Methods of increasing mammalian lifespan

Abstract

Provided herein are methods of reducing or reversing senescence-induced insulin resistance and / or elevated fatty acid comprising a composition comprising a PPAR [gamma] agonist, or a pharmaceutically acceptable salt or prodrug thereof. Provided herein are methods of extending longevity comprising a composition comprising a PPAR [gamma] agonist, or a pharmaceutically acceptable salt or prodrug thereof, and uses of the composition in animal health.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 454,874, filed March 27, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0002] It is well known that chronological age is the greatest risk factor for almost every major cause of death and morbidity in organisms, including humans and companion dogs. Even before observable disease development, the physiological functions of organ systems and tissues gradually decline throughout life. Throughout history, there has been a fervent search for products and methods to promote longevity and extend lifespan. Often, these products and methods have proven ineffective and / or unsafe. Therefore, the need for safe and effective products and methods to promote longevity and extend lifespan remains unmet. Summary of the Invention

[0003] In some embodiments, this document provides a method for alleviating or reversing age-induced insulin resistance in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0004] In some embodiments, this document provides a method for alleviating or reversing insulin resistance in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0005] In some embodiments, this document provides a method for mitigating or reversing age-induced elevations of fatty acids and other lipids in a desired mammal, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0006] In some embodiments, this document provides a method for maintaining healthy function of adipose tissue in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0007] In some embodiments, the method does not lower the glucose level of the mammal. In some embodiments, the method does not raise the glucose level of the mammal. In some embodiments, the method includes lowering the insulin level of the mammal. In some embodiments, lowering the insulin level is a reduction of at least 5%. In some embodiments, lowering the insulin level is a reduction of at least 10%, at least 15%, or at least 20%.

[0008] In some embodiments, the method improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test. In some embodiments, insulin sensitivity is measured by fasting blood insulin levels. In some embodiments, insulin sensitivity is measured by a high insulin positive glucose clamp test.

[0009] In some embodiments, the lipid is aggregated free fatty acid, saturated fatty acid, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the fatty acid is saturated fatty acid, palmitic acid, linoleic acid, or oleic acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is palmitic acid. In some embodiments, the method reduces triglyceride levels in the mammal. In some embodiments, the method reduces cholesterol levels in the mammal. In some embodiments, the method increases adiponectin levels in the mammal.

[0010] In some embodiments, the mammal is a dog, cat, horse, cow, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog or cat. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human. In some embodiments, the mammal is at least 7 years old. In some embodiments, the mammal is at least 10 years old.

[0011] In some embodiments, the formulation comprises about 3% to about 35% of the PPARγ agonist. In some embodiments, the formulation comprises about 10% to about 20% of the PPARγ agonist. In some embodiments, the formulation comprises about 1 mg to about 100 mg of the PPARγ agonist. In some embodiments, the formulation comprises about 4 mg to about 85 mg of the PPARγ agonist. In some embodiments, the PPARγ agonist is administered at 3 mg / kg / day. In some embodiments, the PPARγ agonist is administered at 5 mg / kg / day. In some embodiments, the PPARγ agonist is administered at 10 mg / kg / day. In some embodiments, the formulation is administered for at least about 4 weeks. In some embodiments, the formulation is administered for at least about 12 weeks. In some embodiments, the formulation is administered for at least about 6 months. The formulation is administered for at least about 1 year. In some embodiments, the formulation is administered daily.

[0012] In some embodiments, the PPARγ agonist is pioglitazone. In some embodiments, the pioglitazone is administered at 1 mg / kg / day. In some embodiments, the pioglitazone is administered at 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the PPARγ agonist is rosiglitazone.

[0013] In some embodiments, the formulation is a pharmaceutical formulation. In some embodiments, the formulation is a nutritional formulation.

[0014] In some embodiments, the formulation is in the form of tablets. In some embodiments, the tablets comprise hydrolyzed chicken product. In some embodiments, the tablets comprise 18 mg, 54 mg, or 81 mg of the PPARγ agonist. In some embodiments, the tablets further comprise at least one filler. In some embodiments, the filler is lactose monohydrate. In some embodiments, the amount of lactose monohydrate is from about 10% w / w to about 40% w / w. In some embodiments, the amount of lactose monohydrate is about 22% w / w. In some embodiments, the tablets further comprise carboxymethyl cellulose Na. In some embodiments, the amount of carboxymethyl cellulose Na is from about 2% w / w to about 10% w / w. In some embodiments, the amount of carboxymethyl cellulose Na is about 4% w / w. In some embodiments, the tablets further comprise FlavorPAL X1212. In some embodiments, the amount of FlavorPAL X1212 is from about 10% w / w to about 40% w / w. In some embodiments, the amount of FlavorPAL X1212 is about 20% w / w. In some embodiments, the tablets further comprise magnesium stearate. In some embodiments, the amount of magnesium stearate is from about 0.25% w / w to about 3% w / w. In some embodiments, the amount of magnesium stearate is about 1% w / w.

[0015] In some embodiments, this document provides a method for reducing or delaying age-related disease-related death in mammals of need, the method comprising administering to the mammal a therapeutically effective amount of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, this document provides a method for treating age-related decline in quality of life, the method comprising administering to the mammal a therapeutically effective amount of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0016] In some embodiments, this document provides a method for treating age-related decline in quality of life, the method comprising administering to the mammal a therapeutically effective amount of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0017] In some embodiments, this document provides a method for treating age-related increased frailty, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0018] In some embodiments, the method further includes increasing lifespan, wherein the increased lifespan comprises an increase of at least 5% relative to the expected or median lifespan of a similar species, strain, or breed of mammal. In some embodiments, the increased lifespan comprises an increase of at least 10%, at least 15%, at least 20%, or at least 25%.

[0019] In some embodiments, the method includes mitigating or reversing insulin resistance in the mammal. In some embodiments, the insulin resistance occurs during aging. In some embodiments, the method includes mitigating or reversing elevated free fatty acids (FFA). In some embodiments, the elevated FFA is associated with an age-related disease state. In some embodiments, the age-related disease state is obesity, type 2 diabetes, cardiovascular disease, or sarcopenia. In some embodiments, the elevated FFA is due to advanced chronological age. In some embodiments, FFA is associated with elevated fasting insulin levels with increasing age.

[0020] In some embodiments, the mammal has reached maturity. In some embodiments, the mammal has reached old age. In some embodiments, the mammal is at least 7 years old. In some embodiments, the mammal is at least 10 years old. In some embodiments, the mammal weighs at least 14 pounds.

[0021] In some embodiments, the mammal is a dog, cat, horse, cow, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog or cat. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human.

[0022] In some embodiments, the method comprises about 3% to about 35% of the PPARγ agonist. In some embodiments, the method comprises about 10% to about 20% of the PPARγ agonist. In some embodiments, the method comprises about 1 mg to about 100 mg of the PPARγ agonist. In some embodiments, the method comprises about 4 mg to about 85 mg of the PPARγ agonist. In some embodiments, the PPARγ agonist is administered at 3 mg / kg / day. In some embodiments, the PPARγ agonist is administered at 5 mg / kg / day. In some embodiments, the PPARγ agonist is administered at 10 mg / kg / day. In some embodiments, the PPARγ agonist is administered for at least about 4 weeks. In some embodiments, the PPARγ agonist is administered for at least about 12 weeks. In some embodiments, the PPARγ agonist is administered for at least about 6 months. In some embodiments, the PPARγ agonist is administered for at least about 1 year. In some embodiments, the PPARγ agonist is administered daily.

[0023] In some embodiments, the PPARγ agonist is pioglitazone. In some embodiments, the pioglitazone is administered at 1 mg / kg / day. In some embodiments, the pioglitazone is administered at 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the PPARγ agonist is rosiglitazone. In some embodiments, the formulation is a pharmaceutical formulation. In some embodiments, the formulation is a nutritional formulation.

[0024] In some embodiments, the formulation is in the form of tablets. In some embodiments, the tablets comprise hydrolyzed chicken product. In some embodiments, the tablets comprise 18 mg, 54 mg, or 81 mg of the PPARγ agonist. In some embodiments, the tablets further comprise at least one filler. In some embodiments, the filler is lactose monohydrate. In some embodiments, the amount of lactose monohydrate is from about 10% w / w to about 40% w / w. In some embodiments, the amount of lactose monohydrate is about 22% w / w. In some embodiments, the tablets further comprise carboxymethyl cellulose Na. In some embodiments, the amount of carboxymethyl cellulose Na is from about 2% w / w to about 10% w / w. In some embodiments, the amount of carboxymethyl cellulose Na is about 4% w / w. In some embodiments, the tablets further comprise FlavorPAL X1212. In some embodiments, the amount of FlavorPAL X1212 is from about 10% w / w to about 40% w / w. In some embodiments, the amount of FlavorPAL X1212 is about 20% w / w. In some embodiments, the tablets further comprise magnesium stearate. In some embodiments, the amount of magnesium stearate is from about 0.25% w / w to about 3% w / w. In some embodiments, the amount of magnesium stearate is about 1% w / w.

[0025] In some embodiments, this document provides a formulation comprising pioglitazone or a pharmaceutically acceptable salt thereof, said formulation for reducing or delaying death in companion animals due to age-related diseases, said formulation being administered for at least 2 weeks.

[0026] In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / kg / day to 5 mg / kg / day. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of up to 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least about 4 weeks. In some embodiments, the formulation is administered for at least about 12 weeks. In some embodiments, the formulation is administered for at least about 1 year. In some embodiments, the method comprises reducing the insulin level of the companion animal. In some embodiments, the insulin level is reduced by at least 5%. In some embodiments, the formulation improves insulin sensitivity. In some embodiments, the insulin sensitivity is measured by an oral glucose tolerance test or by a high insulin positive glucose clamp test. In some embodiments, the insulin sensitivity is measured by a short or modified oral glucose tolerance test. In some embodiments, the insulin sensitivity is measured by using fasting insulin blood levels. In some embodiments, the formulation reduces triglyceride levels in the companion animal. In some embodiments, the formulation reduces cholesterol levels in the companion animal. In some embodiments, the use further comprises mitigating age-induced fatty acid elevation, wherein the fatty acids are aggregated free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the formulation comprises about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 4 mg to about 85 mg of pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet comprises 18 mg, 54 mg, or 81 mg of pioglitazone or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, this document provides a method for reducing or delaying death from age-related diseases in companion animals in need, the method comprising orally administering to the companion animal a therapeutically effective amount of a formulation comprising pioglitazone or a pharmaceutically acceptable salt thereof, wherein the formulation is administered for at least 2 weeks.

[0028] In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / kg / day to 5 mg / kg / day. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of up to 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least about 4 weeks. In some embodiments, the formulation is administered for at least about 12 weeks. In some embodiments, the formulation is administered for at least about 1 year. In some embodiments, the method comprises reducing the insulin level of the companion animal. In some embodiments, the insulin level is reduced by at least 5%. In some embodiments, the method improves insulin sensitivity. In some embodiments, the insulin sensitivity is measured by an oral glucose tolerance test or by a high insulin positive glucose clamp test. In some embodiments, the insulin sensitivity is measured by a short or modified oral glucose tolerance test. In some embodiments, the insulin sensitivity is measured by using fasting insulin blood levels. In some embodiments, the method reduces triglyceride levels in the companion animal. In some embodiments, the method reduces cholesterol levels in the companion animal. In some embodiments, the use further comprises mitigating age-induced fatty acid elevation, wherein the fatty acids are aggregated free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the formulation comprises about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 4 mg to about 85 mg of pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the tablet comprises 18 mg, 54 mg, or 81 mg of pioglitazone or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0029] Figure 1 This study demonstrates the relationship between blood insulin levels (calculated as the normalized natural logarithm of insulin) and age (in years). Points are colored based on the following weight groups: below 50 lb, 50 lb to 100 lb, 100 lb to 150 lb, and above 150 lb.

[0030] Figure 2A-2B The relationship between HRQL total score and canine frailty score index and blood insulin level was demonstrated. Figure 2A The relationship between total HRQL score and insulin level (calculated as the normalized natural logarithm (insulin)) is shown. Points are colored based on the following age groups: under 3 years, 3 to 6 years, 6 to 9 years, 9 to 12 years, 12 to 15 years, and over 15 years. Figure 2B The relationship between canine frailty scores and insulin (expressed on its natural scale (mIU / L)) at each age is shown, with each age in years: 4 years, 7 years, 10 years, 15 years, and 18 years, where 4 years is the lower band and gradually rises to 18 years is the higher band.

