WO2021216754A1 - Use of p38 mapk inhibitors for prevention and treatment of aging and aging-related disorders and for boosting an immune system - Google Patents

Use of p38 mapk inhibitors for prevention and treatment of aging and aging-related disorders and for boosting an immune system Download PDF

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Publication number
WO2021216754A1
WO2021216754A1 PCT/US2021/028456 US2021028456W WO2021216754A1 WO 2021216754 A1 WO2021216754 A1 WO 2021216754A1 US 2021028456 W US2021028456 W US 2021028456W WO 2021216754 A1 WO2021216754 A1 WO 2021216754A1
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agent
vaccine
hydrochloride
mammal
inhibitor
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PCT/US2021/028456
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French (fr)
Inventor
Lauren NICOLAISEN
Jarred Heinrich
Matthew DONNE
Wendy COUSIN
An Nguyen
Rachel JACOBSON
Christian Elabd
Ben KOMALO
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Spring Discovery, Inc.
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Publication of WO2021216754A1 publication Critical patent/WO2021216754A1/en

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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/025—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5026—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on cell morphology
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
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    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/50—Cell markers; Cell surface determinants
    • C12N2501/515—CD3, T-cell receptor complex
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system cells
    • C12N2502/1107—B cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2503/00—Use of cells in diagnostics
    • C12N2503/02—Drug screening
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7042—Aging, e.g. cellular aging

Definitions

  • the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal.
  • the present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.
  • An aspect of the present disclosure is a method for increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal.
  • the method comprising administering to the mammal a first composition comprising a therapeutically effective amount of a first agent in which the first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor.
  • MAPK mitogen-activated protein kinases
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • the method further comprises administering to the mammal a second composition comprising a therapeutically effective amount of a second agent.
  • the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the second agent may be selected from L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp- AMS, NAMI- A, PF-4136309, and M AL-di -EG- V al -Cit-P AB -MM AE .
  • the first composition and the second composition may be administered contemporaneously, the first composition may be administered before the second composition is administered, or the second composition is administered before the first composition is administered.
  • the administering is oral, by injection, inhalation, or topical.
  • the administering may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • the mammal is near or has reached maturity or is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the mammal may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • increasing lifespan comprises an at least 5% increase (e.g., an at least 10%, at least 15%, at least 20%, or at least 25% increase) in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.
  • the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy ( e.g Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and
  • the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering topical.
  • the mammal may have at least one aging-related disorder or symptom of aging.
  • the therapeutically effective amount of the first agent boosts the immune system in the mammal.
  • Boosting the immune system may increase an effective immune response against an infectious agent, e.g., a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the bacterium may be Bordatella pertussis or Streptococcocus pneumoniae or the virus may be a Chickenpox virus, Coronavirus (e.g., Sars-CoV-2), Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
  • Coronavirus e.g., Sars-CoV-2
  • Hepatitis A virus Hepatitis B virus
  • Human papillomavirus Human immunodeficiency virus
  • HAV Human immunodeficiency virus
  • influenza Japanese encephalitis virus
  • Measles Measles
  • mumps Measles
  • rubella virus Poliovirus
  • Rabies virus Res
  • the mammal has a healthy immune system or the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the dosage of the first agent and/or the dosage of the second agent is from about 0.01 mg/kg to about 100 mg/kg of the subject’s body weight or the first agent and/or the second agent is provided at a concentration of from about 0.000005 mM to about 20 mM, or the first agent and/or the second agent are in a solution at a percentage from about 0.001% to about 20%.
  • Another aspect of the present disclosure is a method for improving effectiveness of a vaccine in a mammal in need thereof.
  • the method comprises administering a first composition comprising a therapeutically effective amount of a first agent, wherein the first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor in which the mammal contemporaneously and/or subsequently will be administered a vaccine.
  • a first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • the first composition and the vaccine are administered contemporaneously, the vaccine is administered subsequent to the first composition’s administration or after the first composition’s administration.
  • the therapeutically effective amount of the first agent boosts the immune system in the mammal.
  • Boosting the immune system may increasee an immune response against a component contained in the vaccine.
  • the increased immune response may promote future immunity against the component contained in the vaccine.
  • the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • the vaccine is a Chickenpox vaccine, Coronavirus vaccine (e.g., directed against Sars-CoV-2), Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the mammal has a healthy immune system or an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
  • the method further comprises administering to the mammal a second composition comprising a therapeutically effective amount of a second agent.
  • the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • Yet another aspect of the present disclosure is a first composition for use in any herein disclosed method.
  • the present disclosure provides a second composition for use in any herein disclosed method. In yet another aspect, the present disclosure provides a first composition and a second composition for use in any herein disclosed method.
  • FIG. 1 to FIG. 54 are, respectively, graphs showing assays to determine the ability to reverse aging from the following agents: SB 203580 (at two concentrations), SB 203580 (at eight concentrations), Pexmetinib (at two concentrations), Pexmetinib (at eight concentrations), Doramapimod, PH-797804, Dilmapimod, Apilimod, Asp-AMS, Birinapant, Diclazuril, Elacridar (at two concentrations), Elacridar (at eight concentrations), Epinephrine bitartrate, G-5555, Hispidulin, KG-501, Loratadine, MAL-di-EG-Val-Cit-PAB-MMAE, Mancozeb, Meloxicam, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), SM-164 Hydrochloride, Venetoclax, YM-58483, CX-4945, CX-4945 (s
  • FIG. 55 to FIG. 82 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of SB 203580 with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Mubritinib, Vorapaxar, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, PH-797804, CX-4945 (sodium salt), Rapamycin, Meloxicam, Isotretinoin, and Etoposide.
  • FIG. 83 to FIG. Ill are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of Pexmetinib with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar (at two concentrations and eight concentrations, respectively: FIG. 88A and FIG.
  • FIG. 112 to FIG. 136 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of Doramapimod with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Venetoclax, Mubritinib, Diethylstilbestrol, Pexmetinib, PH-797804, Meloxicam, Isotretinoin, Etoposide, Vorapaxar, and Decamethonium bromide.
  • the cell type used in the assays were fibroblasts.
  • FIG. 137 to FIG. 155 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of PH-797804 with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, CX-4945 (sodium salt), SB 203580, Radotinib, Vorapaxar, Ipriflavone, GDC-0152, Pexmetinib, Doramapimod, Rapamycin, Meloxicam, FGF-1, and Venetoclax.
  • the cell type used in the assays were fibroblasts.
  • FIG. 156 to FIG. 175 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of PH-797804 with the following agents: SM-164 Hydrochloride, Hispidulin, Apilimod, Betulonic acid, L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp- AMS, NAMI-A, PF-4136309, or MAL-di-EG-Val-Cit-PAB-MMAE.
  • the cell type used in the assays were fibroblasts.
  • FIG. 176 to FIG. 182 are, respectively, graphs showing assays to determine the ability to reverse aging from the following agents: SB 203580, Pexmetinib, PH-797804, Losmapimod, Acumapimod, LY2228820, and VX-702.
  • the cell type used in the assays were myoblasts.
  • the horizontal line flanked by dashed lines represents the age score of the cells for that experiment when treated with sham agents. In other words, this is the baseline age score for the cells.
  • Asterisk show statistical significance with a single asterisk meaning p ⁇ 0.05 and a double asterisk meaning p ⁇ 0.01.
  • the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal.
  • the present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.
  • Mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy.
  • p38 MAPK inhibitors Persistent activation of the p38 MAPK pathway in muscle satellite cells (muscle stem cells) due to ageing, impairs muscle regeneration.
  • p38 MAPK inhibitors have been developed and are currently in development for many diseases, including rheumatoid arthritis, osteoarthritis, muscular dystrophy, cardiomyopathy, COPD, and cancer. See, Lee et al. , “Inhibition of p38 MAP kinase as a therapeutic strategy.” Immunopharm. 2000;47(2-3):185-201. Some p38 MAPK inhibitors have started clinical trials.
  • compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal comprise administering to the mammal a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen- activated protein kinases (MAPK) inhibitor.
  • a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen- activated protein kinases (MAPK) inhibitor.
  • MAPK mitogen- activated protein kinases
  • the p38 MAPK inhibitor may be a pyridinyl-imidazole, triazanapthalenone, N,N'-diaryl urea, N,N-diaryl urea, benzophenone, pyrazole ketone, indole amide, diamide, quinazolinone, pyrimido[4,5-d]pyrimidinone, pyridylamino-quinazoline, or aryl-pyridinyl-heterocycle.
  • the first agent may be a p38a inhibitor and/or a r38b inhibitors.
  • the first agent may be a p38a inhibitor and a r38b inhibitors.
  • the p38 MAPK inhibitor directly or indirectly competes with ATP binding by p38 MAPK.
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Acumapimod, Neflamapimod, Ralimetinib, VX-702, and Talmapimod.
  • Losmapimod also known as 585543-15-3, GSK-AHAB, GW856553, GW856553X, and 6-[5- [(cyclopropylamino)-oxomethyl]-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)-3- pyridinecarboxamide; CAS Registry number: 585543-15-3) is an orally bioavailable inhibitor of the alpha and beta isoforms of p38 mitogen-activated protein kinase (MAPK), with potential immunomodulating and anti-inflammatory activities.
  • Losmapimod has the following chemical structure:
  • ARRY-797 also known as PF-07265803, P38alpha Inhibitor 1, CHEMBL 1088750, ARRY-
  • Carboxamide is an oral, selective p38 mitogen-activated protein kinase inhibitor.
  • ARRY-797 has the following chemical structure:
  • Acumapimod has the following chemical structure:
  • Neflamapimod (also known as VX-745; 5-(2,6-Dichlorophenyl)-2-((2,4-Difluorophenyl)Thio)- 6H-Pyrimido[l,6-B]Pyridazin-6-One; CAS Registry number: 209410-46-8) is a potent, blood- brain barrier penetrant, highly selective inhibitor of p38a inhibitor with an IC50 for p38a of 10 nM and for r38b of 220 nM.
  • Neflamapimod (VX-745) possesses anti-inflammatory activity.
  • Neflamapimod has the following chemical structure:
  • Ralimetinib also known as LY2228820, Ralimetinib Mesylate, LY2228820 diMesylate,
  • Ralimetinib dimesylate 5-[2-tert-butyl-4-(4-fluorophenyl)-lH-imidazol-5-yl]-3-(2,2- dimethylpropyl)imidazo[4,5-b]pyridin-2-amine;methanesulfonic acid; CAS Registry number: 862507-23-1).
  • Ralimetinib Mesylate is the dimesylate salt form of LY2228820, a tri -substituted imidazole derivative and orally available, p38 mitogen-activated protein kinase (MAPK) inhibitor with potential anti-inflammatory and antineoplastic activities.
  • MAPK mitogen-activated protein kinase
  • Ralimetinib has the following chemical structure:
  • VX-702 also known as 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)pyridine-3- carboxamide; CAS Registry number: 745833-23-2
  • RA rheumatoid arthritis
  • VX-702 has the following chemical structure:
  • Talmapimod also known as SCIO 469, Scios 469, 2-[6-chloro-5-[(2R,5S)-4-[(4- fluorophenyl)methyl]-2,5-dimethylpiperazine-l -carbonyl]- 1 -methylindol-3-yl]-N, N-dimethyl-2- oxoacetamide; CAS Registry number: 309913-83-5
  • MAPK mitogen-activated protein kinase
  • the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, Dilmapimod, Ralimetinib Mesylate, Losmapimod, Acumapimod, Dehydrocorydaline (chloride), VX-702, Neflamapimod, and ARRY-797 (PF-07265803).
  • SB 203580 (also known as 4-[4-(4-fluorophenyl)-2-(4-methylsulfmylphenyl)-lH-imidazol-5- yljpyridine; CAS Registry Number: 152121-47-6) is a specific inhibitor of p38a and r38b which suppresses downstream activation of MAPKAP kinase-2 and heat shock protein 27. At low concentrations, it does not inhibit JNK activity. SB 203580 has the following chemical structure:
  • Pexmetinib also known as ARRY-614 and l-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[[5- fluoro-2-[l -(2-hydroxy ethyl)indazol-5-yl]oxyphenyl]methyl]urea; CAS Registry number:
  • 945614-12-0 is a potent Tie-2 and p38 MAPK dual inhibitor, with IC50s of 1 nM, 35 nM and 26 nM for Tie-2, p38a and r38b, respectively, and can be used in the research of acute myeloid leukemia.
  • PH-797804 has the following chemical structure:
  • Doramapimod also inhibits B-Raf with an IC50 of 83.
  • Doramapimod has the following chemical structure:
  • Dilmapimod (also known as SB-681323 and 8-(2,6-difluorophenyl)-2-(l,3-dihydroxypropan-2- ylamino)-4-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7-one; CAS Registry number: 444606-18-2) is a potent p38 MAPK inhibitor that potentially suppresses inflammation in chronic obstructive pulmonary disease.
  • Dilmapimod has the following chemical structure:
  • a method for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal comprises administering the mammal a first composition and a second composition.
  • the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen - activated protein kinases (MAPK) inhibitor and the second composition comprises a therapeutically effective amount of a second agent.
  • a first agent that is a p38 mitogen - activated protein kinases (MAPK) inhibitor
  • the second composition comprises a therapeutically effective amount of a second agent.
  • the first composition and the second composition are administered contemporaneously.
  • contemporaneously is meant administering the two compositions together or by administering the two compositions at nearly the same time.
  • the first composition is administered before the second composition is administered.
  • the second composition is administered before the first composition is administered.
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, and VX-702.
  • the first agent is selected from SB 203580, Pexmetinib, Doramapimod, PH-797804, and Dilmapimod.
  • the second agent may be classified by a mechanism selected from Acetyltransferase inhibitors, Activin receptor-like kinase (ALK) inhibitor, Adrenergic receptor agonist, Antibacterial, Antifungal, Antiparasitic, aspartyl-tRNA synthetase inhibitor, Bcl-2 inhibitor, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, cAMP response element-binding protein (CREB) inhibitor, Casein kinase 2 inhibitor, Chemokine receptor (CCR) antagonist, COX inhibitor, DNA topoisomerase inhibitor, EGFR inhibitor, HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF- 1, Focal adhesion kinase (FAR) inhibitor, Glutamate receptor antagonist, Glycogen synthase kinase 3 inhibitor, HD AC inhibitor, Histamine HI -receptor agonist, IAP Antagonist, IL-21 inhibitor, IL-23 inhibitor, Isoflavone and derivatives
  • any commercially available, published, or approved drug operating by an above-mentioned mechanism may be used as a second agent in compositions and methods of the present disclosure.
  • the second agent is classified by a mechanism selected from IAP Antagonist, Acetyltransferase inhibitor, Adrenergic receptor agonist, Casein kinase 2 inhibitor, Multidrug resistance protein inhibitor, Calcium release-activated channel inhibitor, Antiparasitic, Isoflavone and derivative, p38 MAPK inhibitor, Muscarinic receptor antagonist, FGF-1, Bcr-Abl inhibitor, Protease- Activated Receptor (PAR) antagonist, Histamine HI -receptor agonist, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, Bcl-2 inhibitor, Nicotinic acetylcholine receptor agonist, Raf inhibitor/p38 MAPK inhibitor, mTOR inhibitor, COX inhibitor, Pim-1 inhibitor, and IL-21 inhibitor/IL-23 inhibitor.
  • IAP Antagonist I
  • the second agent is classified by a mechanism selected from Bcl-2 inhibitor, Bcr- Abl inhibitors, COX inhibitor, EGFR inhibitor, Estrogen Receptor/ERR agonist, FGF-1, HER2 inhibitor, Histamine HI -receptor agonist, IAP Antagonist, IL-21 inhibitor, IL-23 inhibitor, mTOR inhibitor, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p38 MAPK inhibitor, Pim-1 inhibitor, Protease-Activated Receptor (PAR) antagonist, or Raf inhibitor.
  • a mechanism selected from Bcl-2 inhibitor, Bcr- Abl inhibitors, COX inhibitor, EGFR inhibitor, Estrogen Receptor/ERR agonist, FGF-1, HER2 inhibitor, Histamine HI -receptor agonist, IAP Antagonist, IL-21 inhibitor, IL-23 inhibitor, mTOR inhibitor, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p
  • the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, and Diclazuril.
  • the second agent is selected from L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY- 775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, and MAL-di-EG-Val-Cit-PAB- MMAE.
  • the first agent and the second agent are both p38 MAPK inhibitors.
  • the first agent is SB 203580 and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcl-2 inhibitor, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF- 1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p38 MAPK inhibitor, Protease- Activated Receptor (PAR) antagonist, and Raf inhibitor/p38 MAPK inhibitor.
  • a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcl-2 inhibitor, Bcr-Abl inhibitors,
  • the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the first agent is Pexmetinib and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Anti -infective, Antiparasitic, Bcl-2 inhibitor, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF- 1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p38 MAPK inhibitor, Protease- Activated Receptor (PAR) antagonist, and Raf inhibitor/p38 MAPK inhibitor.
  • a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Anti -infective, Antiparasitic, Bcl-2 inhibitor, Calcium release
  • the first agent is Pexmetinib and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • Birinapant CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine
  • the first agent is Pexmetinib and the second agent is SB 203580.
  • the second agent is neither Etoposide, Isotretinoin, nor Radotinib.
  • the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Doramapimod and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcl-2 inhibitor, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF-1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone and derivatives, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, and p38 MAPK inhibitor.
  • a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcl-2 inhibitor, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF-1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone
  • the first agent is Doramapimod and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC-
  • the first agent is Doramapimod and the second agent is SB 203580.
  • the second agent is neither Decamethonium bromide, Etoposide, Isotretinoin, Meloxicam, nor Vorapaxar.
  • the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483.
  • the first agent is SB 203580 and the second agent is Doramapimod, Pexmetinib, or PH-797804. In certain embodiments, when the first agent is SB 203580, the second agent is neither Etoposide nor Isotretinoin.
  • the first agent is PH-797804 and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, p38 MAPK inhibitor, Protease- Activated Receptor (PAR) antagonist, and Raf inhibitor/p38 MAPK inhibitor.
  • a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, p38 MAPK inhibitor, Protease- Activated Receptor (PAR
  • the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM-58483.
  • the first agent is PH-797804 and the second agent is SB 203580.
  • the second agent when the first agent is PH-797804, the second agent is neither FGF-1 nor Venetoclax.
  • the first agent is Dilmapimod and the second agent is classified by a mechanism selected from Antibacterial, Antifungal, cAMP response element-binding protein (CREB) inhibitor, IAP Antagonist, IL-21 inhibitor/IL-23 inhibitor, Muscarinic receptor antagonist, Pim-1 inhibitor, and Raf inhibitor.
  • CREB cAMP response element-binding protein
  • the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride.
  • the second agent when the first agent is Dilmapimod, is neither ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp- AMS, NAMI- A, PF-4136309, or MAL-di-EG-Val-Cit-PAB-MMAE.
  • aspects of the present disclosure comprise first compositions and methods of administering the same to a mammal.
  • the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor.
  • Aspects of the present disclosure further comprise a second composition and methods of administering to a mammal a first composition and a second composition; here, the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor and the second composition comprises a therapeutically effective amount of a second agent.
  • MAPK mitogen-activated protein kinases
  • compositions comprise a therapeutically effective amount of a first agent and/or a therapeutically effective amount of a second agent.
  • therapeutically effective amount is meant to be the amount of the first agent and/or the second agent to increase lifespan, to prevent or treat an aging-related disorder, to reduce a symptom of aging, and/or to boost an immune system in a mammal.
  • therapeutically effective amount also means the amount of the first agent and/or the second agent to improve the effectiveness of a vaccine in a mammal.
  • increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.
  • increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
  • the therapeutically effective amount is meant to be the amount of the first agent and/or the second agent needed to prevent or treat an aging-related disorder and/or to reduce a symptom of aging.
  • the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy ( e.g Sarcopenia and myopenia), frailty,
  • the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical.
  • the mammal has at least one aging-related disorder or symptom of aging.
  • a non-human mammal may have an aging-related disorder or symptom of aging that is homologous to the aging-related disorder or symptom of aging listed above.
  • the therapeutically effective amount of the first agent and/or the second agent is helpful in boosting the immune system in the mammal.
  • boosting the immune system increases an effective immune response against an infectious agent.
  • the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the bacterium is Bordatella pertussis or Streptococcocus pneumoniae.
  • the virus is selected from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado tick fever virus (CTFV), Coronaviruse, Crimean-Congo hemorrhagic fever virus, Cytomegalovirus, Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) , Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV), Flaviviruses, Guanarito virus, Heartland virus, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV), Human metapneumovirus (h
  • the therapeutically effective amount is meant to be the amount of the first agent and/or the second agent sufficient to improve effectiveness of a vaccine in a mammal.
  • the therapeutically effective amount of the first agent and/or the second agent may boost the immune system in the mammal, e.g., by increasing an immune response against a component contained in the vaccine.
  • the increased immune response promotes future immunity against the component contained in the vaccine.
  • the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a coronavirus vaccine.
  • the coronavirus vaccine is directed against Sars-CoV-2.
  • compositions of the present disclosure are formulated to be suitable for in vivo administration to a mammal.
  • Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.
  • Pharmaceutical excipients can be aqueous liquids, such as water or saline.
  • Pharmaceutical excipients can be lipid based, e.g., comprising a liquid or solid oil.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any composition described herein is administered parentally or in some oral formulations.
  • compositions described herein are suspended in a saline buffer (including, without limitation Ringer’s, TBS, PBS, HEPES, HBSS, and the like).
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions.
  • Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Any composition described herein, if desired, can also comprise pH buffering agents.
  • compositions of the present disclosure are formulated for oral administration, for injection, or for topical administration.
  • the administering the first and/or the second composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • First and/or second compositions suitable for parenteral administration include, for example, solutions, suspensions, dispersions, emulsions, and the like, or in another acceptable format used in methods well known in the art.
  • First and/or second compositions suitable for enteral administration may be formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or in another acceptable format used in methods well known in the art.
  • First and/or second compositions suitable for topical administration can be formulated in a solution, gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, aerosol, patch, or the like in a pharmaceutically or cosmetically acceptable format used in methods well known in the art.
  • First and/or second compositions suitable for administration via inhalation Such formulation will likely be in liquid form and will be delivered in a spray bottle, in an inhaler, or in a nebulizer.
  • the dosage of any herein-disclosed composition can depend on several factors including the characteristics of the mammal to be administered. Examples of characteristics include species, strain, breed, sex, age, weight, size, health, and/or disease status. Moreover, the dosage may depend on whether the administration is the first time the subject received a composition of the present disclosure or if the subject has previously received a composition of the present disclosure. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a composition) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific composition being administered, the time of administration, the route of administration, the nature of the formulation, and the rate of excretion. Some variations in the dosage can be expected.
  • the dosage depends on the specific first and/or second agent administered.
  • An illustrative dose of Doramapimod may be about 0.5 to about 30 mg/kg when administered orally or about 5 mg to about 70 mg twice daily.
  • the dose of Doramapimod may be about 1 mg/kg.
  • An illustrative dose of PH-797804 may be about 1 to about 15 mg/kg when administered orally or about .5, 3, 6 or 10 mg once daily.
  • the dose of PH-797804 may between about 0.3 mg/kg and about 5 mg/kg once or twice daily.
  • An illustrative dose of SB 203580 may be about 10 to about 100 mg/kg when administered orally, about 0.15 mg/kg to about 25 mg/kg when administered by injection, e.g, intraperitoneal injection, or in a topical formulation having a concentration of about 1.0 to about 10 mM.
  • An illustrative dose of Losmapimod may be about 1 to about 12 mg/kg administered orally once or twice daily or about 15 mg twice daily or about 1.8 mg/kg when administered by injection, e.g, intraperitoneal injection, or may be in a 0.05% solution when administered topically.
  • An illustrative dose of ARRY-797 may be about 3 mg/kg to about 30 mg/kg administered orally once or twice daily or about 100 mg to about 400 mg twice daily.
  • ARRY-797 may be administered in a 0.05% topical solution.
  • the dosage of the first agent and/or the dosage of the second agent may be from about 0.01 mg/kg to about 100 mg/kg of the subject’s body weight, or any dosage therebetween.
  • the dosage of the first agent and/or the dosage of the second agent may be about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about 0.1 mg/kg.
  • the dosage of the first agent and/or the dosage of the second agent may be about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, or about 1.0 mg/kg.
  • the dosage of the first agent and/or the dosage of the second agent may be about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about
  • the dosage of the first agent and/or the dosage of the second agent may be about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg.
  • the dosage of the first agent and/or the dosage of the second agent may be about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg.
  • the dosage of the first agent and/or the dosage of the second agent may be about 30 mg/kg, about 32 mg/kg, about 34 mg/kg, about 36 mg/kg, about 38 mg/kg, about 40 mg/kg, about 42 mg/kg, about 44 mg/kg, about 46 mg/kg, about 48 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, or about 100 mg/kg.
  • the first agent and/or the second agent may be provided at a concentration of from about 0.000005 mM to about 20 mM, or any concentration therebetween.
  • the concentration may be about 0.125 pM, about 0.25 pM, about 0.5 pM, about 1.0 pM, about 2.5 pM, about 5.0 pM, about 10.0 pM, about 12.0 pM, or about 20.0 pM.
  • the concentration may be about 1.0 pM, about 1.1 pM, about 1.2 pM, about 1.3 pM, about 1.4 pM, about 1.5 pM, about 1.6 pM, about 1.7 pM, about 1.8 pM, about 1.9 pM, about 2.0 pM, about 2.1 pM, about 2.2 pM, about 2.3 pM, about
  • the first agent and/or the second agent are administered in a solution at a percentage from about 0.001% to about 20%, or any percentage therebetween.
  • the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 0.001 %, about 0.002 %, about 0.003 %, about 0.004 %, about 0.005 %, about 0.006 %, about 0.007 %, about 0.008 %, about 0.009 %, or about 0.01 %.
  • the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 0.01 %, about 0.02 %, about 0.03 %, about 0.04 %, about 0.05 %, about 0.06 %, about 0.07 %, about 0.08 %, about 0.09 %, or about 0.1 %.
  • the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 0.1 %, about 0.2 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 0.8 %, about 0.9 %, or about 1.0 %.
  • the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 1.1 %, about 1.2 %, about 1.3 %, about 1.4 %, about 1.5 %, about 1.6 %, about 1.7 %, about 1.8 %, about 1.9 %, or about 2.0 %.
  • the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 %.
  • the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 11 %, about 12 %, about 13 %, about 14 %, about 15 %, about 16 %, about 17 %, about 18 %, about 19 %, or about 20 %.
  • the first agent and/or the second agent may be administered once daily, twice daily, thrice daily, or more times per day.
  • the first agent and/or the second agent may be administered once a week, twice a week, three times a week, four time per week, five times per week, six times per week, or more times per week.
  • the first agent and/or the second agent may be administered once a month, twice a month, three times a month, four time per month, five times per month, six times per month, seven times per month, eight times per month, nine times per month, ten times per month, or more times per month.
  • the dosage of the first agent and/or the second agent may differ from a standard dosage of the first agent and/or the second agent when either agent is administered alone.
  • the dose of the first agent may be lower than a standard dosage when the first agent is administered alone.
  • the dose of the second agent may be lower than a standard dose when the second agent is administered alone.
  • the first and/or second compositions may be formulated to slowly release the first agent and/or the second agent in the mammal and/or to improve stability of a composition.
  • the first agent and/or the second agent are encapsulated in a microcapsule.
  • the microcapsule may be a liposome, an albumin microsphere, a microemulsion, a nanoparticle (e.g, a lipid nanoparticle), and a nanocapsule.
  • microcapsules, e.g, lipid nanoparticles and liposomes include lipids selected from one or more of the following categories: cationic lipids; anionic lipids; neutral lipids; multi-valent charged lipids; and zwitterionic lipids.
  • a cationic lipid and/or cationic polymer may be used to facilitate a charge-charge interaction with a first agent and/or with a second agent.
  • the microcapsule may comprise a PEGylated lipid. Examples of microcapsules and methods for manufacturing the same are described in the art. See, e.g, Prui et al. , Crit Rev Ther Drug Carrier Syst, 2009; 26(6): 523-580; Wakasar, J Drug Target, 2018, 26(4):311-318, Langer, 1990, Science 249:1527-1533; Treat et al.
  • a composition may comprise one or more of capralactone, polylactide (PLA), polylactic-co-glycolic (PLGA), polyethylene glycol (PEG), polylactic-co-hydroxymethylglycolic acid (PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose, gelatin-microcapsules, a poloxamer, or polymethylmethacrylate.
  • PLA polylactide
  • PLA polylactic-co-glycolic
  • PEG polyethylene glycol
  • PLHMGA polylactic-co-hydroxymethylglycolic acid
  • carboxymethylcellulose carboxymethylcellulose
  • hydroxylmethylcellulose gelatin-microcapsules
  • poloxamer a poloxamer
  • polymethylmethacrylate polymethylmethacrylate
  • the composition may comprise delay-release components.
  • a pill or capsule may comprise a coating that slows release of the agents and/or prevents release of the agents until the pill or capsule has arrived at a desired location of the mammal’s digestive system.
  • Another aspect of the present disclosure is a method for boosting the immune system in a mammal.
  • boosting the immune system increases an effective immune response against an infectious agent.
  • the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
  • the bacterium is Bordatella pertussis or Streptococcocus pneumoniae.
  • the virus is selected from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado tick fever virus (CTFV), Coronaviruse, Crimean- Congo hemorrhagic fever virus, Cytomegalovirus, Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) , Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV), Flaviviruses, Guanarito virus, Heartland virus, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV), Human metapneumovirus (hMP
  • the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g, in some severe coronavirus patients.
  • “boosting the immune system” relates to “boosting” a proper immune response. That is, minimizing an overactive immune response.
  • the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • compositions and methods for boosting the immune system can be used with aged and with non-aged mammals.
  • the method for boosting the immune system comprises administering a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen -activated protein kinases (MAPK) inhibitor.
  • the method may further comprise a second composition and methods relate to administering to a mammal a first composition and a second composition; here, the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor and the second composition comprises a therapeutically effective amount of a second agent.
  • the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor
  • the second composition comprises a therapeutically effective amount of a second agent.
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, and Dilmapimod.
  • the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid
  • the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the first agent is Pexmetinib and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Pexmetinib and the second agent is SB 203580.
  • the second agent is neither Etoposide, Isotretinoin, nor Radotinib.
  • the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • CX-4945 Birinapant
  • CX-4945 sodium salt
  • Decamethonium bromide Diclazuril
  • Diethylstilbestrol Elacridar
  • Epinephrine bitartrate FGF-1, GDC-0152
  • Ipriflavone Meloxicam
  • Mubritinib Pirenzepine hydroch
  • the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Doramapimod and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC- 0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide),
  • the first agent is Doramapimod and the second agent is SB 203580.
  • the second agent is neither Decamethonium bromide, Etoposide, Isotretinoin, Meloxicam, nor Vorapaxar.
  • the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • CX-4945 Birinapant
  • CX-4945 sodium salt
  • Decamethonium bromide Diclazuril
  • Diethylstilbestrol Elacridar
  • Epinephrine bitartrate FGF-1, GDC-0152
  • Ipriflavone Meloxicam
  • Mubritinib Pirenzepine hydrochloride
  • the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483.
  • the first agent is SB 203580 and the second agent is Doramapimod, Pexmetinib, or PH-797804. In certain embodiments, when the first agent is SB 203580, the second agent is neither Etoposide nor Isotretinoin.
  • the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM-58483.
  • the first agent is PH-797804 and the second agent is SB 203580.
  • the second agent is neither FGF-1 nor Venetoclax.
  • the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride.
  • the second agent is neither ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or M AL-di -EG- V al -Cit-P AB -MM AE .
  • the administering is oral, by injection, inhalation, or topical.
  • the administering the first and/or the second composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • compositions and methods for improving effectiveness of a vaccine in a mammal relate to compositions and methods for improving effectiveness of a vaccine in a mammal.
  • an aged mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • Influenza is problematic in older adults with increased risk for serious complications and hospitalization.
  • approximately 90% of flu-related deaths occur in this population, with influenza and pneumonia being the eighth leading cause of death among persons over 65 years of age in the United States. Even when death is avoided, older adults have an increased risk for secondary complications and morbidities from flu infection.
  • influenza vaccines show efficacy rates between 60% and 90%.
  • vaccine effectiveness in adults aged 65 and older is usually significantly lower, ranging from an average of 28% protection against fatal and nonfatal complications (with large dispersion), 39% protection against typical influenza-like illness, and 49% protection against disease with confirmed virus infection.
  • Influenza vaccine effectiveness is a significant problem in elderly as compared to young individuals and is associated with high rates of complicated illness including pneumonia, heart attacks, and strokes in the >65 -year-old population.
  • SARS-CoV-2 novel coronavirus
  • compositions and methods for improving effectiveness of a vaccine can be used with non-aged mammals.
  • the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.
  • the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g, in some severe coronavirus patients.
  • “improving a vaccine response” relates to “improving” a proper immune response to a vaccine and, later, when a subject is contacted with an infectious agent. That is, minimizing an overactive immune response and promoting a proper immune response.
  • the method for improving effectiveness of a vaccine comprises administering a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen -activated protein kinases (MAPK) inhibitor.
  • the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, and Dilmapimod.
  • the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid
  • the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • the first agent is Pexmetinib and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Pexmetinib and the second agent is SB 203580.
  • the second agent is neither Etoposide, Isotretinoin, nor Radotinib.
  • the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
  • Pirenzepine hydrochloride Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is Doramapimod and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC- 0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide),
  • the first agent is Doramapimod and the second agent is SB 203580.
  • the second agent is neither Decamethonium bromide, Etoposide, Isotretinoin, Meloxicam, nor Vorapaxar.
  • the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • CX-4945 Birinapant
  • CX-4945 sodium salt
  • Decamethonium bromide Diclazuril
  • Diethylstilbestrol Elacridar
  • Epinephrine bitartrate FGF-1, GDC-0152
  • Ipriflavone Meloxicam
  • Mubritinib Pirenzepine hydrochloride
  • the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
  • the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483.
  • the first agent is SB 203580 and the second agent is Doramapimod, Pexmetinib, or PH-797804. In certain embodiments, when the first agent is SB 203580, the second agent is neither Etoposide nor Isotretinoin.
  • the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM-58483.
  • the first agent is PH-797804 and the second agent is SB 203580.
  • the second agent is neither FGF-1 nor Venetoclax.
  • the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride.
  • the second agent is neither ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or M AL-di -EG- V al -Cit-P AB -MM AE .
  • the administering is oral, by injection, inhalation, or topical.
  • the administering the first and/or the second composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
  • the first composition (with or without a second composition) and the vaccine are administered contemporaneously.
  • the vaccine is administered subsequent to the administration of the first composition (with or without a second composition).
  • the vaccine is administered before the administration of the first composition (with or without a second composition).
  • the therapeutically effective amount is meant to be the amount of the first agent and/or the second agent to improve effectiveness of a vaccine in a mammal.
  • the therapeutically effective amount of the first agent and/or the second agent may boost the immune system in the mammal, e.g., by increasing an immune response against a component contained in the vaccine.
  • the increased immune response promotes future immunity against the component contained in the vaccine.
  • the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
  • the vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a coronavirus vaccine.
  • the coronavirus vaccine is directed against Sars-CoV-2.
  • compositions and methods treat, prevent, reduce the severity of, and/or delay the onset of various aging-associated conditions, e.g, chronic diseases and disabilities/conditions of aging.
  • Illustrative aging-related disorders include actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy (e.g, Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency
  • ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease.
  • Aged non-human subjects experience similar, homologous, and/or equivalent aging-related disorders.
  • the subject is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the mammal is a non-rodent.
  • the mammal is a dog.
  • the subject is a non-human animal, and therefore the invention pertains to veterinary use.
  • the non-human animal is a household pet, e.g, a dog.
  • the non-human animal is a livestock animal.
  • the mammal is a human.
  • the mammal has reached maturity.
  • the term mature or maturity, and the like refers to a mammal that is capable of sexual reproduction and/or a mammal that has achieved its adult height and/or length.
  • the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the mammal may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
  • the human is an adult human.
  • the human has an age in a range of from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old, or older.
  • the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.
  • preventing is meant, at least, avoiding the occurrence of a disease and/or reducing the likelihood of acquiring the disease.
  • treating is meant, at least, ameliorating or avoiding the effects of a disease, including reducing a sign or symptom of the disease.
  • Example 1 Identification of first agents useful in methods of the present disclosure
  • first agents having p38 mitogen-activated protein kinases (MAPK) inhibitory activity and capable of increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system were identified.
  • Sets of cultured cells having either characteristics of young cells or characteristics of old cells are contacted with known p38 MAPK inhibitors.
  • the ability of the p38 MAPK inhibitor to reverse aging in the cells e.g., reducing the characteristics of old cells and promoting characteristics of a young cells was assayed (also known as reducing the predicted age of the cells).
  • p38 MAPK inhibitors at various concentrations ranging from about 0.000005 to about 20 mM, e.g., 0 mM, 0.031 pM, 0.125 pM, 0.25 pM, 0.5 pM, 1.0 pM, 2 pM, 2.5 pM, 4 pM, 5 pM, 10 pM, 16 pM, and 20 pM.
  • p38 MAPK inhibitors showing the ability to reverse aging were further validated.
  • p38 MAPK inhibitors were tested: SB 203580, Pexmetinib, PH-797804, Doramapimod, Dilmapimod, Ralimetinib Mesylate, Losmapimod, Acumapimod, Dehydrocorydaline (chloride), VX-702, SB 203580 (hydrochloride), SB 239063, SKF-86002, Talmapimod, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, SD 0006, TAK-715, Ferulic acid methyl ester, p38a inhibitor 1, Pamapimod, Neflamapimod, Skepinone-L, Tat-NR2B9c (TFA), BMS-582949 (hydrochloride), BMS-582949, Bakuchiol, ITX5061, Asiatic acid, R1487 (Hydrochloride), WAY
  • the following p38 MAPK inhibitors demonstrated surprisingly abilities to alone reverse aging: SB 203580, Pexmetinib, Doramapimod, PH-797804, and Dilmapimod. See, FIG. 1 to FIG. 7.
  • Example 2 Identification of second agents and combinations of first and second agents useful in methods of the present disclosure
  • second agents that contribute (along with the first agents identified in Example 1, above) to increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system were identified.
  • Sets of cultured cells having either characteristics of young cells or characteristics of old cells are contacted with presumptive second agents along with one of the following p38 MAPK inhibitors: Pexmetinib, PH-797804, Doramapimod, SB 203580, and Dilmapimod.
  • p38 MAPK inhibitors Pexmetinib, PH-797804, Doramapimod, SB 203580, and Dilmapimod.
  • p38 MAPK inhibitors and the presumptive second agents were used at various concentrations ranging from about 0.000005 to about 20 mM, e.g., 0 pM, 0.031 pM, 0.125 pM, 0.25 pM, 0.5 pM, 1.0 pM, 2 pM, 2.5 pM, 4 pM, 5 pM, 10 pM, 16 pM, and 20 pM.
  • p38 MAPK inhibitors showing the ability to reverse aging were further validated.
  • Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, CX-4945, Elacridar, YM-58483, and Diclazuril were particularly beneficial in reversing aging in fibroblasts when combined with a first agent, i.e., SB 203580, Pexmetinib, Doramapimod, PH-797804, and Dilmapimod.
  • FIG. 55 to FIG. 82 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of SB 203580 with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Mubritinib, Vorapaxar, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, PH-797804, CX-4945 (sodium salt), Rapamycin, Meloxicam, Isotretinoin, and Etop
  • FIG. 83 to FIG. Ill are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of Pexmetinib with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Mubritinib, Vorapaxar, Diethylstilbestrol, Decamethonium bromide, Rapamycin, Meloxicam, Trihexyphen
  • FIG. 112 to FIG. 136 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of Doramapimod with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Venetoclax, Mubritinib, Diethylstilbestrol, Pexmetinib, PH-797804, Meloxicam, Isotretinoin, Etoposide, Vorapaxar, and Decamethonium bromide.
  • Birinapant Remodelin (hydrobromide)
  • Epinephrine bitartrate Epinephrine bitartrate
  • Elacridar
  • Doramapimod with Birinapant CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF- 1, GDC-0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), SB 203580, Venetoclax, or YM-58483.
  • none of Meloxicam, Isotretinoin, Etoposide, Vorapaxar, or Decamethonium bromide were beneficial in reversing aging when combined with Doramapimod.
  • FIG. 137 to FIG. 155 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of PH-797804 with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, CX-4945 (sodium salt), SB 203580, Radotinib, Vorapaxar, Ipriflavone, GDC-0152, Pexmetinib, Doramapimod, Rapamycin, Meloxicam, FGF-1, and Venetoclax.
  • Birinapant Remodelin (hydrobromide)
  • Epinephrine bitartrate Epinephrine bitartrate
  • Elacridar Epinephrine bitartrate
  • Elacridar Epinephrine bitartrate
  • Elacridar Epinephrine bitartrate
  • Elacridar Epinephrine bitart
  • FIG. 156 to FIG. 175 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of PH-797804 with the following agents: SM-164 Hydrochloride, Hispidulin, Apilimod, Betulonic acid, L-779450, Mancozeb, Salicyl-AMS, KG- 501, ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or M AL-di -EG- V al -Cit-P AB -MM AE .
  • agents SM-164 Hydrochloride, Hispidulin, Apilimod, Betulonic acid, L-779450, Mancozeb, Salicyl-AMS, KG- 501, ACY-775, PHCCC, Palovarotene, G-5555, AZD
  • An assay is performed to determine the determine the ability to reverse aging from the combination of Losmapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • An assay is performed to determine the determine the ability to reverse aging from the combination of ARRY-797 (PF-07265803) with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • An assay is performed to determine the determine the ability to reverse aging from the combination of Ralimetinib with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • An assay is performed to determine the determine the ability to reverse aging from the combination of Acumapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • An assay is performed to determine the determine the ability to reverse aging from the combination of Neflamapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin,
  • An assay is performed to determine the determine the ability to reverse aging from the combination of Talmapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin,
  • An assay is performed to determine the determine the ability to reverse aging from the combination of VX-702 with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betul
  • Example 3 Methods comprising administering a first composition
  • a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity is administered to a mammal for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system.
  • MAPK mitogen-activated protein kinases
  • the first compositions comprise one of the following p38 MAPK inhibitors: Losmapimod, ARRY- 797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • Administration of the first composition is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the first composition is administered orally, by inhalation, or topically.
  • the mammal’s lifespan is measured and the presence, absence, and/or severity of various aging- associated conditions are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
  • Example 4 Methods comprising administering a first composition
  • a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity and a second composition comprising a second agent are administered to a mammal for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system.
  • MAPK mitogen-activated protein kinases
  • the first compositions comprise one of the following p38 MAPK inhibitors: Losmapimod, ARRY- 797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
  • the second compositions comprise one of second agents identified in Example 2, above, e.g., CX- 4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
  • second agents identified in Example 2, above e.g., CX- 4945, Birinapant, Remodelin
  • Administration of the first composition is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the first composition is administered orally, by inhalation, or topically.
  • the second composition is by intravenous injection or infusion, intraperitoneal inj ection, intramuscular inj ection, or subcutaneous inj ection, with a dose depending on the quantity of composition needing to be administered.
  • the second composition is administered orally, by inhalation, or topically.
  • the first composition may be administered before the second composition is administered.
  • the first composition may be administered after the second composition is administered.
  • the first composition and the second composition may be administered contemporaneously (either by combining the two compositions or by administering the two compositions at nearly the same time).
  • the mammal’s lifespan is measured and the presence, absence, and/or severity of various aging- associated conditions are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
  • Example 5 Methods for improving a vaccine response
  • a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity with or without a second composition comprising a second agent are administered to a mammal for improving effectiveness of a vaccine that is administered to the mammal.
  • MAPK mitogen-activated protein kinases
  • the mammal may be administered only a first composition (as described in Example 3) or may be administered both a first composition and a second composition (as described in Example 4).
  • Administration of the first composition may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the first composition may be administered orally, by inhalation, or topically.
  • Administration of the second composition may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the second composition may be administered orally, by inhalation, or topically.
  • Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered.
  • the vaccine may be administered orally, by inhalation, or topically.
  • the first composition (with or without a second composition) and the vaccine are administered contemporaneously. In other cases, the vaccine is administered subsequent to the administration of the first composition (with or without a second composition). In some cases, the vaccine is administered before the administration of the first composition (with or without a second composition).
  • the vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
  • the vaccine is a coronavirus vaccine.
  • the coronavirus vaccine is directed against Sars-CoV-2.
  • the mammal may be aged or not aged.
  • the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.
  • the mammal s ability to fend off a subsequent infection is determined and compared to mammals and/or historical controls who were only administered the vaccine.
  • the mammal s ability to later produce antibodies directed to an infectious agent (related to the vaccine) is determined and compared to mammals and/or historical controls who were only administered the vaccine.
  • Example 6 Methods for treating skin disorders
  • a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity with or without a second composition comprising a second agent are administered to a mammal for improving effectiveness of a vaccine that is administered to the mammal.
  • MAPK mitogen-activated protein kinases
  • the mammal may be administered only a first composition (as described in Example 3) or may be administered both a first composition and a second composition (as described in Example 4).
  • the first composition and/or the second composition may be administered topically.
  • the mammal has a skin disorder, e.g., wrinkles, which may be a result of photoaging or related to actinic keratosis.
  • a skin disorder e.g., wrinkles
  • Other skin disorders the mammal may have includes dermal atrophy (thinning of the skin), lentigines (aging spots), vaginal atrophy, and/or xerosis cutis (skin dryness).
  • the mammal has moderate skin aging (i.e., Glogau Classification III).
  • the mammal is treated with a composition or compositions of the present disclosure.
  • the composition’s or compositions’ ability to reduce wrinkles is determined and compared to mammals and/or historical controls who were not administered the composition or compositions. For example, the determination relates to a change in the Glogau Classification.

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Abstract

Disclosed herein are compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. Also disclosed herein are compositions and methods for improving effectiveness of a vaccine in a mammal. The compositions comprise, at least, a therapeutically effective amount of a p38 mitogen-activated protein kinases (MAPK) inhibitor.

Description

USE OF P38 MAPK INHIBITORS FOR PREVENTION AND TREATMENT OF AGING AND AGING-RELATED DISORDERS AND FOR BOOSTING
AN IMMUNE SYSTEM
CROSS-REFERENCE
This application claims the benefit of U.S. Provisional Application No. 63/013,409, filed April 21, 2020; the contents of which is incorporated by reference herein in its entirety.
BACKGROUND
Of the approximately 150,000 human deaths per day, approximately two-thirds are due to age- related causes. Aging leads to functional deterioration and progressive decline across multiple tissues, organs, and systems, including the immune system, that arise from the progressive accumulation of cellular and tissue damage. This damage may be attributed, in part, to dysfunction or disruption in one or more signaling pathways. Accordingly, there remains an unmet need for compositions and methods that stop, slow, or reverse these dysfunctions or disruptions and are capable of thereby treating aging-related disorders and/or reducing symptoms of aging.
SUMMARY
The present invention addresses this need. Accordingly, the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. The present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal.
An aspect of the present disclosure is a method for increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal. The method comprising administering to the mammal a first composition comprising a therapeutically effective amount of a first agent in which the first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor.
In some embodiments, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
In embodiments, the method further comprises administering to the mammal a second composition comprising a therapeutically effective amount of a second agent.
In embodiments, the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid. The second agent may be selected from L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp- AMS, NAMI- A, PF-4136309, and M AL-di -EG- V al -Cit-P AB -MM AE .
The first composition and the second composition may be administered contemporaneously, the first composition may be administered before the second composition is administered, or the second composition is administered before the first composition is administered.
In embodiments, the administering is oral, by injection, inhalation, or topical. The administering may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
In embodiments, the mammal is near or has reached maturity or is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status. The mammal may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status. In embodiments, the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
In embodiment, increasing lifespan comprises an at least 5% increase (e.g., an at least 10%, at least 15%, at least 20%, or at least 25% increase) in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status. In embodiments, the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy ( e.g Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, (including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness); or the disease includes asthma, deafness, or a viral infections and/or a symptom of the disease comprises sepsis. In some embodiments, the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering topical. The mammal may have at least one aging-related disorder or symptom of aging.
In embodiments, the therapeutically effective amount of the first agent boosts the immune system in the mammal. Boosting the immune system may increase an effective immune response against an infectious agent, e.g., a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite. The bacterium may be Bordatella pertussis or Streptococcocus pneumoniae or the virus may be a Chickenpox virus, Coronavirus (e.g., Sars-CoV-2), Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
In embodiments, the mammal has a healthy immune system or the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In embodiments, the dosage of the first agent and/or the dosage of the second agent is from about 0.01 mg/kg to about 100 mg/kg of the subject’s body weight or the first agent and/or the second agent is provided at a concentration of from about 0.000005 mM to about 20 mM, or the first agent and/or the second agent are in a solution at a percentage from about 0.001% to about 20%.
Another aspect of the present disclosure is a method for improving effectiveness of a vaccine in a mammal in need thereof. The method comprises administering a first composition comprising a therapeutically effective amount of a first agent, wherein the first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor in which the mammal contemporaneously and/or subsequently will be administered a vaccine.
In embodiments, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
In embodiments, the first composition and the vaccine are administered contemporaneously, the vaccine is administered subsequent to the first composition’s administration or after the first composition’s administration.
In embodiments, the therapeutically effective amount of the first agent boosts the immune system in the mammal. Boosting the immune system may increasee an immune response against a component contained in the vaccine. The increased immune response may promote future immunity against the component contained in the vaccine. In embodiments, the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
In embodiments, the vaccine is a Chickenpox vaccine, Coronavirus vaccine (e.g., directed against Sars-CoV-2), Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine. In embodiments, the mammal has a healthy immune system or an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
In embodiments, the method further comprises administering to the mammal a second composition comprising a therapeutically effective amount of a second agent. In embodiments, the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
Yet another aspect of the present disclosure is a first composition for use in any herein disclosed method.
In an aspect, the present disclosure provides a second composition for use in any herein disclosed method. In yet another aspect, the present disclosure provides a first composition and a second composition for use in any herein disclosed method.
It shall be understood that different aspects and/or embodiments of the invention can be appreciated individually, collectively, or in combination with each other. Various aspects and/or embodiments of the invention described herein may be applied to any of the uses set forth below and in other methods for increasing lifespan in a mammal. Any description herein concerning a specific composition and/or method apply to and may be used for any other specific composition and/or method as disclosed herein. Additionally, any composition disclosed herein is applicable to any herein-disclosed method. In other words, any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein. BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 to FIG. 54 are, respectively, graphs showing assays to determine the ability to reverse aging from the following agents: SB 203580 (at two concentrations), SB 203580 (at eight concentrations), Pexmetinib (at two concentrations), Pexmetinib (at eight concentrations), Doramapimod, PH-797804, Dilmapimod, Apilimod, Asp-AMS, Birinapant, Diclazuril, Elacridar (at two concentrations), Elacridar (at eight concentrations), Epinephrine bitartrate, G-5555, Hispidulin, KG-501, Loratadine, MAL-di-EG-Val-Cit-PAB-MMAE, Mancozeb, Meloxicam, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), SM-164 Hydrochloride, Venetoclax, YM-58483, CX-4945, CX-4945 (sodium salt), Epinephrine bitartrate (at eight concentrations), Ipriflavone, Decamethonium bromide, Diethylstilbestrol, FGF-1, GDC-0152, K02288, L-779450, Mubritinib, NAMI-A, PF-4136309, PHCCC, Pirenzepine hydrochloride, Radotinib, Rapamycin (at eight concentrations), Salicyl- AMS, Tetrabenazine (Racemate), Trihexyphenidyl hydrochloride (at eight concentrations), Vorapaxar, ACY-775, AZD1080, Betulonic acid, CP21R7, Etoposide, Isotretinoin, and Palovarotene. In these figures, the cell type used in the assays were fibroblasts.
FIG. 55 to FIG. 82 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of SB 203580 with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Mubritinib, Vorapaxar, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, PH-797804, CX-4945 (sodium salt), Rapamycin, Meloxicam, Isotretinoin, and Etoposide. In these figures, the cell type used in the assays were fibroblasts.
FIG. 83 to FIG. Ill are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of Pexmetinib with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar (at two concentrations and eight concentrations, respectively: FIG. 88A and FIG. 88B), CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Mubritinib, Vorapaxar, Diethylstilbestrol, Decamethonium bromide, Rapamycin, Meloxicam, Trihexyphenidyl hydrochloride (at eight concentrations), Loratadine, Venetoclax, Doramapimod, PH-797804, Isotretinoin, Etoposide, and Radotinib. In these figures, the cell type used in the assays were fibroblasts.
FIG. 112 to FIG. 136 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of Doramapimod with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Venetoclax, Mubritinib, Diethylstilbestrol, Pexmetinib, PH-797804, Meloxicam, Isotretinoin, Etoposide, Vorapaxar, and Decamethonium bromide. In these figures, the cell type used in the assays were fibroblasts.
FIG. 137 to FIG. 155 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of PH-797804 with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, CX-4945 (sodium salt), SB 203580, Radotinib, Vorapaxar, Ipriflavone, GDC-0152, Pexmetinib, Doramapimod, Rapamycin, Meloxicam, FGF-1, and Venetoclax. In these figures, the cell type used in the assays were fibroblasts.
FIG. 156 to FIG. 175 are, respectively, graphs showing assays to determine the ability to reverse aging from the combination of PH-797804 with the following agents: SM-164 Hydrochloride, Hispidulin, Apilimod, Betulonic acid, L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp- AMS, NAMI-A, PF-4136309, or MAL-di-EG-Val-Cit-PAB-MMAE. In these figures, the cell type used in the assays were fibroblasts.
FIG. 176 to FIG. 182 are, respectively, graphs showing assays to determine the ability to reverse aging from the following agents: SB 203580, Pexmetinib, PH-797804, Losmapimod, Acumapimod, LY2228820, and VX-702. In these figures, the cell type used in the assays were myoblasts.
In each of the figures, the horizontal line flanked by dashed lines represents the age score of the cells for that experiment when treated with sham agents. In other words, this is the baseline age score for the cells. Asterisk show statistical significance with a single asterisk meaning p<0.05 and a double asterisk meaning p<0.01.
DETAILED DESCRIPTION OF THE INVENTION
The present invention addresses this need. Accordingly, the present disclosure relates to compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. The present disclosure additionally relates to compositions and methods for improving effectiveness of a vaccine in a mammal. Introduction p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. Persistent activation of the p38 MAPK pathway in muscle satellite cells (muscle stem cells) due to ageing, impairs muscle regeneration. p38 MAPK inhibitors have been developed and are currently in development for many diseases, including rheumatoid arthritis, osteoarthritis, muscular dystrophy, cardiomyopathy, COPD, and cancer. See, Lee et al. , “Inhibition of p38 MAP kinase as a therapeutic strategy.” Immunopharm. 2000;47(2-3):185-201. Some p38 MAPK inhibitors have started clinical trials. However, the literature does not describe use of specific p38 MAPK inhibitors for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. p38 MAPK inhibitors Aspects of the present disclosure relate to compositions and methods for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal. The methods comprise administering to the mammal a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen- activated protein kinases (MAPK) inhibitor. The p38 MAPK inhibitor may be a pyridinyl-imidazole, triazanapthalenone, N,N'-diaryl urea, N,N-diaryl urea, benzophenone, pyrazole ketone, indole amide, diamide, quinazolinone, pyrimido[4,5-d]pyrimidinone, pyridylamino-quinazoline, or aryl-pyridinyl-heterocycle.
The first agent may be a p38a inhibitor and/or a r38b inhibitors. The first agent may be a p38a inhibitor and a r38b inhibitors. In some cases, the p38 MAPK inhibitor directly or indirectly competes with ATP binding by p38 MAPK.
In embodiments, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006
Preferably, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Acumapimod, Neflamapimod, Ralimetinib, VX-702, and Talmapimod. Losmapimod (also known as 585543-15-3, GSK-AHAB, GW856553, GW856553X, and 6-[5- [(cyclopropylamino)-oxomethyl]-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)-3- pyridinecarboxamide; CAS Registry number: 585543-15-3) is an orally bioavailable inhibitor of the alpha and beta isoforms of p38 mitogen-activated protein kinase (MAPK), with potential immunomodulating and anti-inflammatory activities. Losmapimod has the following chemical structure:
Figure imgf000010_0001
ARRY-797 (also known as PF-07265803, P38alpha Inhibitor 1, CHEMBL 1088750, ARRY-
371797, 5-(2,4-Difluorophenoxy)-N-(2-(Dimethylamino)Ethyl)-l -Isobutyl- lH-Indazole-6-
Carboxamide; CAS Registry number: 1034189-82-6 or 1036404-17-7) is an oral, selective p38 mitogen-activated protein kinase inhibitor. ARRY-797 has the following chemical structure:
Figure imgf000010_0002
Acumapimod (also known as 836683-15-9, BCT-197, UNII-2F16KW647L, 3-(5-amino-4-(3- cyanobenzoyl)-lH-pyrazol-l-yl)-N-cyclopropyl-4-methylbenzamide; CAS Registry number: 836683-15-9) is an inhibitor of p38a MAPK (IC50 = <1 mM). Acumapimod has the following chemical structure:
Figure imgf000011_0001
Neflamapimod (also known as VX-745; 5-(2,6-Dichlorophenyl)-2-((2,4-Difluorophenyl)Thio)- 6H-Pyrimido[l,6-B]Pyridazin-6-One; CAS Registry number: 209410-46-8) is a potent, blood- brain barrier penetrant, highly selective inhibitor of p38a inhibitor with an IC50 for p38a of 10 nM and for r38b of 220 nM. Neflamapimod (VX-745) possesses anti-inflammatory activity. Neflamapimod has the following chemical structure:
Figure imgf000011_0002
Ralimetinib (also known as LY2228820, Ralimetinib Mesylate, LY2228820 diMesylate,
Ralimetinib dimesylate, 5-[2-tert-butyl-4-(4-fluorophenyl)-lH-imidazol-5-yl]-3-(2,2- dimethylpropyl)imidazo[4,5-b]pyridin-2-amine;methanesulfonic acid; CAS Registry number: 862507-23-1). Ralimetinib Mesylate is the dimesylate salt form of LY2228820, a tri -substituted imidazole derivative and orally available, p38 mitogen-activated protein kinase (MAPK) inhibitor with potential anti-inflammatory and antineoplastic activities. Ralimetinib has the following chemical structure:
Figure imgf000011_0003
VX-702 (also known as 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)pyridine-3- carboxamide; CAS Registry number: 745833-23-2) is a small molecule investigational oral anti cytokine therapy for treatment of inflammatory diseases, specifically rheumatoid arthritis (RA). It acts as a p38 MAP kinase inhibitor. VX-702 has the following chemical structure:
Figure imgf000012_0001
Talmapimod (also known as SCIO 469, Scios 469, 2-[6-chloro-5-[(2R,5S)-4-[(4- fluorophenyl)methyl]-2,5-dimethylpiperazine-l -carbonyl]- 1 -methylindol-3-yl]-N, N-dimethyl-2- oxoacetamide; CAS Registry number: 309913-83-5) is an orally bioavailable, small-molecule, p38 mitogen-activated protein kinase (MAPK) inhibitor with potential immunomodulating, anti- inflammatory, and antineoplastic activities. Talmapimod specifically binds to and inhibits the phosphorylation of p38 MAPK, which may result in the induction of tumor cell apoptosis, the inhibition of tumor cell proliferation, and the inhibition of tumor angiogenesis. Talmapimod has the following chemical structure:
Figure imgf000012_0002
In some embodiments, the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, Dilmapimod, Ralimetinib Mesylate, Losmapimod, Acumapimod, Dehydrocorydaline (chloride), VX-702, Neflamapimod, and ARRY-797 (PF-07265803).
SB 203580 (also known as 4-[4-(4-fluorophenyl)-2-(4-methylsulfmylphenyl)-lH-imidazol-5- yljpyridine; CAS Registry Number: 152121-47-6) is a specific inhibitor of p38a and r38b which suppresses downstream activation of MAPKAP kinase-2 and heat shock protein 27. At low concentrations, it does not inhibit JNK activity. SB 203580 has the following chemical structure:
Figure imgf000013_0001
Pexmetinib (also known as ARRY-614 and l-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[[5- fluoro-2-[l -(2-hydroxy ethyl)indazol-5-yl]oxyphenyl]methyl]urea; CAS Registry number:
945614-12-0) is a potent Tie-2 and p38 MAPK dual inhibitor, with IC50s of 1 nM, 35 nM and 26 nM for Tie-2, p38a and r38b, respectively, and can be used in the research of acute myeloid leukemia. Pexmetinib has the following chemical structure:
Figure imgf000013_0002
PH-797804 (also known as 3-(3-Bromo-4-((2,4-difluorobenzyl)oxy)-6-methyl-2-oxopyridin- l(2H)-yl)-N,4-dimethylbenzamide; CAS Registry number: 586379-66-0) is an ATP-competitive, selective r38a/r38b inhibitor (IC50=26 nM and Ki=5.8 nM for p38a; Ki=40 nM for r38b) and does not inhibit JNK2. PH-797804 has the following chemical structure:
Figure imgf000013_0003
Doramapimod (also known as BIRB 796 and l-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3- [4-(2-morpholin-4-ylethoxy)naphthalen-l-yl]urea; CAS Registry number: 285983-48-4) is an orally active, highly potent p38 MAPK inhibitor, which has an IC50 for p38a=38 nM, for r38b=65 nM, for r38g=200 nM, and for p385=520 nM. Doramapimod has picomolar affinity for p38 kinase (Kd=0.1 nM). Doramapimod also inhibits B-Raf with an IC50 of 83. Doramapimod has the following chemical structure:
Figure imgf000014_0001
Dilmapimod (also known as SB-681323 and 8-(2,6-difluorophenyl)-2-(l,3-dihydroxypropan-2- ylamino)-4-(4-fluoro-2-methylphenyl)pyrido[2,3-d]pyrimidin-7-one; CAS Registry number: 444606-18-2) is a potent p38 MAPK inhibitor that potentially suppresses inflammation in chronic obstructive pulmonary disease. Dilmapimod has the following chemical structure:
Figure imgf000014_0002
Combination therapies
In some cases, a method for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system in a mammal comprises administering the mammal a first composition and a second composition. The first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen - activated protein kinases (MAPK) inhibitor and the second composition comprises a therapeutically effective amount of a second agent.
