10% of the weight of the disulfiram.
  • the amount of NDGA may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, 100%, or 101% of the weight ofthe disulfiram, and any percentage therebetween.
  • the percentage may be about 10%- 15%, 15%-20%, 20%-25%, 25%-30%, 30°/c 35%, 35°/c 40%, 40°/c 45%, 45%-50%, 50%-56%, 56%-58%, 58%-60%, 60%-62%, 62%-64%, 64%-66%, 66%-68%, 68%-70%, 70%-72%, 72%-74%, 74%-76%, 76%- 78%, 78%-80%, 80%-82%, 82%-84%, 84°/c 86%, 86°/c 88%, 88°/c 90%, 90%-92%, 92%-94%, 94%-96%, 96%-98%, or98%-101%oftheweightofthe disulfiram.
  • the amount of NDGA is about 0.03% to about 101% of the weight of the disulfiram.
  • the amount of NDGA may be about 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0. 11%, 0. 12%, 0. 13%, 0. 14%, 0. 15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% of the weight of the disulfiram.
  • the amount of NDGA may be about 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, 8.8%, 9%, 9.2%, 9.4%, 9.6%, 9.8%, 10%, of the weight of the disulfiram, and any percentage therebetween.
  • the percentage may be about 1%-1.5%, 1.5%-2%, 2%-2.5%, 2.5%-3%, 3%-3.5%, 3.5%-4%, 4%-4.5%, 4.5%-5%, 5%- 5.5%, 5.5%-6%, 6%-6.5%, 6.5%-7%, 7%-7.5%, 7.5%-8%, 8%-8.5%, 8.5%-9%, 9%-9.5%, or 9.5%- 10% of the weight of the disulfiram.
  • the amount of NDGA may be about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, 100%, or 101 % of the weight of the disulfiram, and any percentage therebetween.
  • the percentage may be about 10%- 15%, 15%-20%, 20%-25%, 25%-30%, 30%-35%, 35%-40%, 40%-45%, 45%-50%, 50%-56%, 56%-58%, 58%-60%, 60%-62%, 62%-64%, 64%-66%, 66%-68%, 68%-70%, 70%- 72%, 72%-74%, 74%-76%, 76%-78%, 78°/c 80%, 80°/c 82%, 82°/c 84%, 84%-86%, 86%-88%, 88%-90%, 90%-92%, 92%-94%, 94%-96%, 96%-98%, or 98%-101% of the weight of the disulfiram.
  • compositions of the present disclosure are formulated to be suitable for in vivo administration to a mammal.
  • Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.
  • Pharmaceutical excipients can be aqueous liquids, such as water or saline.
  • Pharmaceutical excipients can be lipid based, e.g., comprising a liquid or solid oil.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any composition described herein is administered parentally or in some oral formulations.
  • compositions described herein are suspended in a saline buffer (including, without limitation Ringer’s, TBS, PBS, HEPES, HBSS, and the like).
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions.
  • Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Any composition described herein, if desired, can also comprise pH buffering agents.
  • compositions of the present disclosure are formulated for oral administration, for injection, or for topical administration.
  • Administering the composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • compositions suitable for parenteral administration include, for example, solutions, suspensions, dispersions, emulsions, and the like, or in another acceptable format used in methods well known in the art.
  • Compositions suitable for enteral administration may be formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge, a pill, or a capsule, or in another acceptable format used in methods well known in the art.
  • the active ingredient (disulfiram) and the potentiating ingredient (TBHQ) are formulated into a single composition, e.g, for oral administration.
  • disulfiram and the potentiating ingredient (TBHQ) are combined into a single tablet or pill during manufacturing of the tablet or pill or by a compounding company/laboratory.
  • disulfiram and the TBHQ are combined into a single capsule by combining the contents of capsules containing disulfiram and capsules containing TBHQ.
  • powders or pellets of disulfiram and the TBHQ may be otherwise obtained and compounded into pills/tablets or combined into capsules.
  • a capsule comprises distinct granules or pellets of disulfiram and granules or pellets of TBHQ.
  • composition of the present disclosure may further comprise one or more additional ingredients (e.g., from Table 1).
  • additional ingredients e.g., from Table 1.
  • the one or more additional ingredients is formulated into the single tablet, pill, or capsule with disulfiram and TBHQ.
  • the active ingredient that is disulfiram and potentiating ingredient are formulated into distinct compositions, e.g. , for oral administration.
  • disulfiram is present in a single tablet, pill, or capsule and the TBHQ is present in another tablet, pill, or capsule.
  • a third composition, tablet, pill, or capsule may include one or more additional ingredients (e.g, from Table 1).
  • the composition may comprise delay-release components.
  • a pill, tablet, or capsule may comprise a coating that slows release of the agents and/or prevents release of the active ingredient (disulfiram) and the potentiating ingredient (TBHQ) until the pill, tablet, or capsule has arrived at a desired location of the mammal’s digestive system.
  • the active ingredient disulfiram
  • TBHQ potentiating ingredient
  • compositions suitable for topical administration can be formulated in a solution, gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, aerosol, patch, or the like in a pharmaceutically or cosmetically acceptable format used in methods well known in the art.
  • compositions may be suitable for administration via inhalation. Such formulation will likely be in liquid form and will be delivered in a spray bottle, in an inhaler, or in a nebulizer. Inhaled compositions are particularly suited for diseases and disorder, including infections, that affect the mammal’s respiratory system and/or are transmitted via the mammal’s respiratory system.
  • any herein- disclosed composition or compositions can depend on several factors including the characteristics of the mammal to be administered. Examples of characteristics include species, strain, breed, sex, age, weight, size, health, and/or disease status. Moreover, the dosage may depend on whether the administration is the first time the subject received a composition of the present disclosure or if the subject has previously received a composition of the present disclosure. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a composition) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific composition being administered, the time of administration, the route of administration, the nature of the formulation, and the rate of excretion. Some variations in the dosage can be expected.
  • the dosage may depend on the specific ingredients administered.
  • the active ingredient (disulfiram) and the potentiating ingredient (TBHQ) are encapsulated in a microcapsules.
  • Disulfiram may be encapsulated in one microcapsule and the one or more additional ingredients may be encapsulated into another microcapsule.
  • Disulfiram and the one or more additional ingredients may be encapsulated into one microcapsule.
  • Disulfiram may be encapsulated in one microcapsule and the one or more additional ingredients may not be encapsulated.
  • Disulfiram may not be encapsulated and the one or more additional ingredients are encapsulated in a microcapsule.
  • microcapsule may be a liposome, an albumin microsphere, a microemulsion, a nanoparticle (e.g, a lipid nanoparticle), and a nanocapsule.
  • microcapsules, e.g, lipid nanoparticles and liposome ⁇ include lipids selected from one or more of the following categories: cationic lipids; anionic lipids; neutral lipids; multi-valent charged lipids; and zwitterionic lipids.
  • a cationic lipid and/or cationic polymer may be used to facilitate a charge-charge interaction with the active ingredient (disulfiram) and the potentiating ingredient (TBHQ).
  • the microcapsule may comprise a PEGylated lipid.
  • PEGylated lipid examples of microcapsules and methods for manufacturing the same are described in the art. S ee, e. g. , Prui et al. , Crit Rev Ther Drug Carrier Syst., 2009; 26(6): 523-580; Wakasar, J Drug Target, 2018, 26(4):311 -318, Langer, 1990, Science 249: 1527-1533; Treated al. , in “Liposomes in the Therapy of Infectious Disease and Cancer”, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Pelaz et al. “Diverse applications of nanomedicine.” (2017): 2313-2381; the contents of each of which is incorporated herein by reference in its entirety.
  • one or more additional ingredients may be encapsulated and the disulfiram and/or TBHQ may be encapsulated, the one or more additional ingredients may be unencapsulated and disulfiram and/or TBHQ may be unencapsulated, and/or combinations thereof.
  • a composition may comprise one or more of capralactone, polylactide (PLA), polylactic- co-glycolic (PLGA), polyethylene glycol (PEG), polylactic-co-hydroxymeihylglycolic acid (PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose, gelatin-microcapsules, a poloxamer, or polymethylmethacrylate.
  • PLA polylactide
  • PLGA polylactic- co-glycolic
  • PEG polyethylene glycol
  • PLHMGA polylactic-co-hydroxymeihylglycolic acid
  • carboxymethylcellulose carboxymethylcellulose
  • hydroxylmethylcellulose gelatin-microcapsules
  • poloxamer a poloxamer
  • polymethylmethacrylate polymethylmethacrylate
  • Disulfiram and the one or more additional ingredients may be administered to a subject in need thereof once per day, twice per day, or thrice per day.
  • Disulfiram and the TBHQ may be administered to a subj ect in need thereof once a week, twice a week, three times a week, four times a week, five times a week, or six times a week.
  • Disulfiram and the TBHQ may be administered to a subject in need thereof once a month, twice a month, three times a month, or four times a month.
  • the administration route of the first composition and the second composition may be the same or may be different.
  • the first composition and the second composition are administrated orally.
  • the first composition and the second composition are administrated by inhalation.
  • the first composition is administrated orally and the second composition is by inj ection, inhalation, or topically.
  • the first composition is administrated by inhalation and the second composition is by injection, orally, or topically.
  • compositions comprising disulfiram as active agent and TBHQ as potentiating ingredient for use in any herein disclosed method.
  • first composition comprising disulfiram and a second composition comprising the one or more additional ingredients for use in any herein disclosed method.
  • compositions of the present disclosure are formulated to be suitable for contacting a cell or an immune cell in vitro or ex vivo.
  • disulfiram and the one or more additional ingredients are formulated into a solution.
  • the solute chosen depends on characteristics of the compound.
  • a water-soluble compound may be included in an aqueous solution, which comprises water or saline.
  • a waterinsoluble compound may be included in a non-aqueous solution, e.g., which comprises a lipid-based fluid or other hydrocarbon-based fluid.
  • Disulfiram and the one or more additional ingredients may be formulated into a single solution. Alternately, disulfiram and the one or more additional ingredients may be formulated into distinct solutions.
  • the one or more additional ingredients is a metal.
  • the metal may be selected from aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.
  • Disulfiram has beai shown to chelate certain metals and/or to be useful in the context of cancer treatments. See, e.g, Viola- Rhenals etal. “Recent Advances in Antabuse (Disulfiram): The Importance of its Metal-binding Ability to its Anticancer Activity”, Curr Med Chem. 2018 Feb 12; 25(4): 506-524; W02018081309A1; and W02019094053A1. The contents of each of which is incorporated herein by reference in its entirety.
  • the metal may be in the form of any metal salt or metal ester described in the present FDA’s list of food additives, e.g, as listed in Table 1.
  • themetai is aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.
  • aluminum is in the form of aluminum hydroxide, aluminum oxide, or aluminum potassium disulfate dodecahydrate.
  • calcium is in the form of anhydrous calcium sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium hydroxide, calcium lactate, calcium orthophosphate, or calcium phosphate.
  • copper is in the form of copper (II) gluconate, copper sulfate, or copper (I) iodide.
  • iron is in the form of ferric ammonium citrate, iron, iron (II) fumarate, or iron (II) sulfate heptahydrate.
  • magnesium is in the form of magnesium hydroxide, magnesium oxide, or magnesium silicate.
  • manganese is in the form of manganese dichloride or manganese sulfate.
  • potassium is in the form of dipotassium carbonate, potassium bromide, or potassium chloride.
  • sodium is in the form of disodium 5'-inosinate, disodium succinate, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate (dihydrate), sodium dodecyl sulfate, sodium formate, sodium gluconate, sodium thiosulfate (pentahydrate), or trisodium citrate.
  • zinc is in the form of zinc sulfate (heptahydrate).
  • the dosage of disulfiram may be about 0. 1 - 60 units and the amount of the one or more additional ingredients, which is a metal, may be about 1 unit, where disulfiram ranges from 50 - 500 mg.
  • the amount of a metal (is an above-described form) may between 0. 1 mg to 30 mg. In an embodiment, the amount of the metal is between 1.5 mg and 3 mg. In embodiments, the metal is copper or zinc and approximately 1.5 mg of the metal is administered.
  • the present disclosure provides a method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal; the present disclosure provides a method for treating, preventing, and/or limiting the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • the methods comprise administering to the mammal a therapeutically effective amount of disulfiram and one or more of the potentiating ingredients (e. g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the potentiating ingredients e. g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguai
  • Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening critical illnesses with substantial morbidity and mortality.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Age is a critical risk factor in progression of ARDS, where incidence increases to 306 cases per 100,000 person years in patients 75 to 84 years of age and mortality increases to 60% in patients 85 years of age and older.
  • ARDS The precipitating conditions associated with the development of ARDS can be classified as direct injury to the lung, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection, pneumonia, and pulmonary contusion and indirect injury to the lung, including sepsis, pancreatitis, and multiple blood transfusions.
  • SARS-CoV2 severe acute respiratory syndrome coronavirus 2
  • ARDS represents a stereotypic response to these various etiologies that is characterized by exaggerated pulmonary inflammation, infiltration of activated neutrophils, accumulation of alveolar interstitial fluid, and hypoxemia.