[0031] Figures 3A-3C It shows the HRQL scores for each group over time. Figure 3A The estimated median sum of HRQL scores is presented for different insulin level groups adjusted for age (in years), weight (in lbs), and BCS. The lowest group was classified as insulin levels from 2.53 mU / L to 12 mU / L, the middle group as insulin levels from 12 mU / L to 20.9 mU / L, and the highest group as insulin levels from 20.9 mU / L to 107 mU / L. Figure 3B This demonstrates how the HRQL kernel density estimate on the Davies scale changes with age (in years). Figure 3C It displays the total HRQL score and age (in years).

[0032] Figure 4A-4G The CFI score and HRQL score are displayed. Figure 4A The relationship between CFI score and age (in years) determined by linear regression analysis is shown. Figure 4B The relationship between HRQL scores and CFI scores, determined by linear regression analysis, is shown. Figure 4C The relationship between age and fatty acid types and aggregates, as determined using linear regression analysis, is shown. Figure 4D The relationship between the natural logarithm (adiponectin) and age, as determined by linear regression analysis, is shown. Figure 4E The relationship between fatty acid types and aggregates and adiponectin, as determined by linear regression analysis, is shown. Figure 4F The relationship between fatty acid types and aggregates and CFI scores within age groups, as determined by linear regression analysis, is shown. Figure 4G The relationship between the natural logarithm (adiponectin) within age groups and CFI, as determined by linear regression analysis, is shown.

[0033] Figures 5A-5DThe data showed glucose and insulin levels. Group 1 consisted of a normal diet plus a placebo, Group 2 consisted of a high-fat diet plus a placebo, Group 3 consisted of a high-fat diet plus 1 mg / kg of pioglitazone, and Group 4 consisted of a high-fat diet plus 2 mg / kg of pioglitazone. Figure 5A Figure A shows the fasting glucose levels before and after treatment, and Figure B shows the percentage change. Figure 5B Figure C shows the fasting insulin level, and Figure D shows the percentage change. Figure 5C Figure A shows the AUC of glucose, and Figure B shows the percentage change. Figure 5D Figure A shows the AUC of insulin, and Figure B shows the percentage change.

[0034] Figures 6A-6E The study demonstrates the quantification of fatty acids under different treatment groups. Group 1 consisted of a normal diet plus a placebo, Group 2 consisted of a high-fat diet plus a placebo, Group 3 consisted of a high-fat diet plus 1 mg / kg of pioglitazone, and Group 4 consisted of a high-fat diet plus 2 mg / kg of pioglitazone. Figure 6A It shows the fatty acid levels of saturated fatty acids. Figure 6B The fatty acid levels of palmitic acid are shown. Figure 6C The fatty acid levels of linoleic acid are shown. Figure 6D It shows the fatty acid level of oleic acid. Figure 6E This demonstrates that the clinical diagnostic assay of NEFA is not sensitive enough to detect physiologically relevant changes. Figure 6F It shows the clinically measured triglyceride levels. Figure 6G The levels of free fatty acids and adiponectin in different groups are shown, with the bars in Group 1, Group 2, Group 3 and Group 4 arranged from left to right.

[0035] Figure 7 Figure 8-10 illustrates the research design.

[0036] Figures 8A-8B This study presents pioglitazone (A) and adiponectin (B) levels in dogs receiving placebo, 1 mg / kg pioglitazone, and 2 mg / kg pioglitazone during a 56-day experimental protocol, two weeks prior to administration of a high-fat diet. All data are presented as mean ± SEM.

[0037] Figures 9A-9B : Shows the OGTT insulin curves at baseline and day 46 ( Figure 9A ) and total 120-minute insulin AUC ( Figure 9B All data are expressed as mean ± SEM.

[0038] Figures 10A-10C The graphs show the rate of glucose disappearance (Rd) of HIEG in dogs receiving placebo, 1 mg / kg pioglitazone, and 2 mg / kg pioglitazone during the 56-day experimental protocol. Figure 10A HIEG glucose disappearance rate AUC ( Figure 10B ) and HIEG glucose infusion rate (GIR, Figure 10C All data are expressed as mean ± SEM.

[0039] Figure 11A-11C (A) shows insulin infusion levels during the HIEG clamp at baseline and day 56. Figure 11B The insulin infusion rates between dogs in the pioglitazone 2 mg / kg group were shown. Figure 11C GIRs of animals undergoing matched insulin infusion in HIEG clamps are shown. All data are expressed as mean ± SEM.

[0040] Figures 12A-12E : Figure 12A The free fatty acid concentrations quantified by GC-MS at baseline and day 56 are shown. Figure 12B The concentrations of saturated fatty acids, quantified by GC-MS at baseline and day 56, are shown. Figure 12C The concentrations of linoleic acid fatty acids, quantified by GC-MS at baseline and day 56, are shown. Figure 12D The concentrations of palmitic acid fatty acids, quantified by GC-MS at baseline and day 56, are shown. Figure 12E Free fatty acid concentrations, quantified by clinical use of NEFA, are presented at baseline and day 56. All data are expressed as mean ± SEM. Detailed Implementation

[0041] Age-related changes in adipose tissue function influence many known biological mechanisms of aging. Visceral adipose tissue increases with age and subcutaneous fat decreases, a phenomenon commonly observed in dogs, rodents, and humans. In all three species, insulin resistance increases with age. The ultimate result of this age-dependent metabolic dysfunction is reduced flexibility in utilizing nutrients as fuel sources, worsening organ dysfunction, and increased frailty. Increased frailty also directly leads to a decline in quality of life. As a major regulator of adipose tissue, PPARγ has unique effects on age-dependent metabolic dysfunction. PPARγ agonists such as pioglitazone have been shown to improve lipid processing, enhance insulin sensitivity, and restore adipose function in cases of obesity and type 2 diabetes mellitus (T2DM). Given the profound benefits already observed in the treatment and prevention of metabolic diseases with pioglitazone, such benefits should also apply to age-related metabolic dysfunction. Delaying or preventing age-related metabolic dysfunction through PPARγ agonists could reduce frailty and extend healthy lifespan and life expectancy.

[0042] definition Unless otherwise defined, all specialized terms, symbols, and other technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some instances, for clarity and / or for timely reference, terms with their commonly understood meanings are defined herein, and such definitions included herein should not be construed as representing a material difference from the meanings commonly understood in the art.

[0043] Throughout this application, various embodiments may be presented in the form of ranges. It should be understood that the descriptions in range form are merely for convenience and brevity and should not be construed as immutable limitations on the scope of this disclosure. Therefore, the descriptions of ranges should be considered as having specifically disclosed all possible subranges and individual numerical values ​​within those ranges. For example, a range description such as 1 to 6 should be considered as having specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0044] As used in the specification and claims, the singular forms “a / an” and “the” include plural objects unless the context clearly indicates otherwise. For example, the term “sample” includes multiple samples, including mixtures thereof.

[0045] When referring to numbers or numerical ranges, the term "about" means that the mentioned numbers or numerical range are approximate values ​​within experimental variability (or statistical experimental error), and therefore the variation in the numbers or numerical range does not exceed 15% of the range. The term "treat / treating / treatment" refers to any sign of success in treating or improving an injury, pathology, symptom, or condition (e.g., pain), including any objective or subjective parameter such as the relief, alleviation, reduction, reversal, or decrease of symptoms, or making the symptoms, injury, pathology, or condition more tolerable to the patient; reducing the frequency or duration of symptoms; or, in some cases, preventing the onset of symptoms. Treatment or improvement of symptoms can be based on any objective or subjective parameter; including, for example, the results of a physical examination.

[0046] As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some respects, the terms “formulation” and “composition” can be used to refer to a mixture of one or more active agents with a carrier or other excipients.

[0047] As used herein, the term "fat" refers to dietary fat. This includes fatty acids, fatty acid esters, and mixtures of both. It can also refer to glycerides, such as, but not limited to, diglycerides and triglycerides; lipids, such as, but not limited to, phospholipids; and sterols, such as, but not limited to, cholesterol. Fat can also refer to free fatty acids and fatty acid conjugates.

[0048] As used herein, the term “administration” refers to oral administration to a subject, administration in suppository form, local contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal or subcutaneous administration, intrathecal administration or intralymphatic administration, droplet inhalation, or implantation of a sustained-release device, such as a microosmotic pump.

[0049] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate quantity of a drug or compound administered that will, to some extent, alleviate one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compounds disclosed herein that is clinically necessary to significantly reduce a disease. Appropriate "effective amounts" in any individual case can be determined using techniques such as dose escalation studies.

[0050] The term "pharmaceutically acceptable salt" refers to a PPARγ agonist that does not cause significant irritation to the mammal to which it is administered and does not significantly eliminate the biological activity and properties of the compound. A variety of pharmaceutically acceptable salts can be formed, and these include: - Acid addition salts formed by reacting PPARγ agonists with organic acids, including aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanic acids, hydroxyalkanic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc., and including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. - Acid addition salts formed by reacting PPARγ agonists with inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.

[0051] The term "metabolic dysfunction" can refer to a state of metabolic imbalance and / or decline. In some embodiments, metabolic dysfunction is caused by natural aging. In some embodiments, metabolic dysfunction is caused by a high-fat diet. In some embodiments, metabolic dysfunction is caused by natural aging. In some embodiments, metabolic dysfunction is caused by a high-fat diet.

[0052] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs, etc.; domesticated animals such as rabbits, dogs, and cats, etc.; laboratory animals, including rodents such as rats, mice, and guinea pigs. In some embodiments, the mammal is a human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a rodent. In some embodiments, the mammal is a companion animal.

[0053] The term "relief" refers to reducing or eliminating one or more symptoms or risk factors associated with a disease or condition, and / or reducing the incidence, delaying the onset, or lessening the severity of one or more symptoms of the disease or condition. In some embodiments, the term "relief" may also refer to the prevention of the disease or condition. In some embodiments, the disease or condition is a metabolic dysfunction. Examples include preventive effects against increases in fasting insulin, free fatty acids, and weakness induced by metabolic dysfunction.

[0054] The term "reversal" refers to the return of a specific biomarker or outcome to clinically healthy levels. Examples include reversing the effects of metabolic dysfunction-induced increases in fasting insulin, free fatty acids, and frailty. In some embodiments, metabolic dysfunction is caused by natural aging. In some embodiments, metabolic dysfunction is caused by a high-fat diet.

[0055] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0056] compound The compounds described herein can be PPARγ agonists, PPARα agonists, or PPARα / PPARγ agonists. The compounds described herein are PPARγ agonists. In some embodiments, the PPARγ agonist is a thiazolidinedione derivative. In some embodiments, the PPARγ agonist is lobeglitazone, troglitazone, ciglitazone, rivoglitazone, empaglitazone, balaglitazone, napoglitazone, pioglitazone, or rosiglitazone. In some embodiments, the PPARγ agonist is lobeglitazone, troglitazone, pioglitazone, or rosiglitazone. In some embodiments, the PPARγ agonist is pioglitazone. In some embodiments, the PPARγ agonist is pioglitazone or a salt thereof. In some embodiments, the pioglitazone is in a free base form. In some embodiments, the PPARγ agonist is pioglitazone hydrochloride. In some embodiments, the PPARγ agonist is pioglitazone. Pioglitazone is a PPARγ agonist having the following structure, shown as HCl pioglitazone: .

[0057] In some embodiments, the PPARγ agonist is rosiglitazone. Rosiglitazone is a PPARγ agonist having the following structure, shown as rosiglitazone maleate: .

[0058] The compounds described herein are PPARα agonists. In some embodiments, the PPARα agonist is fenofibrate, clofibrate, pitinixic acid, WY1, GW735, GW409544, BMS631707, KRP101, AVE8134, or pioglitazone. In some embodiments, the compound may be a dual PPARα / PPARγ agonist.

[0059] In some embodiments, pioglitazone or its salts are administered at an amount from 1 mg / kg to 20 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from 1 mg / kg to 10 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from 1 mg / kg to 5 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from 1 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from 2 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from about 0.1 mg / kg to 5 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from about 2 mg / kg to 3 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from about 1 mg / kg to 3 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from about 2 mg / kg to 5 mg / kg. In some embodiments, pioglitazone or its salts are administered at an amount from about 5 mg / kg to 10 mg / kg. In some embodiments, the pioglitazone or its salts are administered in amounts of at least about 0.1 mg / kg, at least about 1 mg / kg, at least about 2 mg / kg, at least about 4 mg / kg, at least about 6 mg / kg, at least about 7 mg / kg, at least about 9 mg / kg, or at least about 10 mg / kg. In some embodiments, the pioglitazone or its salts are administered in amounts of at most about 20 mg / kg, at most about 10 mg / kg, at most about 9 mg / kg, at most about 8 mg / kg, at most about 7 mg / kg, at most about 6 mg / kg, at most about 5 mg / kg, at most about 4 mg / kg, at most about 3 mg / kg, at most about 2 mg / kg, or at most about 1 mg / kg. In some embodiments, the pioglitazone or its salts are administered enterally. In some embodiments, the pioglitazone or its salts are administered orally. In some embodiments, the pioglitazone or its salts are administered parenterally. In some embodiments, pioglitazone or its salts are administered multiple times daily, twice daily, daily, every other day, weekly, or bi-weekly. In some embodiments, pioglitazone or its salts are administered daily, every other day, weekly, or bi-weekly. In some embodiments, pioglitazone or its salts are administered daily. In some embodiments, pioglitazone or its salts are administered at a dose of 1 mg / kg / day to 20 mg / kg / day. In some embodiments, pioglitazone or its salts are administered at a dose of 1 mg / kg / day to 10 mg / kg / day. In some embodiments, pioglitazone or its salts are administered at a dose of 1 mg / kg / day to 5 mg / kg / day. In some embodiments, pioglitazone or its salts are administered at a dose of 1 mg / kg / day. In some embodiments, pioglitazone or its salts are administered at a dose of 2 mg / kg / day.

[0060] method In some embodiments, this document describes a method for alleviating or reversing insulin resistance in a mammal with or without evidence of metabolic dysfunction, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, this document describes a method for alleviating or reversing insulin resistance in a mammal with or without evidence of metabolic dysfunction, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a free base thereof or a pharmaceutically acceptable salt or prodrug thereof.

[0061] In some embodiments, this document describes a method for delaying the development of age-related insulin resistance in mammals of need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0062] In some embodiments, this document describes a method for maintaining healthy function of adipose tissue in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0063] In some embodiments, this document describes a method for treating age-induced hyperinsulinemia in mammals of need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0064] In some embodiments, this document describes a method for treating age-induced insulin resistance in mammals of need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0065] In some embodiments, this document describes a method for treating aging-induced fatty acid elevation in mammals of need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0066] In some embodiments, this document describes a method for alleviating or reversing age-induced insulin resistance in companion animals of need, regardless of the state of metabolic dysfunction, with or without evidence of metabolic dysfunction, the method comprising administering to the companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof, wherein the companion animal is at least 4 years old. In some embodiments, this document describes a method for alleviating or reversing insulin resistance in companion animals of need, the method comprising administering to the companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof, wherein the companion animal is at least 4 years old.

[0067] In some embodiments, this document describes a method for mitigating or reversing age-induced elevation of lipids (including fatty acids, triglycerides, and cholesterol) in companion animals of need, the companion animals having or not having evidence of metabolic dysfunction, the method comprising administering to the companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof, wherein the companion animal is at least 4 years old. In some embodiments, this document describes a method for mitigating or reversing age-induced elevation of lipids (including fatty acids, triglycerides, and cholesterol) in companion animals of need, the method comprising administering to the companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable free base or a pharmaceutically acceptable salt or prodrug thereof, wherein the companion animal is at least 4 years old. In some embodiments, this document describes a method for maintaining or restoring healthy function of adipose tissue in companion animals of need, the method comprising administering to the companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof, wherein the companion animal is at least 4 years old.

[0068] In some embodiments, the treatment method reduces or reverses insulin resistance induced by a high-fat diet in mammals. In some embodiments, the treatment method reduces or reverses hyperinsulinemia induced by a high-fat diet in mammals. In some embodiments, the treatment method reduces or reverses elevated free fatty acid levels induced by a high-fat diet. Reduction or reversal of insulin resistance includes a reduction in insulin resistance compared to untreated levels. Mammal subjects may have restored insulin sensitivity. Reduction or reversal of hyperinsulinemia includes a reduction in insulin resistance compared to untreated levels. Mammal subjects may have decreased circulating insulin concentrations. Reduction or reversal of elevated free fatty acid levels induced by a high-fat diet includes, but is not limited to, a decrease in the subject's free fatty acid levels compared to untreated levels. Biomarkers used to assess treatment efficacy may include, but are not limited to, measuring the subject's glucose and free fatty acid levels.

[0069] In some embodiments, this document describes a method for mitigating or reversing insulin resistance induced by a high-fat diet (HFD) in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0070] In some embodiments, this document describes a method for alleviating or reversing insulin resistance in a mammal with or without evidence of metabolic dysfunction, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, this document describes a method for alleviating or reversing insulin resistance in a mammal by administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, this document describes a method for alleviating or reversing insulin resistance in a mammal by administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a free base. In some embodiments, reversing insulin resistance also reverses fasting insulin levels back to normal levels.

[0071] In some embodiments, the method does not directly affect glucose levels. In some embodiments, the method does not decrease the glucose levels of the mammal. In some embodiments, the method does not increase the glucose levels of the mammal. In some embodiments, the method comprises administering a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof to a mammal susceptible to changes in glucose levels. In some embodiments, the method comprises administering a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof to a mammal susceptible to elevated glucose levels. In some embodiments, the method comprises administering a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof to a mammal that may benefit from stable glucose levels.

[0072] In some embodiments, the method increases adiponectin levels in mammals by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 50%, or at least 100%.

[0073] In some embodiments, the method reduces insulin levels in mammals. In some embodiments, the insulin levels are reduced by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%. In some embodiments, the insulin levels are reduced by at least 5%, at least 10%, at least 15%, or at least 20%. In some embodiments, the insulin levels are reduced by at least 5%. In some embodiments, the insulin levels are reduced by at least 10%. In some embodiments, the insulin levels are reduced by at least 15%. In some embodiments, the insulin levels are reduced by at least 20%. In some embodiments, the insulin levels are reduced by at least 25%.

[0074] In some embodiments, the method improves insulin sensitivity. Improved insulin sensitivity reduces insulin resistance, causing insulin metabolism to lessen or reverse towards pre-high-fat diet levels. Pre-high-fat diet and / or age-related increases in insulin resistance may be caused by decreased insulin sensitivity. Any useful insulin sensitivity assay known to those skilled in the art can be used. In some embodiments, insulin sensitivity is measured by a glucose clamp method, an intravenous glucose tolerance test, an oral glucose tolerance test, or by using fasting blood insulin levels. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test. In some embodiments, insulin sensitivity is measured by using fasting blood insulin levels.

[0075] Free fatty acids (FFAs) are fatty acids that circulate in the plasma of mammals. Typically, free fatty acid esters are not in their ester form and are usually bound to transport proteins such as, but not limited to, albumin. Free fatty acids can be formed from glycerides such as, but not limited to, triglycerides. In some embodiments, fatty acids can form lipids such as sphingolipids, glycerolipids, and phospholipids.

[0076] In some embodiments, the fatty acid is a saturated fatty acid, palmitic acid, linoleic acid, oleic acid, or a combination thereof. In some embodiments, the fatty acid is a saturated fatty acid, palmitic acid, linoleic acid, or oleic acid. In some embodiments, the fatty acid is a saturated fatty acid. In some embodiments, the fat is palmitic acid. In some embodiments, the fat is linoleic acid. In some embodiments, the fat is oleic acid.

[0077] Triglycerides are circulating fats in blood cells that can be produced by mammals through dietary intake or de novo lipoogenesis. Triglyceride levels typically increase with age and due to metabolic diseases. Administration of PPARγ agonists, such as pioglitazone, can lower triglyceride levels in mammals.

[0078] Triglycerides can be a useful biomarker for determining insulin resistance and insulin sensitivity.

[0079] In some embodiments, the method reduces triglyceride levels in the mammal. In some embodiments, the method reduces triglyceride levels by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, the method reduces triglyceride levels by at least 5%. In some embodiments, the method reduces triglyceride levels by at least 10%. In some embodiments, the method reduces triglyceride levels by at least 15%. In some embodiments, the method reduces triglyceride levels by at least 20%. In some embodiments, the method reduces triglyceride levels by at least 25%.

[0080] Adiponectin is an insulin-sensitized adipokines protein that regulates glucose levels, lipid metabolism, and insulin sensitivity. Adiponectin can activate PPARγ... Adiponectin is upregulated by pioglitazone treatment. The level of PPARγ activation / pioglitazone treatment can dose-dependently upregulate adiponectin. Adiponectin may also be associated with longevity in humans and other mammals. Adiponectin can be a useful biomarker for determining insulin resistance and insulin sensitivity.

[0081] In some embodiments, the method increases adiponectin levels in the mammal. In some embodiments, the method increases adiponectin levels by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%. In some embodiments, the method increases adiponectin levels by at least 5%. In some embodiments, the method increases adiponectin levels by at least 10%. In some embodiments, the method increases adiponectin levels by at least 20%. In some embodiments, the method increases adiponectin levels by at least 30%. In some embodiments, the method increases adiponectin levels by at least 40%. In some embodiments, the method increases adiponectin levels by at least 50%.

[0082] The subjects of this study are mammals. In some embodiments, the mammal is a dog, cat, horse, cow, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the mammal is a rodent. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human.

[0083] The methods described herein describe mammals as subjects. The mammal may be a companion animal. In some embodiments, the mammal is a companion animal. In some embodiments, the companion animal is a dog or a cat. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a cat.

[0084] In some embodiments, the companion animal is at least 2 years old. In some embodiments, the companion animal is at least 3 years old. In some embodiments, the companion animal is at least 4 years old. In some embodiments, the companion animal is at least 5 years old. In some embodiments, the companion animal is at least 6 years old. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 8 years old. In some embodiments, the companion animal is at least 9 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal is at least 11 years old. In some embodiments, the companion animal is at least 12 years old. In some embodiments, the companion animal is at least 13 years old. In some embodiments, the companion animal is at least 14 years old. In some embodiments, the companion animal is at least 15 years old.

[0085] Companion animals may have any weight suitable for the methods described herein. In some embodiments, the companion animal weighs at least 5 pounds. In some embodiments, the companion animal weighs at least 10 pounds. In some embodiments, the companion animal weighs at least 11 pounds. In some embodiments, the companion animal weighs at least 12 pounds. In some embodiments, the companion animal weighs at least 13 pounds. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the companion animal weighs at least 15 pounds. In some embodiments, the companion animal weighs at least 16 pounds. In some embodiments, the companion animal weighs at least 17 pounds. In some embodiments, the companion animal weighs at least 18 pounds. In some embodiments, the companion animal weighs at least 19 pounds. In some embodiments, the companion animal weighs at least 20 pounds. In some embodiments, the companion animal weighs at least 25 pounds. In some embodiments, the companion animal weighs at least 30 pounds.

[0086] In some embodiments, the companion animal is overweight. In some embodiments, the companion animal is obese.

[0087] In some embodiments, a method for increasing lifespan, promoting longevity, and / or preventing, reducing the severity of, or delaying the onset of various age-related conditions in mammals in need is provided, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof is administered to the mammal prior to the onset of age-related metabolic dysfunction.

[0088] In some embodiments, it is a method for increasing lifespan, promoting longevity and / or preventing, reducing the severity of or delaying the onset of various age-related conditions in mammals in need, the method comprising administering to the mammal a therapeutically effective amount of the formulation comprising a PPARγ agonist as described herein.

[0089] In some embodiments, it is a method for treating age-related decline in quality of life, the method comprising administering to a mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0090] In some embodiments, it is a method for treating age-related increased frailty, the method comprising administering to a mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0091] In some embodiments, a method for increasing the lifespan of a mammal in need includes administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the increased lifespan comprises an increase of at least 5% relative to the expected or median lifespan of a similar species, strain, or breed of mammal. In some embodiments, a method for increasing the lifespan of a mammal in need includes administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the increased lifespan comprises an increase of at least 10% relative to the expected or median lifespan of a similar species, strain, or breed of mammal. In some embodiments, a method for increasing the lifespan of a mammal in need includes administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the increased lifespan comprises an increase of at least 15% relative to the expected or median lifespan of a similar species, strain, or breed of mammal. In some embodiments, a method for increasing the lifespan of a mammal in need includes administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the increased lifespan comprises an increase of at least 20% relative to the expected or median lifespan of a similar species, strain, or breed of mammal. In some embodiments, a method for increasing the lifespan of a mammal in need comprises administering a therapeutically effective amount of the formulation described herein to the mammal, wherein the increase in lifespan comprises an increase of at least 25% relative to the expected or median lifespan of a mammal of a similar species, strain, or breed.

[0092] In some embodiments, the method comprises mitigating or reversing insulin resistance in mammals. In some embodiments, the insulin resistance occurs during aging. In some embodiments, the method comprises mitigating or reversing elevated free fatty acids (FFA). In some embodiments, the elevated free fatty acids are associated with age-related disease states. Age-related disease states include, but are not limited to, obesity, type 2 diabetes, cardiovascular disease, sarcopenia, atherosclerosis, arthritis, and hypertension. In some embodiments, the age-related disease state is obesity, type 2 diabetes, cardiovascular disease, or sarcopenia. In some embodiments, the mammals disclosed herein (e.g., companion animals) have diabetes. In some embodiments, the mammals disclosed herein (e.g., companion animals) do not have diabetes. In some embodiments, the mammals do not have alloxan-induced diabetes. In some embodiments, the mammals have not been diagnosed with diabetes.

[0093] In some embodiments, a method for promoting longevity in a desired mammal includes administering a therapeutically effective amount of the formulation described herein to the mammal.

[0094] In some embodiments, the mammal has reached maturity as defined for its species. In some embodiments, the mammal has reached old age as defined for its species.

[0095] In some embodiments, the mammal is a dog, cat, horse, cow, pig, rabbit, rodent, sheep, non-human primate, or human. In some embodiments, the mammal is a dog. In some embodiments, the mammal is a cat. In some embodiments, the mammal is a rodent. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human.

[0096] In some embodiments, the method described herein further comprises administering a combination of a second therapeutic agent and a PPARγ agonist or a salt thereof. In some embodiments, the method described herein further comprises administering a combination of a second therapeutic agent and pioglitazone or a salt thereof. In some embodiments, the second therapeutic agent is a pharmaceutical agent selected from Table 12. In some embodiments, the second therapeutic agent is selected from selegiline, levothyroxine, NSAIDs, steroids, chemotherapeutic agents, sedatives and anesthetics, opioids (excluding tramadol), tramadol, antiparasitic agents (including HW PX, ectoparasite-killing agents, anthelmintics), supplements, prescription diets, nutritional products (including CBD, glucosamine, fish oil), vaccines, antibiotics (e.g., excluding macrolides and fluoroquinolones and macrolides), fluoroquinolone antibiotics (ciprofloxacin, enrofloxacin, difloxacin, orbifloxacin, marbofloxacin), ketoconazole, non-ketoconazole antifungals (miconazole, fluconazole, etc.), and cardiac medications (which are neither ACE inhibitors nor ACE receptor blockers).

[0097] pharmaceutical preparations In some embodiments of the pharmaceutical formulations described herein, the PPARγ agonist is in the form of a free base. In some embodiments of the pharmaceutical formulations described herein, the PPARγ agonist is a salt. In some embodiments of the pharmaceutical formulations described herein, the PPARγ agonist is a hydrochloride salt. In some embodiments of the pharmaceutical formulations described herein, the PPARγ agonist is a maleate salt.

[0098] In some embodiments, one or more excipients described herein are in salt form. In some embodiments, one or more excipients described herein are in free base form.

[0099] It should be understood that references to pharmaceutically acceptable salts include solvation forms (solvents). Solvents contain stoichiometric or non-stoichiometric amounts of solvent and are formed during product formation or separation using pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. Solvents are formed using (but not limited to) three types of solvents. The categories of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents”, Q3C(R3), (November 2005). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholysis is formed. In some embodiments, a solvate of a PPARγ agonist or a pharmaceutically acceptable salt thereof is conveniently prepared or formed during the process described herein. In some embodiments, the solvate of the PPARγ agonist is anhydrous. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in an unsolvated form. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in an unsolvated form and is anhydrous. In some embodiments, one or more excipients described herein are solvated. In some embodiments, one or more excipients described herein are unsolvated.

[0100] In other embodiments, the PPARγ agonist or its pharmaceutically acceptable salt or prodrug is prepared in various forms, including but not limited to amorphous phase, crystalline form, milled form, and nanoparticle form. In some embodiments, the PPARγ agonist or its pharmaceutically acceptable salt or prodrug is amorphous. In some embodiments, the PPARγ agonist or its pharmaceutically acceptable salt or prodrug is amorphous and anhydrous. In some embodiments, the PPARγ agonist or its pharmaceutically acceptable salt or prodrug is crystalline. In some embodiments, the PPARγ agonist or its pharmaceutically acceptable salt or prodrug is crystalline and anhydrous.

[0101] While not intended to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., stability, solubility, and dissolution rate) suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, viscosity, solubility, hygroscopicity, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that affect the specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make certain solid forms suitable for the production of solid dosage forms. As described herein and known in the art, such properties can be determined using specific analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis).

[0102] The pharmaceutical formulations described herein comprise a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof in a solid dosage form, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical formulations described herein comprise pioglitazone and at least one pharmaceutically acceptable excipient, the pharmaceutical formulation being in a solid dosage form selected from powders, tablets, bite-disintegrating tablets, chewable tablets, capsules, sac-like forms, effervescent powders, rapidly disintegrating tablets, abuse prevention tablets, modulated-release tablets, modulated-release capsules, modulated-release capsules, and aqueous suspensions derived from powders. In some embodiments, the pharmaceutical formulation is a liquid formulation, such as a solution or suspension. In some embodiments, the pharmaceutical formulation is a parenteral formulation, such as an injectable formulation. In some embodiments, the pharmaceutical formulation is a solid form. In some embodiments, the pharmaceutical formulation is a powder formulation added to food. In some embodiments, the pharmaceutical formulations described herein comprise a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof in a solid dosage form, and at least one pharmaceutically acceptable excipient. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the pharmaceutical formulation described herein comprises pioglitazone and at least one pharmaceutically acceptable excipient, the pharmaceutical formulation being in a solid dosage form, wherein the solid dosage form is a tablet.

[0103] In some embodiments, the pharmaceutical formulation comprises about 1% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 0.5% to about 10% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 1% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 2% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 3% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 5% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 15% to about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 20% to about 30% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 15% to about 25% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 20% to about 25% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 11% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 12% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 13% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 14% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 15% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 16% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments, the pharmaceutical formulation comprises about 17% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 18% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 19% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 20% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 21% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 22% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 23% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 24% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 25% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 26% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 27% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 28% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 29% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 30% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 31% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 32% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 33% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 34% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 35% of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0104] In some embodiments, the PPARγ agonist is selected from pioglitazone and rosiglitazone.

[0105] In some embodiments, the pharmaceutical formulation comprises about 3% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 5% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 10% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% to about 35% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 20% to about 30% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% to about 25% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 20% to about 25% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 10% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 11% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 12% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 13% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 14% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 16% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 17% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 18% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 19% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 20% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 21% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 22% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 23% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 24% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 25% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 26% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 27% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 28% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 29% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 30% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 31% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 32% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 33% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 34% pioglitazone. In some embodiments, the pharmaceutical formulation comprises about 35% pioglitazone.

[0106] In some embodiments, the pharmaceutical formulation comprises about 5% to about 35% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 10% to about 35% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% to about 35% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 20% to about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% to about 25% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 20% to about 25% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 10% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 11% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 12% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 13% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 14% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 15% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 16% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 17% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 18% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 19% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 20% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 21% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 22% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 23% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 24% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 25% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 26% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 27% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 28% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 29% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 30% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 31% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 32% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 33% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 34% rosiglitazone. In some embodiments, the pharmaceutical formulation comprises about 35% rosiglitazone.

[0107] In some embodiments, the pharmaceutical formulation comprises about 1 mg to about 120 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 1 mg to about 100 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 2 mg to about 120 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 3 mg to about 120 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 4 mg to about 120 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 4 mg to about 85 mg of PPARγ. A PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 5 mg to about 120 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10 mg to about 120 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10 mg to about 110 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10 mg to about 100 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 20 mg to about 100 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 25 mg to about 100 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 30 mg to about 100 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 30 mg to about 90 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 40 mg to about 90 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 40 mg to about 80 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 45 mg to about 80 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 45 mg to about 75 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 50 mg to about 70 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 100 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 90 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 80 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 75 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 70 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 65 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.In some embodiments, the pharmaceutical formulation comprises about 60 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 55 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 50 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 45 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 40 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 30 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 20 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the pharmaceutical formulation comprises about 10 mg of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

[0108] In some embodiments, the pharmaceutical preparation comprises about 1 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 1 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 2 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 3 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 4 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 4 mg to about 85 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 5 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg to about 120 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg to about 110 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 20 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 25 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 30 mg to about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 30 mg to about 90 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 40 mg to about 90 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 40 mg to about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 45 mg to about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 45 mg to about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 45 mg to about 75 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 50 mg to about 70 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 100 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 90 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 80 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 75 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 70 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 65 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 60 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 55 mg of pioglitazone or a salt thereof.In some embodiments, the pharmaceutical preparation comprises about 50 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 45 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 40 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 30 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 20 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation described herein comprises about 18 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation described herein comprises about 16 mg to about 20 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation described herein comprises about 54 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 52 mg to about 56 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 81 mg of pioglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 79 mg to about 83 mg of pioglitazone or a salt thereof.

[0109] In some embodiments, the pharmaceutical preparation comprises about 10 mg to about 120 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg to about 110 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 20 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 25 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 30 mg to about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 30 mg to about 90 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 40 mg to about 90 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 40 mg to about 80 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 45 mg to about 80 mg of rosiglitazone. In some embodiments, the pharmaceutical preparation comprises about 45 mg to about 75 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 50 mg to about 70 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 100 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 90 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 80 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 75 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 70 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 65 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 60 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 55 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 50 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 45 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 40 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 30 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 20 mg of rosiglitazone or a salt thereof. In some embodiments, the pharmaceutical preparation comprises about 10 mg of rosiglitazone or a salt thereof.

[0110] In some embodiments, the PPARγ agonist (such as pioglitazone or rosiglitazone, or a salt thereof) is administered at a dose of 0.01 mg / kg to 100 mg / kg. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg to 20 mg / kg. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg to 10 mg / kg. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg to 5 mg / kg. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg. In some embodiments, the PPARγ agonist is administered at a dose of 2 mg / kg.

[0111] On one hand, this document describes a pharmaceutical formulation in a solid dosage form comprising a PPARγ agonist or a pharmaceutically acceptable salt thereof, and a filler. On the other hand, this document describes a pharmaceutical formulation in a solid dosage form comprising about 5 wt% to about 20 wt% of a PPARγ agonist or a pharmaceutically acceptable salt thereof, and about 80 wt% to about 95 wt% of a filler. In some embodiments, the pharmaceutical formulation further comprises a disintegrant, a binder, a lubricant, a flavoring agent, or a combination thereof. In some embodiments, the disintegrant is present in the formulation in an amount of about 1 wt% to about 10 wt%. In some embodiments, the binder is present in the formulation in an amount of about 1 wt% to about 10 wt%. In some embodiments, the lubricant is present in the formulation in an amount of about 0.3 wt% to about 3 wt%. In some embodiments, the flavoring agent is present in the formulation in an amount of about 0.03 wt% to about 30 wt%. In some embodiments, the flavoring agent is a meat flavoring agent. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in the formulation in an amount of about 1 wt% to about 99 wt%. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in the formulation at an amount of about 7% to about 15% by weight. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in the formulation at an amount of about 10% to about 12% by weight. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in the formulation at an amount of about 11% by weight. In some embodiments, the PPARγ agonist or a pharmaceutically acceptable salt thereof is present in the formulation at an amount of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% by weight.

[0112] In some embodiments, the formulations described herein comprise one or more fillers. In some embodiments, the filler is present in the formulation at an amount of about 10% by weight to about 80% by weight. In some embodiments, the filler is present in the formulation at an amount of about 40% by weight to about 80% by weight. In some embodiments, the filler is present in the formulation at an amount of about 55% by weight to about 70% by weight. In some embodiments, the filler is present in the formulation at an amount of about 20% by weight to about 60% by weight. In some embodiments, the filler is present in the formulation at an amount of about 25% by weight to about 50% by weight. In some embodiments, the filler is present in the formulation at an amount of about 30% by weight to about 45% by weight. In some embodiments, the filler is present in the formulation at an amount of about 45% by weight to about 50% by weight. In some embodiments, the one or more fillers comprise lactose monohydrate, hydroxypropyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.

[0113] Fillers or diluents increase the bulk volume in pharmaceutical formulations. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as Avicel®; dicalcium phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch; compressible sugars such as Di-Pac® (Amstar); hydroxypropyl methylcellulose; sucrose-based diluents; confectionery sugars; calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextrates; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; sodium chloride; inositol; bentonite, etc. In some embodiments, the filler comprises lactose, mannitol, dicalcium phosphate, cellulose, starch (e.g., pregelatinized starch), or combinations thereof. In some embodiments, the filler comprises lactose, mannitol, microcrystalline cellulose, or combinations thereof. In some embodiments, the filler comprises lactose. In some embodiments, the filler comprises lactose monohydrate. In some embodiments, the filler comprises hydroxypropyl cellulose. In some embodiments, the filler comprises sodium carboxymethyl cellulose. In some embodiments, the filler comprises carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate stearate, hydroxyethyl cellulose, hydroxypropyl cellulose ethyl cellulose, microcrystalline cellulose, or combinations thereof. In some embodiments, the filler comprises lactose monohydrate, sodium carboxymethyl cellulose, and hydroxypropyl cellulose.

[0114] Disintegrants promote the breakdown or disintegration of pharmaceutical formulations after application. Examples of disintegrants include starches, such as natural starches like corn starch or potato starch, pregelatinized starches like National 1551 or Amijel®, or sodium starch glycolate like Promogel® or Explotab®; celluloses, such as wood products, or cross-linked celluloses like sodium croscarmellose (Ac-Di-Sol®), croscarmellose, or cross-linked croscarmellose; cross-linked starches, such as sodium starch glycolate; cross-linked polymers, such as crosspovidone; cross-linked polyvinylpyrrolidone; alginates, such as alginic acid or salts of alginic acid, such as sodium alginate; clays, such as Veegum® HV (magnesium aluminum silicate); gums, such as agar, guar gum, locust bean gum, ebony gum, pectin, or tragacanth gum; sodium starch glycolate; bentonite; natural sponges; resins, such as cation exchange resins; citrus pulp; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch, etc. In some embodiments, the pharmaceutical formulation comprises a disintegrant. In some embodiments, the disintegrant is selected from corn starch, potato starch, microcrystalline cellulose, methylcellulose, sodium croscarmellose, sodium starch glycolate, povidone, crospovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, alginate, sodium alginate, agar, guar gum, locust bean gum, black privet gum, pectin, tragacanth, bentonite, citrus pulp, and sodium lauryl sulfate. In some embodiments, the disintegrant is selected from povidone, crospovidone, hydroxypropyl methylcellulose, sodium croscarmellose, hydroxypropyl cellulose, and polyvinyl alcohol. In some embodiments, the disintegrant is polyvinyl alcohol. In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is sodium croscarmellose.

[0115] In some embodiments, the pharmaceutical formulation comprises about 1% to about 10% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1% to about 9% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2% to about 10% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2% to about 9% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2% to about 8% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 3% to about 8% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 3% to about 7% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 3% to about 6% disintegrant. In some embodiments, the pharmaceutical formulation comprises about 4% to about 7% disintegrant.

[0116] Lubricants are compounds that prevent, reduce, or inhibit adhesion or friction between materials. Exemplary lubricants include, for example, stearic acid; calcium hydroxide, talc; hydrocarbons, such as mineral oils; or hydrogenated vegetable oils, such as hydrogenated soybean oil (Sterotex). ®), Lubritab ® Cutina ® Higher fatty acids and their alkali metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, glycerol, talc, waxes, and Stearot. ® Boric acid, sodium acetate, leucine, polyethylene glycol or methoxy polyethylene glycol, such as Carbowax™, sodium oleate, glyceryl behenate (Compitrol 888) ® Precirol ® Colloidal silica, such as Syloid™, Carb-O-Sil ® Starch, such as corn starch, silicone oil, surfactants, etc. Hydrophilic lubricants include, for example, sodium stearate fumarate (currently marketed under the trade name PRUV). ® The pharmaceutical formulation includes, for example, polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, sodium chloride, etc. In some embodiments, the pharmaceutical formulation comprises a lubricant. In some embodiments, the lubricant is selected from magnesium stearate, stearic acid, and sodium stearoyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is stearic acid. In some embodiments, the lubricant is sodium stearoyl fumarate.

[0117] In some embodiments, the pharmaceutical formulation comprises about 0.1% to about 10% of a lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% to about 3% of a lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% to about 2.5% of a lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3% to about 2% of a lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% to about 2% of a lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5% to about 1.5% of a lubricant.

[0118] In some embodiments, the pharmaceutical formulation described herein includes a flavoring agent. In some embodiments, the flavoring agent is natural. In some embodiments, the flavoring agent is artificial. In some embodiments, the pharmaceutical formulation includes a meat flavoring agent. In some embodiments, the meat flavoring agent is natural. In some embodiments, the meat flavoring agent is artificial. In some embodiments, the meat flavoring agent is selected from chicken, pork, and beef. In some embodiments, the flavoring agent is FlavorPal, such as FlavorPal X1212.

[0119] In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% meat seasoning. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% meat seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 25% meat seasoning. In some embodiments, the pharmaceutical formulation comprises about 15% to about 25% meat seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% chicken seasoning. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% chicken seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 25% chicken seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% seasoning. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 25% seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 30% seasoning. In some embodiments, the pharmaceutical formulation comprises about 15% to about 30% seasoning. In some embodiments, the pharmaceutical formulation comprises about 10% to about 25% flavoring agent.

[0120] Gliders improve the flow properties of powder mixtures. Such compounds include, for example, colloidal silica such as Cab-o-sil®; tricalcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silica (Syloid®). In some embodiments of the pharmaceutical formulations described herein, the glider is colloidal silica or talc. In some embodiments, the glider is talc. In some embodiments, the glider is colloidal silica.

[0121] Polymer carriers include compounds such as polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone vinyl acetate (PVPVA 64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetosuccinate (HPMC AS) and methyl methacrylate polymers (Eudragit polymers), etc.

[0122] In some embodiments, the pharmaceutical formulations described herein include one or more pH adjusters or buffers. In some embodiments, the pharmaceutical formulation comprises a buffer selected from acetate, carbonate, phosphate, citrate, and glutamate. In some embodiments, the buffer is selected from potassium dihydrogen phosphate, sodium bicarbonate, magnesium carbonate, sodium citrate, sodium dihydrogen phosphate, dipotassium monohydrogen phosphate, and disodium monohydrogen phosphate. In some embodiments, the buffer is included in an amount necessary to maintain the pH of the pharmaceutical formulation within an acceptable range.

[0123] In some embodiments, a polymer coating is provided around the pharmaceutical composition to provide a physical barrier against taste buds in order to mask the taste of the formulation. In some embodiments, the coating material is selected from hydrophobic or hydrophilic polymers, lipids, and sweeteners. In some embodiments, the coating material is selected from carbohydrates (cellulose), proteins, gelatin, and prolamins. In some embodiments, the coating material is selected from Eudragit E-100, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinyl alcohol, and polyvinyl acetate.

[0124] Stabilizers include compounds such as any antioxidant, such as butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol; buffer solutions, acids, etc. In some embodiments, the pharmaceutical formulation comprises a stabilizer.

[0125] Surfactants include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), d-α-tocopherol polyethylene glycol succinate (vitamin E TPGS), etc. In some embodiments, the pharmaceutical formulation comprises a surfactant.

[0126] In some embodiments, this document describes pharmaceutical formulations in solid dosage form, wherein the pharmaceutical formulation includes internal granulation.

[0127] In some embodiments, this document describes a pharmaceutical formulation in a solid dosage form, the pharmaceutical formulation comprising: (a) pioglitazone or a salt thereof, (b) one or more fillers (e.g., lactose monohydrate, hydroxypropyl cellulose, sodium carboxymethyl cellulose, or combinations thereof), (c) a lubricant (e.g., magnesium stearate), and (d) a flavoring agent. In some embodiments, this document describes a pharmaceutical formulation in a solid dosage form, the pharmaceutical formulation comprising: (a) about 5% by weight to about 20% by weight of pioglitazone or its salts; (b) about 25% by weight to about 50% by weight of lactose (e.g., lactose monohydrate). (c) About 0.1% by weight to about 10% by weight of hydroxypropyl cellulose; (d) Sodium carboxymethyl cellulose, about 1% by weight to about 10% by weight; and (e) Flavorings, if optional.

[0128] In some embodiments, this document describes a pharmaceutical formulation in solid dosage form, the pharmaceutical formulation comprising: (a) about 5% by weight to about 30% by weight of pioglitazone or its salts; (b) about 25% by weight to about 80% by weight of lactose (e.g., lactose monohydrate). (c) About 0.1% by weight to about 10% by weight of hydroxypropyl cellulose; (d) Sodium carboxymethyl cellulose, about 1% to about 25% by weight; and (e) Flavorings, if optional.

[0129] In some embodiments, this document describes a pharmaceutical formulation in solid dosage form, the pharmaceutical formulation comprising: (a) about 10 mg to about 100 mg of pioglitazone or its salts; (b) Approximately 50 mg to approximately 400 mg of lactose (e.g., lactose monohydrate). (c) Hydroxypropyl cellulose, approximately 0.5 mg to approximately 15 mg; (d) Sodium carboxymethyl cellulose, approximately 1 mg to approximately 50 mg; and (e) Flavorings, if optional.

[0130] In some embodiments, this document describes a pharmaceutical formulation in solid dosage form, the pharmaceutical formulation comprising: (a) about 5% to about 20% of pioglitazone or its salts; (b) Approximately 25% to approximately 50% of fillers (lactose, cellulose, etc.); (c) about 0.1% to about 10% of adhesive; (d) optionally about 1% to about 10% of a disintegrant; and (e) Flavorings, if optional.

[0131] In some embodiments, the PPARγ agonist (such as pioglitazone or rosiglitazone) is administered daily, every other day, weekly, or every two weeks. In some embodiments, the PPARγ agonist is administered for at least about 2 weeks. In some embodiments, the PPARγ agonist is administered for at least about 4 weeks. In some embodiments, the PPARγ agonist is administered for at least about 8 weeks. In some embodiments, the PPARγ agonist is administered for at least about 4 months. In some embodiments, the PPARγ agonist is administered for at least about 6 months. In some embodiments, the PPARγ agonist is administered for at least about 8 months. In some embodiments, the PPARγ agonist is administered for at least about 10 months. In some embodiments, the PPARγ agonist is administered for at least about 1 year. In some embodiments, the PPARγ agonist is administered for at least about 2 years. In some embodiments, the PPARγ agonist is administered throughout the entire lifespan of the mammal.

[0132] In some embodiments, the PPARγ agonist is administered daily. In some embodiments, the PPARγ agonist is administered weekly. In some embodiments, the PPARγ agonist is administered once a week. In some embodiments, the PPARγ agonist is administered two or more times a week. In some embodiments, and in some instances, the PPARγ agonist is administered monthly.

[0133] In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg / day to 20 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg / day to 10 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg / day to 5 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 1 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 2 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 3 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 4 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 5 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 6 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 7 mg / kg / day. In some embodiments, the PPARγ agonist is administered at a dose of 8 mg / kg / day. In some embodiments, the PPARγ agonist is administered at 9 mg / kg / day. In some embodiments, the PPARγ agonist is administered at 10 mg / kg / day. In some embodiments, the PPARγ agonist is a salt of pioglitazone. In some embodiments, the PPARγ agonist is an HCl salt of pioglitazone. In some embodiments, the PPARγ agonist is pioglitazone. In some embodiments, the pioglitazone or its salt is administered at 1 mg / kg / day to 20 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 1 mg / kg / day to 10 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 1 mg / kg / day to 5 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 1 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 2 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 3 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 4 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 5 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 6 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 7 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 8 mg / kg / day. In some embodiments, the pioglitazone or its salt is administered at 9 mg / kg / day.In some embodiments, the pioglitazone or its salt is administered at 10 mg / kg / day.

[0134] In some embodiments, the PPARγ agonist (such as pioglitazone or rosiglitazone or a salt thereof) is administered over a period of 1 day to 20 years. In some embodiments, the PPARγ agonist is administered over a period of 1 day to 15 years. In some embodiments, the PPARγ agonist is administered over a period of 1 day to 10 years. In some embodiments, the PPARγ agonist is administered over a period of 1 week to 1 year. In some embodiments, the PPARγ agonist is administered over a period of at least 1 day, 1 week, 1 month, 3 months, or 6 months. In some embodiments, the PPARγ agonist is administered over a period of up to 1 month, 3 months, 6 months, 9 months, 1 year, or 2 years. In some embodiments, the PPARγ agonist is administered long-term. In some embodiments, the PPARγ agonist is administered throughout the remaining lifespan of a mammal (such as a companion animal).

[0135] The formulation and PPARγ agonist may be in the form of a suitable oral formulation for administration to companion animals by oral administration. In some embodiments, the formulation is in a solid dosage form. In some embodiments, the formulation is in the form of a tablet. In some embodiments, the PPARγ agonist is in the form of a tablet. In some embodiments, the PPARγ agonist is in the form of a capsule. In some embodiments, in some examples, the tablet is a flavored tablet. In some embodiments, the tablet or capsule contains a chicken, pork, beef, lamb, or fish seasoning. In some embodiments, the tablet or capsule contains a chicken, pork, beef, or lamb seasoning. In some embodiments, the tablet or capsule contains a hydrolyzed chicken product or chicken seasoning.

[0136] In some embodiments, the tablet contains about 18 mg, 54 mg, or 81 mg of a PPARγ agonist. In some embodiments, the tablet contains about 18 mg of a PPARγ agonist. In some embodiments, the tablet contains about 54 mg of a PPARγ agonist. In some embodiments, the tablet contains about 81 mg of a PPARγ agonist. In some embodiments, the capsule contains about 18 mg, 54 mg, or 81 mg of a PPARγ agonist. In some embodiments, the capsule contains about 18 mg of a PPARγ agonist. In some embodiments, the capsule contains about 54 mg of a PPARγ agonist. In some embodiments, the capsule contains about 81 mg of a PPARγ agonist. In some embodiments, the PPARγ agonist is pioglitazone hydrochloride.

[0137] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises at least one filler. In some embodiments, the solid dosage form comprises at least two fillers. In some embodiments, the solid dosage form comprises at least three fillers. In some embodiments, the filler is lactose monohydrate. In some embodiments, the amount of lactose monohydrate is 10% w / w to 40% w / w. In some embodiments, the amount of lactose monohydrate is 10% w / w to 30% w / w. In some embodiments, the amount of lactose monohydrate is about 15% w / w to 25% w / w. In some embodiments, the amount of lactose monohydrate is 30% w / w to 40% w / w. In some embodiments, the amount of lactose monohydrate is 32% w / w to 40% w / w. In some embodiments, the amount of lactose monohydrate is 35% w / w to 40% w / w. In some embodiments, the amount of lactose monohydrate is about 36% w / w to about 38% w / w. In some embodiments, the amount of lactose monohydrate is about 37% w / w. In some embodiments, the amount of lactose monohydrate is about 22% w / w.

[0138] In some embodiments, the solid dosage form further comprises carboxymethyl cellulose (Na). In some embodiments, the amount of carboxymethyl cellulose is from about 1% w / w to about 10% w / w. In some embodiments, the amount of carboxymethyl cellulose is from about 2% w / w to about 10% w / w. In some embodiments, the amount of carboxymethyl cellulose is from about 2% w / w to about 8% w / w. In some embodiments, the amount of carboxymethyl cellulose is from about 2% w / w to about 6% w / w. In some embodiments, the amount of carboxymethyl cellulose is from about 3% w / w to about 5% w / w. In some embodiments, the amount of carboxymethyl cellulose is about 4% w / w.

[0139] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises hydroxypropyl cellulose. In some embodiments, the amount of hydroxypropyl cellulose is from about 0.1% w / w to about 5% w / w. In some embodiments, the amount of hydroxypropyl cellulose is from about 0.25% w / w to about 3% w / w. In some embodiments, the amount of hydroxypropyl cellulose is from about 0.5% w / w to about 2% w / w. In some embodiments, the amount of hydroxypropyl cellulose is about 1% w / w.

[0140] The hydroxypropyl cellulose grades usable in this invention include different viscosity grades with an average molecular weight ranging from 20 kDa to 1500 kDa. The hydroxypropyl cellulose grades usable in this invention may include, but are not limited to, EXF grade. The viscosity of EXF grade can be from about 300 mPa•s to 600 mPa•s.

[0141] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises a flavoring agent, such as FlavorPALX1212. In some embodiments, the amount of the flavoring agent is from about 10% w / w to 40% w / w. In some embodiments, the amount of the flavoring agent is from about 10% w / w to 30% w / w. In some embodiments, the amount of the flavoring agent is from about 15% w / w to 25% w / w. In some embodiments, the amount of the flavoring agent is from about 20% w / w. In some embodiments, the flavoring agent is a meat seasoning.

[0142] In some embodiments, the solid dosage form (e.g., tablets or capsules) further comprises magnesium stearate. In some embodiments, the amount of magnesium stearate is from about 0.25% w / w to 5% w / w. In some embodiments, the amount of magnesium stearate is from about 0.25% w / w to 3% w / w. In some embodiments, the amount of magnesium stearate is from about 0.25% w / w to 2% w / w. In some embodiments, the amount of magnesium stearate is from about 0.5% w / w to 1.5% w / w. In some embodiments, the amount of magnesium stearate is about 1% w / w.

[0143] In some embodiments, the mammals described herein are companion animals. In some embodiments, the companion animal is a dog or a cat. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is a cat. In some embodiments, the mammals described herein are dogs, cats, horses, cattle, pigs, rabbits, rodents, sheep, non-human primates, or humans. In some embodiments, the mammal is a dog. In some embodiments, the rodent is a mouse or rat. In some embodiments, the mammal is a human.

[0144] In some embodiments, the mammal is a dog of any age. In some embodiments, the mammal is a dog 7 years of age or older. In some embodiments, the mammal is a dog 1-8 years of age. In some embodiments, the mammal is a dog 1-3 years of age. In some embodiments, the mammal is a dog 4-8 years of age. In some embodiments, the mammal is a dog at least 7 years of age. In some embodiments, the mammal is a dog at least 9 years of age. In some embodiments, the mammal is a dog at least 10 years of age. In some embodiments, the mammal is a dog at least 11 years of age. In some embodiments, the mammal is a dog at least 12 years of age. In some embodiments, the mammal is a dog at least 13 years of age. In some embodiments, the mammal is a dog at least 14 years of age. In some embodiments, the mammal is a dog at least 15 years of age. In some embodiments, the mammal is a dog showing signs of aging. In some embodiments, the mammal is a dog that may benefit from stable glucose levels. In some embodiments, the mammal is a dog susceptible to changes in glucose levels. In some embodiments, the mammal is a dog susceptible to elevated glucose levels. In some embodiments, the mammal is a dog showing signs of aging. In some embodiments, the mammal is a dog that may benefit from lower levels of saturated fatty acids in the body. In some embodiments, the mammal is a dog with high levels of saturated fatty acids in the body. In some embodiments, the mammal is a dog with high levels of palmitic acid in the body.

[0145] Other embodiments In some embodiments, this document provides a formulation comprising pioglitazone or a pharmaceutically acceptable salt thereof, said formulation for reducing or delaying age-related death in companion animals, said formulation being administered for at least 2 weeks. In some embodiments, said pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, said pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg / kg / day to 3 mg / kg / day. In some embodiments, said pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / kg / day to 5 mg / kg / day. In some embodiments, said pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of up to 10 mg / kg / day. In some embodiments, said formulation is administered once daily. In some embodiments, said formulation is administered for at least about 4 weeks. In some embodiments, said formulation is administered for at least about 12 weeks. In some embodiments, said formulation is administered for at least about 1 year. In some embodiments, the method comprises reducing insulin levels in the companion animal. In some embodiments, said insulin levels are reduced by at least 5%. In some embodiments, said formulation improves insulin sensitivity. In some embodiments, said insulin sensitivity is measured by an oral glucose tolerance test or by a high insulin positive glucose clamp test. In some embodiments, insulin sensitivity is measured by a short or modified oral glucose tolerance test. In some embodiments, insulin sensitivity is measured by fasting insulin blood levels. In some embodiments, the formulation reduces triglyceride levels in the companion animal. In some embodiments, the formulation reduces cholesterol levels in the companion animal. In some embodiments, the use further comprises mitigating age-induced fatty acid elevation, wherein the fatty acids are aggregated free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the formulation contains about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation contains about 4 mg to about 85 mg of pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in tablet form. In some embodiments, the tablet contains 18 mg, 54 mg, or 81 mg of pioglitazone or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, this document provides a method for reducing or delaying age-related disease-related death in companion animals of need, the method comprising orally administering to the companion animal a therapeutically effective amount of a formulation comprising pioglitazone or a pharmaceutically acceptable salt thereof, wherein the formulation is administered for at least 2 weeks. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is pioglitazone hydrochloride. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg / kg / day to 3 mg / kg / day. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg / kg / day to 5 mg / kg / day. In some embodiments, the pioglitazone or a pharmaceutically acceptable salt thereof is administered at a dose of up to 10 mg / kg / day. In some embodiments, the formulation is administered once daily. In some embodiments, the formulation is administered for at least about 4 weeks. In some embodiments, the formulation is administered for at least about 12 weeks. In some embodiments, the formulation is administered for at least about 1 year. In some embodiments, the method comprises reducing the insulin level of the companion animal. In some embodiments, the insulin level is reduced by at least 5%. In some embodiments, the method improves insulin sensitivity. In some embodiments, insulin sensitivity is measured by an oral glucose tolerance test or by a high insulin positive glucose clamp test. In some embodiments, insulin sensitivity is measured by a short or modified oral glucose tolerance test. In some embodiments, insulin sensitivity is measured by fasting insulin blood levels. In some embodiments, the method reduces triglyceride levels in the companion animal. In some embodiments, the method reduces cholesterol levels in the companion animal. In some embodiments, the use further comprises mitigating age-induced fatty acid elevation, wherein the fatty acids are aggregated free fatty acids, saturated fatty acids, palmitic acid, linoleic acid, or oleic acid, or any combination thereof. In some embodiments, the companion animal is a dog. In some embodiments, the companion animal is at least 7 years old. In some embodiments, the companion animal is at least 10 years old. In some embodiments, the companion animal weighs at least 14 pounds. In some embodiments, the formulation comprises about 5% to about 15% pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation comprises about 4 mg to about 85 mg of pioglitazone or a pharmaceutically acceptable salt thereof. In some embodiments, the formulation is in tablet form. In some embodiments, the tablets contain 18 mg, 54 mg, or 81 mg of pioglitazone or a pharmaceutically acceptable salt thereof.

[0147] Example The following illustrative examples represent embodiments of the stimuli, systems, and methods described herein and are not intended to be limiting in any way.

[0148] Example 1. Metabolic aging biomarkers in HRQL studies An observational healthy lifespan study was conducted, involving health-related quality of life assessment (HRQL). Study endpoints included owner assessments of HRQL and veterinary assessments of physical examination, body condition score (BCS), muscle condition score, complete blood count, biochemical profile, serum T4 measurement, urinalysis, insulin-like growth factor-1 measurement, and canine frailty index (CFI). Blood samples were collected to assess serum fasting insulin and adiponectin levels. DNA samples were also collected. Target statistics were collected from 451 eligible adult dogs, of which 43.6% were mixed breeds and 56.4% were purebreds. The target age and size of the dogs used for inclusion are shown in Table 1 below. Approximately 451 dogs were evaluated, and approximately 450 dogs were assessed using HRQL. Fasting insulin levels were assessed in approximately 409 dogs, and adiponectin levels were assessed in approximately 352 dogs. The bivariate relationships found between insulin and age, insulin and weight, insulin and BCS, insulin and HRQL, and insulin and CFI are shown in Table 2 below.

[0149] Table 1: Statistical data of dogs included in the HRQL study

[0150] Table 2: Correlation coefficients for evaluating the bivariate relationships among the factors of interest in HRQL research

[0151] The data from the HRQL study were analyzed using quantile regression models to estimate the joint effects of the variables in Table 2. Multiple median regressions were performed using full main effects models, age-weight interaction models, and age-BCS interaction models, as shown in Table 3 below. Figure 1 A graphical representation of the relationship between age and standardized logarithm (insulin) in dogs of different weight groups is shown.

[0152] Table 3: Results of Multiple Median Regression of Variables in the HRQL Study

[0153] In the Healthy Lifespan Study, fasting insulin levels were examined to determine their relationship with HRQL scores. To determine HRQL, a survey was conducted with the participants' owners to understand their perceptions of their dogs' quality of life. The questionnaire consisted of approximately 22 questions covering the effects of aging, disease, and the clinical management of disease. These questions encompassed inquiries about the dog's behavior, including energetic / enthusiastic (E / E), happy / content (H / C), active / comfortable (A / C), and calm / relaxed (C / R). Answers to these questions were synthesized or combined into an individual score, termed the total HRQL score. The Davies transformation (Davies 2019) was applied to normalize the scores. A multivariate median regression model was used to identify the relationship between insulin and HRQL. The standardized logarithm (insulin) was the primary variable, with age, weight, and BCS as covariates; the results are shown in Table 4A below. Figure 2A In this study, multiple ordinary least squares regression models were used to identify the relationship between insulin and CFI, and its acceleration with age. The standardized logarithm (insulin) and its interaction with age were the principal variables, with weight and BCS as covariates. The results are shown in Table 4B and 4C. Figure 2B middle.

[0154] Table 4A: Multivariate median regression of insulin serum levels adjusted for age, weight, and BCS for HRQL

[0155] Table 4B: Multiple linear regression analysis of the interaction effect between age and standardized insulin on standardized CFI Return.

[0156]

[0157] The total HRQL score was then compared to fasting insulin levels by categorizing insulin levels into three equal-sized groups, or tertiles. The tertiles reflected the insulin levels in the lowest, middle, and highest thirds of the sample. Based on each insulin tertile, quantile median regression was used to estimate the total HRQL score adjusted for covariates including age, weight, and BCS. The 407 insulin measures were grouped together with the total HRQL score into insulin tertiles, defined as: lowest insulin level (n = 137, range = [2.53 mU / L, 12 mU / L]), highest insulin level (n = 136, range = [20.9 mU / L, 107 mU / L]), and intermediate insulin level (n = 136, range = [12 mU / L, 20.9 mU / L]). The tertiles were within normal laboratory reference ranges. Multivariate quantile median regression was performed for each insulin tertile, as shown in Table 5 below. The covariate-adjusted HRQL scores for each insulin tertiary group are shown below. Figure 3A The kernel density estimates of HRQL were analyzed and presented in [the table / reference]. Figure 3B The changes in the total HRQL score on the Davies scale with age were analyzed, and the results are shown in the figure. Figure 3C middle.

[0158] Table 5: Multivariate quantile median regression model (n = 407) showing the effects of insulin tertiles adjusted for age, weight, and BCS as covariates.

[0159]

[0160] The Canine Fatlessness Index (CFI) score is based on the dog participant's medical history and physical examination provided by a veterinarian. The CFI is calculated by summing the response scores and then dividing by the total number of questions. A CFI of 0 indicates that the dog is not at all frail. Lower CFI scores indicate fewer health deficiencies and milder frailty, while higher CFI scores indicate more severe health deficiencies or more severe frailty. An analysis of the relationship between CFI scores and age is shown in... Figure 4A The relationship between CFI score and total HRQL score was analyzed, such as... Figure 4B As shown.

[0161] Longitudinal data can be collected to advance healthy lifespan studies, including HRQL and mortality data for canine participants. Lipid levels can also be analyzed based on HRQL scores, CFI scores, or both.

[0162] Fatty acid quantification was performed using stored serum samples from the study. Only 61 dogs had sufficient volume for testing. Free fatty acids (FFA), saturated fatty acids (SFA), palmitic acid (PA, 16:0 saturated fatty acid), oleic acid (OA, 18:1n9 monounsaturated fatty acid), and linoleic acid (LA, 18:2n6 polyunsaturated fatty acid) were measured using gas chromatography-mass spectrometry (GC-MS; Metabolon, Inc.). Insulin concentration values ​​were missing from one of the 61 dogs and were not included in any analyses or models involving insulin.

[0163] Age was significantly positively correlated with all measured fatty acid types and aggregates (p < 0.05, Table 6). The relationship between age and each fatty acid type and aggregate is presented in the table below. Figure 4C middle.

[0164] surface 6 Multiple regression analysis to estimate the major effects of age and BCS associated with FFA, SFA, PA, OA, and LA.

[0165]

[0166] Age-related changes in adiponectin adjusted for covariates (weight and BCS) were estimated using multiple linear regression. A natural logarithmic transformation of adiponectin was performed to address nonnormality. Adiponectin decreased significantly with age (slope and 95% CI = -0.09 (-0.11, -0.07), p < 0.001), adjusted for the effects of body size, weight, and BCS. These results indicate that annual increases in age are associated with an increase in ln(adiponectin) of -0.09. The logarithmic transformation results can be explained by percentage change, and therefore annual increases in age are associated with a decrease in adiponectin of 100*-0.09 = 9%. Figure 4D The observed and predicted changes in adiponectin values ​​across age are shown.

[0167] To estimate the covariate-adjusted association between fatty acids and adiponectin, a multiple regression model was used to estimate the relationship between fatty acids and adiponectin, considering the effects of age, weight, and BCS. To find the most concise model, covariates with p < 0.10 were retained in all models. Huber-White robust standard errors were used to address heteroscedasticity. Fatty acids and adiponectin were standardized (mean = 0, SD = 1) due to the different scales used for fatty acids, other covariates, and adiponectin. All fatty acid types and concentrations were significantly negatively correlated with adiponectin (Table 7, all p < 0.05). The coefficient estimates can be interpreted as a decrease in adiponectin by -0.25 to -0.44 standard deviations for every one standard deviation increase in fatty acid concentration. Figure 4EThe predictive relationships of covariate adjustment observed on the natural scale are shown.

[0168] Table 7: Multiple regression tests on the covariate adjustment relationships between FFA, SFA, PA, OA, and LA and adiponectin.

[0169]

[0170] Multiple linear regression was used to estimate the relationship between fatty acid types and aggregates and CFI. The main effects of fatty acids and their interaction with age were tested.

[0171] In the age-adjusted main effects model, fatty acid measurements were not significantly correlated with CFI. However, significant interaction effects between all fatty acids (free fatty acids, saturated fatty acids, palmitic acid, oleic acid, and linoleic acid) and age were detected (p < 0.05, Table 8). Figure 4F All coefficients of the interaction between age and fatty acid measurements were >0, suggesting that these effects appear to be stronger in older dogs.

[0172] Table 8: Multiple regression analysis of the interaction between FFA, SFA, PA, OA and LA ages on CFI score.

[0173]

[0174] Multiple regression was used to estimate the covariate-adjusted relationship between adiponectin and CFI, testing the primary effect of adiponectin and its interaction with age. CFI was considered the outcome, and adiponectin was considered the primary predictor of interest. A natural logarithmic transformation was performed on adiponectin to account for nonlinearity. Covariates included age, weight, and BCS. The covariate-adjusted relationship (i.e., slope) between adiponectin and CFI was estimated using marginal linear trends.

[0175] Because of the significant differences between adiponectin and the CFI scale, standardized regression coefficients are reported in Table 9. After adjusting for age, weight, and BCS, the main effect of adiponectin on CFI was not statistically significant (coefficient (95% CI) = 0.01 (-0.10, 0.13), p = 0.797, Table 9). However, this may be due to a significant interaction effect between adiponectin and age (coefficient of interaction term (95% CI) = -0.03 (-0.06, 0.00), p = 0.026, Table 9), suggesting a stronger association between decreasing CFI and increasing adiponectin levels with increasing age. Estimated linear trends from the interaction model test and observed data are presented in... Figure 4G middle. Figure 4GIn Figure A, all observed and predicted values ​​are shown, while Figure B shows the same data stratified by age group. These analyses show that the relationship between adiponectin and CFI is relatively flat until the dogs reach approximately 10 years of age, at which point an association between a decrease in CFI and an increase in adiponectin begins to be seen. Figure 4G (Figure B). The results of these analyses provide evidence that CFI decreases with increasing adiponectin levels, especially in older dogs.

[0176] Table 9: Main effects of covariate adjustment between adiponectin and CFI and their interaction with age. Multiple regressions.

[0177]

[0178] Example 2. Effects of pioglitazone treatment on glucose and insulin. This study determined whether pioglitazone could reverse the development of high-fat diet (HFD)-induced insulin resistance and decline in metabolic health in dogs by improving insulin sensitivity, as demonstrated by oral glucose tolerance test (OGTT) results and circulating analytes after 5 weeks of HFD treatment and 7 weeks of pioglitazone (1 mg / kg / day or 2 mg / kg / day) treatment.

[0179] Pioglitazone activates peroxisome proliferator-activated receptor γ (PPARγ) and stimulates the release of adiponectin from adipose tissue. It is hypothesized that this drug will alleviate or reverse impairment of insulin sensitivity induced by chronic HFD feeding. Interventions that improve glucose tolerance and reduce insulin resistance (i.e., calorie restriction, metformin) have increased healthy lifespan (years of disease-free life) and lifespan in several model organisms (including rodents, dogs, and monkeys). This study aims to provide evidence that pioglitazone, when used as an intervention after HFD-induced metabolic dysfunction has already occurred, has a metabolic protective effect (i.e., alleviating and / or reversing the development of clinical manifestations of insulin resistance).

[0180] This 17-week HFD (Highly Active Food Discharge) metabolic reversal study was conducted in four groups (n=12 per group) of beagles. All dogs included in the study were male, aged 3–7 years, and weighed 12.05–22.95 kg. After 63 days (9 weeks) of normal diet or HFD feeding, groups 1 and 2 received a placebo daily, while groups 3 and 4 received pioglitazone orally daily. The dogs tolerated the placebo / pioglitazone administration well.

[0181] Clinical examinations and weight measurements were performed throughout the study to monitor the animals' health. Routine daily health observations and fecal examinations were also conducted throughout the study.

[0182] The animal's daily food ration (g) is distributed in portions. Each feeding (morning or afternoon) consists of approximately half of the animal's daily food ration and is provided approximately every 4 hours. Give the dog approximately 2 hours to consume each ration and weigh any leftover food at each feeding.

[0183] For all baseline measurements prior to the start of the study, all dogs were randomly fed a “normal diet” (ND) consisting of 55% fat. Prior to the start of the study, dogs were randomly assigned to either the ND diet or a high-fat diet (HFD) consisting of 74% fat, and they maintained the corresponding diet for approximately 9 weeks. After 9 weeks, prior to drug administration, the HFD-fed animals were further randomly assigned to the treatment group based on fasting insulin levels as the primary factor and total body weight as a secondary factor. Dogs in the ND group continued with the ND diet until the end of the study.

[0184] Throughout the study, blood collections were performed for chemistry, hematology, triglycerides, cholesterol, metabolomics and lipidomics, efficacy biomarkers (adiponectin, fasting insulin and leptin), pioglitazone pharmacokinetics, cytokines (IL-6 and TNFα), and non-esterified fatty acids (NEFA) to assess the effects of diet and medication on safety and metabolic function biomarkers. Baseline (day -56) and pre-treatment (day 0) readings for each parameter were compared with treatment (day 57) readings.

[0185] Oral glucose tolerance tests (OGTT) were performed before treatment (day -14) and during treatment (day 42) to assess glucose and insulin kinetics and insulin sensitivity. The OGTT was performed as previously described by Coate et al. (2010). Briefly, dogs were fasted overnight before the procedure. Blood samples were taken 20 minutes and 0 minutes before the glucose pellet, and serum and plasma were separated to determine fasting glucose and insulin levels. At 0 minutes (t=0), the glucose pellet (0.9 g / kg, po) was delivered. Blood samples were collected at 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 120, 180, and 240 minutes after the glucose pellet. Serum glucose and plasma insulin levels were then analyzed at each time point.

[0186] Before treatment (day -21) (when the dog has been on ND or HFD for 5 weeks) and at the treatment (day 49) time points, use systemic administration of D2O (deuterium oxide) and 2 H2 18 Blood samples were collected after O (double-labeled water) treatment to measure body composition and resting energy expenditure. Dogs were fasted for at least 12 hours prior to the first blood draw on each sampling day. D2O and... were prepared using autoclaved glassware and instruments. 2 H2 18O, weigh separately and aspirate into individual syringes. Weigh the samples on the day of sampling, and then add the prepared D2O and 2 H2 18 O2 was inhaled into a separate syringe for each animal and weighed to three decimal places before administration. 50 mg / kg of 99% D2O and 150 mg / kg of 97% D2O were administered orally via syringe. 2 H2 18 Before O, collect two milliliters (mL) of blood. Then, in the initial D2O+... 2 H2 18 Blood samples were collected 2, 24, 72, 120, and 168 hours after O administration. Following collection, blood plasma was separated in K2EDTA tubes and stored at -80°C until analysis.

[0187] Determine baseline or pre-treatment readings for all parameters (blood tests, body weight, food consumption, OGTT, body composition / energy expenditure) for each animal and each group, and compare these results with treatment outcomes. Perform individual and aggregate statistics, arithmetic means, percentage changes, and within-group and between-group comparisons.

[0188] The fasting glucose and fasting insulin measurements of each group of subjects were analyzed, such as... Figure 5A (Fasting glucose) and Figure 5B (Fasting insulin) is shown. (As shown) Figure 5C and Figure 5D As shown, the AUC values ​​of glucose and insulin in response to treatment were analyzed after administering pioglitazone to the subjects.

[0189] This study indicates that pioglitazone treatment has no effect on fasting glucose measurements or on glucose fluctuations during glucose tolerance tests. Figure 5A and Figure 5C Furthermore, the study indicated that pioglitazone affects fasting insulin and insulin's response to glucose, independent of any effect on glucose. Figure 5B and Figure 5C This finding differs from the literature, which indicates that PPARγ The activator (i.e., pioglitazone) promotes metabolic health by stimulating glucose fluctuations and systemic insulin sensitivity, and these studies suggest that the metabolic benefits in dogs are not dependent on glucose.

[0190] Example 3. Effects of pioglitazone treatment on harmful fatty acids This study demonstrates that pioglitazone dose-dependently modulates the levels of metabolically harmful fatty acids in dogs. These fatty acids include all aggregated saturated fatty acids (SFAs), palmitic acid, linoleic acid, and oleic acid. Exogenous injection of these lipids (20% Intralipid, containing linoleic acid [44-62%], oleic acid [19-30%], palmitic acid [7-14%], linolenic acid [4-11%], and stearic acid [1.4-5.5%]) into dogs reproduced several aspects of metabolic dysfunction in humans and impaired insulin sensitivity in muscles and the liver.

[0191] Subjects were treated with pioglitazone, and blood samples were analyzed for fatty acids. Fatty acids were detected, analyzed, and quantified by type. The effect of pioglitazone treatment on saturated fatty acids was analyzed, such as... Figure 6A As shown. Furthermore, the effects of pioglitazone on each different type of fatty acid were analyzed, such as... Figure 6B (palmitic acid) Figure 6C (Linoleic acid) and Figure 6D (Oleic acid) is shown. Fatty acids were measured at baseline, before treatment with pioglitazone, and after treatment with pioglitazone, as shown. Figure 6E As shown.

[0192] SFA is associated with metabolic dysfunction and insulin resistance. Pioglitazone treatment has been shown to reverse HFD-induced increases in SFA. Figure 6A Similarly, pioglitazone treatment leads to a reduction in palmitic acid, which is one of the largest single lipid classes contributing to the SFA pool. Figure 6B Palmitic acid is known to directly impair insulin signaling in the liver and muscles; therefore, the palmitic acid-specific reduction induced by pioglitazone administration further supports the improvement of overall and species-specific lipid profiles following HFD-induced metabolic dysfunction by TI. These data demonstrate for the first time the improvement in fatty acid levels in dogs treated with pioglitazone.

[0193] This study also showed that using clinical diagnostic assays (NEFA) to measure FFA: (1) cannot distinguish fatty acid types and (2) when measured by a more sensitive direct-measurement-based GC-MS method, it does not represent fatty acid levels. Indirect measurements using spectrophotometer-based clinical assays did not detect any significant changes, nor did they reflect the trends observed in direct measurements. These data suggest that clinically used fatty acid quantification tools are not sensitive enough to detect physiologically relevant changes. Figure 6E ).

[0194] Example 4. Effects of pioglitazone treatment on metabolic dysfunction in HFD This study concluded that dogs subjected to HFD showed increased food consumption and body weight (p < 0.05; not shown), which led to increased fat mass (p < 0.05; not shown) and significant changes in the dogs' metabolic composition. Observed changes included significant increases in cholesterol, triglycerides, FFA, SFA, leptin, and resting energy expenditure. Conversely, HFD had no significant effect on adiponectin, cytokines, and NEFA levels.

[0195] Importantly, HFD induced a state of hyperinsulinemia characterized by a significant increase in fasting insulin while fasting glucose remained unchanged. This HFD-induced hyperinsulinemia was supplemented by functional data from an oral glucose tolerance test (OGTT) that showed a significant increase in insulin AUC and Cmax levels. Combined with the biochemical profile (e.g., significant increases in circulating triglycerides and cholesterol), these changes indicate that HFD successfully induced a severe clinically relevant metabolic dysfunction.

[0196] In HFD-fed dogs treated with pioglitazone, several pieces of evidence were observed suggesting that pioglitazone, when administered as an intervention after 9 weeks of HFD feeding, alleviated or reversed metabolic damage associated with 17 weeks of HFD. First, evidence of significant upregulation of adiponectin by pioglitazone was noted; adiponectin is a putative biomarker of target binding and a known insulin-sensitizing protein. Second, compared to the HFD-fed placebo group, pioglitazone treatment successfully further alleviated HFD-induced hyperinsulinemia, hyperlipidemia (e.g., significantly reduced circulating triglycerides and cholesterol), and normalized harmful fatty acid profiles. Third, compared to the HFD-fed placebo group, HFD-fed dogs treated with pioglitazone exhibited markers of increased insulin sensitivity, such as those measured by a decrease in insulin secretion in response to glucose, which was measured by assessing the insulin AUC after administration. Finally, compared to the HFD-fed placebo group, pioglitazone treatment induced changes in body composition by increasing fat mass. Histological examination of visceral and subcutaneous adipose tissue revealed that pioglitazone treatment reduced the size of adipocytes in the viscera, indicating a relative increase in subcutaneous fat. It is also noteworthy that pioglitazone exerted a metabolic protective effect and influenced body composition without affecting food consumption, calorie intake, or leptin levels, suggesting that pioglitazone improves metabolic function through a mechanism independent of appetite or weight loss.

[0197] In summary, these data demonstrate that the HFD canine model induces a severe state of metabolic dysfunction that can be alleviated and, in some cases, reversed by interventional pioglitazone administration, strongly supporting the use of pioglitazone as a therapeutic strategy to improve / maintain metabolic function in dogs.

[0198] Example 5. Treatment with pioglitazone to prevent metabolic dysfunction Research Design The aim of this study was to evaluate the effects of pioglitazone on HFD-induced insulin resistance, hyperinsulinemia, and fatty acid regulation in pioglitazone dogs. It was hypothesized that administration of pioglitazone to metabolically dysfunctional dogs fed with HFD would (1) upregulate adiponectin levels, (2) protect systemic insulin sensitivity as measured by the oral glucose tolerance test (OGTT) and the hyperinsulin-positive glucose clamp (HIEG), and (3) prevent the increase in harmful fatty acid levels in the face of HFD.

[0199] Study design: Twenty-four animals (1 to 2 years old) were acclimatized for at least 2 weeks and underwent surgical implantation of a femoral artery catheter under anesthesia. Two baseline tests were performed before any treatment: OGTT and HIEG clamp.

[0200] The dogs were then randomly assigned to one of three groups: a placebo group receiving empty capsules daily (n=8), a group receiving 1 mg / kg pioglitazone in 15 mg pill form (dose 1, n=8), and a group receiving 2 mg / kg pioglitazone in 15 mg pill form (dose 2, n=8). Pioglitazone pills (Actos, Teva Pharmaceuticals, NJ) were administered immediately before feeding each day, dissolved in 5 mL of water.

[0201] Two weeks after the start of treatment, all animals underwent HFD (research diet 5SQ1, a test diet from Purina). On days 46 and 56 after the start of pioglitazone treatment, animals were given an OGTT and a HIEG clamp, respectively, to compare their metabolic responses to their baseline. On days 46 and 56, placebo and pioglitazone were administered one hour before intensive feeding and one hour before the start of somatostatin infusion. Despite the animals' weight gain, the same amount of glucose and the same rate of insulin and hormones were administered during the clamp as in the initial OGTT study, as it was known that animals primarily gain fat (a tissue unresponsive to insulin levels).

[0202] In addition, blood was collected from each animal every two weeks for various chemical measurements (adiponectin, Superchem plate (performed by Antech Diagnostics)) prior to pioglitazone administration and feeding. Serum pioglitazone levels were also measured every two weeks, collected one hour after administration of the pills and feeding.

[0203] This study concluded that HFD (high-fat diet) for 5-6 weeks led to metabolic dysfunction in beagles. This was evident in all 8 dogs, manifested as: 1) a 25% increase in fasting insulin; 2) a slight increase in fasting FFA (20%), indicating mild lipopathy; 3) a 39% increase in insulin response during the oral glucose tolerance test (OGTT), thus compensating for the deficiencies caused by HFD feeding; 4) hyperinsulinemia, with normal glucose clamp data showing a 25% decrease in GIR and a 37% decrease in Rd after 6 weeks of high-fat feeding at the same insulin, glucose, and glucagon levels; and 5) a 25% increase in fasting FFA levels and a significantly reduced ability of insulin to inhibit lipolysis after 6 weeks of HFD feeding.

[0204] In both pioglitazone-treated groups, circulating adiponectin significantly increased after the start of daily pioglitazone administration (up to day 14). The placebo group showed a significant but smaller and transient increase in adiponectin on day 28. The increase in the pioglitazone group was larger and more sustained than that in the placebo group.

[0205] 1) In both pioglitazone-treated groups, insulin response during the OGTT was reduced compared to the placebo group. Therefore, pioglitazone can normalize glucose metabolism without increasing insulin secretion. 2) Based on glucose clamp data (excluding four dogs with incomparable insulin levels in the clamps on day-1 and day-56, which may be due to increased insulin clearance), both doses of pioglitazone were able to overcome GIR and Rd deficiencies induced by HFD. 3) In the clamp experiment, pioglitazone reduced fasting FFA levels and improved inhibition of lipolysis.

[0206] Example 6. Treatment with pioglitazone on aging biomarkers The effects of pioglitazone on aging biomarkers could be determined in customer-owned dogs. Approximately 60 dogs were enrolled and randomly assigned to either group in a 3:1 treatment-to-control ratio. Dogs were screened at the first visit 7 days prior to the study and again at the second visit on day 0 of the study. Treatment was randomized and initiated on day 0. Participant dogs were enrolled for approximately 3 months, with evaluation visits every 30 days for biomarker measurements and safety assessments. Blood levels of HRQL, CFI, insulin, and FFA were measured.

[0207] Commercially available pioglitazone can also be used to measure the effect of pioglitazone treatment on insulin levels and FFA data in dogs that adhere to HFD.

[0208] Research procedures and evaluation To assess owners' perceptions of quality of life, the VetMetrica HRQL instrument, a web-based questionnaire completed by owners, will be used. HRQL is a validated tool for assessing four aspects of a dog's quality of life: Energy / Enthusiasm (E / E), Happiness / Contentment (H / C), Activity / Comfort (A / C), and Calm / Relaxation (C / R). HRQL detects age-related differences in dogs and illnesses perceived by owners.

[0209] The first HRQL survey will be completed by the homeowner during the screening visit / first study visit and before the investigator's physical examination (PE). For the 4th–6th study visits, the HRQL questionnaire must always be completed by the homeowner seven (7) days prior to the scheduled visit date or during the visit prior to the PE. The investigator will confirm that the HRQL survey has been completed on the PhysicalExam eCRF (PhysicalExam eCRF) prior to each PE. Homeowners will not be able to view or access previously completed HRQL surveys. