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WO2021232041A1 - N-acétylcystéine et glycine pour le traitement de symptômes de la covid-19 et post-covid-19 - Google Patents

N-acétylcystéine et glycine pour le traitement de symptômes de la covid-19 et post-covid-19 Download PDF

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WO2021232041A1
WO2021232041A1 PCT/US2021/070523 US2021070523W WO2021232041A1 WO 2021232041 A1 WO2021232041 A1 WO 2021232041A1 US 2021070523 W US2021070523 W US 2021070523W WO 2021232041 A1 WO2021232041 A1 WO 2021232041A1
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individual
covid
patients
glycine
administering step
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Rajagopal V. Sekhar
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Baylor College of Medicine
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Baylor College of Medicine
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present disclosure is directed at least to the fields of virology, biochemistry, cell biology, chemistry, molecular biology, immunology, and medicine.
  • Tong-Covid patients who have recovered from COVID
  • COVID-19 is mild and asymptomatic in most patients, emerging evidence from multiple published studies in hospitalized COVID-19 patients have shown that these patients have severely elevated inflammation, suppressed immune function, and viral pneumonia.
  • elevated inflammatory cytokines such as IL-6 and C-reactive protein (CRP) correlated negatively with CD4+ T-Cells, CD8+T-Cells, B-cells and NK cells of the immune system in these patients, suggesting that elevated inflammation is linked to immunosuppression (Wang et ah, 2020; Shou el ah, 2020).
  • COVID-19 progresses, there is oxygen desaturation requiring mechanical oxygenated ventilation to save lives.
  • Infections such as pneumonias are associated with severe and harmful oxidative stress, and an imbalance between free radicals and antioxidants in the body (Trefler el ah, 2014; Khomich el ah, 2018).
  • Increased oxidative stress has been shown to adversely vascular endothelial function and impair red-blood function and oxygen delivery to tissues (Mohanty et ah, 2014).
  • GSH glutathione
  • Acute viral infections such as influenza have been shown to result in GSH deficiency (Sies, 1999), and cell-culture studies have shown that increasing GSH levels can have a viricidal effect (for example, by inhibiting replication of the influenza vims (Amatore et ah, 2019)).
  • GSH deficiency elevated oxidative stress, endothelial dysfunction, inflammation, and/or immunosuppression combine to contribute to the severely elevated mortality due to COVID-19.
  • oxidative stress as evaluated through as plasma levels of TBARS (a marker of oxidative stress)
  • oxidant damage measured as plasma levels of F2-isoprostanes
  • intracellular glutathione concentrations were measured in 32 was found to be about 12-fold higher in 9 hospitalized COVID patients and found to be significantly abnormal when compared to than 2759 uninfected humans.
  • Oxidative stress and oxidant damage were higher in all age groups in COVID patients, but the highest levels were seen in older humans in the 60- 80y age range.
  • glutathione levels were lower in all age groups but were lowest in the 60-80y age range.
  • GlyNAC Supplementing glycine and N-acetylcysteine (a cysteine donor) - combination termed GlyNAC - successfully corrected deficiency of intracellular glycine and cysteine in elderly humans, HIV -patients and diabetic patients within 14-days (Sekhar et al, 2011 Sept.; Nguyen et al, 2014; Sekhar et al, 2011 Jan.), and improved/corrected GSH deficiency and lowered oxidative stress in elderly humans, HIV- patients and diabetic patients within 14-days (Sekhar et al, 2011 Sept.; Sekhar et al ., 2011 Jan.; Nguyen et ah, 2014).
  • supplementing GlyNAC in patients infected, or that had previously been infected, with the SARS- CoV-2 vims can effectively treat or prevent or delay onset of or reduce severity of or reduce post infection effects of COVID-19 by correcting GSH deficiency and lowering oxidative stress, inflammation, mitochondrial dysfunction, endothelial dysfunction and defective immune function, physical function (strength and exercise capacity) and cognitive function in patients with COVID- 19.
  • GlyNAC supplementation in patients with COVID-19, or who had COVID-19 could lead to significant decline in morbidity, mortality and healthcare expenditure, and result in clinical improvement, accelerated recovery and increased survival. Additional evidence to support this comes from measuring oxidative stress in hospitalized COVID patients, and available data from 9 patients show an extremely elevated level of plasma oxidative stress marker TBARS which is about 10-times higher than uninfected young healthy participants studied in previous trials. Because GlyNAC effectively targets and lowers oxidative stress, this has the potential to do the same in patients with COVID-19.
  • the present disclosure is directed to methods and compositions for treating, preventing, delaying the onset of, reducing severity of one or more symptoms of, and/or reducing or preventing the post-infection effects of a viral infection in an individual in need thereof, specifically a viral infection caused by a virus of the Coronaviridae family, including at least SARS-CoV-2.
  • the Coronaviridae vims is a betacoronavims.
  • the Coronaviridae vims is SARS-CoV-2 or SARS-CoV, including any strain or variant thereof.
  • the methods and compositions comprise targeting the vims itself and/or targeting the uptake of the vims into a host cell, including directly or indirectly targeting binding of a receptor on a host cell by the vims, such as for viral uptake.
  • the methods and compositions comprise targeting the host cells, including targeting the cells such that the vims cannot be up taken by the cell.
  • the methods and compositions comprise preventing the synthesis of viral RNA, inhibiting viral replication, blocking viral binding to cell receptors, and/or inhibiting viral self-assembly.
  • the methods and compositions comprise inhibiting viral replication by inhibiting papain-like protease (PLpro).
  • the methods and compositions comprise competitively binding to host cell angiotensin-converting enzyme 2 (ACE2) receptors.
  • the methods comprise inducing gene expression signals in host cells that induce an unfavorable cellular environment for viral replication.
  • the methods comprise identifying or targeting the individual in need.
  • the individual in need thereof is or is not at risk of being infected with the virus, has or has not been exposed to an individual infected with the vims, has or has not been tested for the viral infection, has or has not tested positive for the viral infection, or is or is not symptomatic of the viral infection.
  • the individual may or may not have flu-like symptoms and be suspected of having viral infection, including viral infection by a vims of the Coronaviridae family.
  • the individual may or may not have had vaccination for a vims of the Coronaviridae family.
  • the individual has normal intracellular GSH levels.
  • the individual has low intracellular GSH levels, elevated oxidative stress, inflammation, immunosuppression, endothelial dysfunction, mitochondrial dysfunction, genomic damage, impaired autophagy, impaired mitophagy, insulin resistance, cellular senescence, stem cell defects, stem cell fatigue, stem cell impairment, stem cell failure, epigenetic alterations, impaired cognition, functional limitation, tinnitus, physical limitations, decrease in exercise capacity or muscle strength or gait speed, fatigability, limitation in lung function or a combination thereof.
  • the individual is an elderly individual, such as an individual greater in age than 70, 75, 80, 85, 90, or 95.
  • the individual is not elderly, such as younger in age than 70 including younger than 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, or 10.
  • the individual is an individual with diabetes.
  • the individual is an individual with pre-diabetes, such as an individual having a fasting glucose value between 100-125 mg/dl.
  • the individual is an obese individual, such as an individual having a BMI of 30 or more.
  • the individual is an immune-compromised individual.
  • the individual is a mammal.
  • the mammals can be of any kind and can include humans, dogs, cats, horses, pigs, sheep, and goats, for example.
  • the methods and compositions comprise administration of cysteine and glycine, or their various precursors (such as any of the precursor amino acids including, but not limited to, serine and methionine), derivatives, or other forms, to an individual in need thereof.
  • the cysteine and glycine precursors, derivatives, or other forms include, but are not limited to, N-acetylcysteine (NAC), L-glycine, L- glycine ethyl ester, or dipeptide forms, such as cysteine and glycine dipeptide forms.
  • cysteine and glycine dipeptide forms include cysteinylglycine or n- acetylcysteinylglycine.
  • Certain embodiments concern compositions, and methods of administering, precursors of cysteine, n-acetylcysteine, and/or glycine.
  • the precursors may include serine, methionine, and/or any other precursor including any composition in the one- carbon metabolism pathway (also known as the folate cycle) and/or the methionine cycle.
  • the methods and compositions comprise increasing the level of intracellular GSH in an individual in need thereof, including an individual infected by or at risk of being infected by a virus of the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to increase the intracellular GSH levels of the individual.
  • the methods and compositions further comprise increasing an intracellular GSH deficiency in an individual in need thereof by administration of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to increase the deficient intracellular GSH levels of the individual.
  • the methods and compositions further comprise treating, preventing, delaying onset of, reducing severity of, and/or reducing or preventing one or more post-infection effects of a Coronaviridae family viral infection in an individual in need thereof by increasing intracellular GSH levels in the individual in need by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to treat, prevent, delay onset of, reduce severity of, and/or reduce or prevent one or more post-infection effects of a Coronaviridae family viral infection in the individual.
  • the methods and compositions further comprise increasing the survival rate of an individual infected with a Coronaviridae family virus. In specific embodiments, the methods and compositions further comprise reducing the recovery time of an individual infected with a Coronaviridae family vims. In specific embodiments, the methods and compositions further comprise treating, preventing, delaying onset of, reducing severity of, and/or reducing or preventing one or more post-infection effects of the symptoms of a Coronaviridae family viral infection in an individual.
  • the methods and compositions further comprise treating, preventing, delaying onset of, reducing severity of, and/or reducing or preventing one or more post- infection effects of cellular, tissue, organ, or system damage caused by a Coronaviridae family viral infection in an individual.
  • the effective amount is effective to prevent the synthesis of viral RNA, inhibit viral replication, block viral binding to cell receptors, and/or inhibit viral self-assembly in the individual.
  • the effective amount is effective to inhibit viral replication by inhibiting papain-like protease (PLpro) in the individual.
  • the effective amount is effective to competitively bind host cell angiotensin converting enzyme 2 (ACE2) receptors in the individual.
  • the effective amount is effective to inhibit virus associated gene expression in the individual.
  • the effective amount is effective to inhibit vims associated gene expression of genes selected from the group consisting of: IFIH1, OAS2, DDX58, RTP4, TRIM21, CD86, CH25H, TDRD7, TIMELESS, FCGR2C, TANK, EDEM1, LCP2, and APOL6.
  • Low GSH levels further predispose an individual to increased oxidative stress, measured by plasma markers of oxidative stress, for example.
  • the methods and compositions further comprise reducing and/or preventing oxidative stress in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce and/or prevent oxidative stress in the individual of the individual.
  • the methods and compositions further comprise reducing the plasma concentration of markers of oxidative stress and/or damage due to oxidative stress in the individual.
  • the oxidative stress markers are thiobarbituric acid reactive substances (TBARS), malondialdehyde, lipid-peroxide, F2-isoprostane levels, F3-isoprostane, F2- isoprostane levels, neuroprostanes, F4-isoprostane levels, a hydroxynonenal or a combination thereof.
  • TBARS thiobarbituric acid reactive substances
  • the methods and compositions further comprise reducing or preventing endothelial dysfunction in an individual in need thereof, such as one infected by or at risk of being infected by a vims from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent endothelial dysfunction in the individual.
  • the methods and compositions further comprise reducing endothelial dysfunction by reducing the plasma concentration of endothelial dysfunction markers in the individual.
  • the endothelial dysfunction markers are sICAMl, sVCAMl, E-selectin, EndoPAT, vascular reactivity, ultrasound flow mediated dilation, or a combination thereof.
  • Low GSH levels and oxidative stress further predispose an individual to elevated inflammation.
  • the methods and compositions further comprise reducing or preventing inflammation in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent inflammation in the individual.
  • the methods and compositions further comprise reducing inflammation by reducing the plasma concentration of inflammatory markers (also known as biomarkers of inflammation) in the individual.
  • the markers of inflammatory response include but are not limited to IL-6, CRP, TNF-alpha, IL-10, MCP-lor a combination thereof.
  • Elevated inflammation is further correlated with immunosuppression.
  • the methods and compositions further comprise reducing or preventing immunosuppression in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent immunosuppression in the individual.
  • the methods and compositions further comprise reducing immunosuppression by increasing the plasma concentration and improve or normalize the activity of cells of the immune system in the individual.
  • the immune cells include but are not limited to are CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, antigen- presenting cells or a combination thereof.
  • the methods and compositions comprise reducing or preventing mitochondrial dysfunction in an individual in need thereof, such as one infected by or at risk of being infected by a vims from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent mitochondrial dysfunction in the individual.
  • the effective amount is effective to increase fasted mitochondrial FA oxidation and to decrease fasted glucose oxidation in the individual.
  • Mitrochondrial FA oxidation and glucose oxidation can be measured by calorimetry, molecular biology, respirometry, and other established methodologies.
  • Low GSH levels further predispose an individual to genomic damage.
  • the methods and compositions further comprise reducing or preventing genomic damage in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent genomic damage in the individual.
  • Genomic damage can be measured by assays and molecular biology techniques.
  • Low GSH levels further predispose an individual to impaired autophagy, mitophagy, or a combination thereof.
  • the methods and compositions further comprise reducing or preventing impaired autophagy, mitophagy, or a combination thereof, in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent impaired autophagy, mitophagy, or a combination thereof, in the individual.
  • Autophagy and mitophagy can be measured using molecular biology techniques.
  • Low GSH levels further predispose an individual to insulin resistance (low insulin sensitivity).
  • the methods and compositions further comprise reducing or preventing insulin resistance in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent insulin resistance in the individual.
  • Insulin sensitivity tests can be measured using the homeostatic modeling assessment (HOMA-IR), fasting glucose and insulin levels, and also by the clamp methods, such as the hyperglycemic clamp method and the hyperinsulinemic-euglycemic clamp method.
  • Low GSH levels further predispose an individual to impaired cognition.
  • the methods and compositions further comprise reducing or preventing impaired cognition in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent cognitive impairment in the individual.
  • the individual does not have detectable impairment of cognitive function.
  • the individual has detectable impairment of cognitive function, including impairment for any reason.
  • the methods and compositions allow a delay of the onset of cognitive impairment or the enhancement of normal cognitive function.
  • cognitive function may be defined as the mental process of knowing, including aspects such as sensation, attention, memory, awareness, perception, reasoning, and judgment, including but not limited to that which comes to be known, as through perception, reasoning, or intuition, knowledge, problem-solving, decision making, motor coordination, language, thought and intelligence.
  • the effective amount is effective to improve normal or impaired memory in the individual.
  • Neuropsychological assessments for cognitive function are known in the art, including the Mini-Mental State Exam (MMSE) and Montreal cognitive assessment (MoCA) which are a widely used test of cognitive function among the elderly and tests orientation, attention, memory, language and visual-spatial skills.
  • MMSE Mini-Mental State Exam
  • MoCA Montreal cognitive assessment
  • GSH-deficient COVID-19 patients have impaired fasted FA oxidation and higher fasted glucose oxidation, suggesting a mitochondrial defect. Because elevated glucose oxidation in the fasted state occurs either by increased gluconeogenesis mainly from muscle protein, or by direct utilization of muscle proteins for energy needs, both routes lead to muscle loss. In certain aspects, loss of muscle strength and/or mass, gait speed, 6-minute walk test and exercise capacity correlate to low levels of GSH associated with a Coronaviridae viral infection.
  • the methods and compositions comprise reducing or preventing functional limitation in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent functional limitation in the individual.
  • the functional limitation is impaired muscle strength and/or muscle mass, gait speed, and exercise capacity.
  • the functional limitation is loss of muscle strength.
  • the functional limitation is loss of skeletal muscle.
  • the functional limitation is cachexia.
  • the effective amount is effective to prevent, slow, reduce, or reverse weight loss or fatigue in the individual, or a combination thereof.
  • the functional limitation is loss of bone mass.
  • the functional limitation is loss of bone strength, including osteopenia and osteoporosis.
  • Physical assessments including body composition, muscle strength, and/or bone density assessments, are known in the art.
  • Low levels of GSH are correlated with functional limitation, including at least declines in muscle strength and/or muscle mass, gait speed, and exercise capacity.
  • functional limitation including at least declines in muscle strength and/or muscle mass, gait speed, and exercise capacity.
  • because the process of breathing (respiration) requires adequate strength in the muscles of respiration GSH deficient COVID-19 patients have decreased lung function as measured by standard clinical pulmonary function tests and oxygen saturation tests.
  • limitation in lung function correlates to low levels of GSH associated with a Coronaviridae viral infection.
  • the methods and compositions comprise reducing or preventing limitation in lung function in an individual in need thereof, such as one infected by or at risk of being infected by a virus from the Coronaviridae family, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce or prevent limitation in lung function in the individual.
  • the limitation in lung function is impaired pulmonary function and oxygen saturation.
  • the limitation in lung function is impaired pulmonary function.
  • the functional limitation is impaired oxygen saturation. Assessments of pulmonary function and/or oxygen saturation are known in the art.
  • the methods and compositions comprise increasing the survival rate of an individual infected with a Coronaviridae family virus, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to increase the survival rate of an individual infected with a Coronaviridae family virus.
  • the effective amount is effective to increase the survival rate of an individual infected with SARS-CoV-2.
  • Standards for determining clinical survival and improvement rates are known (e.g ., the World Health Organization (WHO) Ordinal Scale’ for assessing interventions for COVID-19).
  • the methods and compositions further comprise reducing the recovery time of an individual infected with a Coronaviridae family virus, by administration of an effective amount of cysteine and glycine, or their various precursors, derivatives, or other forms, to the individual.
  • the effective amount is effective to reduce the recovery time of an individual infected with a Coronaviridae family vims.
  • the effective amount is effective to reduce the recovery time of an individual infected with SARS-CoV-2.
  • Standards for determining clinical survival and improvement rates are known (e.g ., the World Health Organization (WHO) Ordinal Scale’ for assessing interventions for COVID-19).
  • the glycine or functional derivative thereof and the N-acetylcysteine or functional derivative thereof may be provided to the individual in the same composition or different compositions.
  • the glycine or functional derivative thereof and the N-acetylcysteine or functional derivative may be provided orally to the individual.
  • the cysteine and glycine, or their various precursors, derivatives, or forms comprise comestibles, including at least dietary supplements, comprising glycine and n-acetylcysteine.
  • the glycine derivative is selected from the group consisting of D-Allylglycine; N-[Bis(methylthio)methylene]glycine methyl ester; Boc-allyl-Gly- OH (dicyclohexylammonium) salt; Boc-D-Chg-OH; Boc-Chg-OH; (R)-N-Boc-(2'- chlorophenyl)glycine; Boc-L-cyclopropylglycine; Boc-L-cyclopropylglycine; (R)-N-Boc-4- fluorophenylglycine; Boc-D-propargylglycine; Boc-(S)-3-thienylglycine; Boc-(R)-3- thienylglycine; D-a-Cyclohexylglycine; L-a-Cyclopropylglycine; N-(2-fluorophenyl)-N- (methylsulf
  • compositions consisting essentially of glycine and N-acetylcysteine.
  • compositions consisting of glycine and N-acetylcysteine.
  • Methods of the disclosure include use of either of these particular compositions for treatment or prevention of infection by a virus from the Coronaviridae family.
  • FIG. 1 shows oxidative stress, via Thiobarbituric acid reactive substances (TBARS) and F2-isoprostantes (I) measurements, in COVID-19 patients and healthy controls.
  • TBARS Thiobarbituric acid reactive substances
  • I F2-isoprostantes
  • FIG. 2 shows correlation between RBC-GSH concentrations and increasing age.
  • FIG. 3 shows relation between older humans in the 60-80y age group when comparing those with COVID and without COVID.
  • FIG. 4 demonstrates relation between younger humans in the 21-60y age group when comparing those with COVID and without COVID.
  • FIG. 5 demonstrates correlation between oxidative stress and age.
  • FIG. 6 shows the relation between humans in the 60-80y age group when comparing those with COVID and without COVID for oxidative stress.
  • FIG. 7 provides the relation between younger humans in the 21-60y age group when comparing COVID-positive and COVID-negative humans.
  • FIG. 8 shows correlation between oxidant damage and age.
  • FIG. 9 shows relation between humans in the 60-80y age group when comparing those with COVID and without COVID for oxidant damage.
  • FIG. 10 demonstrates relation between COVID-positive and COVID- negative younger humans in the 21-60y age group.
  • the term “active infection” in specific embodiments refers to an infection, including any viral infection, in which a virus is actively replicating in an individual. Such an infection may be characterized by the spread of the virus to other cells, tissues, and/or organs in the individual, from the cells, tissues, and/or organs initially infected by the virus in the individual.
  • the term “complications from diabetes” in specific embodiments refers to diabetic nephropathy, neuropathy, retinopathy, diabetic obesity, diabetic dyslipidemia, cardiometabolic syndrome, and combinations thereof, for example.
  • the term “effective amount” refers to an amount of glycine and n-acetylcysteine (or functional derivatives thereof) that is required to improve at least one symptom of a medical condition in an individual; in specific embodiments, the medical condition exists in the individual directly or indirectly because of insufficient levels of glutathione. In specific embodiments, the effective amount refers to the amount of glycine and n-acetylcysteine that is utilized to increase glutathione levels in the individual.
  • the term “elderly” refers to an individual over the age of at least 60, 65, 70, 75, 80, 85, 90, 95, or more years of age.
  • oxidative stress refers to the state in an individual, or cell or tissue of an individual, of an imbalance between the production of reactive oxygen and the ability to detoxify the reactive intermediates or easily repair the resulting damage in a biological system.
  • the natural reducing environment within cells is maintained by processes using a constant input of metabolic energy, and disturbances in this normal redox state can result in toxic effects through the production of, for example, free radicals and peroxides that damage cellular components, such as proteins, lipids, and/or DNA, for example.
  • post-infection effect refers to one or more effects, such as one or more symptoms and/or syndromes that occur, or continue to occur, in an individual after the individual has cleared an active infection.
  • a post- infection effect results from a chronic infection, including where one or more symptoms and/or syndromes occur, or continue to occur, in an individual after the individual has been said to have recovered from an infection.
  • a “post-infection effect” refers to one or more effects, including one or more symptoms and/or syndromes, that occur in an individual that has recovered from an infection.
  • Embodiments of the disclosure include methods and compositions useful for treating, preventing, delaying onset of, reducing the severity of, or reducing post-infection effect(s) of a viral infection in an individual in need thereof.
  • Particular embodiments of the disclosure include methods and compositions useful for treating, preventing, delaying onset of, or reducing severity of a Coronaviridae family viral infection in an individual in need thereof.
  • the methods and compositions further comprise increasing blood levels of cysteine and glycine (e.g ., cysteinylglycine) to correct GSH deficiency, elevated oxidative stress, inflammation, immunosuppression, endothelial dysfunction, mitochondrial dysfunction, genomic damage, impaired autophagy, impaired mitophagy, insulin resistance, impaired cognition, functional limitation, or a combination thereof.
  • the methods and compositions deliver to the individual at least glycine and N-acetylcysteine, in particular as precursor amino acids to facilitate raising GSH levels in the individual.
  • Intracellular GSH measuring assays are known in the art (Rahman et al., 2007).
  • an individual in need thereof is administered amounts of compositions as described herein that are effective to raise intracellular levels of GSH, cysteine, and/or glycine for the explicit purpose of treating, preventing, delaying onset of, or reducing severity of a viral infection in the individual, including a Coronaviridae family viral infection, including SARS-CoV-2.
  • methods of the disclosure include the diagnosis of insufficient levels of intracellular GSH in an individual to treat, prevent, delay onset of, or reduce severity of a viral infection; the individual may or may not be subject to determination of insufficient levels of intracellular GSH upon onset of one or more viral infection symptoms, such as one or more flu-like symptoms.
  • the present disclosure encompasses treatment or prevention of infection of any vims in the Coronaviridae family.
  • the disclosure encompasses treatment or prevention of infection of any vims in the subfamily Coronavirinae and including the four genera, Alpha-, Beta-, Gamma-, and Deltacoronavims.
  • the disclosure encompasses treatment or prevention of infection of any vims in the genus of Betacoronavims, including the subgenus Sarbecovims and including the species of severe acute respiratory syndrome-related coronavims.
  • the disclosure encompasses treatment or prevention of infection of any vims in the species of severe acute respiratory syndrome -related coronavims, including the strains severe acute respiratory syndrome coronavims (SARS-CoV) and severe acute respiratory syndrome coronavims 2 (SARS-CoV-2, the vims that causes COVID-19).
  • the disclosure encompasses treatment or prevention of infection any isolate, strain, type (including Type A, Type B and Type C; Forster et al., 2020, PNAS, https://doi.org/10.1073/pnas.2004999117), cluster, or sub-cluster of the species of severe acute respiratory syndrome-related coronavims, including at least SARS-CoV-2.
  • the vims being treated with methods and compositions of the disclosure is not SARS-CoV and is not MERS-CoV. In specific embodiments, the vims being treated with methods and compositions of the disclosure is SARS-CoV or is MERS-CoV. In specific embodiments, the vims has a genome length between about 29000 to about 30000, between about 29100 and 29900, between about 29200 and 29900, between about 29300 and 29900, between about 29400 and 29900, between about 29500 and 29900, between about 29600 and 29900, between about 29700 and 29900, between about 29800 and 29900, or between about 29780 and 29900 base pairs in length.
  • SARS-CoV-2 viruses include the following listed in the NCBI GenBank® Database, and these GenBank® Accession sequences are incorporated by reference herein in their entirety: (a) LC534419 and LC534418 and LC528233 and LC529905 (examples of different strains from Japan); (b) MT281577 and MT226610 and NC_045512 and MN996531 and MN908947 (examples of different strains from China); (c) MT281530 (Iran); (d) MT126808 (Brazil); (e) MT020781 (Finland); (f) MT093571 (Sweden); (g) MT263074 (Peru); (h) MT292582 and MT292581 and MT292580 and MT292579 (examples of different strains from Spain); (i) examples from the United States, such as MT276331 (TX); MT276330 (TX); MT27
  • the disclosure encompasses treatment or prevention of infection of any of these or similar viruses, including viruses whose genome has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to any of these viruses.
  • the disclosure encompasses treatment or prevention of infection of any of these or similar viruses, including viruses whose genome has its entire sequence that is greater than 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to any of these viruses.
  • the present disclosure includes methods of treatment or prevention of infection of a virus having a genome sequence as represented by GenBank® Accession No.
  • NC_045512 (origin Wuhan, China) and any virus having a genome sequence with at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to this virus.
  • Infection with any strain of SARS-CoV-2 may be treated or prevented, including at least B.1.526, B.1.526.1, B.1.525, B.1.1.7, B.1.351, B.1.427, B.1.429, B.1.617, P.1, and P.2.
  • An individual in need thereof may be an individual having one or more symptoms of infection by a virus of the Coronaviridae family, such as SARS-CoV-2 or SARS- CoV.
  • a virus of the Coronaviridae family such as SARS-CoV-2 or SARS- CoV.
  • Common initial signs and symptoms of SARS-CoV-2 may include fever, cough, shortness of breath or difficulty breathing, tiredness, aches, chills, sore throat, loss of smell, loss of taste, headache, diarrhea, dizziness, and/or vomiting.
  • the individual may develop pneumonia or acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the virus is SARS-CoV-2, and in certain embodiments the virus is not SARS-CoV or MERS.
  • an individual having one or more post-infection effects is administered any composition described herein.
  • an individual having one or more post-infection effects is administered compositions consisting of, consisting essentially of, or comprising glycine (or a functional derivative or precursor thereof) and N- acetylcysteine (or a functional derivative or precursor thereof).
  • a post-infection effect may be a chronic syndrome, a chronic illness, a chronic disorder, and/or a chronic disease.
  • post-infection effects may result from a chronic infection.
  • a post-infection effect may start during or after an active infection.
  • one or more post-infection effects last in an individual for 1, 2, 3, 4, 5, 6, 7 days; 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or 1, 2, 3, 4, 5, or more years after an active infection.
  • one or more post-infection effects comprise post-COVID-19 syndrome and/or long COVID-19.
  • An individual suffering from at least one post-infection effect may be a COVID long hauler.
  • any symptom referred to herein with respect to acute-Covid could also apply to long-Covid.
  • An individual considered to be a COVID long hauler may be one that is recovered from the acute phase of the illness and no longer has live coronavirus in the body and that would test negative for the coronavirus, but they still have one or more symptoms.
  • This individual may also be referred to as having post-acute sequelae of SARS-CoV-2, post-COVID syndrome, long COVID, or long-term COVID.
  • Some of these individuals may have fatigue, shortness of breath, cough, joint pain, chest pain, cognitive problems, difficulty concentrating, depression, muscle pain, headache, rapid heartbeat, and/or intermittent fever.
  • long haulers may have breathing issues, including from lung scarring; heart problems, including from inflammation of the heart muscle; kidney damage; lost or distorted senses of smell and/or taste; neurological problems, including brain fog, fatigue, headaches and/or dizziness; autonomic nervous system symptoms, including Postural orthostatic tachycardia syndrome, headache, fatigue, brain fog, difficulties in thinking or concentrating, and/or insomnia; mental health issues, including anxiety and/or depression; and/or development of type 2 diabetes.
  • breathing issues including from lung scarring
  • heart problems including from inflammation of the heart muscle; kidney damage; lost or distorted senses of smell and/or taste
  • neurological problems including brain fog, fatigue, headaches and/or dizziness
  • autonomic nervous system symptoms including Postural orthostatic tachycardia syndrome, headache, fatigue, brain fog, difficulties in thinking or concentrating, and/or insomnia
  • mental health issues including anxiety and/or depression; and/or development of type 2 diabetes.
  • Post-infection effects may include fatigue (including chronic fatigue syndrome), shortness of breath, cough, congestion, joint pain, chest pain, abdominal pain, difficulty with thinking and/or difficulty with concentration, brain fog, confusion, depression, muscle pain, headache, tinnitus, intermittent fever, fast-beating and/or pounding heart (also known as heart palpitations), diarrhea, nausea, cardiovascular issues (including heart inflammation), impairment of exercise capacity, pulmonary embolism, stroke, blot clots, immunological issues, respiratory issues (including lung function abnormalities), renal issues (including acute kidney injury), dermatologic issues (including rash or hair loss), neurological issues (including smell and taste problems, sleep issues, post-traumatic stress disorder, or memory problems), psychiatric issues (including anxiety or changes in mood), or a combination thereof.
  • fatigue including chronic fatigue syndrome
  • shortness of breath cough, congestion, joint pain, chest pain, abdominal pain, difficulty with thinking and/or difficulty with concentration
  • brain fog confusion
  • depression depression
  • muscle pain headache
  • tinnitus intermittent fever
  • a post-infection effect may occur in an individual that has recovered from an infection, including an active infection.
  • the determination of whether an individual has recovered from an infection, including an active infection is done by a person skilled in the art.
  • an individual has recovered from an infection 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or more days after being diagnosed with the infection and/or after developing symptoms caused by or associated with the infection.
  • an individual has recovered when the individual is able to return to normal daily functions, such as returning to work or school.
  • an individual has recovered from an infection if at least 1, 2, 3, 4, 5 or more days have passed without the individual having a fever, including while the individual is not taking fever-reducing medication. In some embodiments, an individual has recovered from an infection if at least 1, 2, 3, 4, 5 or more days have passed without any active infection symptom, or any symptom has decreased in severity. In some embodiments, an individual has recovered from an infection when the individual has developed an adaptive immune response to the infection source, such as the vims comprising the infection. In some embodiments, an individual has recovered from an infection when the individual is no longer contagious to other individuals. In some embodiments, an individual has recovered from an infection if the individual tests negative for the infection at least once after having been diagnosed with, or testing positive for, the infection. The test for the infection may comprise any laboratory test, any swab test, any PCR test, any antibody test, any antigen test, any imaging test (such as a CT scan), or any other test capable of determining whether an individual has an infection.
  • the present disclosure is directed to pharmaceutical compositions for use in treating, preventing, delaying onset of, or reducing severity of a viral infection in an individual, including at least in some cases a viral infection that is directly or indirectly related to reduced intracellular GSH levels.
  • the compositions consist of, consisting essentially of, or comprise glycine (or a functional derivative thereof) and N-acetylcysteine (or a functional derivative thereof).
  • a functional derivative of glycine is defined as a glycine derivative that is effective in an individual in by itself or in conjunction with N-acetylcysteine (or a functional derivative thereof) to increase intracellular GSH levels.
  • a functional derivative of N-acetylcysteine is defined as a N-acetylcysteine derivative that is effective in an individual in by itself or in conjunction with glycine (or a functional derivative thereof) to increase intracellular GSH levels.
  • a “cysteine” derivative i.e., a functional derivative of cysteine that is effective in an individual in by itself or in conjunction with glycine, may be employed.
  • the glycine component and N-acetylcysteine component may be provided together or separately.
  • the glycine component and N-acetylcysteine component may or may not be provided in the same formulation.
  • the composition comprises N- acetylcysteinylglycine; cysteinylglycine and all its forms, e.g., L-cysteinylglycine; and so forth.
  • Examples of glycine derivatives includes at least D-Allylglycine; N- [Bis(methylthio)methylene]glycine methyl ester; Boc-allyl-Gly-OH (dicyclohexylammonium) salt; Boc-D-Chg-OH; Boc-Chg-OH; (R)-N-Boc-(2'-chlorophenyl)glycine; Boc-L- cyclopropylglycine; Boc-L-cyclopropylglycine; (R)-N-Boc-4-fluorophenylglycine; Boc-D- propargylglycine; Boc-(S)-3-thienylglycine; Boc-(R)-3-thienylglycine; D-a-Cyclohexylglycine; L-a-Cyclopropylglycine; N-(2-fluorophenyl)-N-(methylsulfonyl) glycine; N-
  • the pharmaceutical compositions comprise N- acetylcysteine (NAC), F-glycine, F-glycine ethyl ester, and/or dipeptide forms, e.g., cysteinylglycine.
  • NAC N- acetylcysteine
  • F-glycine F-glycine
  • F-glycine ethyl ester F-glycine ethyl ester
  • dipeptide forms e.g., cysteinylglycine.
  • glycine is administered at 1-150 mg/kg/day and NAC is administered at 1-150 mg/kg/day for a particular period of time.
  • the range of dose for either or both may be 1-150, 1-125, 1-100, 1-75, 1-50, 1-25, 1-20, 1-10, 1-5, 10-150, 10-125, 10- 100, 10-75, 10-50, 10-25, 25-150, 25-125, 25-100, 25-75, 25-50, 50-150, 50-125, 50-100, 50-75, 75-150, 75-125, 75-100, 100-150, 100-125, or 125-150 mg/kg/day, for example.
  • glycine is administered at 1.33 mmol/kg/d and NAC is administered at 0.83 mmol/kg/d for a particular period of time. Durations of treatment may last for one or more days, 1 week, 2 weeks, 3 weeks, one month, two months, three months, four months, five months, six months, one year, two years, five years, ten years, fifteen years, twenty years, twenty-five years, thirty years, and so forth, for example.
  • an individual with acute-Covid is treated from 1-30 days, including 1-25, 1-20, 1-15, 1-10, 1-5, 5-30, 5-25, 5-20, 5-15, 5-10, 10-30, 10-25, 10-20, 10-15, 15-30, 15-25, 15-20, 20-30, 20-25, 25-30, and so forth.
  • an individual with long-Covid is treated from 3 months to lifelong, 3 months to 70 years (yrs), 3 months to 60 yrs, 3 months to 50 yrs, 3 months to 40yrs, 3 months to 30 yrs, 3 months to 20 yrs, 3 months to 10 yrs, 3 months to 5 yrs, 3 months to 1 yr, and any range derivable therein.
  • the treatment lasts for the remaining life of the individual.
  • the administration occurs until no detectable symptoms of the viral infection remain or until one or more symptoms have disappeared, such as ARDS, pneumonia, and/or fever, for example.
  • the administration occurs until a detectable improvement of at least one symptom occurs and, in further cases, continues to remain ameliorated.
  • the treatment may occur on individuals who are not hospitalized but are quarantining or recovering at home.
  • compositions of the disclosure are directed to treating with the compounds of the present disclosure
  • administration of the compounds of the disclosure with a suitable pharmaceutical excipient as necessary can be carried out via any of the accepted modes of administration.
  • the compounds may be comprised in a pharmaceutically acceptable excipient, which may be considered as a molecular entity and/or composition that does not produce an adverse, allergic and/or other untoward reaction when administered to an animal, as appropriate. It includes any and/or all solvents, dispersion media, coatings, antibacterial and/or antifungal agents, isotonic and/or absorption delaying agents and/or the like. The use of such media and/or agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media and/or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • administration can be, for example, intravenous, topical, subcutaneous, transcutaneous, intramuscular, oral, intra-joint, parenteral, peritoneal, intranasal, intravesical or by inhalation.
  • Suitable sites of administration thus include, but are not limited to, skin, bronchial, gastrointestinal, anal, vaginal, eye, bladder, and ear.
  • the formulations may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, aerosols or the like, e.g., in unit dosage forms suitable for simple administration of precise dosages.
  • the compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, and the like. In specific embodiments, the composition will be about 5% to 75% by weight of a compound or compounds of the disclosure, with the remainder consisting of suitable pharmaceutical excipients.
  • excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the composition may take the form of a solution, suspension, tablet, pill, capsule, powder, sustained-release formulation, and the like.
  • the pharmaceutical compositions take the form of a pill, tablet or capsule, and thus, the composition can contain, along with the biologically active conjugate, any of the following: a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
  • a diluent such as lactose, sucrose, dicalcium phosphate, and the like
  • a disintegrant such as starch or derivatives thereof
  • a lubricant such as magnesium stearate and the like
  • a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
  • the active compounds of the formulas may be formulated into a suppository comprising, for example, about 0.5% to about 50% of a compound of the disclosure, disposed in a polyethylene glycol (PEG) carrier (e.g., PEG 1000 [96%] and PEG 4000 [4%]).
  • PEG polyethylene glycol
  • Liquid compositions can be prepared by dissolving or dispersing compound (about 0.5% to about 20%), and optional pharmaceutical adjuvants in a carrier, such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol and the like, to form a solution or suspension, e.g., for intravenous administration.
  • a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol and the like, to form a solution or suspension, e.g., for intravenous administration.
  • a carrier such as, for example, aqueous saline (e.g., 0.9% w/v sodium chloride), aqueous dextrose, glycerol, ethanol and the like.
  • the active compounds may also be formulated into a retention
  • the composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as, for example, sodium acetate, sorbitan monolaurate, or triethanolamine oleate.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as, for example, sodium acetate, sorbitan monolaurate, or triethanolamine oleate.
  • the composition is administered in any suitable format, such as a lotion or a transdermal patch.
  • the composition can be delivered as a dry powder (e.g ., Inhale Therapeutics) or in liquid form via a nebulizer.
  • compositions to be administered will, in any event, contain a quantity of the pro- drug and/or active compound(s) in a pharmaceutically effective amount for relief of the condition being treated when administered in accordance with the teachings of this disclosure.
  • the compounds of the disclosure are administered in a therapeutically effective amount, i.e., a dosage sufficient to effect treatment, which will vary depending on the individual and condition being treated.
  • a therapeutically effective daily dose is from 0.1 to 100 mg/kg of body weight per day of drug.
  • Most conditions respond to administration of a total dosage of between about 1 and about 30 mg/kg of body weight per day, or between about 70 mg and 2100 mg per day for a 70 kg person.
  • Stability of the conjugate can be further controlled by chemical alterations, including D amino acid residues in the polypeptide chain as well as other peptidomimetic moieties. Furthermore, stability of the conjugates could also be enhanced by unnatural carbohydrate residues.
  • the glycine and N-acetylcysteine components may be formulated in a particular ratio, whether or not they are present in the same formulation.
  • the components are provided to the individual in the following exemplary ratios (including in specific cases in the same formulation): 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100, 1:150, 1:200, 1:300, 1:400, 1:500, 1:600, 1:750, 1:1000, 1:10,000, and so forth, for example.
  • the formulation may comprise the components in the following percentages by formulation (either the same or different percentages for each): 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99%, for example.
  • Glycine (or a functional derivative) and N-acetylcysteine (or a functional derivative) may be delivered in the same composition or in different compositions.
  • the regimen for their separate delivery may be of any suitable kind.
  • the glycine is provided to the individual prior to the N- acetylcysteine, at the same time as N-acetylcysteine, or subsequent to N-acetylcysteine.
  • Separate deliveries may encompass the same route of administration but at different times or may be different routes of administration.
  • an additional viral therapy or preventative may be provided in combination with the disclosed treatment.
  • the additional viral therapy or preventative is for a Coronaviridae family infection (including SARS-CoV-2) selected from the group consisting of Azithromycin, AC-55541, Apicidin, AZ3451, AZ8838, Bafilomycin Al, CCT 365623, Daunorubicin, E-52862, Entacapone, GB110, H-89, Haloperidol, Indomethacin, JQ1, Loratadine, Merimepodib, Metformin, Midostaurin, Migalastat, Mycophenolic acid, PB28, PD- 144418, Ponatinib, Ribavirin, RS-PPCC, Ruxolitinib, RVX-208, S-verapamil, Silmitasertib , TMCB, UCPH-101, Valproic Acid, XL413, ZINC
  • the disclosed treatment may precede, follow, or both an additional viral treatment or preventative by intervals ranging from minutes to weeks to months.
  • the disclosed treatment and the additional agent are provided separately to an individual, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the disclosed treatment and the additional agent would still be able to exert an advantageously combined effect on the cell.
  • kits associated with the compositions of the present disclosure comprise another aspect of the present disclosure.
  • Such kits will generally contain, in suitable container means, an inventive composition of the present disclosure.
  • the kit may have a single container means that contains the inventive composition or it may have distinct container means for the inventive composition and other reagents that may be included within such kits.
  • the components of the kit may be provided as liquid solution(s), or as dried powder(s).
  • the liquid solution is an aqueous or non-aqueous solution, including at least a sterile aqueous or non-aqueous solution.
  • the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent may also be provided in another container means.
  • the container means will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which the composition may be placed, and, in some embodiments, suitably aliquoted. Where a second agent is provided, the kit will also generally contain a second vial or other container into which this agent may be placed.
  • the kits of the present disclosure will also typically include a means for containing the agent containers in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which the desired vials are retained, for example.
  • the glycine (or functional derivative thereof) and the N-acetylcysteine (or functional derivative thereof) may be provided separately or in a mixture together.
  • the kit comprises one or more reagents for diagnosis of a viral infection of the Coronaviridae family, including SARS-CoV-2.
  • reagents include primers for viral nucleic acid detection and/or antibodies for viral antigen detection.
  • patients infected with Coronaviridae vims have severely elevated inflammation, suppressed immune function, and viral pneumonia - specifically, suppressed plasma levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen- presenting cells of the immune system in these patients correlate inversely with elevated inflammatory markers IL-6, CRP, TNF-alpha, IL-10, and/or MCP-1.
  • Coronaviridae viral infections are associated with severe and harmful oxidative stress, vascular endothelial dysfunction, impaired red-blood function and impaired oxygen delivery to tissues.
  • cells protect themselves from the ravages of oxidative stress by synthesizing glutathione (GSH).
  • GSH glutathione
  • cortiridae viral infections result in GSH deficiency, and cell-culture studies show that increasing GSH levels have a viricidal effect by inhibiting replication of Coronaviridae viruses.
  • the combination of GSH deficiency, elevated oxidative stress, endothelial dysfunction, inflammation, and/or immunosuppression combine to contribute to the severely elevated mortality due to COVID-19.
  • Coronaviridae viral infections have significantly elevated oxidative stress, inflammation and immunosuppression.
  • tracer studies demonstrate that the reason for elevated oxidative stress in Coronaviridae viral infections is severe deficiency of the endogenous antioxidant protein glutathione (GSH), and the GSH deficiency occurs due to diminished availability of its precursor amino-acids glycine and cysteine.
  • GlyNAC N-acetylcysteine
  • results show correction of intracellular GSH deficiency together with a significant decrease in plasma oxidative stress (measured as plasma concentrations of TBARS, malondialdehyde, lipid-peroxide, and/or F2-isoprostanes), severely elevated inflammation (plasma IL-6, CRP, TNF-alpha, IL-10, and/or MCP-1), and endothelial dysfunction (plasma sICAMl, s VC AMI and/or E-selectin). In certain aspects, this is associated with significant improvement of key functional measures in Coronaviridae viral infection patients.
  • supplementing GlyNAC in patients infected with a Coronaviridae vims, particularly the SARS-CoV-2 virus effectively treats or prevents or delay onset of or reduces severity of COVID- 19 by correcting GSH deficiency and lowering oxidative stress, inflammation, endothelial dysfunction and defective immune function in patients.
  • a corthelial dysfunction effectively treats or prevents or delay onset of or reduces severity of COVID- 19 by correcting GSH deficiency and lowering oxidative stress, inflammation, endothelial dysfunction and defective immune function in patients.
  • such a treatment leads to significant decline in morbidity, mortality and healthcare expenditure.
  • Glutathione (GSH) in COVID-19 patients by age group In certain aspects, in a randomized trial, intracellular GSH concentrations are studied in patients diagnosed with COVID-19 (ages 20-90y), and results are compared to patients without COVID-19. Intracellular GSH levels are measured in all subjects from red-blood cells. Results are stratified by age and show that COVID-19 patients have a severe intracellular GSH deficiency, and this becomes progressively worse with advancing age. Regarding COVID-19, comparing young patients (age range 20-30 years), with middle aged patients (age 40-50 years) with elderly patients (60-90 years) shows that GSH levels are highest in the young group and progressively decline with advancing age to be lowest in the elderly group.
  • GlyNAC glycine and cysteine (as N-acetylcysteine)
  • placebo for 14-21 days, and GSH concentratrations improve only in patients supplemented with GlyNAC (but not placebo), but the increase in GSH levels is higher with advancing age such that at the end of the supplementation period, all patients have similar GSH values.
  • Glutathione in COVID-19 patients with HIV In certain aspects, in a randomized clinical trial, intracellular GSH concentrations are studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Intracellular GSH levels are measured in all subjects from red-blood cells. Results show that GSH concentrations at the end of supplementation improve only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Glutathione in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, intracellular GSH concentrations are studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID- 19 serves as a control. Intracellular GSH levels are measured in all subjects from red-blood cells. Results show that GSH concentrations at the end of supplementation improve only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that the GSH levels in diabetic COVID-19 subjects increase to approximate values in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Glutathione in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • intracellular GSH concentrations are studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Intracellular GSH levels are measured in all subjects from red-blood cells. Results show that GSH concentrations at the end of supplementation improve only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses show that the GSH levels in prediabetic COVID-19 subjects increase to approximate values in subjects without prediabetes or diabetes or COVID-19.
  • Glutathione in obese COVID-19 patients In certain aspects, in a randomized clinical trial, intracellular GSH concentrations are studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID- 19 serves as a control. Intracellular GSH levels are measured in all subjects from red-blood cells. Results show that GSH concentrations at the end of supplementation improve only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that the GSH levels in obese COVID-19 subjects increase to approximate values in subjects without obesity, diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • all COVID-19 patients have greater GSH deficiency than the non-COVID-19 control group because of decreased availability of its precursors cysteine and glycine, while older COVID-19 patients have significantly lower GSH levels than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly lower GSH levels than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly lower GSH levels than non-prediabetic, non-diabetic, non-COVID- 19 patients.
  • Obese patients with COVID-19 have significantly lower GSH levels than non-obese non-COVID-19 patients.
  • Cysteine and glycine supplementation increase GSH levels in all patients with COVID-19.
  • Coronaviridae viral infections are associated with severe and harmful oxidative stress, an imbalance between free radicals and antioxidants in the body.
  • a surplus amount of free radicals for example reactive oxygen species (ROS)
  • ROS reactive oxygen species
  • Oxidative degradation of lipids by ROS forms highly reactive and unstable lipid peroxides.
  • Decomposition of lipid peroxides results in the formation of Thiobarbituric Acid Reactive Substances (TBARS), malondialdehyde, lipid-peroxide, and/or F2-isoprostanes (F2-isoPs) which are useful as biomarkers for oxidative stress.
  • TBARS Thiobarbituric Acid Reactive Substances
  • F2-isoPs F2-isoprostanes
  • Oxidative stress in COVID-19 patients by age group in certain aspects, in a randomized trial, biomarkers of oxidative stress are studied in patients diagnosed with COVID-19 (ages 20-90y), and results are compared to patients without COVID-19. Levels of biomarkers of oxidative stress are measured in all subjects as plasma levels of TBARS, malondialdehyde, lipid-peroxide, and/or F2-isoPs in blood. Results are stratified by age and will show that COVID-19 patients will have a higher levels of biomarkers of oxidative stress, and this is progressively higher with advancing age.
  • Biomarkers of oxidative stress in COVID-19 patients with HIV are studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • Levels of biomarkers of oxidative stress are measured in all subjects as plasma levels of TBARS, malondialdehyde, lipid- peroxide, and/or F2-isoPs in blood. Results show that levels of biomarkers of oxidative stress improve only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • Biomarkers of oxidative stress COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, levels of biomarkers of oxidative stress in plasma are studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Levels of biomarkers of oxidative stress are measured in all subjects as plasma levels of TBARS, malondialdehyde, lipid-peroxide, and/or F2-isoPs in blood.
  • GlyNAC cysteine plus glycine
  • Biomarkers of oxidative stress in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • levels of biomarkers of oxidative stress are studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Levels of biomarkers of oxidative stress are measured in all subjects as plasma levels of TBARS, malondialdehyde, lipid-peroxide, and/or F2-isoPs in blood. Results show that levels of biomarkers of oxidative stress improve only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses show that the levels of biomarkers of oxidative stress in prediabetic COVID-19 subjects decrease to approximate values in subjects without diabetes or COVID-19.
  • Biomarkers of oxidative stress in obese COVID-19 patients In certain aspects, in a randomized clinical trial, levels of biomarkers of oxidative stress are studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID-19 serves as a control. Levels of biomarkers of oxidative stress are measured as plasma levels of TBARS, malondialdehyde, lipid-peroxide, and/or F2-isoPs in blood in all subjects.
  • GlyNAC cysteine plus glycine
  • Results show that levels of biomarkers of oxidative stress improve only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that the levels of biomarkers of oxidative stress in obese COVID- 19 subjects decrease to approximate values in subjects without obesity, diabetes or COVID-19.
  • all COVID-19 patients have greater levels of biomarkers of oxidative stress than the non-COVID-19 control group because of decreased availability of its precursors cysteine and glycine, while older COVID-19 patients have significantly higher levels of biomarkers of oxidative stress than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher levels of biomarkers of oxidative stress than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher levels of biomarkers of oxidative stress than patients without prediabetes or diabetes or COVID-19.
  • IL-6 is a pro-inflammatory cytokine produced in response to tissue damage and infections. Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine. IL-6 has long been considered a biomarker for inflammation.
  • Tumor necrosis factor a (TNFa) is a pro-inflammatory cytokine produced by activated macrophages, T and B lymphocytes, natural killer cells, astrocytes, endothelial cells, smooth muscle cells, some tumor cells, and epithelial cells. TNFa is also a useful biomarker for inflammation.
  • elevated IL-6 and TNFa are associated with Coronaviridae viral infections, where IL-6 and TNFa may lead to a ‘cytokine storm' response that leads to acute lung injury or its more severe form of acute respiratory distress syndrome.
  • C-reactive protein is an acute-phase protein found in the blood plasma, and is synthesized by the liver. Levels of CRP rise in response to inflammation, and therefore it is considered a biomarker for conditions associated with increased inflammation. CRP is also a useful biomarker for cardiovascular disease - levels >3 pg/ml are considered undesirable, and levels ⁇ 1 pg/ml are optimal. In certain aspects, elevated CRP is linked to Coronaviridae viral infections.
  • Inflammation in COVID-19 patients by age group In certain aspects, in a randomized trial, levels of biomarkers of inflammation are studied in patients diagnosed with COVID-19 (ages 20-90y), and results are compared to patients without COVID-19. Levels of biomarkers of inflammation are measured in all subjects as plasma levels of IL-6, TNFa, and/or CRP in blood. Results are stratified by age and show that COVID-19 patients have higher levels of biomarkers of inflammation, and this is progressively higher with advancing age.
  • Biomarkers of inflammation in COVID-19 patients with HIV are studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Levels of biomarkers of inflammation are measured in all subjects as plasma levels of IL-6, TNFa, and/or CRP in blood. Results show that levels of biomarkers of inflammation improve only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Biomarkers of inflammation in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, levels of biomarkers of inflammation are studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Levels of biomarkers of inflammation are measured in all subjects as plasma levels of IL-6, TNFa, and/or CRP in blood. Results show that levels of biomarkers of inflammation will improve only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that the levels of biomarkers of inflammation in diabetic COVID-19 subjects decrease to approximate values in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Biomarkers of inflammation in COVID-19 patients with prediabetes are studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Levels of biomarkers of inflammation will be measured in all subjects as plasma levels of IL-6, TNFa, and/or CRP in blood.
  • Biomarkers of inflammation in obese COVID-19 patients In certain aspects, in a randomized clinical trial, levels of biomarkers of inflammation are studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID-19 serves as a control.
  • GlyNAC cysteine plus glycine
  • Levels of biomarkers of inflammation are measured in all subjects as plasma levels of IL-6, TNFa, and/or CRP in blood. Results show that levels of biomarkers of inflammation at the end of supplementation will improve only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that the levels of biomarkers of inflammation in obese COVID-19 subjects decrease to approximate values in subjects without obesity, diabetes or COVID-19.
  • all COVID-19 patients have greater levels of biomarkers of inflammation than the non-COVID-19 control group because of decreased availability of its precursors cysteine and glycine, while older COVID-19 patients have significantly higher levels of biomarkers of inflammation than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher levels of biomarkers of inflammation than non- HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher levels of biomarkers of inflammation than non-prediabetic, non-diabetic, non- COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher levels of biomarkers of inflammation than non-obese non-COVID-19 patients.
  • Cysteine and glycine supplementation lower levels of biomarkers of inflammation in all patients with COVID-19.
  • plasma levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen-presenting cells of the immune system in patients correlate inversely with elevated inflammatory markers IL-6 and C-reactive protein (CRP).
  • CRP C-reactive protein
  • Immunosuppression in COVID-19 patients by age group In certain aspects, in a randomized trial, immunosuppression are studied in patients diagnosed with COVID- 19 (ages 20-90y), and results compared to patients without COVID-19. Immunosuppression is measured in all subjects as blood levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen -presenting cells in blood. Results are stratified by age and show that COVID-19 patients have a severe immune cell deficiency, and this becomes progressively worse with advancing age.
  • Immunosuppression in COVID-19 patients with HI is studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Immunosuppression is measured in all subjects as levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen-presenting cells in blood. Results show that immune cell levels at the end of supplementation improve only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Immunosuppression in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, immunosuppression is studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Immunosuppression is measured in all subjects as plasma levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen-presenting cells in blood. Results show that plasma immune cell levels at the end of supplementation improve only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that the plasma immune cell levels in diabetic COVID-19 subjects increase to approximate values in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Immunosuppression in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • prediabetes defined as fasting glucose values between 100-125 mg/dl
  • immunosuppression is studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control. Immunosuppression is measured in all subjects as levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen-presenting cells in blood.
  • results show that immune cell levels at the end of supplementation improve only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses show that the immune cell levels in prediabetic COVID-19 subjects increase to approximate values in subjects without diabetes or COVID-19.
  • Immunosuppression in obese COVID-19 patients In certain aspects, in a randomized clinical trial, immunosuppression is studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID- 19 serves as a control. Immunosuppression is measured in all subjects as levels of CD4+ T-Cells, CD8+ T-Cells, B-cells, NK cells, and/or antigen-presenting cells in blood. Results show that immune cell levels at the end of supplementation improve only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that the immune cell levels in obese COVID-19 subjects increase to approximate values in subjects without obesity, diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • all COVID-19 patients have a greater immune cell deficiency than the non-COVID-19 control group, while older COVID-19 patients have significantly lower immune cell levels than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly lower immune cell levels than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly lower immune cell levels than patients without prediabetes or diabetes or COVID-19.
  • Obese patients with COVID-19 have significantly lower plasma immune cell levels than non-obese non-COVID-19 patients. Cysteine and glycine supplementation increase immune cell levels in all patients with COVID-19.
  • CAMs are a class of cell surface binding proteins that are secreted from the surface of dysfunctional endothelium cells.
  • elevated plasma levels of soluble CAMs including sICAMl, sVCAMl, and E-selectin, are linked to endothelium dysfunction associated with Coronaviridae viral infections.
  • Endothelial dysfunction in COVID-19 patients by age group In certain aspects, in a randomized trial, levels of biomarkers of endothelial dysfunction are studied in patients diagnosed with COVID-19 (ages 20-90y), and results are compared to patients without COVID-19.
  • Levels of biomarkers of endothelial dysfunction are measured in all subjects as plasma levels of sICAMl, sVCAMl, and/or E-selectin in blood. Results are stratified by age and show that COVID-19 patients have elevated levels of biomarkers of endothelial dysfunction, and this becomes progressively worse with advancing age. Regarding COVID-19, comparing young patients (age range 20-30 years), with middle aged patients (age 40-50 years) with elderly patients (60-90 years) shows that levels of biomarkers of endothelial dysfunction are lowest in the young group and progressively increase with advancing age to be highest in the elderly group.
  • GlyNAC glycine and cysteine (as N-acetylcysteine)
  • placebo for 14-21 days, and levels of biomarkers of endothelial dysfunction improve only in patients supplemented with GlyNAC (but not placebo), but the decrease in levels of biomarkers of endothelial dysfunction is higher with advancing age, such that at the end of the supplementation period all patients have similar levels of biomarkers of endothelial dysfunction.
  • Biomarkers of endothelial dysfunction in COVID-19 patients with HIV In certain aspects, in a randomized clinical trial, levels of biomarkers of endothelial dysfunction are studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Levels of biomarkers of endothelial dysfunction are measured in all subjects as plasma levels of sICAMl, sVCAMl, and/or E-selectin in blood. Results show that levels of biomarkers of endothelial dysfunction improve only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Biomarkers of endothelial dysfunction in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, levels of bio markers of endothelial dysfunction are studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Levels of biomarkers of endothelial dysfunction are measured in all subjects as plasma levels of sICAMl, sVCAMl, and/or E-selectin in blood.
  • GlyNAC cysteine plus glycine
  • results show that levels of biomarkers of endothelial dysfunction improve only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that the levels of biomarkers of endothelial dysfunction in diabetic COVID-19 subjects decrease to approximate values in subjects without diabetes or COVID-19.
  • Biomarkers of endothelial dysfunction in COVID-19 patients with prediabetes are studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Levels of biomarkers of endothelial dysfunction are measured in all subjects as plasma levels of sICAMl, sVCAMl, and/or E-selectin in blood.
  • results show that levels of biomarkers of endothelial dysfunction at the end of supplementation improve only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses show that the levels of biomarkers of endothelial dysfunction in prediabetic COVID-19 subjects decrease to approximate values in subjects without diabetes or COVID-19.
  • Biomarkers of endothelial dysfunction in obese COVID-19 patients In certain aspects, in a randomized clinical trial, levels of biomarkers of endothelial dysfunction are studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID-19 serves as a control. Levels of biomarkers of endothelial dysfunction are measured in all subjects as plasma levels of sICAMl, sVCAMl, and/or E-selectin in blood.
  • GlyNAC cysteine plus glycine
  • results show that levels of biomarkers of endothelial dysfunction at the end of supplementation improve only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that the levels of biomarkers of endothelial dysfunction in obese COVID-19 subjects decrease to approximate values in subjects without obesity, diabetes or COVID-19.
  • all COVID-19 patients have greater levels of biomarkers of endothelial dysfunction than the non-COVID-19 control group, while older COVID-19 patients have significantly higher levels of biomarkers of endothelial dysfunction than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher levels of biomarkers of endothelial dysfunction than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher levels of bio markers of endothelial dysfunction than non-diabetic non-COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher levels of biomarkers of endothelial dysfunction than non-obese non-COVID- 19 patients.
  • Cysteine and glycine supplementation lower the levels of biomarkers of endothelial dysfunction in all patients with COVID-19.
  • GSH deficiency results in impaired fasted mitochondrial nonesterified fatty acid (NEFA) oxidation, forcing a shift to glucose oxidation for energy needs.
  • NEFA fatty acids
  • F fatty acids
  • Mitochondrial dysfunction in COVID-19 patients by age group In certain aspects, in a randomized trial, mitochondrial dysfunction is studied in patients diagnosed with COVID-19 (ages 20-90y), and results are compared to patients without COVID-19. Mitochondrial dysfunction are measured in all subjects as impaired FA oxidation and as elevated fasting glucose oxidation at the whole-body and at the cellular levels. Results are stratified by age and will show that COVID-19 patients have severe mitochondrial dysfunction, and this becomes progressively worse with advancing age.
  • Mitochondrial dysfunction in COVID-19 patients with HIV In certain aspects, in a randomized clinical trial, mitochondrial dysfunction are studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Mitochondrial dysfunction are measured in all subjects as impaired FA oxidation and as elevated fasting glucose oxidation at the whole-body and at the cellular levels. Results show that mitochondrial dysfunction will improve only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Mitochondrial dysfunction in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, mitochondrial dysfunction is studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Mitochondrial dysfunction are measured in all subjects as impaired FA oxidation and as elevated fasting glucose oxidation at the whole-body and at the cellular levels. Results show that mitochondrial dysfunction improves only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that mitochondrial dysfunction in diabetic COVID-19 subjects improves to approximate values in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Mitochondrial dysfunction in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • mitochondrial dysfunction is studied in prediabetic patients diagnosed with COVID- 19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Mitochondrial dysfunction are measured in all subjects as impaired FA oxidation and as elevated fasting glucose oxidation at the whole-body and at the cellular levels.
  • Mitochondrial dysfunction in obese COVID-19 patients In certain aspects, in a randomized clinical trial, mitochondrial dysfunction is studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID-19 serves as a control.
  • GlyNAC cysteine plus glycine
  • Mitochondrial dysfunction are measured in all subjects as impaired FA oxidation and as elevated fasting glucose oxidation at the whole-body and at the cellular levels. Results show that mitochondrial dysfunction at the end of supplementation improves only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that mitochondrial dysfunction in obese COVID-19 subjects improves to approximate values in subjects without obesity, diabetes or COVID-19.
  • all COVID-19 patients have greater mitochondrial dysfunction than the non-COVID-19 control group, while older COVID-19 patients have significantly higher mitochondrial dysfunction than younger COVID-19 patients.
  • HIV patients with COVID-19 will have significantly higher mitochondrial dysfunction than non-HIV non- COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher mitochondrial dysfunction than non-diabetic non-COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher mitochondrial dysfunction than non-obese non-COVID-19 patients. Cysteine and glycine supplementation lower mitochondrial dysfunction by improving mitochondrial function in all patients with COVID-19.
  • Insulin sensitivity can be measured by the homeostatic modeling assessment (HOMA-IR), fasting glucose and insulin levels, and also by the clamp methods, such as the hyperglycemic clamp method and the hyperinsulinemic-euglycemic clamp method.
  • Insulin resistance in COVID-19 patients by age group In certain aspects, in a randomized trial, insulin resistance is studied in patients diagnosed with COVID-19 (ages 20-90y), and results compared to patients without COVID-19. Insulin resistance is measured in all subjects. Results are stratified by age and show that COVID-19 patients have severe insulin resistance, and this becomes progressively worse with advancing age. Regarding COVID-19, comparing young patients (age range 20-30 years), with middle aged patients (age 40-50 years) with elderly patients (60-90 years) shows that insulin resistance is lowest in the young group and progressively increases with advancing age to be highest in the elderly group.
  • GlyNAC glycine and cysteine (as N-acetylcysteine)
  • placebo for 14-21 days, and insulin resistance improves only in patients supplemented with GlyNAC (but not placebo), but the decrease in insulin resistance is higher with advancing age, such that at the end of the supplementation period all patients have similar insulin resistance.
  • Insulin resistance in COVID-19 patients with HI In certain aspects, in a randomized clinical trial, insulin resistance is studied in HIV patients diagnosed with COVID- 19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Insulin resistance is measured in all subjects. Results show that insulin resistance improves only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Insulin resistance in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, insulin resistance is studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Insulin resistance is measured in all subjects. Results show that insulin resistance improves only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that insulin resistance in diabetic COVID-19 subjects decreases to approximate insulin resistance values in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Insulin resistance in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • insulin resistance is studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control. Insulin resistance will be measured in all subjects. Results will show that insulin resistance at the end of supplementation will improve only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses will show that insulin resistance in prediabetic COVID-19 subjects will decrease to approximate insulin resistance values in subjects without prediabetes, diabetes, or COVID-19.
  • Insulin resistance in obese COVID-19 patients In certain aspects, in a randomized clinical trial, insulin resistance is studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes, or COVID-19, serves as a control. Insulin resistance is measured in all subjects. Results show that insulin resistance at the end of supplementation improves only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that insulin resistance in obese COVID-19 subjects decreases to approximate insulin resistance values in subjects without obesity, diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • all COVID-19 patients have greater insulin resistance than the non-COVID-19 control group, while older COVID-19 patients have significantly higher levels of insulin resistance than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher insulin resistance than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher insulin resistance than non-diabetic non-COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher insulin resistance than non-obese non-COVID-19 patients.
  • Cysteine and glycine supplementation lower insulin resistance in all patients with COVID-19.
  • GSH Global System for Mobile Communications
  • cognitive impairment is correlated with low levels of GSH which is associated with a Coronaviridae viral infection.
  • Neuropsychological assessments for cognitive function include, for example, the Mini-Mental State Exam (MMSE) and Montreal cognitive assessment (MoCA) which are widely used tests of cognitive function which tests orientation, attention, memory, language and visual-spatial skills.
  • MMSE Mini-Mental State Exam
  • MoCA Montreal cognitive assessment
  • Cognitive impairment in COVID-19 patients by age group In certain aspects, in a randomized trial, cognitive impairment is studied in patients diagnosed with COVID- 19 (ages 20-90y), and results compared to patients without COVID-19. Cognitive impairment is measured in all subjects.
  • Results are stratified by age and show that COVID-19 patients have cognitive impairment, and this becomes progressively worse with advancing age.
  • COVID-19 comparing young patients (age range 20-30 years), with middle aged patients (age 40- 50 years) with elderly patients (60-90 years) shows that cognitive impairment is lowest in the young group and progressively increases with advancing age to be highest in the elderly group.
  • Patients receive supplementation with GlyNAC (glycine and cysteine (as N-acetylcysteine)) or placebo for 14-21 days, and cognitive impairment improves only in patients supplemented with GlyNAC (but not placebo), but the decrease in cognitive impairment is higher with advancing age, such that at the end of the supplementation period all patients have similar levels of cognitive function.
  • GlyNAC glycine and cysteine
  • placebo placebo
  • Cognitive impairment in COVID-19 patients with HIV In certain aspects, in a randomized clinical trial, cognitive impairment is studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Cognitive impairment is measured in all subjects. Results show that cognitive impairment improves only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Cognitive impairment in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, cognitive impairment is studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID- 19 serves as a control. Cognitive impairment is measured in all subjects and will be lower in diabetic patients. Results show that cognitive impairment improves only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that cognitive impairment in diabetic COVID-19 subjects decreases to approximate cognitive function in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Cognitive impairment in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • cognitive impairment is studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Cognitive impairment is measured in all subjects, and will be lower in prediabetic patients. Results show that cognitive impairment at the end of supplementation improves only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses show that cognitive impairment in prediabetic COVID-19 subjects decreases to approximate cognitive function in subjects without diabetes or COVID-19.
  • Cognitive impairment in obese COVID-19 patients In certain aspects, in a randomized clinical trial, cognitive impairment is studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID- 19 serves as a control. Cognitive impairment is measured in all subjects, and is lower in obese subjects. Results show that cognitive impairment at the end of supplementation improves only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that cognitive impairment in obese COVID-19 subjects decreases to approximate cognitive function in subjects without obesity, diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • all COVID-19 patients have greater cognitive impairment than the non-COVID-19 control group, while older COVID-19 patients have significantly higher cognitive impairment than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher cognitive impairment than non-HIV/non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher cognitive impairment than non-diabetic non-COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher cognitive impairment than non-obese non-COVID-19 patients.
  • Cysteine and glycine supplementation lower cognitive impairment in all patients with COVID-19.
  • GSH-deficient COVID-19 patients have impaired fasted FA oxidation and higher fasted glucose oxidation, suggesting a mitochondrial defect. Because elevated glucose oxidation in the fasted state occurs either by increased gluconeogenesis mainly from muscle protein, or by direct utilization of muscle proteins for energy needs, both routes lead to muscle loss. In certain aspects, loss of muscle strength and/or mass, gait speed, 6-minute walk test and exercise capacity correlate to low levels of GSH associated with a Coronaviridae viral infection.
  • Functional limitation in COVID-19 patients by age group In certain aspects, in a randomized trial, functional limitation is studied in patients diagnosed with COVID- 19 (ages 20-90y), and results are compared to patients without COVID-19. Functional limitation is measured in all subjects as decreased muscle mass and/or muscle strength, gait speed, 6-minute walk test and exercise capacity. Results are stratified by age and show that COVID-19 patients have elevated functional limitation, and this becomes progressively worse with advancing age. Regarding COVID-19, comparing young patients (age range 20-30 years), with middle aged patients (age 40-50 years) with elderly patients (60-90 years) shows that functional limitation is lowest in the young group and progressively increases with advancing age to be highest in the elderly group.
  • GlyNAC glycine and cysteine (as N- acetylcysteine)
  • placebo for 14-21 days, and functional limitation improves only in patients supplemented with GlyNAC (but not placebo), but the improvement in functional limitation is higher with advancing age, such that at the end of the supplementation period all patients have similar functional ability.
  • Functional limitation in COVID-19 patients with HIV In certain aspects, in a randomized clinical trial, functional limitation is studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Functional limitation is measured in all subjects as muscle mass and/or muscle strength, gait speed, 6-minute walk test and exercise capacity. Results show that functional limitation improves only in HIV patients with COVID-19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Functional limitation in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, functional limitation is studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Functional limitation is measured in all subjects as muscle mass and/or muscle strength, gait speed, 6-minute walk test and exercise capacity. Results show that functional limitation improves only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that functional limitation in diabetic COVID-19 subjects decreases to approximate functional ability in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Functional limitation in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • functional limitation is studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control.
  • Functional limitation is measured in all subjects as muscle mass and/or muscle strength, gait speed, 6-minute walk test and exercise capacity. Results show that functional limitation at the end of supplementation improves only in prediabetic patients with COVID-19 who receive GlyNAC supplementation, and not in prediabetic patients who receive placebo. Further analyses show that functional limitation in prediabetic COVID-19 subjects decreases to approximate functional ability in subjects without diabetes or COVID-19.
  • Functional limitation in obese COVID-19 patients In certain aspects, in a randomized clinical trial, functional limitation is studied in obese patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without obesity, diabetes or COVID- 19 serves as a control. Functional limitation is measured in all subjects as muscle mass and/or muscle strength, gait speed, 6-minute walk test and exercise capacity. Results show that functional limitation at the end of supplementation improves only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that functional limitation in obese COVID-19 subjects decreases to approximate functional ability in subjects without obesity, diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • all COVID-19 patients have greater functional limitation than the non-COVID-19 control group, while older COVID-19 patients have significantly higher functional limitation than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher functional limitation than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher functional limitation than non-diabetic non-COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher functional limitation than non-obese non-COVID-19 patients.
  • Cysteine and glycine supplementation lower the functional limitation in muscle strength, gait speed, 6-minute walk test, exercise capacity and muscle loss in all patients with COVID-19.
  • GSH-deficient COVID-19 patients have impaired fasted FA oxidation and higher fasted glucose oxidation, suggesting a mitochondrial defect. Because the process of breathing (respiration) requires adequate strength in the muscles of respiration, GSH deficient COVID-19 patients have decreased lung function as measured by standard clinical pulmonary function tests and oxygen saturation tests. In certain aspects, limitation in lung function correlates to low levels of GSH associated with a Coronaviridae viral infection.
  • Limitation in pulmonary function and oxygen saturation in COVID-19 patients by age group In certain aspects, in a randomized trial, limitation in pulmonary function and oxygen saturation is studied in patients diagnosed with COVID-19 (ages 20-90y), and results are compared to patients without COVID-19. Pulmonary function and oxygen saturation are measured in all subjects. Results are stratified by age and show that COVID-19 patients have limitations in pulmonary function and oxygen saturation, and this becomes progressively worse with advancing age. Regarding COVID-19, comparing young patients (age range 20-30 years), with middle aged patients (age 40-50 years) with elderly patients (60-90 years) shows that limitations in pulmonary function and oxygen saturation are lowest in the young group and progressively increase with advancing age to be highest in the elderly group.
  • GlyNAC glycine and cysteine (as N-acetylcysteine)
  • placebo for 14-21 days, and limitations in pulmonary function and oxygen saturation improve only in patients supplemented with GlyNAC (but not placebo), but the improvement in pulmonary function and oxygen saturation is higher with advancing age, such that at the end of the supplementation period all patients have similar pulmonary function and oxygen saturation.
  • Limitation in pulmonary function and oxygen saturation in COVID-19 patients with HIV In certain aspects, in a randomized clinical trial, limitation in pulmonary function and oxygen saturation are is studied in HIV patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. Pulmonary function and oxygen saturation are measured in all subjects. Results show that pulmonary function and oxygen saturation improve only in HIV patients with COVID- 19 who receive GlyNAC supplementation, and not in patients who receive placebo.
  • GlyNAC cysteine plus glycine
  • Limitation in pulmonary function and oxygen saturation in COVID-19 patients with diabetes In certain aspects, in a randomized clinical trial, limitation in pulmonary function and oxygen saturation is studied in diabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days. A group of subjects without diabetes or COVID-19 serves as a control. Pulmonary function and oxygen saturation are measured in all subjects. Results show that pulmonary function and oxygen saturation improve only in diabetic patients with COVID-19 who receive GlyNAC supplementation, and not in diabetic patients who receive placebo. Further analyses show that limitation in pulmonary function and oxygen saturation in diabetic COVID-19 subjects decreases to approximate functional ability in subjects without diabetes or COVID-19.
  • GlyNAC cysteine plus glycine
  • Limitation in pulmonary function and oxygen saturation in COVID-19 patients with prediabetes (defined as fasting glucose values between 100-125 mg/dl):
  • limitation in pulmonary function and oxygen saturation is studied in prediabetic patients diagnosed with COVID-19 before and after supplementation with cysteine plus glycine (GlyNAC) as GSH precursors, or placebo, for 14-21 days.
  • GlyNAC cysteine plus glycine
  • a group of subjects without prediabetes or diabetes or COVID-19 serves as a control. Pulmonary function and oxygen saturation are measured in all subjects.
  • a group of subjects without obesity, diabetes or COVID-19 serves as a control. Pulmonary function and oxygen saturation are measured in all subjects. Results show that pulmonary function and oxygen saturation at the end of supplementation improve only in obese patients with COVID-19 who receive GlyNAC supplementation, and not in obese patients who receive placebo. Further analyses show that limitation in pulmonary function and oxygen saturation in obese COVID-19 subjects decreases to approximate pulmonary function and oxygen saturation in subjects without obesity, diabetes or COVID-19.
  • all COVID-19 patients have greater limitation in pulmonary function and oxygen saturation than the non-COVID-19 control group, while older COVID-19 patients have significantly higher limitation in pulmonary function and oxygen saturation than younger COVID-19 patients.
  • HIV patients with COVID-19 have significantly higher limitation in pulmonary function and oxygen saturation than non-HIV non-COVID-19 patients.
  • Diabetic and prediabetic patients with COVID-19 have significantly higher limitation in pulmonary function and oxygen saturation than non-diabetic non-COVID-19 patients.
  • Obese patients with COVID-19 have significantly higher limitation in pulmonary function and oxygen saturation than non-obese non-COVID-19 patients.
  • Cysteine and glycine supplementation lower the limitation in pulmonary function and oxygen saturation in all patients with COVID-19.
  • Coronaviridae infections including those that cause COVID-19, are associated with increased mortality, and have been linked to a “cytokine inflammatory storm”.
  • Populations at higher risk of COVID complications and mortality include the elderly, obese individuals, diabetic patients and immunocompromised patients (such as from HIV or cancer treatment).
  • GSH antioxidant protein glutathione
  • Studies of these 3 populations over the past 20 years have found that they all have deficiency of the endogenous antioxidant protein glutathione (GSH), elevated oxidative stress, inflammation, impaired mitochondrial function, immune dysfunction, and endothelial dysfunction.
  • GSH antioxidant protein glutathione
  • GlyNAC refers to the combination of glycine and N-acetylcysteine.
  • the prevalence and extent of these defects are evaluated in individuals with COVID-19 admitted to the hospital, and the response to supplementing GlyNAC or placebo for 2-weeks is also evaluated. Because individuals with COVID-19 are also being reported to have fatigue and cognitive impairment, certain aspects measure fatigue and cognition at admission, 1-week, and 2-weeks after beginning supplementation with GlyNAC. The supplementation is stopped after completing 2-weeks, and these outcomes are measured again after 4-weeks and 8-weeks after stopping supplementation.
  • Certain aspects characterize associated defects in the following two populations of patients with COVID-19: (1) a GlyNAC supplemented population, and (2) a placebo population. Hospitalized patients admitted for COVID-19 will sign an informed consent form, and be randomized to receive either active (Glycine plus N-acetylcysteine) or a placebo (alanine) supplementation for 2-weeks. On day-0, the participants have a single blood draw to measure oxidative stress, Glutathione levels, inflammatory cytokines, endothelial dysfunction, mitochondrial dysfunction, immune dysfunction, and complete questionnaires to assess fatigue, activity and cognition. Additional clinical and lab information is obtained from the hospital electronic medical records. These measurements will be repeated 1-week and 2-weeks after starting supplementation, and at 4-weeks and 8-weeks after stopping supplementation.
  • Oxidative stress is a harmful condition caused by elevated levels of toxic reactive oxygen species, and results in oxidant damage to cells, tissues and organs. Elevated oxidative stress has been implicated in many human illnesses involving aging, diabetes and HIV- infection, which also happen to be three key, highly vulnerable populations for COVID-related morbidity and mortality. However, no studies have measured oxidative stress in patients infected with COVID-19.
  • COVID-19 The global pandemic caused by the novel coronavims Sars-Cov-2 results in the disease known as COVID-19, with development of a viral pneumonia, dyspnea, progressing to respiratory distress requiring oxygen and possibly ventilatory support.
  • COVID-19 has ravaged the world and resulted in over 560,000 American deaths, and currently exploding in India with over 450,000 cases being reported every day.
  • the key drug Remdesivir has not worked, and there is an advisory from the World Health Organization on its failure in COVID-19. There is a heightened sense of urgency on increasing our understanding on why COVID-19 leads to health compromise, respiratory distress, organ failure, and death.
  • Oxidative stress is a toxic and damaging state which occurs due to increased accumulation of damaging and toxic reactive oxygen species, and results in oxidant damage.
  • GSH Glutathione
  • the present example concerns a study to measure intracellular GSH concentrations (in red blood cells), oxidative stress (as concentrations of TBARS) and oxidant damage (as plasma concentrations of F2-isoprostanes) in patients admitted to the hospital with COVID-19. Patients admitted for any reason other than complications associated with COVID- 19 were excluded.
  • FIG. 3 shows the relation between older humans in the 60-80y age group when comparing those with COVID and without COVID. As can be seen, the patients with COVID had the lowest levels of intracellular RBC-GSH concentrations. This indicates that these older humans could be at high risk of oxidative stress and oxidant damage (Table 1).
  • FIG. 4 shows the relation between younger humans in the 21-60y age group when comparing those with COVID and without COVID. As can be seen, the patients with COVID again had the lowest levels of intracellular RBC-GSH concentrations. This is particularly surprising because people in this age range without COVID do not have GSH deficiency, and these data indicates that when younger humans become infected with the coronavirus to develop COVID, they have severe glutathione deficiency (Table 1).
  • FIG. 6 shows the relation between humans in the 60-80y age group when comparing those with COVID and without COVID for oxidative stress. As can be seen, COVID- positive patients had significantly higher oxidative stress compared to COVID-negative people (Table 1).
  • FIG. 7 shows the relation between younger humans in the 21-60y age group when comparing COVID-positive and COVID-negative humans.
  • COVID patients had significantly highest oxidative stress (Table 1). This is particularly surprising because younger people without COVID do not have elevated oxidative stress. These data indicates that when younger humans develop COVID, they have severe oxidative stress (Table 1).
  • FIG. 10 shows the relation between humans in the 60-80y age group when comparing those with COVID and without COVID for oxidant damage. As can be seen, COVID- positive patients had significantly higher oxidant damage compared to COVID-negative people (Table 1).
  • GlyNAC supplementation is an important nutritional approach to improving the health of patients with COVID- 19, in particular embodiments.
  • Glutathione increase by the n-butanoyl glutathione derivative inhibits viral replication and induces a predominant Thl immune profile in old mice infected with influenza vims.
  • Glutathione increase by the n-butanoyl glutathione derivative (GSH- C4) inhibits viral replication and induces a predominant Thl immune profile in old mice infected with influenza vims.
  • Sekhar RV Correcting glutathione deficiency reverses mitochondrial dysfunction and accelerated aging in patients with HIV. Innov Aging. 2019 Nov; 3(Suppl 1): S549. doi: 10.1093/geroni/igz038.2025.
  • PMCID PMC6841332

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Abstract

La présente invention concerne des compositions et des procédés associés à l'administration à un individu d'une composition comprenant une quantité efficace de glycine ou un dérivé fonctionnel de celle-ci et de N-acétylcystéine ou un dérivé fonctionnel de celle-ci, ou des précurseurs de glycine et de cystéine comprenant de la sérine, de la méthionine ou des dérivés de celle-ci, une infection virale étant traitée, empêchée, son apparition étant retardée, sa gravité étant réduite ou les effets suivant l'infection étant réduits chez l'individu. Les compositions et les procédés concernent en outre le traitement, la prévention, le retardement de l'apparition ou la réduction de la gravité d'une infection virale provoquée par un virus respiratoire, en particulier un coronavirus, comprenant au moins le SARS-CoV-2. Les compositions et les procédés concernent en outre un individu ayant une déficience en GSH, un stress oxydatif élevé, une inflammation, un dysfonctionnement mitochondrial, une résistance à l'insuline, une immunosuppression, un dysfonctionnement endothélial, une limitation fonctionnelle, une déficience cognitive ou une combinaison de ceux-ci.
PCT/US2021/070523 2020-05-09 2021-05-10 N-acétylcystéine et glycine pour le traitement de symptômes de la covid-19 et post-covid-19 Ceased WO2021232041A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023133555A3 (fr) * 2022-01-10 2023-09-21 Zilker Sciences Llc Traitement à base de palmitoyléthanolamide pour une inflammation liée à la covid-19

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040234457A1 (en) * 1999-10-19 2004-11-25 The Procter & Gamble Company Methods of preventing and treating SARS using low pH respiratory tract compositions
US8106170B2 (en) * 2004-11-11 2012-01-31 Crucell Holland B.V. Compositions against SARS-coronavirus and uses thereof
WO2020064946A2 (fr) * 2018-09-27 2020-04-02 Société des Produits Nestlé S.A. Compositions et procédés utilisant au moins une glycine ou un dérivé de celle-ci, au moins une n-acétylcystéine ou un dérivé de celle-ci, et au moins un précurseur de nicotinamide riboside ou de nad+

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040234457A1 (en) * 1999-10-19 2004-11-25 The Procter & Gamble Company Methods of preventing and treating SARS using low pH respiratory tract compositions
US8106170B2 (en) * 2004-11-11 2012-01-31 Crucell Holland B.V. Compositions against SARS-coronavirus and uses thereof
WO2020064946A2 (fr) * 2018-09-27 2020-04-02 Société des Produits Nestlé S.A. Compositions et procédés utilisant au moins une glycine ou un dérivé de celle-ci, au moins une n-acétylcystéine ou un dérivé de celle-ci, et au moins un précurseur de nicotinamide riboside ou de nad+

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023133555A3 (fr) * 2022-01-10 2023-09-21 Zilker Sciences Llc Traitement à base de palmitoyléthanolamide pour une inflammation liée à la covid-19

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