  • Abrogating the hyperinflammatory response early in ALI patients may be a potential clinical strategy to limit the progression of ARDS.
  • route of administration is oral, by injection, inhalation, or topical.
  • the injection is intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • one composition comprising disulfiram is administered and a second composition comprising the one or more potentiating ingredients (e.g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered.
  • a second composition comprising the one or more potentiating ingredients e.g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered.
  • the one or more potentiating ingredients e.g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1 is administered.
  • the mammal is near or has reached maturity.
  • the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status. In embodiments, the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status. In embodiment ⁇ increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
  • the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the mammal is ahuman.
  • TBHQ tert- Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • the aging- related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin- Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), Inflammatory Bowel Diseases (including Crohn’ s disease, Ulcerative Colitis, Irritable Bowel Syndrome), lentigines (aging spots), liver conditions (including nonalcoholic fatty liver disease, nonalcoholic steatohepati), liver conditions
  • the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and the administration route is oral or topical.
  • the mammal has at least one aging-related disorder or symptom of aging.
  • a non-human mammal may have an aging-related disorder or symptom of aging that is homologous to the aging-related disorder or symptom of aging listed above.
  • a composition comprising disulfiram and TBHQ, or distinct compositions of a first composition comprising disulfiram and a second composition comprising TBHQ (with or without one or more additional ingredients, e. g. , of Table 1) are administered to a mammal, e. g. , a human, for preventing or treating a respiratory disease or disorder, e.g. , acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI).
  • Administration of the composition(s) is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition(s) needing to be administered.
  • composition(s) are administered orally, by inhalation, or topically.
  • Combinations of administration routes may be used.
  • Treatment is identified as an improvement in the administered mammal in one or more of the following symptoms severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness. The improvement may be relative to the pre-administration state for the mammal.
  • the underlying cause for the ALI and/or ARDS may be sepsis (e.g , a serious and widespread infection of the bloodstream); inhalation of a harmful substance (e.g , smoke, chemical fumes, asbestos, dust, particulates, vomit, and water); viral or bacterial pneumonia (which may affect up to all five lobes of the lungs) and other respiratory disorders including those caused by a coronavirus (e.g., SARS, MERS, and COVID-19), influenzas (influenza A, influenza B, or parainfluenza), pneumococcal infection, adenovirus ⁇ respiratory syncytial virus (RSV), enter ovims and/or other respiratory viral infections; and ahead, chest or other major injury; or another cause (e.g.
  • a coronavirus e.g., SARS, MERS, and COVID-19
  • influenzas influenza A, influenza B, or parainfluenza
  • pneumococcal infection
  • ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease.
  • the composition or compositions prevent or treat idiopathic pulmonary fibrosis and/or chronic obstructive pulmonary disease.
  • a composition comprising disulfiram and TBHQ, or distinct compositions of a first composition comprising disulfiram and a second composition comprising TBHQ (with or without one or more additional ingredients, e. g. , of Table 1) are administered to a mammal, e. g. , a human, for treating dry eye.
  • the composition(s) may be administered topically (e.g. , via eye drops or an eye ointment), with a dose depending on the quantity of composition(s) needing to be administered.
  • compositions comprising disulfiram and TBHQ, or distinct compositions of a first composition comprising disulfiram and a second composition comprising TBHQ (with or without one or more additional ingredients, e.g. , of Table 1) are administered to a mammal, e. g.
  • composition(s) may be administered topically (e.g., alopecia, actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, psoriasis, shingles, whitening or graying of hair, prolonged/ineffi ci ent wound healing, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness).
  • the composition(s) may be administered topically (e.g.
  • composition may be administered orally, by injection, or by inhalation.
  • a composition comprising disulfiram and TBHQ, or distinct compositions of a first composition comprising disulfiram and a second composition comprising TBHQ are administered to a mammal, e.g. , a human, for treating a skin disorder, e.g. , wrinkles, which may be a result of photoaging or related to actinic keratosis.
  • a skin disorder e.g. , wrinkles, which may be a result of photoaging or related to actinic keratosis.
  • Other skin disorders include dermal atrophy (thinning of the skin), lentigines (aging spots), vaginal atrophy, prolonged/inefficient wound healing, and/or xerosis cutis (skin dryness).
  • composition(s) may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g. , a patch)).
  • the composition(s) may be administered orally or topically, with a dose depending on the quantity of composition(s) needing to be administered Alternately, the composition(s) may be administered by injection or by inhalation. Combinations of administration routes may be used.
  • a composition comprising disulfiram and TBHQ, or distinct compositions of a first composition comprising disulfiram and a second composition comprising TBHQ (with or without one or more additional ingredients, e.g. , of Table 1) are administered to a mammal, e.g. , a human, for treating a skin cancer, e.g. , (e.g. , basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)).
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g. , a patch)).
  • the composition may be administered orally, by injection, or by inhalation. Combinations of administration routes may be used.
  • a therapeutically effective amount of disulfiram as the active agent and the potentiating ingredients treats or prevents a disease or a symptom thereof; as examples, the disease may be asthma, deafness, or a viral infections and a symptom thereof may be sepsis.
  • the potentiating ingredients e.g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) treats or prevents a disease or a symptom thereof; as examples, the disease may be asthma, deafness, or a viral infections and a symptom thereof may be sepsis.
  • a therapeutically effective amount of the active agent disulfiram and the potentiating ingredient TBHQ boosts the immune system in the mammal.
  • cells from older donors treated with disulfiram exhibited phenotypes of younger cells in response to viral infection.
  • disulfiram reduced inflammasome- mediated pyroptotic cell death.
  • the combination of disulfiram and TBHQ showed a synergistic effect on reduction of inflammasome activation, as shown in the below working examples.
  • boosting the immune system increases an effective immune response against an infectious agent.
  • the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus ⁇ Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
  • the Coronavirus is Sars-CoV-2.
  • the route of administration is oral or by inhalation.
  • the mammal has a healthy immune system. In embodiments, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the present disclosure provides an in vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell comprising contacting the cell or the immune cell with a disulfiram and one or more of the potentiating ingredients (e.g., tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the potentiating ingredients e.g., tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • disulfiram and the one or more potentiating ingredients are administered to a subject, e.g, parenterally or enterally, and di sulfiram and the one more potentiating ingredients (e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) are administered to a subject, e.g, parenterally or enterally, and di sulfiram and the one more potentiating ingredients (e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) contacts the cell or immune cell within the subject, e.g, by being carried through the subject’s blood stream or the subject’s lymphatic system or within extracellular spaces.
  • TBHQ tert-Butylhydroquino
  • the present disclosure provides an in vitro or ex vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell, the method comprises contacting the cell or the immune cell with a disulfiram and one or more of the potentiating ingredients (e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the potentiating ingredients e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the cell or the immune cell is in a culturing vessel, e.g, a petri dish, tissue culture plate, or culture flask, and disulfiram and the one or more potentiating ingredients (e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) are added to a medium (e.g, growth medium or buffer solution) surrounding the cell or immune cell.
  • a culturing vessel e.g, a petri dish, tissue culture plate, or culture flask
  • the one or more potentiating ingredients e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) are added to a medium (e.g, growth medium or buffer solution) surrounding the cell or immune
  • the one or more additional ingredients is a metal (e.g, copper and zinc).
  • the potentiating ingredient is tert- Butylhydroquinone (TBHQ).
  • TBHQ tert- Butylhydroquinone
  • Another aspect of the present disclosure is a method for boosting the immune system in a mammal.
  • the method for boosting an immune system in a mammal comprises administering to the mammal a therapeutically effective amount of disulfiram and one or more of the potentiating ingredients (e.g. , tert- Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the potentiating ingredients e.g. , tert- Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • boosting the immune system increases an effective immune response against an infectious agent.
  • the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the bacterium is Bordatella pertussis or Streptococcus pneumoniae.
  • the virus is selected from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado tick fever virus (CTFV), Coronavirus, Crimean-Congo hemorrhagic fever virus.
  • Cytomegalovirus Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) , Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV), Flaviviruses, Guanarito virus, Heartland vims, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV), Human metapneumovirus (hMPV), Human papillomaviruses (HPV), Human parainfluenza viruses (HPIV), Influenza, Japanese encephalitis virus, JC virus, Junin virus, Lassa virus, Lymphoc
  • Respiratory syncytial virus RSV
  • Rhinovirus Rift Valley fever virus, Rotavirus
  • Rubella virus Sabia virus
  • SARS coronavirus SARS coronavirus
  • Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2
  • Shingles virus Sin Nombre virus, Smallpox
  • Varicella zoster virus VZV
  • Variola major or Variola minor Venezuelan equine encephalitis virus, West Nile virus, Yellow fever virus, and Zika virus.
  • the Coronavirus is Sars-CoV-2.
  • the infectious agent affects the mammal’s respiratory system or is transmitted via the mammal’s respiratory system and the route of administration is by inhalation.
  • the route of administration is oral or by inhalation.
  • the mammal has a healthy immune system. In other cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the term dysfunctional immune system may be an overactive immune system, e.g, resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, eg, in some severe coronavirus patients.
  • “boosting the immune system” relates to “boosting” a proper immune response. That is, minimizing an overactive immune response.
  • the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • compositions and methods for boosting the immune system can be used with aged and with non-aged mammals.
  • the route of administration is oral, by injection, inhalation, or topical.
  • the administration route may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • one composition comprising disulfiram is administered and a second composition comprising the one or more potentiating ingredients (e.g. , tert-Butylhydroquinone (TBHQ), ci nn am aldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered.
  • a second composition comprising the one or more potentiating ingredients e.g. , tert-Butylhydroquinone (TBHQ), ci nn am aldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered.
  • the one or more potentiating ingredients e.g. , tert-Butylhydroquinone (TBHQ), cinnamaldehy de, or nordihydroguaiaretic add (NDGA), or another additional ingredient (as disclosed in Table 1 is administered
  • the one or more additional ingredients may be a metal (e.g., copper and zinc).
  • the potentiating ingredient is tert-Butylhydroquinone (TBHQ).
  • the present disclosure also provides a method for improving effectiveness of a vaccine in a mammal in need thereof.
  • the method comprises administering a therapeutically effective amount of disulfiram and one or more of the potentiating ingredients (e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehy de, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • the mammal may contemporaneously and/or subsequently be administered a vaccine.
  • disulfiram and the one or more of the potentiating ingredients e.g , tert- Butylhydroquinone (TBHQ), cinnamaldehy de, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) and the vaccine are administered contemporaneously.
  • the vaccine is administered subsequent to administering disulfiram and the one or more of the potentiating ingredients (e. g. , tert-Butylhydroquinone (TBHQ), cinnamaldehy de, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • a therapeutically effective amount of disulfiram with the one or more of the potentiating ingredients boots the immune system in the mammal.
  • the potentiating ingredients e. g. , tert-Butylhydroquinone (TBHQ), cinnamaldehy de, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) boots the immune system in the mammal.
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • another additional ingredient as disclosed in Table 1
  • an aged mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Influenza is problematic in older adults with increased risk for serious complications and hospitalization In addition, approximately 90% of flu-related deaths occur in this population, with influenza and pneumonia being the eighth leading cause of death among persons over 65 years of age in the United States. Even when death is avoided, older adults have an increased risk for secondary complications and morbidities from flu infection. Depending on how successful the WHO predicts the influenza strains causing seasonal epidemics, the produced vaccines show efficacy rates between 60% and 90%. However, vaccine effectiveness in adults aged 65 and older is usually significantly lower, ranging from an average of 28% protection against fatal and nonfatal complications (with large dispersion), 39% protection against typical influenza-like illness, and 49% protection against disease with confirmed virus infection. Influenza vaccine effectiveness is a significant problem in elderly as compared to young individuals and is associated with high rates of complicated illness including pneumonia, heart attacks, and strokes in the >65 -year-old population.
  • the outbreak of the novel coronavirus has had devastating effects on the aged and those with pre-existing health conditions.
  • a mammal would particularly benefit from a composition of the present disclosure and methods of administering the same to improve effectiveness of a SARS-CoV-2 vaccine.
  • mammals who are not aged may benefit from improved effectiveness of a vaccine.
  • the compositions and methods for improving effectiveness of a vaccine can be used with non-aged mammals.
  • the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the mammal has a healthy immune system.
  • the term dysfunctional immune system may be an overactive immune system, e.g, resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, eg, in some severe coronavirus patients.
  • “improving a vaccine response” relates to “improving” a proper immune response to a vaccine and, later, when a subject is contacted with an infectious agent. That is, minimizing an overactive immune response and promoting a proper immune response.
  • the increased immune response promotes future immunity against the component contained in the vaccine.
  • the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a coronavirus vaccine, e.g., directed against Sars-CoV-2.
  • disulfiram and the one or more of the potentiating ingredients e.g , tert- Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered orally, by injection, by inhalation, or topically.
  • the vaccine is administered orally, by injection, by inhalation, or topically.
  • the injection is intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • one composition comprising disulfiram is administered and a second composition comprising the one or more potentiating ingredients (e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered.
  • a second composition comprising the one or more potentiating ingredients e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) is administered.
  • the one or more potentiating ingredients e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1 is administered.
  • the one or more additional ingredients may be a metal (e.g., copper and zinc).
  • the potentiating ingredient is tert-Butylhydroquinone (TBHQ).
  • An aspect of the present disclosure is a method for reducing a predicted biological age of a cell.
  • the method comprises contacting the cell with a therapeutically effective amount of disulfiram and one or more potentiating ingredients (e.g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1).
  • TBHQ tert-Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • cells from older donors treated with disulfiram exhibited phenotypes similar to younger donors. For instance, disulfiram significantly reduced several proinflammatory cytokines and significantly reduced the percentage of mitochondria with reticular shape. In addition, T cells from older donors treated with disulfiram exhibited a younger phenotype as compared to untreated controls.
  • the cell is in vitro, ex vivo, or in vivo.
  • the one or more additional ingredients may be a metal (e.g., copper and zinc).
  • Assays and formulations used in methods for reducing a predicted biological age of a cell may be related to those described in US20190228840, the entire contents of which is incorporated by reference its entirety.
  • the potentiating ingredient is tert-Butylhydroquinone (TBHQ). Aging-related disorders
  • compositions and methods treat, prevent, reduce the severity of, and/or delay the onset of various aging-related disorders, e.g, chronic diseases and disabilities/conditions of aging.
  • Illustrative aging-related disorders include one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin-Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative
  • disulfiram and the one or potentiating ingredients e.g. , tert- Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) mitigates dysfunction of or rejuvenates a signaling pathway disrupted by aging where the dysfunction can ultimately lead to aging-related disorders.
  • TBHQ tert- Butylhydroquinone
  • NDGA nordihydroguaiaretic acid
  • the potentiating ingredient is tert-Butylhydroquinone (TBHQ).
  • disulfiram and the one or more potentiating ingredients e. g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) inhibits pyroptosis in a cell.
  • potentiating ingredients e. g. , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) inhibits pyroptosis in a cell.
  • Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. Pyroptosis has a distinct morphology and mechanism compared to those of other forms of cell death. For example, unlike apoptosis-type programmed cell death, in a cell that undergoes pyroptosis, gasdermin D pores are formed on the plasma membrane, resulting in water influx and cell lysis, and in some cases, release of IL- IP, IL-18 and HMGBl l.
  • potentiating ingredients e.g , tert-Butylhydroquinone (TBHQ), cinnamaldehyde, or nordihydroguaiaretic acid (NDGA), or another additional ingredient (as disclosed in Table 1) as disclosed herein, enhance disulfiram’s ability to inhibit pyroptosis.
  • the potentiating ingredient is tert-Butylhydroquinone (TBHQ).
  • the subject is a mammal, e.g, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the mammal is a non-rodent.
  • the mammal is a dog.
  • the subject is a non- human animal, and therefore the invention pertains to veterinary use.
  • the non- human animal is a household pet, e.g, a dog.
  • the non-human animal is a livestock animal.
  • the mammal is a human.
  • the mammal has reached maturity.
  • the term mature or maturity, and the like refers to a mammal that is capable of sexual reproduction and/or a mammal that has achieved its adult height and/or length.
  • the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the mammal may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the human is an adult human.
  • the human has an age in a range of from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old, or older.
  • the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.
  • Embodiment AL A method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal comprising: administering to the mammal a composition comprising a therapeutically effective amount of disulfiram and one or more of additional ingredients listed in Table 1.
  • Embodiment A2 The method of Embodiment Al , wherein the combination of disulfiram and the one or more of additional ingredients listed in Table 1 provides a synergistic effect.
  • Embodiment A3 The method of Embodiment Al or Embodiment A2, wherein the administering is oral, by injection, inhalation, or topical.
  • Embodiment A4 The method of Embodiment A3, wherein the administering comprises one composition comprising disulfiram and a second composition comprising the one or more additional ingredients listed in Table 1 or wherein the administering comprises one composition comprising both disulfiram and the one or more additional ingredients listed in Table 1.
  • Embodiment A5 The method of any one of Embodiment Al to A4, wherein the mammal is near or has reached maturity.
  • Embodiment A6 The method of any one of Embodiment Al to A5, wherein the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Embodiment A7 The method of Embodiment A6, wherein the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Embodiment A8 The method of any one of Embodiment Al to A7, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • Embodiment A9 The method of Embodiment A8, wherein the mammal is a human.
  • Embodiment A10 The method of any one of Embodiment Al to A9, wherein increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.
  • Embodiment Al l The method of Embodiment Al 0, wherein increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
  • Embodiment A12 The method of any one of Embodiment Al to Al 1, wherein the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin-Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), lentigines (aging spots), liver conditions
  • Embodiment Al 3 The method of Embodiment Al 2, wherein the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • Embodiment A14 The method of Embodiment A12 or Embodiment A13, wherein the mammal has at least one aging-related disorder or symptom of aging.
  • Embodiment A15 The method of any one of Embodiment Al to A14, wherein the therapeutically effective amount of disulfiram and the one or more additional ingredients boosts the immune system in the mammal.
  • Embodiment Al 6. The method of Embodiment Al 5, wherein boosting the immune system increases an effective immune response against an infectious agent.
  • Embodiment Al 7 The method of Embodiment Al 6, wherein the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • Embodiment Al 8 The method of Embodiment Al 7, wherein the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
  • the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus,
  • Embodiment A19 The method of Embodiment Al 8, wherein the Coronavirus is Sars-CoV-2.
  • Embodiment A20 The method of any one of Embodiment Al to Al 9, wherein the administering is oral or by inhalation.
  • Embodiment A21 The method of any one of Embodiment Al 6 to A20, wherein the infectious agent affects the mammal’s respiratory system or is transmitted via the mammal’s respiratory system and wherein the administering is by inhalation.
  • Embodiment A22 The method of any one of Embodiment Al to A21, wherein the mammal has a healthy immune system.
  • Embodiment A23 The method of any one of Embodiment Al to A23, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Embodiment A24 A method for improving effectiveness of a vaccine in a mammal in need thereof, the method comprises administering a therapeutically effective amount of disulfiram and one or more of the additional ingredients listed in Table 1, wherein the mammal contemporaneously and/or subsequently will be administered a vaccine.
  • Embodiment A25 The method of Embodiment A24, wherein disulfiram and one or more of the additional ingredients listed in Table 1 and the vaccine are administered contemporaneously.
  • Embodiment A26 The method of Embodiment A24 or Embodiment A25, wherein the vaccine is administered subsequent to administering disulfiram and the one or more of the additional ingredients listed in Table 1.
  • Embodiment A27 The method of any one of Embodiment A24 to A26, wherein the therapeutically effective amount of disulfiram and the one or more additional ingredients boosts the immune system in the mammal.
  • Embodiment A28 The method of Embodiment A27, wherein boosting the immune system increases an immune response against a component contained in the vaccine.
  • Embodiment A29 The method of Embodiment A28, wherein the increased immune response promotes future immunity against the component contained in the vaccine.
  • Embodiment A30 The method of Embodiment A29, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • Embodiment A31 The method of any one of Embodiment A24 to A30, wherein the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haem
  • Embodiment A32 The method of Embodiment A31 , wherein the vaccine is a coronavirus vaccine.
  • Embodiment A33 The method of Embodiment A32, wherein the coronavirus vaccine is directed against Sars-CoV-2.
  • Embodiment A34 The method of any one of Embodiment A24 to A33, wherein the mammal has ahealihy immune system.
  • Embodiment A34 The method of any one of Embodiment A24 to A34, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Embodiment A36 The method of any one of Embodiment A24 to A35, wherein the administering of disulfiram and the one or more additional ingredients is oral, by injection, inhalation, or topical.
  • Embodiment A37 The method of any one of Embodiment A24 to A36, wherein administering comprises one composition comprising disulfiram and a second composition comprising the one or more additional ingredients or wherein the administering comprises one composition comprising both disulfiram and the one or more additional ingredients
  • Embodiment A38 The method of any one of Embodiment A24 to A37, wherein the administering of the vaccine is oral, by injection, inhalation, or topical.
  • Embodiment A39 The method of any one of Embodiment Al to A38, wherein at least one of the one or more additional ingredients is a metal.
  • Embodiment A40 The method of Embodiment A39, wherein the metal aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.
  • Embodiment A41 The method of Embodiment A40, wherein the metal is aluminum hydroxide, aluminum oxide, aluminum potassium disulfate dodecahydrate, anhydrous calcium sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium hydroxide, calcium lactate, calcium orthophosphate, calcium phosphate, copper (II) gluconate, copper sulfate, copper (I) iodide, ferric ammonium citrate, iron, iron (II) fumarate, iron (II) sulfate heptahydrate, magnesium hydroxide, magnesium oxide, magnesium silicate, manganese di chloride, manganese sulfate, dipotassium carbonate, potassium bromide, potassium chloride, disodium 5'-inosinate, disodium succinate, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate (dihydrate), sodium dodecy
  • Embodiment A42 The method of Embodiment A41 wherein the metal is copper (II) gluconate, copper sulfate, copper (I) iodide, or zinc sulfate (heptahydrate).
  • Embodiment A43 The method of any one of Embodiment A39 to A42, wherein the amount of the metal is between about 0. 1 mg to about 30 mg.
  • Embodiment A44 The method of Embodiment A43, wherein the amount of the metal is between about 1.5 mg and 3 mg.
  • Embodiment A45 The method of Embodiment A44, wherein the metal is copper or zinc and approximately 1.5 mg of the metal is administered per dose.
  • Embodiment A46 A method for limiting the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI), the method comprising administrating a composition comprising an active ingredient that is disulfiram and one or more of additional ingredients listed in Table 1.
  • Embodiment A47 The method of Embodiment A46, wherein the combination of disulfiram and the one or more of additional ingredients listed in Table 1 provides a synergistic effect.
  • Embodiment A48 The method of Embodiment A46 or Embodiment A47, wherein the administering is oral, by injection, inhalation, or topical.
  • Embodiment A49 The method of Embodiment A48, wherein the administering comprises one composition comprising disulfiram and a second composition comprising the one or more additional ingredients listed in Table 1 or wherein the administering comprises one composition comprising both disulfiram and the one or more additional ingredients listed in Table 1.
  • Embodiment A50 The method of any one of Embodiment A46 to A49, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • Embodiment A51 The method of Embodiment A50, wherein the mammal is a human.
  • Embodiment A52 A method for inhibiting and/or reducing pyroptotic cell death in a cell, the method comprising contacting the cell with an active agent that is disulfiram and one or more of additional ingredients listed in Table 1 Embodiment A53.
  • a method for inhibiting and/or reducing pyroptotic cell death in a cell comprising contacting the cell with an active agent that is disulfiram and one or more of additional ingredients listed in Table 1, wherein the combination of disulfiram and the one or more of additional ingredients listed in Table 1 treats acute lung injury (ALI), acute respiratory distress syndrome (ARDS), actinic keratosis, alopecia, chronic obstructive pulmonary disease, Cryopyrin-Associated Periodic Syndrome (CAPS), dry eye, gout or gouty arthritis, idiopathic pulmonary fibrosis, Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), liver conditions (including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis), macular degeneration, multiple sclerosis, psoriasis, skin cancer, and/or uveitis.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Embodiment A54 A method for boosting activity of an immune cell, the method comprising contacting the immune cell with an active agent that is disulfiram and one or more of additional ingredients listed in Table 1.
  • Embodiment A55 A method for reducing a predicted biological age of a cell comprising contacting the cell with a therapeutically effective amount of disulfiram and one or more additional ingredients listed in Table 1.
  • Embodiment A56 An in vivo, in vitro, or ex vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell comprising contacting the cell or the immune cell with disulfiram and one or more of the additional ingredients listed in Table 1.
  • Embodiment A57 The method of any one of Embodiment A52 to A56, wherein the cell is ahuman cell.
  • Embodiment A58 The method of any one of Embodiment A52 to A56, wherein the cell is in vivo, in vitro, or ex vivo.
  • Embodiment A59 The method of any one of Embodiment Al to A58, wherein the disulfiram is a variant of disulfiram and having the structure of Formula (II).
  • Embodiment A60 A composition comprising disulfiram and one or more of the additional ingredients listed in Table 1.
  • Embodiment A61 A composition comprising disulfiram and one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Al to A59.
  • Embodiment A62 A plurality of compositions comprising a first composition comprising disulfiram and a second composition comprising one or more of the additional ingredients listed in Table 1.
  • Embodiment A63 A plurality of compositions comprising a first composition comprising disulfiram and a second composition comprising one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Al to A59.
  • Embodiment A64 The composition of Embodiment A60 or the plurality of compositions of Embodimait A62, wherein the disulfiram is a variant of disulfiram and has the structure of Formula (II).
  • Embodiment B A method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal comprising: administering to the mammal a composition comprising a therapeutically effective amount of a gasdermin D inhibitor and one or more of additional ingredients listed in Table 1.
  • Embodiment B2 The method of Embodiment Bl, wherein the combination of the gasdermin D inhibitor and the one or more of additional ingredients listed in Table 1 provides a synergistic effect.
  • Embodiment B3 The method of Embodiment Bl or Embodiment B2, wherein the administering is oral, by injection, inhalation, or topical.
  • Embodiment B4 The method of Embodiment B3, wherein the administering comprises one composition comprising the gasdermin D inhibitor and a second composition comprising the one or more additional ingredients listed in Table 1 or wherein the administering comprises one composition comprising both the gasdermin D inhibitor and the one or more additional ingredients listed in Table 1.
  • Embodiment B5 The method of any one of Embodiment Bl to Embodiment B4, wherein the mammal is near or has reached maturity.
  • Embodiment B6 The method of any one of Embodiment Bl to Embodiment B5, wherein the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Embodiment B7 The method of Embodiment B6, wherein the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Embodiment B8 The method of any one of Embodiment Bl to Embodiment B7, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • Embodiment B9 The method of Embodiment B8, wherein the mammal is a human.
  • Embodiment B10 The method of any one of Embodiment Bl to Embodiment B9, wherein increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.
  • Embodiment Bl 1. The method of Embodiment B10, wherein increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
  • Embodiment Bl 2 The method of any one of Embodiment Bl to Embodiment Bl 1, wherein the aging - related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin-Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), len
  • Embodiment B13 The method of Embodiment B12, wherein the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • Embodiment B14 The method of Embodiment B12 or Embodiment Bl 3, wherein the mammal has at least one aging-related disorder or symptom of aging.
  • Embodiment Bl 5 The method of any one of Embodiment Bl to Embodiment Bl 4, wherein the therapeutically effective amount of the gasdermin D inhibitor and the one or more additional ingredients boosts the immune system in the mammal.
  • Embodiment Bl 6 The method of Embodiment Bl 5, wherein boosting the immune system increases an effective immune response against an infectious agent.
  • Embodiment B17 The method of Embodiment Bl 6, wherein the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • Embodiment B18 The method of Embodiment B17, wherein the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
  • the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus
  • Embodiment B19 The method of Embodiment B18, wherein the Coronavirus is Sars-CoV-2.
  • Embodiment B20 The method of any one of Embodiment Bl to Embodiment Bl 9, wherein the administering is oral or by inhalation.
  • Embodiment B21 The method of any one ofEmbodiment B16 to Embodiment B20, wherein the infectious agent affects the mammal’s respiratory system or is transmitted via the mammal’s respiratory system and wherein the administering is by inhalation.
  • Embodiment B22 The method of any one of Embodiment Bl to Embodiment B21, wherein the mammal has a healthy immune system.
  • Embodiment B23 The method of any one of Embodiment Bl to Embodiment B23, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Embodiment B24 A method for improving effectiveness of a vaccine in a mammal in need thereof, the method comprises administering a therapeutically effective amount of a gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1, wherein the mammal contemporaneously and/or subsequently will be administered a vaccine.
  • Embodiment B25 The method of Embodiment B24, wherein the gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1 and the vaccine are administered contemporaneously.
  • Embodiment B26 The method of Embodiment B24 or Embodiment B25, wherein the vaccine is administered subsequent to administering the gasdermin D inhibitor and the one or more of the additional ingredients listed in Table 1.
  • Embodiment B27 The method of any one of Embodiment B24 to Embodiment B26, wherein the therapeutically effective amount of the gasdermin D inhibitor and the one or more additional ingredients boosts the immune system in the mammal.
  • Embodiment B28 The method of Embodiment B27, wherein boosting the immune system increases an immune response against a component contained in the vaccine.
  • Embodiment B29 The method of Embodiment B28, wherein the increased immune response promotes future immunity against the component contained in the vaccine.
  • Embodiment B30 The method of Embodiment B29, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • Embodiment B31 The method of any one of Embodiment B24 to Embodiment B30, wherein the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (partofthe DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine
  • Embodiment B32 The method of Embodiment B31 , wherein the vaccine is a coronavirus vaccine.
  • Embodiment B33 The method of Embodiment B32, wherein the coronavirus vaccine is directed against Sars-CoV-2.
  • Embodiment B34 The method of any one of Embodiment B24 to Embodiment B33, wherein the mammal has a healthy immune system.
  • Embodiment B34 The method of any one of Embodiment B24 to Embodiment B34, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Embodiment B36 The method of any one of Embodiment B24 to Embodiment B35, wherein the administering of the gasdermin D inhibitor and the one or more additional ingredients is oral, by injection, inhalation, or topical.
  • Embodiment B37 The method of any one of Embodiment B24 to Embodiment B36, wherein administering comprises one composition comprising the gasdermin D inhibitor and a second composition comprising the one or more additional ingredients or wherein the administering comprises one composition comprising both the gasdermin D inhibitor and the one or more additional ingredients
  • Embodiment B39 The method of any one of Embodiment Bl to Embodiment B38, wherein at least one of the one or more additional ingredients is a metal.
  • Embodiment B40 The method of Embodiment B39, wherein the metal aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.
  • Embodiment B41 The method of Embodiment B40, wherein the metal is aluminum hydroxide, aluminum oxide, aluminum potassium disulfate dodecahydrate, anhydrous calcium sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium hydroxide, calcium lactate, calcium orthophosphate, calcium phosphate, copper (II) gluconate, copper sulfate, copper (I) iodide, ferric ammonium citrate, iron, iron (II) fumarate, iron (II) sulfate heptahydrate, magnesium hydroxide, magnesium oxide, magnesium silicate, manganese di chloride, manganese sulfate, dipotassium carbonate, potassium bromide, potassium chloride, disodium 5'-inosinate, disodium succinate, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate (dihydrate), sodium dodecy
  • Embodiment B42 The method of Embodiment B41 wherein the metal is copper (II) gluconate, copper sulfate, copper (I) iodide, or zinc sulfate (heptahydrate).
  • Embodiment B43 The method of any one of Embodiment B39 to Embodiment B42, wherein the amount of the metal is between about 0. 1 mg to about 30 mg.
  • Embodiment B44 The method of Embodiment B43, wherein the amount of the metal is between about 1.5 mg and 3 mg.
  • Embodiment B45 The method of Embodiment B44, wherein the metal is copper or zinc and approximately 1.5 mg of the metal is administered per dose.
  • Embodiment B46 A method for limiting the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI), the method comprising administrating a composition comprising an active ingredient that is a gasdermin D inhibitor and one or more of additional ingredients listed in Table 1.
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • Embodiment B47 The method of Embodiment B46, wherein the combination of the gasdermin D inhibitor and the one or more of additional ingredients listed in Table 1 provides a synergistic effect.
  • Embodiment B48 The method of Embodiment B46 or Embodiment B47, wherein the administering is oral, by injection, inhalation, or topical.
  • Embodiment B49 The method of Embodiment B48, wherein the administering comprises one composition comprising the gasdermin D inhibitor and a second composition comprising the one or more additional ingredients listed in Table 1 or wherein the administering comprises one composition comprising both the gasdermin D inhibitor and the one or more additional ingredients listed in Table 1.
  • Embodiment B50 The method of any one of Embodiment B46 to Embodiment B49, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non -human primate, such as a monkey, chimpanzee, or baboon.
  • Embodiment B51 The method of Embodiment B50, wherein the mammal is a human.
  • Embodiment B52 A method for inhibiting and/or reducing pyroptotic cell death in a cell, the method comprising contacting the cell with an active agent that is a gasdermin D inhibitor and one or more of additional ingredients listed in Table 1
  • a method for inhibiting and/or reducing pyroptotic cell death inacell comprising contacting the cell with an active agent that is a gasdermin D inhibitor and one or more of additional ingredients listed in Table 1, wherein the combination of the gasdermin D inhibitor and the one or more of additional ingredients listed in Table 1 treats acute lung injury (ALI), acute respiratory distress syndrome (ARDS), actinic keratosis, alopecia, chronic obstructive pulmonary disease, Cryopyrin-Associated Periodic Syndrome (CAPS), dry eye, gout or gouty arthritis, idiopathic pulmonary fibrosis, Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), liver conditions (including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis), macular degeneration, multiple sclerosis, psoriasis, skin cancer, and/or uveitis.
  • an active agent that is a gasdermin D inhibitor
  • Embodiment B54 A method for boosting activity of an immune cell, the method comprising contacting the immune cell with an active agent that is a gasdermin D inhibitor and one or more of additional ingredients listed in Table 1.
  • Embodiment B55 A method for reducing a predicted biological age of a cell comprising contacting the cell with a therapeutically effective amount of a gasdermin D inhibitor and one or more additional ingredients listed in Table 1.
  • Embodiment B56 An in vivo, in vitro, or ex vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell comprising contacting the cell or the immune cell with a gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1.
  • Embodiment B57 The method of any one of Embodiment B52 to Embodiment B56, wherein the cell is a human cell.
  • Embodiment B58 The method of any one of Embodiment B52 to Embodiment B56, wherein the cell is in vivo, in vitro, or ex vivo.
  • Embodiment B59 The method of any one of Embodiment Bl to Embodiment B58, wherein the gasdermin D inhibitor is disulfiram, aloe emodin, 2-iodomelatonin, LDC7559, necrosulfonamide, tasimelteon, ramelteon, melatonin, emodin, or BAY 11-7082.
  • the gasdermin D inhibitor is disulfiram, aloe emodin, 2-iodomelatonin, LDC7559, necrosulfonamide, tasimelteon, ramelteon, melatonin, emodin, or BAY 11-7082.
  • Embodiment B60 A composition comprising a gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1.
  • Embodiment B61 A composition comprising a gasdermin D inhibitor and one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Bl to Embodiment B59.
  • Embodiment B62 A plurality of compositions comprising a first composition comprising a gasdermin D inhibitor and a second composition comprising one or more of the additional ingredients listed in Table 1.
  • Embodiment B63 A plurality of compositions comprising a first composition comprising a gasdermin D inhibitor and a second composition comprising one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Bl to Embodiment B59.
  • Embodiment B64 The composition of Embodiment B60 or the plurality of compositions of Embodiment B62, wherein the gasdermin D inhibitor is disulfiram, aloe emodin, 2 -iodomelatonin, LDC7559, necrosulfonamide, tasimelteon, ramelteon, melatonin, emodin, or BAY 11-7082.
  • the gasdermin D inhibitor is disulfiram, aloe emodin, 2 -iodomelatonin, LDC7559, necrosulfonamide, tasimelteon, ramelteon, melatonin, emodin, or BAY 11-7082.
  • Embodiment C A method for increasing lifespan in a mammal, for preventing or treating disease including an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal comprising: administering to the mammal a composition comprising a therapeutically effective amount of an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1.
  • ALDH aldehyde dehydrogenase
  • Embodiment C2 The method of Embodiment Cl, wherein the combination of the ALDH modulator and the one or more of additional ingredients listed in Table 1 provides a synergistic effect.
  • Embodiment C3 The method of Embodiment Cl or Embodiment C2, wherein the administering is oral, by injection, inhalation, or topical.
  • Embodiment C4 The method of Embodiment C3, wherein the administering comprises one composition comprising the ALDH modulator and a second composition comprising the one or more additional ingredients listed in Table 1 or wherein the administering comprises one composition comprising both the ALDH modulator and the one or more additional ingredients listed in Table 1.
  • Embodiment C5. The method of any one of Embodiment Cl to Embodiment C4, wherein the mammal is near or has reached maturity.
  • Embodiment C6 The method of any one of Embodiment Cl to Embodiment C5, wherein the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Embodiment C7 The method of Embodiment C6, wherein the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Embodiment C8 The method of any one of Embodiment Cl to Embodiment C7, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non -human primate, such as a monkey, chimpanzee, or baboon.
  • the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non -human primate, such as a monkey, chimpanzee, or baboon.
  • Embodiment C9 The method of Embodiment C8, wherein the mammal is a human.
  • Embodiment CIO The method of any one of Embodiment Cl to Embodiment C9, wherein increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.
  • Embodiment Cl 1. The method of Embodiment CIO, wherein increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
  • Embodiment Cl 2 The method of any one of Embodiment Cl to Embodiment Cl 1, wherein the aging - related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin-Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), lentigines (
  • Embodiment C13 The method of Embodiment C12, wherein the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • Embodiment C14 The method of Embodiment C12 or Embodiment C13, wherein the mammal has at least one aging-related disorder or symptom of aging.
  • Embodiment Cl 5 The method of any one of Embodiment Cl to Embodiment Cl 4, wherein the therapeutically effective amount of the ALDH modulator and the one or more additional ingredients boosts the immune system in the mammal.
  • Embodiment Cl 6 The method of Embodiment Cl 5, wherein boosting the immune system increases an effective immune response against an infectious agent.
  • Embodiment C17 The method of Embodiment C16, wherein the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • Embodiment C18 The method of Embodiment C17, wherein the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
  • the bacterium is Bordatella pertussis or Streptococcus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus
  • Embodiment C19 The method of Embodiment C18, wherein the Coronavirus is Sars-CoV-2.
  • Embodiment C20 The method of any one of Embodiment Cl to Embodiment Cl 9, wherein the administering is oral or by inhalation.
  • Embodiment C21 The method of any one ofEmbodiment C16 to Embodiment C20, wherein the infectious agent affects the mammal’s respiratory system or is transmitted via the mammal’s respiratory system and wherein the administering is by inhalation.
  • Embodiment C22 The method of any one ofEmbodiment Cl to Embodiment C21, wherein the mammal has a healthy immune system.
  • Embodiment C23 The method of any one ofEmbodiment Cl to Embodiment C23, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Embodiment C24 A method for improving effectiveness of a vaccine in a mammal in need thereof, the method comprises administering a therapeutically effective amount of an aldehyde dehydrogenase (ALDH) modulator and one or more of the additional ingredients listed in Table 1, wherein the mammal contemporaneously and/or subsequently will be administered a vaccine.
  • ALDH aldehyde dehydrogenase
  • Embodiment C25 The method of Embodiment C24, wherein the ALDH modulator and one or more of the additional ingredients listed in Table 1 and the vaccine are administered contemporaneously.
  • Embodiment C26 The method of Embodiment C24 or Embodiment C25, wherein the vaccine is administered subsequent to administering the ALDH modulator and the one or more of the additional ingredients listed in Table 1.
  • Embodiment C27 The method of any one of Embodiment C24 to Embodiment C26, wherein the therapeutically effective amount of the ALDH modulator and the one or more additional ingredients boosts the immune system in the mammal.
  • Embodiment C28 The method of Embodiment C27, wherein boosting the immune system increases an immune response against a component contained in the vaccine.
  • Embodiment C29 The method of Embodiment C28, wherein the increased immune response promotes future immunity against the component contained in the vaccine.
  • Embodiment C30 The method of Embodiment C29, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • Embodiment C31 The method of any one ofEmbodiment C24 to Embodiment C30, wherein the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (partofthe DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B
  • Embodiment C32 The method of Embodiment C31, wherein the vaccine is a coronavirus vaccine.
  • Embodiment C33 The method of Embodiment C32, wherein the coronavirus vaccine is directed against Sars-CoV-2.
  • Embodiment C34 The method of any one of Embodiment C24 to Embodiment C33, wherein the mammal has a healthy immune system.
  • Embodiment C34 The method of any one of Embodiment C24 to Embodiment C34, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Embodiment C36 The method of any one of Embodiment C24 to Embodiment C35, wherein the administering of the ALDH modulator and the one or more additional ingredients is oral, by injection, inhalation, or topical.
  • Embodiment C37 The method of any one of Embodiment C24 to Embodiment C36, wherein administering comprises one composition comprising the ALDH modulator and a second composition comprising the one or more additional ingredients or wherein the administering comprises one composition comprising both the ALDH modulator and the one or more additional ingredients
  • Embodiment C39 The method of any one of Embodiment Cl to Embodiment C38, wherein at least one of the one or more additional ingredients is a metal.
  • Embodiment C40 The method of Embodiment C39, wherein the metal aluminum, calcium, copper, iron, magnesium, manganese, potassium, sodium, or zinc.
  • Embodiment C41 The method of Embodiment C40, wherein the metal is aluminum hydroxide, aluminum oxide, aluminum potassium disulfate dodecahydrate, anhydrous calcium sulfate, calcium carbonate, calcium citrate tetrahydrate, calcium gluconate, calcium glycerol phosphate, calcium hydrogen phosphate dihydrate, calcium hydroxide, calcium lactate, calcium orthophosphate, calcium phosphate, copper (II) gluconate, copper sulfate, copper (I) iodide, ferric ammonium citrate, iron, iron (II) fumarate, iron (II) sulfate heptahydrate, magnesium hydroxide, magnesium oxide, magnesium silicate, manganese di chloride, manganese sulfate, dipotassium carbonate, potassium bromide, potassium chloride, disodium 5'-inosinate, disodium succinate, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate (dihydrate), sodium dodecy
  • Embodiment C42 The method of Embodiment C41 wherein the metal is copper (II) gluconate, copper sulfate, copper (I) iodide, or zinc sulfate (heptahydrate).
  • Embodiment C43 The method of any one of Embodiment C39 to Embodiment C42, wherein the amount of the metal is between about 0. 1 mg to about 30 mg.
  • Embodiment C44 The method of Embodiment C43, wherein the amount of the metal is between about 1.5 mg and 3 mg.
  • Embodiment C45 The method of Embodiment C44, wherein the metal is copper or zinc and approximately 1.5 mg of the metal is administered per dose.
  • Embodiment C46 A method for limiting the progression of acute respiratory distress syndrome (ARDS) in patients with or without acute lung injury (ALI), the method comprising administrating a composition comprising an active ingredient that is an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1.
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • Embodiment C47 The method of Embodiment C46, wherein the combination of the ALDH modulator and the one or more of additional ingredients listed in Table 1 provides a synergistic effect.
  • Embodiment C48 The method of Embodiment C46 or Embodiment C47, wherein the administering is oral, by injection, inhalation, or topical.
  • Embodiment C49 The method of Embodiment C48, wherein the administering comprises one composition comprising the ALDH modulator and a second composition comprising the one or more additional ingredients listed in Table 1 or wherein the administering comprises one composition comprising both the ALDH modulator and the one or more additional ingredients listed in Table 1.
  • Embodiment C50 The method of any one of Embodiment C46 to Embodiment C49, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non -human primate, such as a monkey, chimpanzee, or baboon.
  • Embodiment C51 The method of Embodiment C50, wherein the mammal is a human.
  • Embodiment C52 A method for inhibiting and/or reducing pyroptotic cell death in a cell, the method comprising contacting the cell with an active agent that is an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1
  • an active agent that is an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1
  • Embodiment C53 A method for inhibiting and/or reducing pyroptotic cell death in a cell, the method comprising contacting the cell with an active agent that is an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1, wherein the combination of the ALDH modulator and the one or more of additional ingredients listed in Table 1 treats acute lung injury (ALI), acute respiratory distress syndrome (ARDS), actinic keratosis, alopecia, chronic obstructive pulmonary disease, Cryopyrin-Associated Periodic Syndrome (CAPS), dry eye, gout or gouty arthritis, idiopathic pulmonary fibrosis, Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), liver conditions (including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis), macular degeneration, multiple sclerosis, psoriasis, skin cancer, and/or
  • Embodiment C54 A method for boosting activity of an immune cell, the method comprising contacting the immune cell with an active agent that is an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1.
  • an active agent that is an aldehyde dehydrogenase (ALDH) modulator and one or more of additional ingredients listed in Table 1.
  • ALDH aldehyde dehydrogenase
  • Embodiment C55 A method for reducing a predicted biological age of a cell comprising contacting the cell with a therapeutically effective amount of an aldehyde dehydrogenase (ALDH) modulator and one or more additional ingredients listed in Table 1.
  • ALDH aldehyde dehydrogenase
  • Embodiment C56 An in vivo, in vitro, or ex vivo method for increasing lifespan of a cell and/or boosting activity of an immune cell comprising contacting the cell or the immune cell with an aldehyde dehydrogenase (ALDH) modulator and one or more of the additional ingredients listed in Table 1.
  • Embodiment C57 The method of any one of Embodiment C52 to Embodiment C56, wherein the cell is a human cell.
  • Embodiment C58 The method of any one of Embodiment C52 to Embodiment C56, wherein the cell is in vivo, in vitro, or ex vivo.
  • Embodiment C59 The method of any one of Embodiment Cl to Embodiment C58, wherein the ALDH modulator is disulfiram, NCT-501, 4-Di ethylaminobenzaldehyde, Daidzin, CM10, EN40, 4- Hydroxynonenal, RV01, CVT-10216, 3-Hydroxybenzaldehyde, or ANS-66372.
  • the ALDH modulator is disulfiram, NCT-501, 4-Di ethylaminobenzaldehyde, Daidzin, CM10, EN40, 4- Hydroxynonenal, RV01, CVT-10216, 3-Hydroxybenzaldehyde, or ANS-66372.
  • Embodiment C60 A composition comprising an aldehyde dehydrogenase (ALDH) modulator and one or more of the additional ingredients listed in Table 1.
  • ALDH aldehyde dehydrogenase
  • Embodiment C61 A composition comprising an aldehyde dehydrogenase (ALDH) modulator and one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Cl to Embodiment C59.
  • a composition comprising an aldehyde dehydrogenase (ALDH) modulator and one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Cl to Embodiment C59.
  • a composition comprising an aldehyde dehydrogenase (ALDH) modulator and one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Cl to Embodiment C59.
  • ALDH aldehyde dehydrogenase
  • Embodiment C62 A plurality of compositions comprising a first composition comprising an aldehyde dehydrogenase (ALDH) modulator and a second composition comprising one or more of the additional ingredients listed in Table 1.
  • ADH aldehyde dehydrogenase
  • Embodiment C63 A plurality of compositions comprising a first composition comprising an aldehyde dehydrogenase (ALDH) modulator and a second composition comprising one or more of the additional ingredients listed in Table 1 for use in the method of any one of Embodiment Cl to Embodiment C59.
  • ADH aldehyde dehydrogenase
  • Embodiment C64 The composition of Embodiment C60 or the plurality of compositions of Embodiment C62, wherein the ALDH modulator is disulfiram, NCT-501 , 4-Diethylaminobenzaldehy de, Daidzin, CM10, EN40, 4-Hydroxynonenal, RV01, CVT-10216, 3-Hydroxybenzaldehyde, or ANS-66372.
  • disulfiram includes the compound disulfiram itself as well as its metabolites and/or derivatives.
  • disulfiram includes the compound having the structure of Formula (I).
  • disulfiram includes a variant of disulfiram which includes compounds having the structure of Formula (II). The disulfiram itself as well as its metabolites and/or derivatives.
  • additional ingredient(s) includes the additional ingredient(s) as well as its/their metabolites and/or derivatives.
  • preventing is meant, at least, avoiding the occurrence of a disease and/or reducing the likelihood of acquiring the disease.
  • treating is meant, at least, ameliorating or avoiding the effects of a disease, including reducing a sign or symptom of the disease.
  • one or more is meant at least one, e.g. , one, two, three, four, five, six, seven, eight, nine, ten or more.
  • the “boosting the immune system” in various embodiments, relates to “boosting” a proper (e.g, non- pathological) immune response. In some cases, this will minimize an overactive immune response.
  • the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g, in some severe coronavirus patients.
  • this will improve, activate, and/or enhance a proper immune response, e.g., when exposed to a vaccine comprising an antigen obtained from, related to, homologous to, or expressed by an infectious agent, when exposed to an infectious agent, and/or when exposed to an atypical cell in need of being attacked by an immune cell.
  • a vaccine comprising an antigen obtained from, related to, homologous to, or expressed by an infectious agent, when exposed to an infectious agent, and/or when exposed to an atypical cell in need of being attacked by an immune cell.
  • Example 1 Identification of combinations of disulfiram and one or more additional ingredients useful in methods of the present disclosure
  • disulfiram or variant thereof
  • one or more additional ingredients capable of increasing lifespan in a mammal, of preventing or treating a disease including an aging-related disorder in a mammal, of reducing a symptom of aging in a mammal, and/or of boosting an immune system were identified.
  • Sets of cultured cells fibroblasts, peripheral blood mononuclear cells (PBMCs including lymphocytes and monocytes, and/or myoblasts — having either characteristics of young cells or characteristics of old cells are contacted with a combination of disulfiram (or variant thereof) and one or more additional ingredients listed in Table 1.
  • the ability of disulfiram and one or more additional ingredients to reverse aging in the cells e.g., reducing the characteristics of old cells and promoting characteristics of a young cells was assayed (also known as reducing the predicted age of the cells).
  • Disulfiram and one or more additional ingredients inhibitors were used at various concentrations ranging from 0.000005 to 20 pM. Combinations of disulfiram and one or more additional ingredients showing the ability to reverse aging were further validated.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with the one or more additional ingredients listed in Table 1.
  • Example 2 Methods that comprise administering a composition comprising disulfiram and one or more additional ingredients
  • compositions comprising disulfiram (or variant thereof) and one or more additional ingredients listed in Table 1 or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising the one or more additional ingredients are administered to a mammal for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system (e.g., for treating an infection).
  • compositions are by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • the mammal s lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the composition administered.
  • the mammal may be aged or not aged.
  • the mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Illustrative diseases treated in this example may be asthma, deafness, or a viral infections and an illustrative symptom thereof may be sepsis.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with the one or more additional ingredients listed in Table 1.
  • Example 3 Methods for improving a vaccine response
  • compositions comprising disulfiram (or variant thereof) and one or more additional ingredients listed in Table 1 or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising the one or more additional ingredients are administered to a mammal for improving effectiveness of a vaccine that is administered to the mammal.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the vaccine may be administered orally, by inhalation, or topically.
  • the composition(s) comprising the combination of disulfiram and/or one or more additional ingredients and the vaccine are administered contemporaneously.
  • the vaccine is administered subsequent to the administration of the combination(s) of disulfiram and/or one or more additional ingredients.
  • the vaccine is administered before the administration of the combination(s) of disulfiram and/or one or more additional ingredients.
  • a subject may be administered vaccines and/or combination(s) of disulfiram and/or one or more additional ingredients multiple times and in any order.
  • the vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine. Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency vims (HIV) vaccine.
  • Human papillomavirus vaccine influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a coronavirus vaccine.
  • the coronavirus vaccine is directed against Sars-CoV -2.
  • the mammal may be aged or not aged.
  • the mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the mammal s ability to fend off a subsequent infection is determined and compared to mammals and/or historical controls who were only administered the vaccine.
  • the mammal ability to later produce antibodies directed to an infectious agent (related to the vaccine) is determined and compared to mammals and/or historical controls who were only administered the vaccine.
  • the dose of disulfiram is from about 5 mg to about 500 mg and the dose of TBHQ is from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with the one or more additional ingredients listed in Table 1.
  • Example 4 Methods for treating skin disorders
  • compositions comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal, e.g., a human, for treating a skin disorder.
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered orally or topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation Combinations of administration routes may be used.
  • the mammal has a skin disorder, e.g, wrinkles, which may be a result of photoaging or related to actinic keratosis.
  • a skin disorder e.g, wrinkles
  • the mammal has moderate skin aging (/. e., Glogau Classification III).
  • compositions or compositions ability to treat a skin disorder, e.g, wrinkles, is determined and compared to the mammals before administration and/or to historical controls who were not administered the composition or compositions. For example, the determination relates to a change in the Glogau Classification.
  • an ALDH modulator or gasdermin D inhibitor as disclosed herein, is used in combination with TBHQ.
  • Example 5 Illustrative assays
  • disulfiram was shown to modify quantifiable parameters in virally-infected cells from older donors that reflects those observed in cells from younger donor.
  • PBMCs peripheral blood mononuclear cells
  • PBMCs were cryopreserved in CryoStor® CS10 (BioLife Solutions, Bothell, WA, USA), frozen using CoolCell® FTS30 freezing containers (BioCision, San Rafael, CA, USA), and stored in the liquid nitrogen vapor phase until use.
  • CryoStor® CS10 BioLife Solutions, Bothell, WA, USA
  • CoolCell® FTS30 freezing containers BioCision, San Rafael, CA, USA
  • T cells T cells
  • B cells B cells
  • NK cells EasySepTM Human NK Cell Enrichment Kit
  • monocytes CD14+
  • 10 pL of5* trigger medium including vesicular stomatitis virus encoding a red fluorescent protein (rVSV -AG-mCherry), DMSO, test compound, and FBS
  • rVSV -AG-mCherry red fluorescent protein
  • DMSO vesicular stomatitis virus encoding a red fluorescent protein
  • test compound test compound
  • FBS red fluorescent protein
  • rVSV- AG-mCherry infected monocytes and macrophages, which subsequently created a highly inflamed environment for the lymphocytes and other cells.
  • rVSV- AG-mCherry was used because of its ability to model the innate immune activation pathways of prevalent respiratory RNA viruses and because it was safe to use in a high-throughput laboratory with biosafety level one.
  • Virally-infected cells were contacted different concentrations of disulfiram (e.g, 0.00 pM, 0.02 pM, 0. 10 pM, 0.33 pM, 1.65 pM, 6.25 pM, and 25.02 pM).
  • concentrations of disulfiram e.g, 0.00 pM, 0.02 pM, 0. 10 pM, 0.33 pM, 1.65 pM, 6.25 pM, and 25.02 pM).
  • Cytokine levels in the cellular supernatant were evaluated using the FirePlex-HT assay system with the Human Cytokines FirePlex-HT Panel 1 (ab234897; Abeam). Morphological/cellular phenotypes were assayed.
  • Disulfiram demonstrated notable effects on cellular phenotypes in older immune cells that were suggestive of a rejuvenation of the response to infection.
  • MCP1, IL-ip, IL-6, and TNFa all significantly decreased in at least 2 doses (FIG. 1A).
  • These anti-inflammatory effects caused disulfiram showing its potential to improve older viral immune responses to infection.
  • Disulfiram improved the appearance of vir ally -infected cells.
  • Untreated and treated PBMCs were exposed to 10x MOI rVSV, yet, at several doses, disulfiram made the cells appear like they were responding to a lower viral load.
  • the higher doses of disulfiram also saw significant, beneficial reductions in the T-cell age score (0.33 pM [ ⁇ .001] ; 1.65 pM [ ⁇ 001] ; 6.25 pM [ ⁇ 001]; 25.02 pM [ ⁇ 001]; FIG. 1C).
  • Machine learning model predictions of the immune response resulting from different viral loads were notably different with disulfiram treatment compared with untreated control cells. At higher disulfiram concentrations, the model indicated that monocytes responded at a lower MOI than did untreated control cells.
  • Disulfiram treatment induced apoptosis.
  • the three highest concentrations of disulfiram increased dead cells and infected monocytes by 12% and decreased T cells by 13%. This trend is in the opposite direction of a young phenotype.
  • Disulfiram also appeared to operate via several anti-inflammatory mechanisms, including an ability to inhibit NLRP3 inflammasome-mediated pyroptotic cell death.
  • the inflammasome-blocking mechanisms of disulfiram ultimately inhibits pyroptosis by stopping formation of pores in the cell membrane that lead to cell lysis and release of proinflammatory molecules such as IL-ip and IL- 18.
  • the data presented herein show that disulfiram restores aspects of the old viral immune response.
  • Disulfiram reduced the proinflammatory cytokines MCP1, IL-ip, IL-6, and TNFa while also rejuvenating several other features in aging profile such as T-cell age score, viral load response, and mitochondrial function.
  • These immunomodulatory mechanisms could be related to the ability of disulfiram to block the final step in inflammasome-mediated pyroptosis and cytokine release.
  • Disulfiram may also operate by ultimately reducing pore formation on the cell membrane of neutrophils, which would allow for the release of neutrophil extracellular traps (NETs), a process known as NETosis.
  • NETs neutrophil extracellular traps
  • disulfiram an attractive treatment for hyperinflammatory infections such as COVID-19 and sepsis.
  • Disulfiram has already been shown to protect mice from lethal lipopolysaccharide-induced septic shock.
  • disulfiram may be a useful agent for treating infection, e.g, caused by a virus such as SARS-CoV2.
  • Serafrompatients with severe COVID- 19 demonstrated increased NETs andan autopsy ofalung specimen from a patient with COVID- 19 showed extensive neutrophil infiltration.
  • Proinflammatory cytokines in patients with severe COVID- 19 were significantly higher than in moderate cases. This includes elevated levels of IL-ip that result from inflammasome activation. Given the relationship between NETosis, the inflammasome, and COVID- 19 pathology, the ability of disulfiram to target these pathways, treatments with disulfiram could provide substantial clinical benefit.
  • disulfiram may have antiviral effects on SARS-CoV2.
  • Disulfiram has been shown to inhibit papain-like proteases of deadly coronaviruses such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoVl, which may disrupt the replication and IFN suppression mechanisms of these viruses.
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • SARS-CoVl Middle East respiratory syndrome coronavirus
  • This experiment is performed by contacting the virus-infected cells with different concentrations of disulfiram in combination of TBHQ. Cell parameters such as cytokine levels and morphological/ cellular phenotypes are assayed to demonstrate potential to improve old immune response to infection.
  • Example 6 Methods that comprise administering a first composition and a second composition
  • a composition comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mamma, e.g. , a human, 1 for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system (e.g, treating an infection).
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • Administration of the compositions is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • the first composition is administered orally, by inhalation, injection, or topically.
  • the second composition is administered orally, by inhalation, inj ection, or topically.
  • the administration route of the first composition and the second composition may be the same or may be different.
  • the first composition may be administered before the second composition is administered.
  • the first composition may be administered after the second composition is administered.
  • the first composition and the second composition may be administered contemporaneously (either by combining the two compositions or by administering the two compositions at nearly the same time).
  • the mammal’s lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
  • the mammal may be aged or not aged.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 7 Inhibition of pyroptosis in cells
  • THP1-HMGB1 -LuciaTM cells are pyroptosis and necroptosis reporter monocytes, where following inflammasome-mediated pyroptosis, pores are formed in the cell membrane and HMGB1 : :Lucia is released in the extracellular milieu. Levels of HMGBl::Lucia in the supernatant can be readily monitored by measuring the light signal produced after addition of QUANT! -LucTM. These cells are derived from THP-1 human monocytic cell line and are used to study regulated necrosis.
  • THP1 -HMGB1 -LuciaTM cells stably express in the cytoplasm a 46.5 kDa fusion protein, HMGB1 : :Lucia, in which the C-terminus of HMGB1 is fused to the Lucia luciferase.
  • These cells respond to commonly used inflammasome inducers such as Nigericin, and to necroptosis cocktail inducers such as INF receptor or PRR agonist + Z-VAD-FMK (pancaspase inhibitor) + BV6 (cIAP inhibitor). Following necroptosis or mnammasome-mediated-pyroptosis. pores are formed in the cell membrane and HMGB1 : :Lucia is released in the extracellular milieu. Levels of HMGB1 : : Lucia in the supernatant can be readily monitored by measuring the light signal produced after addition of QUANT! -LucTM.
  • the reporter monocytes were cultured in growth medium comprising RPMI 1640, 2 mM L-glutamine, 25 mMHEPES, 10% heat-inactivated fetal bovine serum (FBS; 30 min at 56 °C), 100 pg/ml NormocinTM, Pen-Strep (100 U/ml-100 pg/ml).
  • FBS heat-inactivated fetal bovine serum
  • 100 pg/ml NormocinTM 100 pg/ml NormocinTM
  • Pen-Strep 100 U/ml-100 pg/ml.
  • 100 pg/ml of Zeodn was added to the growth medium every other passage.
  • the reporter cells were passaged every 3 days by inoculating 5 x 10 5 cells/ml.
  • the reporter cells were treated with disulfiram across a range of doses from 0.002 to 125 pM.
  • the reporter cells were also treated with disulfiram across the range in the presence of 10 mM Copper (II) Gluconate.
  • the reporter cells were treated with 20 pl of LPS-EK (1 pg/ml final concentration) per well of a flat-bottom 96- well plate.
  • the THP1-HMGB1 -LuciaTM cells were prepared in suspension at approximately 1 x 10 6 cells/ml. The cells were then dispensed into each well at 180 pl of cell suspension (-200,000 cells) per well. The cells were then incubated at 37 °C in 5% CO2 for 3 h. The growth medium was then removed and 180 pl of fresh test medium was added.
  • the cells were measured immediately to obtain end-point readings using a luminometer with an injector with the following parameters: 50 pl of inj ection, end-point measurement with a 4 second start time and 0.1 second reading time. 10-20 pl of sample per well was added into a 96-well white (opaque) or black plate, or a luminometer tube. The injector was primed with the QUANTI-LucTM assay solution and proceeded immediately with the measurement.
  • Disulfiram treatment of the reporter monocytes was shown to inhibit pyroptosis across a range of doses from 0.002 to 125 pMn of disulfiram (FIG. 2).
  • Disulfiram in the presence of 10 mM Copper (II) Gluconate was also shown to inhibit pyroptosis in the reporter monocytes (FIG. 2).
  • IC50 for disulfiram only was determined to be 15.58pM.
  • IC50 for disulfiram in the presence of copper was determined to be 4.60pM.
  • disulfiram’s IC50 based on pyroptosis was reduced 3.4-fold.
  • Example 8 Synergistic effect of disulfiram and TBHQ
  • luciferase assay was performed as described briefly: 125k THP 1 pyroptosis reporter cells/ml final density were plated on 384 well plates and incubated with disulfiram, TBHQ, or disulfiram and TBHQ for 20 minutes. 1 pg/ml LPS was added to the wells, and the plate was incubated for 3 hours, followed by addition of 10 pM nigericin. After three hours, supernatants were harvested and the presence of HMGB1 luciferase reporter protein was quantified using QUANTI-Luc.
  • FIG. 2 shows the effect on pyroptosis of the combination of disulfiram and TBHQ as compared to each individual compound.
  • FIG. 3 shows the potentiating effects of varying constant concentrations of TBHQ added to disulfiram titration curves.
  • FIG. 4 shows the effect of cells treated with TBHQ and different concentrations of disulfiram.
  • HMGB1 Lucia cells Invivogen. These cells code for a luciferase reporter protein (HMGB1) that is released from cells during pyroptosis. HMGB1 levels in the supernatant can therefore be used to quantify pyroptosis.
  • Concentration matrices of disulfiram titration curves mixed with titration curves of TBHQ were tested.
  • Disulfiram curves at each concentration of TBHQ were plotted and fit using a log( agonist) vs. response variable slope (four parameters) least squares fit model. The diagonal of each matrix was representative of a dose response curve of disulfiram plus TBHQ combinations titrated at a constant ratio.
  • Synergy fold ratio was measured by calculating the ratio of actual effect over expected effect: [(TBHQ+disulfiram) / no treatment] / [(disulfiram alone / no treatment) x (TBHQ alone / no treatment)] at each concentration combination. Values greater than 1 were considered synergistic.
  • the synergy score is calculated using ye, and determined to be the difference between the observed effect and the expected effect. Score negativity or positivity determines whether the combination is synergistic or antagonist, respectively.
  • FIG. 5A to FIG. 5C show the synergistic effect of the combination of disulfiram and TBHQ mediated inhibition of pyroptosis.
  • IC50s were calculated using the log( agonist) vs. response variable slope (four parameters) least squares fit model from the GraphPad Prism software package.
  • Curves of disulfiram + constant concentrations of TBHQ were plotted using the log of disulfiram concentration.
  • FIG. 6 is a table showing the percent leftward shift in IC50 mediated by TBHQ relative to disulfiram alone in a dose-dependent matter, while TBHQ alone has no effect on pyroptosis inhibition or IC50. Accordingly, these data show synergistic effects on pyroptotic inhibition when cells are subjected to a combination of disulfiram and TBHQ.
  • Example 9 Methods for preventing and/or treating a respiratory disease or disorder
  • a composition comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administeredto a mammal, e.g., ahuman, for preventing and/or treating a respiratory disease or disorder, e.g., acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) or pulmonary fibrosis.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions are by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Treatment is identified as an improvement in the administered mammal in one or more of the following symptoms severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness.
  • the improvement may be relative to the pre-administration state for the mammal.
  • the mammal may be aged or not aged.
  • the underlying cause for the ALI and/or ARDS may be sepsis (e.g., a serious and widespread infection of the bloodstream); inhalation of a harmful substance (e.g, smoke, chemical fumes, asbestos, dust, particulates, vomit, and water); viral or bacterial pneumonia (which may affect up to all five lobes of the lungs) and other respiratory disorders including those caused by a coronavirus (e.g, SARS, MERS, and COVID-19), influenzas (influenza A, influenza B, or parainfluenza), pneumococcal infection, adenovirus ⁇ respiratory syncytial virus (RSV), enterovirus and/or other respiratory viral infections; and ahead, chest or other major injury; or another cause (e.g., pancreatitis which is inflammation of the pancreas, a massive blood transfusion, and severe bums).
  • a coronavirus e.g, SARS, MERS, and COVID-19
  • influenzas in
  • ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease.
  • composition or compositions prevent or treat idiopathic pulmonary fibrosis and/or chronic obstructive pulmonary disease.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 10 Methods for improving a vaccine response
  • a composition comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal, e.g, ahuman, for improving effectiveness of a vaccine that is administered to the mammal.
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the vaccine may be administered orally, by inhalation, or topically. In some embodiments, rather than disulfiram, an ALDH modulator or gasdermin D inhibitor, as disclosed herein, is used in combination with TBHQ.
  • Example 11 Methods for treating dry eye
  • compositions comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal, e.g., a human, for treating dry eye.
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as eye drops or as eye ointments.
  • compositions or compositions ability to treat dry eyes, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 12 Methods for treating alopecia
  • compositions comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal, e.g, a human, for treating alopecia.
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • compositions or compositions ability to treat alopecia, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • compositions comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal, e.g., a human, for treating liver conditions, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis.
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of di sulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the liver condition, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 14 Methods for treating a skin cancer
  • a composition comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal, e.g., a human, for treating a skin cancer, e.g, (e.g, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)).
  • a skin cancer e.g, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the skin cancer, e.g, BCC and SCC, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 15 Methods for treating an aging-related disorder or reducing a symptom of aging
  • compositions comprising disulfiram (or variant thereof) and TBHQ, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising TBHQ are administered to a mammal (e.g., a human) for treating an aging-related disorder or reducing a symptom of aging, e. g.
  • age-related macular degeneration AMD
  • Alzheimer ’ s disease s disease
  • arthritis ⁇ atherosclerosis and cardiovascular disease benign prostatic hyperplasia (BPH)
  • BPH benign prostatic hyperplasia
  • BPH benign prostatic hyperplasia
  • COPD chronic obstructive pulmonary disease
  • Cryopyrin-Associated Periodic Syndrome CAS
  • constipation decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), Inflammatory Bowel Diseases (including Crohn’s disease, Ulcerative Colitis, Irritable Bowel Syndrome), macular degeneration, memory loss, metabolic syndrome, multiple sclerosis, muscle atrophy (e.g., Sarcopenia and myopenia), muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the aging-related disorder or reduce a symptom of aging, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 16 Method of treating Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening critical illnesses with substantial morbidity and mortality. Despite improvements in clinical care for these patients there are still no effective pharmacologic therapies to treat patients with ALI/ARDS, and the hospital mortality for severe ARDS is still as high as 40%. ALI/ARDS is characterized by exaggerated pulmonary inflammation, infiltration of activated neutrophils, accumulation of alveolar interstitial fluid, and hypoxemia.
  • NLRP3 inflammasome is cytosolic multi-protein complex assembled in response to infection and cellular stress (pathogen (PAMPs) and endogenous activators (DAMPs), and are crucial for the activation of inflammatory caspases and the subsequent processing and release of pro-inflammatory mediators. Excessive activation of NLRP3 inflammasome can contribute to development of inflammatory diseases and cancer.
  • PAMPs pathogen
  • DAMPs endogenous activators
  • Activation of NLRP3 results in the autoactivation and cleavage of pro-caspase- 1 into caspase- 1, which activates pro-IL-ip and pro-IL-18 into IL-ip and IL- 18, respectively.
  • activation of the NLRP3 inflammasome is a host defense mechanism to eliminate invading pathogens in infectious diseases, excessive activation of the NLRP3 inflammasome is also central to aberrant inflammation, progression to tissue injury, and organ dysfunction.
  • NLRP3 inflammasome plays a pivotal role in the progression of ALI/ARDS caused by various pathogenic microorganisms, such as influenza A virus, Pseudomonas aeruginosa and Staphylococcus aureus.
  • Inflammasomes-activated caspases also process gasdermin D (GSDMD). Cleaved GSDMD forms pores at the plasma membrane, leading to cytokine release and inflammatory cell death (pyroptosis).
  • Disulfiram has been shown to be an inhibitor of pore formation by GSDMD. At nanomolar concentration, disulfiram covalently modifies human Cysl91/Cysl92 in GSDMD to block pore formation. Disulfiram still allows IL- ip and GSDMD processing, but abrogates pore formation, thereby preventing IL-ip release and pyroptosis. The use of disulfiram may be a potential pharmacological approach to treating NLRP3 -driven diseases. Inhibiting GSDMD is an attractive strategy to curb inflammation in ARDS.
  • Subjects aged 18 - 85 years, hospitalized for 7 days or less before screening showing chest radiography or CT findings that are compatible with ALI / ARDS are treated with Disulfiram (500 mg) and tert- Butylhydroquinone (TBHQ) (37 mg) once daily via oral or enteral administration for 14 days.
  • Patients undergoing combination therapy with Disulfiram and TBHQ experience reduced 28 day morbidity; additional ventilator free days; and/or a reduction in IL- 18, IL-1, IL-6, IL-ip, and Procalcitonin, and other related biomarkers when compared to patients not treated with Disulfiram (500 mg) and tert- Butylhydroquinone (TBHQ) (37 mg) once daily.
  • a patient has ARDS with ALI. In other cases, a patient has ARDS without ALL And, in other cases, a patient has ALI without ARDS.
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of the TBHQ may be from about 0.001 mg to about 280 mg.
  • the dose of disulfiram may be about 250 mg and the dose of TBHQ may be about 18.5 mg and the dose of disulfiram may about 500 mg and the dose of TBHQ about 37 mg.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with TBHQ.
  • Example 17 Synergistic effect of disulfiram and cinnamaldehyde
  • luciferase assay was performed as described briefly: 125k THP 1 pyroptosis reporter cells/ml final density were plated on 384 well plates and incubated with disulfiram, cinnamaldehyde, or disulfiram and cinnamaldehyde for 20 minutes. 1 pg/ml LPS was added to the wells, and the plate was incubated for 3 hours, followed by addition of 10 pM nigericin. After three hours, supernatants were harvested and the presence of HMGB1 luciferase reporter protein was quantified using QUANT! -Luc.
  • FIG. 7 shows the effect on pyroptosis of the combination of disulfiram and cinnamaldehyde as compared to each individual compound.
  • FIG. 8 shows the potentiating effects of varying constant concentrations of cinnamaldehyde added to disulfiram titration curves.
  • HMGB1 Lucia cells Invivogen. These cells code for a luciferase reporter protein (HMGB1) that is released from cells during pyroptosis. HMGB1 levels in the supernatant can therefore be used to quantify pyroptosis.
  • Concentration matrices of disulfiram titration curves mixed with titration curves of cinnamaldehyde were tested. Disulfiram curves at each concentration of cinnamaldehyde were plotted and fit using a log(agonist) vs. response variable slope (four parameters) least squares fit model. The diagonal of each matrix was representative of a dose response curve of disulfiram plus cinnamaldehyde combinations titrated at a constant ratio.
  • Synergy fold ratio was measured by calculating the ratio of actual effect over expected effect: [(cinnamaldehyde+disulfiram) / no treatment] / [(disulfiram alone / no treatment) x (cinnamaldehyde alone / no treatment)] at each concentration combination. Values greater than 1 were considered synergistic.
  • the synergy score is calculated using ye, and determined to be the difference between the observed effect and the expected effect. Score negativity or positivity determines whether the combination is synergistic or antagonist, respectively.
  • FIG. 9A to 9C show the synergistic effect of the combination of disulfiram and cinnamaldehyde mediated inhibition of pyroptosis. IC50 Calculations
  • IC50s were calculated using the log( agonist) vs. response variable slope (four parameters) least squares fit model from the GraphPad Prism software package.
  • FIG. 10 is a table showing the percent leftward shift in IC50 mediated by cinnamaldehyde relative to disulfiram alone in a dose-dependent matter, while cinnamaldehyde alone has no effect on pyroptosis inhibition or IC50. Accordingly, these data show synergistic effects on pyroptotic inhibition when cells are subjected to a combination of disulfiram and cinnamaldehyde.
  • Example 18 Methods that comprise administering disulfiram and cinnamaldehyde
  • a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., a human, for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system (e.g., for treating an infection).
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions are by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • the mammal s lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the composition administered.
  • the mammal may be aged or not aged.
  • the mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Illustrative diseases treated in this example may be asthma, deafness, or a viral infections and an illustrative symptom thereof may be sepsis.
  • Assays and formulations used in this example are related to those described in US20190228840, the entire contents of which is incorporated by reference its entirety.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 19 Methods for preventing and/or treating a respiratory disease or disorder
  • a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g., ahuman, for preventing and/or treating a respiratory disease or disorder, e.g., acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) or pulmonary fibrosis.
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions are by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Treatment is identified as an improvement in the administered mammal in one or more of the following symptoms severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness.
  • the improvement may be relative to the pre-administration state for the mammal.
  • the mammal may be aged or not aged.
  • the underlying cause for the ALI and/or ARDS may be sepsis (e.g., a serious and widespread infection of the bloodstream); inhalation of a harmful substance (e.g, smoke, chemical fumes, asbestos, dust, particulates, vomit, and water); viral or bacterial pneumonia (which may affect up to all five lobes of the lungs) and other respiratory disorders including those caused by a coronavirus (e.g, SARS, MERS, and COVID-19), influenzas (influenza A, influenza B, or parainfluenza), pneumococcal infection, adenovirus ⁇ respiratory syncytial virus (RSV), enterovirus and/or other respiratory viral infections; and ahead, chest or other major injury; or another cause (e.g, pancreatitis which is inflammation of the pancreas, a massive blood transfusion, and severe bums).
  • a coronavirus e.g, SARS, MERS, and COVID-19
  • influenzas influ
  • ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease.
  • composition or compositions prevent or treat idiopathic pulmonary fibrosis and/or chronic obstructive pulmonary disease.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 20 Methods for improving a vaccine response
  • compositions comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g, a human, for improving effectiveness of a vaccine that is administered to the mammal.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the vaccine may be administered orally, by inhalation, or topically.
  • the composition(s) comprising the combination of disulfiram and/or cinnamaldehyde and the vaccine are administered contemporaneously.
  • the vaccine is administered subsequent to the administration of the combination(s) of disulfiram and/or one or more additional ingredients.
  • the vaccine is administered before the administration of the combination(s) of disulfiram and/or cinnamaldehyde.
  • a subject may be administered vaccines and/or combination(s) of disulfiram and/or one cinnamaldehyde multiple times and in any order.
  • the vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a coronavirus vaccine.
  • the coronavirus vaccine is directed against Sars-CoV- 2.
  • the mammal may be aged or not aged.
  • the mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the mammal s ability to fend off a subsequent infection is determined and compared to mammals and/or historical controls who were only administered the vaccine.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 21 Methods for treating skin disorders
  • compositions comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g, a human, for treating a skin disorder.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions may be administered orally or topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g, a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • the mammal has a skin disorder, e.g, actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, psoriasis, shingles, vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/ sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness).
  • a skin disorder e.g, actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, psoriasis, shingles, vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/ sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness).
  • the mammal has moderate skin aging (/. e. , Glogau Classification III).
  • compositions or compositions ability to treat a skin disorder, e.g, wrinkles, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions. For example, the determination relates to a change in the Glogau Classification.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 22 Methods for treating alopecia
  • compositions comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g, a human, for treating alopecia.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • compositions or compositions ability to treat alopecia, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g, a human, for treating liver conditions, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the liver condition, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 24 Methods for treating a skin cancer
  • a composition comprising disulfiram and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal, e.g, a human, for treating askin cancer, e.g, (e.g., basal cell carcinoma (BCQ and squamous cell carcinoma (SCC)).
  • a mammal e.g, a human
  • askin cancer e.g, (e.g., basal cell carcinoma (BCQ and squamous cell carcinoma (SCC)).
  • BCQ basal cell carcinoma
  • SCC squamous cell carcinoma
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the skin cancer, e.g, BCC and SCC, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 25 Methods for treating an aging-related disorder or reducing a symptom of aging
  • a composition comprising disulfiram (or variant thereof) and cinnamaldehyde, or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising cinnamaldehyde are administered to a mammal (e.g, a human) for treating an aging-related disorder or reducing a symptom of aging, e.g, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin- Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (AMD),
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the aging-related disorder or reduce a symptom of aging, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 26 Methods that comprise administering a first composition and a second composition
  • a first composition comprises a therapeutically effective amount of disulfiram and a second composition comprising cinnamaldehyde are administered to a mammal for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the cinnamaldehyde is from about 0.001 mg to about 223 mg.
  • the first composition is administered orally, by inhalation, injection, or topically.
  • the second composition is administered orally, by inhalation, inj ection, or topically.
  • the administration route of the first composition and the second composition may be the same or may be different.
  • the first composition may be administered before the second composition is administered.
  • the first composition may be administered after the second composition is administered.
  • the first composition and the second composition may be administered contemporaneously (either by combining the two compositions or by administering the two compositions at nearly the same time).
  • the mammal’s lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • luciferase assay was performed as described briefly: 125k THP 1 pyroptosis reporter cells/ml final density were plated on 384 well plates and incubated with disulfiram, nordihydroguaiaretic acid (NDGA), or disulfiram and NDGA for 20 minutes. 1 pg/ml LPS was added to the wells, and the plate was incubated for 3 hours, followed by addition of 10 pM nigericin. After three hours, supernatants were harvested and the presence of HMGB1 luciferase reporter protein was quantified using QUANTI-Luc.
  • FIG. 11 shows the effect on pyroptosis of the combination of disulfiram and NDGA as compared to each individual compound.
  • FIG. 12 shows the potentiating effects of varying constant concentrations of NDGA added to disulfiram titration curves.
  • HMGB1 Lucia cells Invivogen. These cells code for a luciferase reporter protein (HMGB1) that is released from cells during pyroptosis. HMGB1 levels in the supernatant can therefore be used to quantify pyroptosis.
  • Concentration matrices of disulfiram titration curves mixed with titration curves of NDGA were tested. Disulfiram curves at each concentration of NDGA were plotted and fit using a log(agonist) vs. response variable slope (four parameters) least squares fit model. The diagonal of each matrix was representative of a dose response curve of disulfiram plus NDGA combinations titrated at a constant ratio.
  • Synergy fold ratio was measured by calculating the ratio of actual effect over expected effect: [(NDGA+disulfiram) / no treatment] / [(disulfiram alone / no treatment) x (NDGA alone / no treatment)] at each concentration combination. Values greater than 1 were considered synergistic.
  • the synergy score is calculated using ye, and determined to be the difference between the observed effect and the expected effect. Score negativity or positivity determines whether the combination is synergistic or antagonist, respectively.
  • Loewe S. (1953) The problem of synergism and antagonism of combined drugs. Arzneistoffforschung 3, 285-290; Loewe, S. (1928). Die quantitativen probl erne der pharmakologie.The Physiol. 27, 47-187, the contents of which is incorporated by referenced in its entirety.
  • FIG. 13A to 13C show the synergistic effect of the combination of disulfiram and NDGA mediated inhibition of pyroptosis.
  • IC50s were calculated using the log( agonist) vs. response variable slope (four parameters) least squares fit model from the GraphPad Prism software package.
  • FIG. 14 is a table showing the percent leftward shift in IC50 mediated by NDGA relative to disulfiram alone in a dose-dependent matter, while NDGA alone has no effect on pyroptosis inhibition or IC50. Accordingly, these data show synergistic effects on pyroptotic inhibition when cells are subjected to a combination of disulfiram and NDGA.
  • Example 28 Methods that comprise administering disulfiram and NDGA
  • a composition comprising disulfiram and nordihydroguaiaretic acid (NDGA), or distinct compositions of a first composition comprising disulfiram and a second composition comprising NDGA are administered to a mammal, e.g., a human, for increasing lifespan, for preventing or treating a disease including an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system (e.g., for treating an infection).
  • a mammal e.g., a human
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions are by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • the mammal s lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the composition administered.
  • the mammal may be aged or not aged.
  • the mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • Illustrative diseases treated in this example may be asthma, deafness, or a viral infections and an illustrative symptom thereof may be sepsis.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • Example 29 Methods for preventing and/or treating a respiratory disease or disorder
  • a composition comprising disulfiram and nordihydroguaiaretic acid (NDGA), or distinct compositions of a first composition comprising disulfiram and a second composition comprising NDGA are administered to amammal, e.g. , ahuman, for preventing and/or treating arespiratory disease or disorder, e.g, acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) or pulmonary fibrosis.
  • amammal e.g. ahuman
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions are by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the compositions are administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Treatment is identified as an improvement in the administered mammal in one or more of the following symptoms severe shortness of breath, labored and unusually rapid breathing, low blood pressure, and confusion and extreme tiredness.
  • the improvement may be relative to the pre-administration state for the mammal.
  • the mammal may be aged or not aged.
  • the underlying cause for the ALI and/or ARDS may be sepsis (e.g., a serious and widespread infection of the bloodstream); inhalation of a harmful substance (e.g, smoke, chemical fumes, asbestos, dust, particulates, vomit, and water); viral or bacterial pneumonia (which may affect up to all five lobes of the lungs) and other respiratory disorders including those caused by a coronavirus (e.g, SARS, MERS, and COVID-19), influenzas (influenza A, influenza B, or parainfluenza), pneumococcal infection, adenovirus, respiratory syncytial virus (RSV), enter ovims and/or other respiratory viral infections; and ahead, chest or other major injury; or another cause (e.g., pancreatitis which is inflammation of the pancreas, a massive blood transfusion, and severe bums).
  • a coronavirus e.g, SARS, MERS, and COVID-19
  • ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease.
  • composition or compositions prevent or treat idiopathic pulmonary fibrosis and/or chronic obstructive pulmonary disease.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • Example 30 Methods for improving a vaccine response
  • a composition comprising disulfiram and nordihydroguaiaretic acid (NDGA), or distinct compositions of a first composition comprising disulfiram and a second composition comprising NDGA are administered to a mammal, e.g., a human, for improving effectiveness of a vaccine that is administered to the mammal.
  • NDGA nordihydroguaiaretic acid
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the vaccine may be administered orally, by inhalation, or topically.
  • the composition(s) comprising the combination of disulfiram and/or NDGA and the vaccine are administered contemporaneously.
  • the vaccine is administered subsequent to the administration of the combination(s) of disulfiram and/or one or more additional ingredients.
  • the vaccine is administered before the administration of the combination(s) of disulfiram and/or NDGA
  • a subject may be administered vaccines and/or combination(s) of disulfiram and/or one NDGA multiple times and in any order.
  • the vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine.
  • Hepatitis B vaccine Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine.
  • HIV Human immunodeficiency virus
  • RSV Respiratory syncytial virus
  • the vaccine is a coronavirus vaccine.
  • the coronavirus vaccine is directed against Sars-CoV- 2.
  • the mammal may be aged or not aged.
  • the mammal may have a healthy immune system or the mammal may have an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the mammal s ability to fend off a subsequent infection is determined and compared to mammals and/or historical controls who were only administered the vaccine.
  • an ALDH modulator or gasdermin D inhibitor as disclosed herein, is used in combination with NDGA.
  • compositions comprising disulfiram and nordihydroguaiaretic acid are administered to a mammal, e. g. , a human, for treating a skin disorder.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered orally or topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g.. a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • the mammal has a skin disorder, e.g. , wrinkles, which may be a result of photoaging or related to actinic keratosis.
  • a skin disorder e.g. , wrinkles
  • the mammal has moderate skin aging (i.e., Glogau Classification III).
  • compositions or compositions ability to treat a skin disorder, e.g, wrinkles, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions. For example, the determination relates to a change in the Glogau Classification.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • Example 32 Methods for treating dry eye
  • compositions comprising disulfiram and nordihydroguaiaretic acid are administered to a mammal for improving treating dry eye.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as eye drops or as eye ointments.
  • compositions or compositions ability to treat dry eyes, is determined and compared to mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • Example 33 Methods for treating alopecia
  • compositions comprising disulfiram and nordihydroguaiaretic acid are administered to a mammal, e.g., a human, for treating alopecia.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • compositions or compositions ability to treat alopecia, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • a composition comprising disulfiram and NDGA, or distinct compositions of a first composition comprising disulfiram and a second composition comprising NDGA are administered to a mammal, e.g, a human, for treating liver conditions, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the liver condition, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • Example 35 Methods for treating a skin cancer
  • a composition comprising disulfiram and nordihydroguaiaretic acid (NDGA), or distinct compositions of a first composition comprising disulfiram and a second composition comprising NDGA are administered to a mammal, e.g., a human, for treating a skin cancer, e.g, (e.g, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)).
  • a skin cancer e.g, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)
  • BCC basal cell carcinoma
  • SCC squamous cell carcinoma
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered topically, with a dose depending on the quantity of composition needing to be administered.
  • the compositions may be formulated as a gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, or aerosol or administered via an impregnated solid support (e.g., a patch)).
  • the composition may be administered by injection or by inhalation.
  • the composition(s) may be administered orally. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the skin cancer, e.g. , BCC and SCC, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.
  • Example 36 Methods for treating an aging-related disorder or reducing a symptom of aging
  • a composition comprising disulfiram (or variant thereof) and nordihydroguaiaretic acid (NDGA), or distinct compositions of a first composition comprising disulfiram (or variant thereof) and a second composition comprising NDGA are administered to a mammal (e.g., ahuman) for treating an aging- related disorder or reducing a symptom of aging, e.g, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), Cryopyrin-Associated Periodic Syndrome (CAPS), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, diminished peripheral vision, frailty, gout or gouty arthritis, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza
  • the dose of disulfiram may be from about 5 mg to about 500 mg.
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose oftheNDGA is from about 0.001 mg to about 510 mg.
  • compositions may be administered by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the composition may be administered orally, by inhalation, or topically. Combinations of administration routes may be used.
  • compositions or compositions ability to treat the aging-related disorder or reduce a symptom of aging, is determined and compared to the mammal before administration and/or to historical controls who were not administered the composition or compositions.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with cinnamaldehyde.
  • Example 37 Methods that comprise administering a first composition and a second composition
  • a first composition comprises a therapeutically effective amount of disulfiram and a second composition comprising nordihydroguaiaretic acid (NDGA) are administered to a mammal for increasing lifespan, for preventing or treating a disease including an aging -related disorder, for reducing a symptom of aging, and/or boosting an immune system.
  • NDGA nordihydroguaiaretic acid
  • the dose of disulfiram is from about 5 mg to about 500 mg.
  • the dose of the NDGA is from about 0.001 mg to about 510 mg.
  • the first composition is administered orally, by inhalation, injection, or topically.
  • the second composition is administered orally, by inhalation, inj ection, or topically.
  • the administration route of the first composition and the second composition may be the same or may be different.
  • the first composition may be administered before the second composition is administered.
  • the first composition may be administered after the second composition is administered.
  • the first composition and the second composition may be administered contemporaneously (either by combining the two compositions or by administering the two compositions at nearly the same time).
  • the mammal’s lifespan is measured and the presence, absence, and/or severity of various aging-related disorders are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
  • an ALDH modulator or gasdermin D inhibitor is used in combination with NDGA.

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Abstract

Sont divulgués ici, des méthodes et des compositions destinées à inhiber et/ou à réduire la mort cellulaire pyroptotique dans une cellule, la composition comprenant du disulfirame en tant que principe actif et un ingrédient de potentialisation (par exemple, la tert-butylhydroquinone (TBHQ)). Sont également divulgués, des méthodes et des compositions destinées à limiter la progression du syndrome de détresse respiratoire aiguë (SDRA) chez des patients avec ou sans lésion pulmonaire aiguë (ALI), la méthode consistant à administrer une composition comprenant du disulfirame et un ingrédient de potentialisation (par exemple, la TBHQ).
PCT/US2021/050961 2020-09-18 2021-09-17 Polythérapies comprenant du disulfiram Ceased WO2022061171A1 (fr)

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CN115463142A (zh) * 2022-10-14 2022-12-13 广东省科学院动物研究所 柚皮苷二氢查尔酮在制备治疗肺纤维化药物中的应用
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