In embodiments, the first composition and the second composition are administered contemporaneously. By contemporaneously is meant administering the two compositions together or by administering the two compositions at nearly the same time. In embodiments, the first composition is administered before the second composition is administered. In embodiments, the second composition is administered before the first composition is administered.
In embodiments, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
Preferably, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, and VX-702.
In some cases, the first agent is selected from SB 203580, Pexmetinib, Doramapimod, PH-797804, and Dilmapimod.
The second agent may be classified by a mechanism selected from Acetyltransferase inhibitors, Activin receptor-like kinase (ALK) inhibitor, Adrenergic receptor agonist, Antibacterial, Antifungal, Antiparasitic, aspartyl-tRNA synthetase inhibitor, Bcl-2 inhibitor, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, cAMP response element-binding protein (CREB) inhibitor, Casein kinase 2 inhibitor, Chemokine receptor (CCR) antagonist, COX inhibitor, DNA topoisomerase inhibitor, EGFR inhibitor, HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF- 1, Focal adhesion kinase (FAR) inhibitor, Glutamate receptor antagonist, Glycogen synthase kinase 3 inhibitor, HD AC inhibitor, Histamine HI -receptor agonist, IAP Antagonist, IL-21 inhibitor, IL-23 inhibitor, Isoflavone and derivatives, Monoamine transporter inhibitor, mTOR inhibitor, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p21-activated kinase (PAR) inhibitor, p38 MAPK inhibitor, Pim-1 inhibitor, Protease- Activated Receptor (PAR) antagonist, Raf inhibitor, Raf inhibitor/p38 MAPK inhibitor, Retinoic acid receptor agonist, and Tubulin inhibitor. In embodiments, any commercially available, published, or approved drug operating by an above-mentioned mechanism may be used as a second agent in compositions and methods of the present disclosure. Preferably, the second agent is classified by a mechanism selected from IAP Antagonist, Acetyltransferase inhibitor, Adrenergic receptor agonist, Casein kinase 2 inhibitor, Multidrug resistance protein inhibitor, Calcium release-activated channel inhibitor, Antiparasitic, Isoflavone and derivative, p38 MAPK inhibitor, Muscarinic receptor antagonist, FGF-1, Bcr-Abl inhibitor, Protease- Activated Receptor (PAR) antagonist, Histamine HI -receptor agonist, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, Bcl-2 inhibitor, Nicotinic acetylcholine receptor agonist, Raf inhibitor/p38 MAPK inhibitor, mTOR inhibitor, COX inhibitor, Pim-1 inhibitor, and IL-21 inhibitor/IL-23 inhibitor.
More preferably, the second agent is classified by a mechanism selected from Bcl-2 inhibitor, Bcr- Abl inhibitors, COX inhibitor, EGFR inhibitor, Estrogen Receptor/ERR agonist, FGF-1, HER2 inhibitor, Histamine HI -receptor agonist, IAP Antagonist, IL-21 inhibitor, IL-23 inhibitor, mTOR inhibitor, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p38 MAPK inhibitor, Pim-1 inhibitor, Protease-Activated Receptor (PAR) antagonist, or Raf inhibitor.
In embodiments, the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
Preferably, the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, and Diclazuril.
Alternately, the second agent is selected from L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY- 775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, and MAL-di-EG-Val-Cit-PAB- MMAE.
In embodiments, the first agent and the second agent are both p38 MAPK inhibitors.
In embodiments, the first agent is SB 203580 and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcl-2 inhibitor, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF- 1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p38 MAPK inhibitor, Protease- Activated Receptor (PAR) antagonist, and Raf inhibitor/p38 MAPK inhibitor.
In embodiments, the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
In embodiments, the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
In embodiments, the first agent is Pexmetinib and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Anti -infective, Antiparasitic, Bcl-2 inhibitor, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF- 1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, Nicotinic acetylcholine receptor agonist, p38 MAPK inhibitor, Protease- Activated Receptor (PAR) antagonist, and Raf inhibitor/p38 MAPK inhibitor.
In embodiments, the first agent is Pexmetinib and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Pexmetinib and the second agent is SB 203580. In certain embodiments, when the first agent is Pexmetinib, the second agent is neither Etoposide, Isotretinoin, nor Radotinib.
In embodiments, the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Doramapimod and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcl-2 inhibitor, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, FGF-1, Histamine HI -receptor agonist, IAP Antagonist, Isoflavone and derivatives, Multidrug resistance protein inhibitors, Muscarinic receptor antagonist, and p38 MAPK inhibitor.
In embodiments, the first agent is Doramapimod and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC-
0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), SB 203580, Venetoclax, and YM-58483.
In embodiments, the first agent is Doramapimod and the second agent is SB 203580. In certain embodiments, when the first agent is Doramapimod, the second agent is neither Decamethonium bromide, Etoposide, Isotretinoin, Meloxicam, nor Vorapaxar.
In embodiments, the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483.
In embodiments, the first agent is SB 203580 and the second agent is Doramapimod, Pexmetinib, or PH-797804. In certain embodiments, when the first agent is SB 203580, the second agent is neither Etoposide nor Isotretinoin.
In embodiments, the first agent is PH-797804 and the second agent is classified by a mechanism selected from Acetyltransferase inhibitors, Adrenergic receptor agonist, Antiparasitic, Bcr-Abl inhibitors, Calcium release-activated channel inhibitors, Casein kinase 2 inhibitor, COX inhibitor, IAP Antagonist, Isoflavone and derivatives, mTOR inhibitor, Multidrug resistance protein inhibitors, p38 MAPK inhibitor, Protease- Activated Receptor (PAR) antagonist, and Raf inhibitor/p38 MAPK inhibitor. In embodiments, the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM-58483.
In embodiments, the first agent is PH-797804 and the second agent is SB 203580.
In certain embodiments, when the first agent is PH-797804, the second agent is neither FGF-1 nor Venetoclax.
In embodiments, the first agent is Dilmapimod and the second agent is classified by a mechanism selected from Antibacterial, Antifungal, cAMP response element-binding protein (CREB) inhibitor, IAP Antagonist, IL-21 inhibitor/IL-23 inhibitor, Muscarinic receptor antagonist, Pim-1 inhibitor, and Raf inhibitor.
In embodiments, the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride.
In certain embodiments, when the first agent is Dilmapimod, the second agent is neither ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp- AMS, NAMI- A, PF-4136309, or MAL-di-EG-Val-Cit-PAB-MMAE.
Methods, Compositions, and Administrations
Aspects of the present disclosure comprise first compositions and methods of administering the same to a mammal. The first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor. Aspects of the present disclosure further comprise a second composition and methods of administering to a mammal a first composition and a second composition; here, the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor and the second composition comprises a therapeutically effective amount of a second agent.
The compositions comprise a therapeutically effective amount of a first agent and/or a therapeutically effective amount of a second agent. The term therapeutically effective amount is meant to be the amount of the first agent and/or the second agent to increase lifespan, to prevent or treat an aging-related disorder, to reduce a symptom of aging, and/or to boost an immune system in a mammal. The term therapeutically effective amount also means the amount of the first agent and/or the second agent to improve the effectiveness of a vaccine in a mammal. In some cases, increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status. In embodiments, increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
In some cases, the therapeutically effective amount is meant to be the amount of the first agent and/or the second agent needed to prevent or treat an aging-related disorder and/or to reduce a symptom of aging. In embodiments, the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy ( e.g Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, (including acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness). In embodiments, the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, prolonged/inefficient wound healing, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering is oral or topical. In embodiments, the mammal has at least one aging-related disorder or symptom of aging. A non-human mammal may have an aging-related disorder or symptom of aging that is homologous to the aging-related disorder or symptom of aging listed above.
In some cases, the therapeutically effective amount of the first agent and/or the second agent is helpful in boosting the immune system in the mammal. In embodiments, boosting the immune system increases an effective immune response against an infectious agent. In embodiments, the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite. In embodiments, the bacterium is Bordatella pertussis or Streptococcocus pneumoniae. In embodiments, the virus is selected from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado tick fever virus (CTFV), Coronaviruse, Crimean-Congo hemorrhagic fever virus, Cytomegalovirus, Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) , Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV), Flaviviruses, Guanarito virus, Heartland virus, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV), Human metapneumovirus (hMPV), Human papillomaviruses (HPV), Human parainfluenza viruses (HPIV), Influenza, Japanese encephalitis virus, JC virus, Junin virus, Lassa virus, Lymphocytic choriomeningitis virus (LCMV), Machupo virus, Marburg virus, Measles virus, Middle East respiratory syndrome coronavirus, Molluscum contagiosum virus (MCV), Monkeypox virus, Mumps virus, Nipah virus, Norovirus, Orthomyxoviridae species, Parvovirus B19, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rhinovirus, Rift Valley fever virus, Rotavirus, Rubella virus, Sabia virus, SARS coronavirus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Shingles virus, Sin Nombre virus, Smallpox , Varicella zoster virus (VZV), Variola major or Variola minor, Venezuelan equine encephalitis virus, West Nile virus, Yellow fever virus, and Zika virus. In embodiments, the Coronavirus is Sars-CoV-2.
In some cases, the therapeutically effective amount is meant to be the amount of the first agent and/or the second agent sufficient to improve effectiveness of a vaccine in a mammal. The therapeutically effective amount of the first agent and/or the second agent may boost the immune system in the mammal, e.g., by increasing an immune response against a component contained in the vaccine. In embodiments, the increased immune response promotes future immunity against the component contained in the vaccine. In embodiments, the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent. In embodiments, the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine. In embodiments, the vaccine is a coronavirus vaccine. In embodiments, the coronavirus vaccine is directed against Sars-CoV-2.
The first and/or second compositions of the present disclosure are formulated to be suitable for in vivo administration to a mammal. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration. Pharmaceutical excipients can be aqueous liquids, such as water or saline. Pharmaceutical excipients can be lipid based, e.g., comprising a liquid or solid oil. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. The pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any composition described herein is administered parentally or in some oral formulations. In embodiments, the compositions described herein are suspended in a saline buffer (including, without limitation Ringer’s, TBS, PBS, HEPES, HBSS, and the like). Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, glycerol monostearate, mannitol, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any composition described herein, if desired, can also comprise pH buffering agents.
In embodiments, the compositions of the present disclosure are formulated for oral administration, for injection, or for topical administration. The administering the first and/or the second composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
First and/or second compositions suitable for parenteral administration (e.g, intravenous injection or infusion, intraarterial injection or infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, and intra-arterial injection or infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like, or in another acceptable format used in methods well known in the art.
First and/or second compositions suitable for enteral administration (e.g, oral administration) may be formulated as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or in another acceptable format used in methods well known in the art.
First and/or second compositions suitable for topical administration can be formulated in a solution, gel, lotion, ointment, cream, suspension, paste, liniment, powder, tincture, aerosol, patch, or the like in a pharmaceutically or cosmetically acceptable format used in methods well known in the art.
First and/or second compositions suitable for administration via inhalation. Such formulation will likely be in liquid form and will be delivered in a spray bottle, in an inhaler, or in a nebulizer.
The dosage of any herein-disclosed composition can depend on several factors including the characteristics of the mammal to be administered. Examples of characteristics include species, strain, breed, sex, age, weight, size, health, and/or disease status. Moreover, the dosage may depend on whether the administration is the first time the subject received a composition of the present disclosure or if the subject has previously received a composition of the present disclosure. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a composition) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific composition being administered, the time of administration, the route of administration, the nature of the formulation, and the rate of excretion. Some variations in the dosage can be expected.
Moreover, the dosage depends on the specific first and/or second agent administered. An illustrative dose of Doramapimod may be about 0.5 to about 30 mg/kg when administered orally or about 5 mg to about 70 mg twice daily. When administered by injection, e.g., IV, the dose of Doramapimod may be about 1 mg/kg. An illustrative dose of PH-797804 may be about 1 to about 15 mg/kg when administered orally or about .5, 3, 6 or 10 mg once daily. When administered by injection, e.g., intraperitoneal injection or subcutaneously, the dose of PH-797804 may between about 0.3 mg/kg and about 5 mg/kg once or twice daily. An illustrative dose of SB 203580 may be about 10 to about 100 mg/kg when administered orally, about 0.15 mg/kg to about 25 mg/kg when administered by injection, e.g, intraperitoneal injection, or in a topical formulation having a concentration of about 1.0 to about 10 mM. An illustrative dose of Losmapimod may be about 1 to about 12 mg/kg administered orally once or twice daily or about 15 mg twice daily or about 1.8 mg/kg when administered by injection, e.g, intraperitoneal injection, or may be in a 0.05% solution when administered topically. An illustrative dose of ARRY-797 may be about 3 mg/kg to about 30 mg/kg administered orally once or twice daily or about 100 mg to about 400 mg twice daily. ARRY-797 may be administered in a 0.05% topical solution. In some embodiments, the dosage of the first agent and/or the dosage of the second agent may be from about 0.01 mg/kg to about 100 mg/kg of the subject’s body weight, or any dosage therebetween. As examples, the dosage of the first agent and/or the dosage of the second agent may be about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about 0.1 mg/kg. The dosage of the first agent and/or the dosage of the second agent may be about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, or about 1.0 mg/kg. The dosage of the first agent and/or the dosage of the second agent may be about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about
1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, or about 2.0 mg/kg. The dosage of the first agent and/or the dosage of the second agent may be about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg. The dosage of the first agent and/or the dosage of the second agent may be about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, or about 20 mg/kg. The dosage of the first agent and/or the dosage of the second agent may be about 30 mg/kg, about 32 mg/kg, about 34 mg/kg, about 36 mg/kg, about 38 mg/kg, about 40 mg/kg, about 42 mg/kg, about 44 mg/kg, about 46 mg/kg, about 48 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, or about 100 mg/kg.
The first agent and/or the second agent may be provided at a concentration of from about 0.000005 mM to about 20 mM, or any concentration therebetween. As examples, the concentration may be about 0.125 pM, about 0.25 pM, about 0.5 pM, about 1.0 pM, about 2.5 pM, about 5.0 pM, about 10.0 pM, about 12.0 pM, or about 20.0 pM. As examples, the concentration may be about 1.0 pM, about 1.1 pM, about 1.2 pM, about 1.3 pM, about 1.4 pM, about 1.5 pM, about 1.6 pM, about 1.7 pM, about 1.8 pM, about 1.9 pM, about 2.0 pM, about 2.1 pM, about 2.2 pM, about 2.3 pM, about
2.4 pM, about 2.5 pM, about 2.6 pM, about 2.7 pM, about 2.8 pM, about 2.9 pM, about 3.0 pM, about 3.1 pM, about 3.2 pM, about 3.3 pM, about 3.4 pM, about 3.5 pM, about 3.6 pM, about 3.7 pM, about 3.8 pM, about 3.9 pM, about 4.0 pM, about 4.1 pM, about 4.2 pM, about 4.3 pM, about
4.4 pM, about 4.5 pM, about 4.6 pM, about 4.7 pM, about 4.8 pM, about 4.9 pM, about 5.0 pM, about 5.1 pM, about 5.2 pM, about 5.3 pM, about 5.4 pM, about 5.5 pM, about 5.6 pM, about 5.7 pM, about 5.8 pM, about 5.9 pM, about 6.0 pM, about 6.1 pM, about 6.2 pM, about 6.3 pM, about
6.4 pM, about 6.5 pM, about 6.6 pM, about 6.7 pM, about 6.8 pM, about 6.9 pM, about 70 pM, about 7.1 pM, about 7.2 pM, about 7.3 pM, about 7.4 pM, about 7.5 pM, about 7.6 pM, about 7.7 mM, about 7.8 mM, about 7.9 mM, about 8.0 mM, about 8.1 mM, about 8.2 mM, about 8.3 mM, about 8.4 mM, about 8.5 mM, about 8.6 mM, about 8.7 mM, about 8.8 mM, about 8.9 mM, about 9.0 mM, about 9.1 mM, about 9.2 mM, about 9.3 mM, about 9.4 mM, about 9.5 mM, about 9.6 mM, about 9.7 mM, about 9.8 mM, about 9.9 mM, about 10.0 mM, about 10.1 mM, about 10.2 mM, about 10.3 mM, about 10.4 mM, about 10.5 mM, about 10.6 mM, about 10.7 mM, about 10.8 mM, about 10.9 mM, about 11.0 mM, about 11.1 mM, about 11.2 mM, about 11.3 mM, about 11.4 mM, about 11.5 mM, about 11.6 mM, about 11.7 mM, about 11.8 mM, about 11.9 mM, or about 12.0 mM. about 12.1 mM, about 12.2 mM, about 12.3 mM, about 12.4 mM, about 12.5 mM, about 12.6 mM, about 12.7 mM, about 12.8 mM, about 12.9 mM, about 13.0 mM, about 13.1 mM, about 13.2 mM, about 13.3 mM, about 13.4 mM, about 13.5 mM, about 13.6 mM, about 13.7 mM, about 13.8 mM, about 13.9 mM, about 14.0 mM, about 14.1 mM, about 14.2 mM, about 14.3 mM, about 14.4 mM, about 14.5 mM, about 14.6 mM, about 14.7 mM, about 14.8 mM, about 14.9 mM, about 15.0 mM, about 15.1 mM, about 15.2 mM, about 15.3 mM, about 15.4 mM, about 15.5 mM, about 15.6 mM, about 15.7 mM, about 15.8 mM, about 15.9 mM, about 16.0 mM, about 16.1 mM, about 16.2 mM, about 16.3 mM, about 16.4 mM, about 16.5 mM, about 16.6 mM, about 16.7 mM, about 16.8 mM, about 16.9 mM, about 17.0 mM, about 17.1 mM, about 17.2 mM, about 17.3 mM, about 17.4 mM, about 17.5 mM, about 17.6 mM, about 17.7 mM, about 17.8 mM, about 17.9 mM, about 18.0 mM, about 18.1 mM, about 18.2 mM, about 18.3 mM, about 18.4 mM, about 18.5 mM, about 18.6 mM, about 18.7 mM, about 18.8 mM, about 18.9 mM, about 19.0 mM, about 19.1 mM, about 19.2 mM, about 19.3 mM, about 19.4 mM, about 19.5 mM, about 19.6 mM, about 19.7 mM, about 19.8 mM, about 19.9 mM, or about 20.0 mM. In some embodiments a dosage (in mM, e.g., when used in a cell culture) can be converted to a dosage (e.g., % solution, mM, and/or mg/kg) for in vivo administration.
In some embodiments, the first agent and/or the second agent are administered in a solution at a percentage from about 0.001% to about 20%, or any percentage therebetween. As examples, the solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 0.001 %, about 0.002 %, about 0.003 %, about 0.004 %, about 0.005 %, about 0.006 %, about 0.007 %, about 0.008 %, about 0.009 %, or about 0.01 %. The solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 0.01 %, about 0.02 %, about 0.03 %, about 0.04 %, about 0.05 %, about 0.06 %, about 0.07 %, about 0.08 %, about 0.09 %, or about 0.1 %. The solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 0.1 %, about 0.2 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 0.8 %, about 0.9 %, or about 1.0 %. The solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 1.1 %, about 1.2 %, about 1.3 %, about 1.4 %, about 1.5 %, about 1.6 %, about 1.7 %, about 1.8 %, about 1.9 %, or about 2.0 %. The solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 %. The solution’s percentage of the first agent and/or the solution’s percentage of the second agent may be about 11 %, about 12 %, about 13 %, about 14 %, about 15 %, about 16 %, about 17 %, about 18 %, about 19 %, or about 20 %.
The first agent and/or the second agent may be administered once daily, twice daily, thrice daily, or more times per day. The first agent and/or the second agent may be administered once a week, twice a week, three times a week, four time per week, five times per week, six times per week, or more times per week. The first agent and/or the second agent may be administered once a month, twice a month, three times a month, four time per month, five times per month, six times per month, seven times per month, eight times per month, nine times per month, ten times per month, or more times per month.
Of course, when a second agent is administered (before, after, or contemporaneously with the first agent), the dosage of the first agent and/or the second agent may differ from a standard dosage of the first agent and/or the second agent when either agent is administered alone. For example, when a first agent and a second agent are administered, the dose of the first agent may be lower than a standard dosage when the first agent is administered alone. Similarly, the dose of the second agent may be lower than a standard dose when the second agent is administered alone.
The first and/or second compositions may be formulated to slowly release the first agent and/or the second agent in the mammal and/or to improve stability of a composition.
In embodiments, the first agent and/or the second agent are encapsulated in a microcapsule. The microcapsule may be a liposome, an albumin microsphere, a microemulsion, a nanoparticle (e.g, a lipid nanoparticle), and a nanocapsule. In embodiments, microcapsules, e.g, lipid nanoparticles and liposomes, include lipids selected from one or more of the following categories: cationic lipids; anionic lipids; neutral lipids; multi-valent charged lipids; and zwitterionic lipids. In some cases, a cationic lipid and/or cationic polymer may be used to facilitate a charge-charge interaction with a first agent and/or with a second agent. The microcapsule may comprise a PEGylated lipid. Examples of microcapsules and methods for manufacturing the same are described in the art. See, e.g, Prui et al. , Crit Rev Ther Drug Carrier Syst, 2009; 26(6): 523-580; Wakasar, J Drug Target, 2018, 26(4):311-318, Langer, 1990, Science 249:1527-1533; Treat et al. , in “Liposomes in the Therapy of Infectious Disease and Cancer”, Lopez -Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Pelaz et al. “Diverse applications of nanomedicine.” (2017): 2313-2381; the contents of each of which is incorporated herein by reference in its entirety.
In embodiments, a composition may comprise one or more of capralactone, polylactide (PLA), polylactic-co-glycolic (PLGA), polyethylene glycol (PEG), polylactic-co-hydroxymethylglycolic acid (PLHMGA), carboxymethylcellulose, hydroxylmethylcellulose, gelatin-microcapsules, a poloxamer, or polymethylmethacrylate.
When the first composition and/or the second composition is for oral administration and is in solid form ( e.g a pill or capsule), the composition may comprise delay-release components. For example, a pill or capsule may comprise a coating that slows release of the agents and/or prevents release of the agents until the pill or capsule has arrived at a desired location of the mammal’s digestive system.
Boosting the immune system
Another aspect of the present disclosure is a method for boosting the immune system in a mammal.
In embodiments, boosting the immune system increases an effective immune response against an infectious agent. In embodiments, the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite. In embodiments, the bacterium is Bordatella pertussis or Streptococcocus pneumoniae. In embodiments, the virus is selected from Alphavirus, BK virus, Bunyaviridae, Chickenpox virus, Colorado tick fever virus (CTFV), Coronaviruse, Crimean- Congo hemorrhagic fever virus, Cytomegalovirus, Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) , Ebolavirus (EBOV), Enteroviruses, mainly Coxsackie A virus and enterovirus 71 (EV71), Epstein-Barr virus (EBV), Flaviviruses, Guanarito virus, Heartland virus, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D Virus, Hepatitis E virus, Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Human bocavirus (HBoV), Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), Human immunodeficiency virus (HIV), Human metapneumovirus (hMPV), Human papillomaviruses (HPV), Human parainfluenza viruses (HPIV), Influenza, Japanese encephalitis virus, JC virus, Junin virus, Lassa virus, Lymphocytic choriomeningitis virus (LCMV), Machupo virus, Marburg virus, Measles virus, Middle East respiratory syndrome coronavirus, Molluscum contagiosum virus (MCV), Monkeypox virus, Mumps virus, Nipah virus, Norovirus, Orthomyxoviridae species, Parvovirus B19, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rhinovirus, Rift Valley fever virus, Rotavirus, Rubella virus, Sabia virus, SARS coronavirus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Shingles virus, Sin Nombre virus, Smallpox , Varicella zoster virus (VZV), Variola major or Variola minor, Venezuelan equine encephalitis virus, West Nile virus, Yellow fever virus, and Zika virus. In embodiments, the Coronavirus is Sars-CoV-2. In some cases, the mammal has a healthy immune system. In other cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
In embodiments, the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g, in some severe coronavirus patients. In these cases, “boosting the immune system”, relates to “boosting” a proper immune response. That is, minimizing an overactive immune response.
In embodiments, the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status. In embodiments, the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
Of course, any mammal may benefit from a boost in the immune system. Thus, the compositions and methods for boosting the immune system can be used with aged and with non-aged mammals.
The method for boosting the immune system comprises administering a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen -activated protein kinases (MAPK) inhibitor. The method may further comprise a second composition and methods relate to administering to a mammal a first composition and a second composition; here, the first composition comprises a therapeutically effective amount of a first agent that is a p38 mitogen-activated protein kinases (MAPK) inhibitor and the second composition comprises a therapeutically effective amount of a second agent. In embodiments, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006. In embodiments, the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, and Dilmapimod.
In embodiments, the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid
In embodiments, the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
In embodiments, the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
In embodiments, the first agent is Pexmetinib and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483. In embodiments, the first agent is Pexmetinib and the second agent is SB 203580. In certain embodiments, when the first agent is Pexmetinib, the second agent is neither Etoposide, Isotretinoin, nor Radotinib.
In embodiments, the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Doramapimod and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC- 0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide),
SB 203580, Venetoclax, and YM-58483. In embodiments, the first agent is Doramapimod and the second agent is SB 203580. In certain embodiments, when the first agent is Doramapimod, the second agent is neither Decamethonium bromide, Etoposide, Isotretinoin, Meloxicam, nor Vorapaxar. In embodiments, the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483. In embodiments, the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483. In embodiments, the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483. In embodiments, the first agent is SB 203580 and the second agent is Doramapimod, Pexmetinib, or PH-797804. In certain embodiments, when the first agent is SB 203580, the second agent is neither Etoposide nor Isotretinoin.
In embodiments, the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM-58483. In embodiments, the first agent is PH-797804 and the second agent is SB 203580. In certain embodiments, when the first agent is PH-797804, the second agent is neither FGF-1 nor Venetoclax.
In embodiments, the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride. In certain embodiments, when the first agent is Dilmapimod, the second agent is neither ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or M AL-di -EG- V al -Cit-P AB -MM AE .
In embodiments, the administering is oral, by injection, inhalation, or topical. The administering the first and/or the second composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
Improving a vaccine response
Aspects of the present disclosure relate to compositions and methods for improving effectiveness of a vaccine in a mammal.
It has been reported in the art that aged mammals respond less strongly to vaccines than mammal who are less aged. Accordingly, methods for improving effectiveness of a vaccine in an aged mammal are needed.
In embodiments, an aged mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status. In embodiments, the aged mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status. Influenza is problematic in older adults with increased risk for serious complications and hospitalization. In addition, approximately 90% of flu-related deaths occur in this population, with influenza and pneumonia being the eighth leading cause of death among persons over 65 years of age in the United States. Even when death is avoided, older adults have an increased risk for secondary complications and morbidities from flu infection. Depending on how successful the WHO predicts the influenza strains causing seasonal epidemics, the produced vaccines show efficacy rates between 60% and 90%. However, vaccine effectiveness in adults aged 65 and older is usually significantly lower, ranging from an average of 28% protection against fatal and nonfatal complications (with large dispersion), 39% protection against typical influenza-like illness, and 49% protection against disease with confirmed virus infection. Influenza vaccine effectiveness is a significant problem in elderly as compared to young individuals and is associated with high rates of complicated illness including pneumonia, heart attacks, and strokes in the >65 -year-old population.
Furthermore, the outbreak of the novel coronavirus (SARS-CoV-2) has had devastating effects on the aged and those with pre-existing health conditions. A mammal would particularly benefit from a composition of the present disclosure and methods of administering the same to improve effectiveness of a SARS-CoV-2 vaccine.
Of course, mammals who are not aged may benefit from improved effectiveness of a vaccine. Thus, the compositions and methods for improving effectiveness of a vaccine can be used with non-aged mammals.
In some cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.
In embodiments, the term dysfunctional immune system may be an overactive immune system, e.g., resulting in a cytokine storm; such overactive immune systems are observed in certain viral infections, e.g, in some severe coronavirus patients. In these cases, “improving a vaccine response”, relates to “improving” a proper immune response to a vaccine and, later, when a subject is contacted with an infectious agent. That is, minimizing an overactive immune response and promoting a proper immune response.
The method for improving effectiveness of a vaccine comprises administering a first composition comprising a therapeutically effective amount of a first agent that is a p38 mitogen -activated protein kinases (MAPK) inhibitor. In embodiments, the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
In embodiments, the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, and Dilmapimod.
In embodiments, the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid
In embodiments, the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
In embodiments, the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
In embodiments, the first agent is Pexmetinib and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483. In embodiments, the first agent is Pexmetinib and the second agent is SB 203580. In certain embodiments, when the first agent is Pexmetinib, the second agent is neither Etoposide, Isotretinoin, nor Radotinib.
In embodiments, the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib,
Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is Doramapimod and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC- 0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide),
SB 203580, Venetoclax, and YM-58483. In embodiments, the first agent is Doramapimod and the second agent is SB 203580. In certain embodiments, when the first agent is Doramapimod, the second agent is neither Decamethonium bromide, Etoposide, Isotretinoin, Meloxicam, nor Vorapaxar. In embodiments, the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483. In embodiments, the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
In embodiments, the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483. In embodiments, the first agent is SB 203580 and the second agent is Doramapimod, Pexmetinib, or PH-797804. In certain embodiments, when the first agent is SB 203580, the second agent is neither Etoposide nor Isotretinoin.
In embodiments, the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM-58483. In embodiments, the first agent is PH-797804 and the second agent is SB 203580. In certain embodiments, when the first agent is PH-797804, the second agent is neither FGF-1 nor Venetoclax.
In embodiments, the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride. In certain embodiments, when the first agent is Dilmapimod, the second agent is neither ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or M AL-di -EG- V al -Cit-P AB -MM AE .
In embodiments, the administering is oral, by injection, inhalation, or topical. The administering the first and/or the second composition may comprise intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
In some cases, the first composition (with or without a second composition) and the vaccine are administered contemporaneously. In other cases, the vaccine is administered subsequent to the administration of the first composition (with or without a second composition). In some cases, the vaccine is administered before the administration of the first composition (with or without a second composition). In some cases, the therapeutically effective amount is meant to be the amount of the first agent and/or the second agent to improve effectiveness of a vaccine in a mammal. The therapeutically effective amount of the first agent and/or the second agent may boost the immune system in the mammal, e.g., by increasing an immune response against a component contained in the vaccine. In embodiments, the increased immune response promotes future immunity against the component contained in the vaccine. In embodiments, the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
The vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine. In embodiments, the vaccine is a coronavirus vaccine. In embodiments, the coronavirus vaccine is directed against Sars-CoV-2.
Aging-associated conditions
The herein-disclosed compositions and methods treat, prevent, reduce the severity of, and/or delay the onset of various aging-associated conditions, e.g, chronic diseases and disabilities/conditions of aging. Illustrative aging-related disorders include actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy (e.g, Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, (including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness). In some embodiments, ALI differs from ARDS in that ALI exists during early stage of a respiratory disease and ARDS exists during a later state of the respiratory disease. Aged non-human subjects experience similar, homologous, and/or equivalent aging-related disorders.
Subjects
In embodiments, the subject is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In embodiments, the mammal is a non-rodent. In embodiments, the mammal is a dog. In embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet, e.g, a dog. In another specific embodiment, the non-human animal is a livestock animal. In embodiments, the mammal is a human.
In embodiments, the mammal has reached maturity. As used herein, the term mature or maturity, and the like, refers to a mammal that is capable of sexual reproduction and/or a mammal that has achieved its adult height and/or length.
In embodiments, the mammal is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status. The mammal may have reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
In embodiments, the human is an adult human. In embodiments, the human has an age in a range of from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old, or older.
In some cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system. DEFINITIONS
The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting.
As used herein, unless otherwise indicated, the terms “a”, “an” and “the” are intended to include the plural forms as well as the single forms, unless the context clearly indicates otherwise.
The terms “comprise”, “comprising”, “contain,” “containing,” “including”, “includes”, “having”, “has”, “with”, or variants thereof as used in either the present disclosure and/or in the claims, are intended to be inclusive in a manner similar to the term “comprising.”
By preventing is meant, at least, avoiding the occurrence of a disease and/or reducing the likelihood of acquiring the disease. By treating is meant, at least, ameliorating or avoiding the effects of a disease, including reducing a sign or symptom of the disease.
The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean 10% greater than or less than the stated value. In another example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” should be assumed to mean an acceptable error range for the particular value.
Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.
EXAMPLES
The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art. Example 1: Identification of first agents useful in methods of the present disclosure
In this example, first agents having p38 mitogen-activated protein kinases (MAPK) inhibitory activity and capable of increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system were identified.
Sets of cultured cells (fibroblasts or myoblasts) having either characteristics of young cells or characteristics of old cells are contacted with known p38 MAPK inhibitors. The ability of the p38 MAPK inhibitor to reverse aging in the cells, e.g., reducing the characteristics of old cells and promoting characteristics of a young cells was assayed (also known as reducing the predicted age of the cells). p38 MAPK inhibitors at various concentrations ranging from about 0.000005 to about 20 mM, e.g., 0 mM, 0.031 pM, 0.125 pM, 0.25 pM, 0.5 pM, 1.0 pM, 2 pM, 2.5 pM, 4 pM, 5 pM, 10 pM, 16 pM, and 20 pM. p38 MAPK inhibitors showing the ability to reverse aging were further validated.
The following p38 MAPK inhibitors were tested: SB 203580, Pexmetinib, PH-797804, Doramapimod, Dilmapimod, Ralimetinib Mesylate, Losmapimod, Acumapimod, Dehydrocorydaline (chloride), VX-702, SB 203580 (hydrochloride), SB 239063, SKF-86002, Talmapimod, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, SD 0006, TAK-715, Ferulic acid methyl ester, p38a inhibitor 1, Pamapimod, Neflamapimod, Skepinone-L, Tat-NR2B9c (TFA), BMS-582949 (hydrochloride), BMS-582949, Bakuchiol, ITX5061, Asiatic acid, R1487 (Hydrochloride), WAY-637221-A, WAY-639009, UM-164 , WAY-327527, and ARRY-797.
Among which, SB 203580, Pexmetinib, PH-797804, Doramapimod, Dilmapimod, Ralimetinib Mesylate, Losmapimod, Acumapimod, Dehydrocorydaline (chloride), VX-702, SB 203580 (hydrochloride), SB 239063, SKF-86002, Talmapimod, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, SD 0006, Neflamapimod, and ARRY-797 (PF-07265803) showed the ability to reverse aging when the agents contacted fibroblasts.
The following agents were tested for their ability to alone reverse aging in fibroblasts: ACY-775, Apilimod, Asp-AMS, AZD1080, Betulonic acid, Birinapant, CP21R7, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Elacridar - 8, Epinephrine bitartrate, Etoposide, FGF-1, G-5555, GDC-0152, Hispidulin, Ipriflavone, Isotretinoin, K02288, KG-501, L-779450, Loratadine, M AL-di -EG- V al -Cit-P AB -MM AE, Mancozeb, Meloxicam, Mubritinib, NAMI-A, Palovarotene, PF-4136309, PHCCC, Pirenzepine hydrochloride, Radotinib, Rapamycin, Remodelin (hydrobromide), Salicyl-AMS, SM-164 Hydrochloride, Tetrabenazine (Racemate), Trihexyphenidyl hydrochloride, Venetoclax, Vorapaxar, and YM-58483. See, FIG. 1 to FIG. 54.
Additionally, the following agents were tested for their ability to reverse aging in myoblasts: SB 203580, Pexmetinib, PH-797804, Losmapimod, Acumapimod, LY2228820, and VX-702. See,
FIG. 176 to FIG. 182
The following p38 MAPK inhibitors demonstrated surprisingly abilities to alone reverse aging: SB 203580, Pexmetinib, Doramapimod, PH-797804, and Dilmapimod. See, FIG. 1 to FIG. 7.
Assays used in this example are related to those described in US20190228840, the entire contents of which is incorporated by reference its entirety.
Example 2: Identification of second agents and combinations of first and second agents useful in methods of the present disclosure
In this example, second agents that contribute (along with the first agents identified in Example 1, above) to increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system were identified.
Sets of cultured cells (fibroblasts or myoblasts) having either characteristics of young cells or characteristics of old cells are contacted with presumptive second agents along with one of the following p38 MAPK inhibitors: Pexmetinib, PH-797804, Doramapimod, SB 203580, and Dilmapimod. The ability of the combination of a presumptive second agent and the p38 MAPK inhibitor to reverse aging in the cells, e.g., reducing the characteristics of old cells and promoting characteristics of a young cells was assayed (also known as reducing the predicted age of the cells). p38 MAPK inhibitors and the presumptive second agents were used at various concentrations ranging from about 0.000005 to about 20 mM, e.g., 0 pM, 0.031 pM, 0.125 pM, 0.25 pM, 0.5 pM, 1.0 pM, 2 pM, 2.5 pM, 4 pM, 5 pM, 10 pM, 16 pM, and 20 pM. p38 MAPK inhibitors showing the ability to reverse aging were further validated.
The following presumptive second agents were tested: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX- 4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Mubritinib, Vorapaxar, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, Betulonic acid, L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, and MAL-di-EG-Val- Cit-PAB-MMAE.
Among which, CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid showed the ability to reverse aging in fibroblasts when treated along with the p38 MAPK inhibitor.
Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, CX-4945, Elacridar, YM-58483, and Diclazuril were particularly beneficial in reversing aging in fibroblasts when combined with a first agent, i.e., SB 203580, Pexmetinib, Doramapimod, PH-797804, and Dilmapimod.
FIG. 55 to FIG. 82 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of SB 203580 with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Mubritinib, Vorapaxar, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, PH-797804, CX-4945 (sodium salt), Rapamycin, Meloxicam, Isotretinoin, and Etoposide. Among which, the following combinations demonstrated surprisingly abilities to reverse aging: SB 203580 with GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH- 797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, or YM-58483. On the other hand, neither Etoposide nor Isotretinoin were beneficial in reversing aging when combined with SB 203580. FIG. 83 to FIG. Ill are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of Pexmetinib with the following agents: Birinapant, Remodelin (hydrobromide) (at two concentrations), Remodelin (hydrobromide) (at eight concentrations), Epinephrine bitartrate (at two concentrations), Epinephrine bitartrate (at eight concentrations), Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Mubritinib, Vorapaxar, Diethylstilbestrol, Decamethonium bromide, Rapamycin, Meloxicam, Trihexyphenidyl hydrochloride (at eight concentrations), Loratadine, Venetoclax, Doramapimod, PH-797804, Isotretinoin, Etoposide, and Radotinib. Among which, the following combinations demonstrated surprisingly abilities to reverse aging: Pexmetinib with Birinapant, CX-4945, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, or YM- 58483. On the other hand, none of Isotretinoin, Etoposide, or Radotinib were beneficial in reversing aging when combined with Pexmetinib.
FIG. 112 to FIG. 136 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of Doramapimod with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Loratadine, Venetoclax, Mubritinib, Diethylstilbestrol, Pexmetinib, PH-797804, Meloxicam, Isotretinoin, Etoposide, Vorapaxar, and Decamethonium bromide. Among which, the following combinations demonstrated surprisingly abilities to reverse aging: Doramapimod with Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF- 1, GDC-0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), SB 203580, Venetoclax, or YM-58483. On the other hand, none of Meloxicam, Isotretinoin, Etoposide, Vorapaxar, or Decamethonium bromide were beneficial in reversing aging when combined with Doramapimod.
FIG. 137 to FIG. 155 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of PH-797804 with the following agents: Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, CX-4945, YM-58483, Diclazuril, CX-4945 (sodium salt), SB 203580, Radotinib, Vorapaxar, Ipriflavone, GDC-0152, Pexmetinib, Doramapimod, Rapamycin, Meloxicam, FGF-1, and Venetoclax. Among which the following combinations demonstrated surprisingly abilities to reverse aging: PH-797804 Birinapant, CX- 4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, or YM-58483. On the other hand, neither of FGF-1 nor Venetoclax were beneficial in reversing aging when combined with PH-797804.
FIG. 156 to FIG. 175 are, respectively, graphs showing assays to determine the ability to reverse aging in fibroblasts from the combination of PH-797804 with the following agents: SM-164 Hydrochloride, Hispidulin, Apilimod, Betulonic acid, L-779450, Mancozeb, Salicyl-AMS, KG- 501, ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or M AL-di -EG- V al -Cit-P AB -MM AE . Among which, the following combinations demonstrated surprisingly abilities to reverse aging: Dilmapimod with Apilimod, Betulonic acid, Hispidulin, or SM-164 Hydrochloride. On the other hand, none of ACY-775, PHCCC, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, or MAL-di-EG-Val-Cit-PAB- MMAE were beneficial in reversing aging when combined with Doramapimod.
Excellent results were also obtained in fibroblasts when both the first agent and the second agent were p38 MAPK inhibitors. For example, Pexmetinib as first agent with the second agent being Doramapimod, PH-797804, or SB 203580; PH-797804 as first agent with the second agent being Doramapimod, Pexmetinib, or SB 203580; Doramapimod as first agent with the second agent being Pexmetinib, PH-797804, or SB 203580; and SB 203580 as first agent and the second agent being Doramapimod, Pexmetinib, or PH-797804.
An assay is performed to determine the determine the ability to reverse aging from the combination of Losmapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
An assay is performed to determine the determine the ability to reverse aging from the combination of ARRY-797 (PF-07265803) with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
An assay is performed to determine the determine the ability to reverse aging from the combination of Ralimetinib with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
An assay is performed to determine the determine the ability to reverse aging from the combination of Acumapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
An assay is performed to determine the determine the ability to reverse aging from the combination of Neflamapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin,
Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
An assay is performed to determine the determine the ability to reverse aging from the combination of Talmapimod with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin,
Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid. An assay is performed to determine the determine the ability to reverse aging from the combination of VX-702 with the following second agent: CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
Assays used in this example are related to those described in E1S20190228840, the entire contents of which is incorporated by reference its entirety.
Example 3: Methods comprising administering a first composition
In this example, a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity is administered to a mammal for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system.
The first compositions comprise one of the following p38 MAPK inhibitors: Losmapimod, ARRY- 797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
Administration of the first composition is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the first composition is administered orally, by inhalation, or topically.
The mammal’s lifespan is measured and the presence, absence, and/or severity of various aging- associated conditions are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
Example 4: Methods comprising administering a first composition
In this example, a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity and a second composition comprising a second agent are administered to a mammal for increasing lifespan, for preventing or treating an aging-related disorder, for reducing a symptom of aging, and/or boosting an immune system.
The first compositions comprise one of the following p38 MAPK inhibitors: Losmapimod, ARRY- 797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
The second compositions comprise one of second agents identified in Example 2, above, e.g., CX- 4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid. Administration of the first composition is by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the first composition is administered orally, by inhalation, or topically.
Administration of the second composition is by intravenous injection or infusion, intraperitoneal inj ection, intramuscular inj ection, or subcutaneous inj ection, with a dose depending on the quantity of composition needing to be administered. Alternately, the second composition is administered orally, by inhalation, or topically.
The first composition may be administered before the second composition is administered.
The first composition may be administered after the second composition is administered. The first composition and the second composition may be administered contemporaneously (either by combining the two compositions or by administering the two compositions at nearly the same time). The mammal’s lifespan is measured and the presence, absence, and/or severity of various aging- associated conditions are determined; these are compared to control mammals and/or to historical controls to determine the effectiveness of the first composition administered.
Example 5: Methods for improving a vaccine response
In this example, a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity with or without a second composition comprising a second agent are administered to a mammal for improving effectiveness of a vaccine that is administered to the mammal.
The mammal may be administered only a first composition (as described in Example 3) or may be administered both a first composition and a second composition (as described in Example 4).
Administration of the first composition may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the first composition may be administered orally, by inhalation, or topically.
Administration of the second composition may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the second composition may be administered orally, by inhalation, or topically.
Administration of the vaccine may be by intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection, with a dose depending on the quantity of composition needing to be administered. Alternately, the vaccine may be administered orally, by inhalation, or topically.
In some cases, the first composition (with or without a second composition) and the vaccine are administered contemporaneously. In other cases, the vaccine is administered subsequent to the administration of the first composition (with or without a second composition). In some cases, the vaccine is administered before the administration of the first composition (with or without a second composition).
The vaccine may be a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human immunodeficiency virus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine. In embodiments, the vaccine is a coronavirus vaccine. In embodiments, the coronavirus vaccine is directed against Sars-CoV-2.
The mammal may be aged or not aged.
In some cases, the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system. In other cases, the mammal has a healthy immune system.
The mammal’s ability to fend off a subsequent infection is determined and compared to mammals and/or historical controls who were only administered the vaccine.
The mammal’s ability to later produce antibodies directed to an infectious agent (related to the vaccine) is determined and compared to mammals and/or historical controls who were only administered the vaccine.
Example 6: Methods for treating skin disorders
In this example, a first composition comprising a first agent having p38 mitogen-activated protein kinases (MAPK) inhibitory activity with or without a second composition comprising a second agent are administered to a mammal for improving effectiveness of a vaccine that is administered to the mammal.
The mammal may be administered only a first composition (as described in Example 3) or may be administered both a first composition and a second composition (as described in Example 4).
The first composition and/or the second composition may be administered topically.
The mammal has a skin disorder, e.g., wrinkles, which may be a result of photoaging or related to actinic keratosis. Other skin disorders the mammal may have includes dermal atrophy (thinning of the skin), lentigines (aging spots), vaginal atrophy, and/or xerosis cutis (skin dryness). In examples, the mammal has moderate skin aging (i.e., Glogau Classification III).
The mammal is treated with a composition or compositions of the present disclosure. The composition’s or compositions’ ability to reduce wrinkles is determined and compared to mammals and/or historical controls who were not administered the composition or compositions. For example, the determination relates to a change in the Glogau Classification.

Claims

CLAIMS What is claimed is:
1. A method for increasing lifespan in a mammal, for preventing or treating an aging-related disorder in a mammal, for reducing a symptom of aging in a mammal, and/or boosting an immune system in a mammal comprising: administering to the mammal a first composition comprising a therapeutically effective amount of a first agent, wherein the first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor.
2. The method of claim 1, wherein the first agent is a p38a inhibitor and/or a r38b inhibitors.
3. The method of claim 2, wherein the first agent is a p38a inhibitor and a r38b inhibitors.
4. The method of any one of claims 1 to 3, wherein the p38 MAPK inhibitor is a pyridinyl- imidazole, triazanapthalenone, N,N'-diaryl urea, N,N-diaryl urea, benzophenone, pyrazole ketone, indole amide, diamide, quinazolinone, pyrimido[4,5-d]pyrimidinone, pyridylamino-quinazoline, or aryl-pyridinyl-heterocycle.
5. The method of any one of claims 1 to 4, wherein the p38 MAPK inhibitor directly or indirectly competes with ATP binding by p38 MAPK.
6. The method of any one of claims 1 to 5, wherein the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
7. The method of any one of claims 1 to 6, wherein the first agent is selected from Losmapimod, ARRY-797 (PF-07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, and Dilmapimod.
8. The method of any one of claims 1 to 6, wherein the first agent is selected from SB 203580, Pexmetinib, PH-797804, Doramapimod, and Dilmapimod.
9. The method of any one of claims 1 to 8, further comprising administering to the mammal a second composition comprising a therapeutically effective amount of a second agent.
10. The method of claim 9, wherein the first composition and the second composition are administered contemporaneously.
11. The method of claim 9, wherein the first composition is administered before the second composition is administered.
12. The method of claim 9, wherein the second composition is administered before the first composition is administered.
13. The method of any one of claims 9 to 12, wherein the second agent is classified by a mechanism selected from IAP Antagonist, Acetyltransferase inhibitor, Adrenergic receptor agonist, Casein kinase 2 inhibitor, Multidrug resistance protein inhibitor, Calcium release-activated channel inhibitor, Antiparasitic, Isoflavone and derivative, p38 MAPK inhibitor, Muscarinic receptor antagonist, FGF-1, Bcr-Abl inhibitor, Protease-Activated Receptor (PAR) antagonist, Histamine HI -receptor agonist, EGFR inhibitor/HER2 inhibitor, Estrogen Receptor/ERR agonist, Bel -2 inhibitor, Nicotinic acetylcholine receptor agonist, Raf inhibitor/p38 MAPK inhibitor, mTOR inhibitor, COX inhibitor, Pim-1 inhibitor, and IL-21 inhibitor/IL-23 inhibitor.
14. The method of any one of claims 9 to 13, wherein the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
15. The method of any one of claims 9 to 14, wherein the second agent is selected from L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF- 4136309, and MAL-di-EG-Val-Cit-PAB-MMAE.
16. The method of any one of claims 9 to 15, wherein the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
17. The method of any one of claims 9 to 15, wherein the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
18. The method of any one of claims 9 to 15, wherein the first agent is Pexmetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
19. The method of any one of claims 9 to 15, wherein the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
20. The method of any one of claims 9 to 15, wherein the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
21. The method of any one of claims 9 to 15, wherein the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
22. The method of any one of claims 9 to 15, wherein the first agent is Doramapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), SB 203580, Venetoclax, and YM-58483.
23. The method of any one of claims 9 to 15, wherein the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
24. The method of any one of claims 9 to 15, wherein the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
25. The method of any one of claims 9 to 15, wherein the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH-797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483.
26. The method of any one of claims 9 to 15, wherein the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM- 58483.
27. The method of any one of claims 9 to 17, wherein the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride.
28. The method of any one of claims 1 to 27, wherein the administering is oral, by injection, inhalation, or topical.
29. The method of any one of claims 1 to 28, wherein the administering of the first and/or the second composition comprises intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.
30. The method of any one of claims 1 to 29, wherein the mammal is near or has reached maturity or is nearing or has reached halfway to its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
31. The method of claim 30, wherein the mammal has reached an age that is at least 60%, 70%, 80%, 90%, or 100% of its expected lifespan for the mammal’s species, size, sex, age, and/or health status.
32. The method of any one of claims 1 to 31, wherein the mammal is a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon.
33. The method of claim 32, wherein the mammal is a human.
34. The method of any one of claims 1 to 33, wherein increasing lifespan comprises an at least 5% increase in lifespan relative to the expected or median lifespan of a mammal of similar species, sex, age, and/or health status.
35. The method of claim 34, wherein increasing lifespan comprises an at least 10%, at least 15%, at least 20%, or at least 25% increase in lifespan.
36. The method of any one of claims 1 to 35, wherein the aging-related disorder or symptom of aging selected from one or more of actinic keratosis, age-related macular degeneration (AMD), Alzheimer’s disease, arthritis, atherosclerosis and cardiovascular disease, benign prostatic hyperplasia (BPH), bone atrophy, cachexia, cancer, cardiomyopathy, cataracts, chronic obstructive pulmonary disease (COPD), constipation, decrease in overall energy, decrease in visual acuity, delirium, dementia, depression, dermal atrophy (thinning of the skin), diminished peripheral vision, dry eye, greater risk of heat stroke or hypothermia, hearing loss, hypertension, increased susceptibility to infection (including influenza and pneumonia), lentigines (aging spots), memory loss, metabolic syndrome, muscle atrophy ( e.g Sarcopenia and myopenia), frailty, muscle repair or rejuvenation deficiency, muscular dystrophy, osteoarthritis, osteoporosis, periodontitis, photoaging, reduced metabolism (including increased risk for obesity), reduced reflexes and coordination including difficulty with balance, respiratory disease, (including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)), rheumatoid arthritis, sarcopenic obesity, sexual dysfunction, shingles, type 2 diabetes, urologic changes (including incontinence), vaginal atrophy, whitening or graying of hair, prolonged/inefficient wound healing, wrinkling/sagging skin (including loss of skin elasticity), and xerosis cutis (skin dryness); or the disease includes asthma, deafness, or a viral infections and/or a symptom of the disease comprises sepsis.
37. The method of claim 36, wherein the aging-related disorder or symptom of aging is actinic keratosis, dermal atrophy (thinning of the skin), lentigines (aging spots), photoaging, vaginal atrophy, wrinkles, and/or xerosis cutis (skin dryness) and wherein the administering topical.
38. The method of claim 36 or claim 37, wherein the mammal has at least one aging -related disorder or symptom of aging.
39. The method of any one of claims 1 to 38, wherein the therapeutically effective amount of the first agent boosts the immune system in the mammal.
40. The method of claim 39, wherein boosting the immune system increases an effective immune response against an infectious agent.
41. The method of claim 40, wherein the infectious agent is a virus, a bacterium, a fungus, a protozoan, a helminth, a prion, or a parasite.
42. The method of claim 41, wherein the bacterium is Bordatella pertussis or Streptococcocus pneumoniae or the virus is a Chickenpox virus, Coronavirus, Hepatitis A virus, Hepatitis B virus, Human papillomavirus, Human immunodeficiency virus (HIV), influenza, Japanese encephalitis virus, Measles, mumps, or rubella virus, Poliovirus, Rabies virus, Respiratory syncytial virus (RSV), Rotavirus, Shingles virus, Smallpox, Varicella virus, or Yellow fever virus.
43. The method of claim 42, wherein the Coronavirus is Sars-CoV-2.
44. The method of any one of claims 39 to 43, wherein the mammal has a healthy immune system.
45. The method of any one of claims 39 to 43, wherein has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
46. The method of any one of claims 39 to 45, wherein the dosage of the first agent and/or the dosage of the second agent is from about 0.01 mg/kg to about 100 mg/kg of the subject’s body weight or the first agent and/or the second agent is provided at a concentration of from about 0.000005 mM to about 20 pM, or the first agent and/or the second agent are in a solution at a percentage from about 0.001% to about 20%.
47. A method for improving effectiveness of a vaccine in a mammal in need thereof comprising administering a first composition comprising a therapeutically effective amount of a first agent, wherein the first agent is a p38 mitogen-activated protein kinases (MAPK) inhibitor, wherein the mammal contemporaneously and/or subsequently will be administered a vaccine.
48. The method of claim 47, wherein the first agent is selected Losmapimod, ARRY-797 (PF- 07265803), Pexmetinib, Ralimetinib Mesylate, Acumapimod, Neflamapimod, Doramapimod, Talmapimod, VX-702, Dilmapimod, PH-797804, SB 203580, SB 203580 (hydrochloride), Dehydrocorydaline (chloride), SB 239063, SKF-86002, TA-02, Pseudolaric Acid B, SB 202190, Skatole, TA-01, SB 242235, PD 169316, p38-a MAPK-IN-1, Na-1, and SD 0006.
49. The method of any one of claims 46 to 48, wherein the first agent is selected from Pexmetinib, PH-797804, Doramapimod, SB 203580, and Dilmapimod.
50. The method of any one of claims 46 to 49, wherein the first composition and the vaccine are administered contemporaneously.
51. The method of any one of claims 46 to 49, wherein the vaccine is administered subsequent to the first composition’s administration or after the first composition’s administration.
52. The method of any one of claims 46 to 51, wherein the therapeutically effective amount of the first agent boosts the immune system in the mammal.
53. The method of claim 52, wherein boosting the immune system increases an immune response against a component contained in the vaccine.
54. The method of claim 53, wherein the increased immune response promotes future immunity against the component contained in the vaccine.
55. The method of claim 54, wherein the component contained in the vaccine is an antigen obtained from, related to, homologous to, or expressed by an infectious agent.
56. The method of any one of claims 46 to 55, wherein the vaccine is a Chickenpox vaccine, Coronavirus vaccine, Diphtheria vaccine, Hepatitis A vaccine, Hepatitis B vaccine, Haemophilus influenzae type b vaccine, Human Immunovirus (HIV) vaccine, Human papillomavirus vaccine, influenza vaccine, Japanese encephalitis vaccine, Measles, mumps, or rubella (including MMR combined vaccine) vaccine, Meningococcal disease vaccine, Pneumococcal disease vaccine, Polio vaccine, Rabies vaccine, Respiratory syncytial virus (RSV) vaccine, Rotavirus vaccine, Shingles vaccine, Smallpox vaccine, Tetanus vaccine, Varicella virus vaccine, Whooping cough (part of the DTaP combined vaccine) vaccine, or Yellow fever vaccine.
57. The method of claim 56, wherein the vaccine is a coronavirus vaccine.
58. The method of claim 57, wherein the coronavirus vaccine is directed against Sars-CoV-2
59. The method of any one of claims 46 to 58, wherein the mammal has a healthy immune system.
60. The method of any one of claims 46 to 58, wherein the mammal has an unhealthy immune system, dysfunctional immune system, and/or weakened immune system.
61. The method of any one of claims 46 to 58, further comprising administering to the mammal a second composition comprising a therapeutically effective amount of a second agent.
62. The method of claim 61, wherein the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
63. The method of claim 62, wherein the second agent is selected from L-779450, Mancozeb, Salicyl-AMS, KG-501, ACY-775, PHCCC, Isotretinoin, Palovarotene, G-5555, AZD1080, CP21R7, K02288, Etoposide, Tetrabenazine (Racemate), Asp-AMS, NAMI-A, PF-4136309, and M AL-di -EG- V al -Cit-P AB -MM AE .
64. The method of any one of claims 61 to 63, wherein the first agent is Losmapimod and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
65. The method of any one of claims 61 to 63, wherein the first agent is ARRY-797 (PF-07265803) and the second agent is selected from CX-4945, Birinapant, Remodelin (hydrobromide), Epinephrine bitartrate, Elacridar, YM-58483, Diclazuril, Ipriflavone, GDC-0152, CX-4945 (sodium salt), SB 203580, Pirenzepine hydrochloride, FGF-1, Radotinib, Voraxapar, Loratadine, Mubritinib, Diethylstilbestrol, Venetoclax, Decamethonium bromide, Pexmetinib, Doramapimod, Rapamycin, PH-797804, Meloxicam, SM-164 Hydrochloride, Hispidulin, Apilimod, Trihexyphenidyl hydrochloride, and Betulonic acid.
66. The method of any one of claims 61 to 63, wherein the first agent is Pexmetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
67. The method of any one of claims 61 to 63, wherein the first agent is Ralimetinib and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
68. The method of any one of claims 61 to 63, wherein the first agent is Acumapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
69. The method of any one of claims 61 to 63, wherein the first agent is Neflamapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin
(hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
70. The method of any one of claims 61 to 63, wherein the first agent is Doramapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Loratadine, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), SB 203580, Venetoclax, and YM-58483.
71. The method of any one of claims 61 to 63, wherein the first agent is Talmapimod and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin
(hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
72. The method of any one of claims 61 to 63, wherein the first agent is VX-702 and the second agent is selected from CX-4945, Birinapant, CX-4945 (sodium salt), Decamethonium bromide, Diclazuril, Diethylstilbestrol, Elacridar, Epinephrine bitartrate, FGF-1, GDC-0152, Ipriflavone, Meloxicam, Mubritinib, Pirenzepine hydrochloride, Rapamycin, Remodelin (hydrobromide), SB 203580, Trihexyphenidyl hydrochloride, Vorapaxar, and YM-58483.
73. The method of any one of claims 61 to 63, wherein the first agent is SB 203580 and the second agent is selected from GDC-0152, Birinapant, CX-4945, Decamethonium bromide, Diclazuril, Diethylstilbestrol, Doramapimod, Elacridar, Epinephrine bitartrate, FGF-1, Ipriflavone, Loratadine, Mubritinib, Pexmetinib, PH-797804, Pirenzepine hydrochloride, Radotinib, Remodelin (hydrobromide), Venetoclax, Vorapaxar, and YM-58483.
74. The method of any one of claims 61 to 63, wherein the first agent is PH-797804 and the second agent is selected from Birinapant, CX-4945, CX-4945 (sodium salt), Diclazuril, Elacridar, Epinephrine bitartrate, Radotinib, Remodelin (hydrobromide), SB 203580, Vorapaxar, and YM- 58483.
75. The method of any one of claims 61 to 63, wherein the first agent is Dilmapimod and the second agent is selected from Apilimod, Betulonic acid, Hispidulin, and SM-164 Hydrochloride.
76. A first composition for use in the method of any one of claims 1 to 75.
77. A second composition for use in the method of any one of claims 9 to 45 or 61 to 75.
78. A first composition and a second composition for use in the method of any one of claims 9 to 45 or 61 to 75.
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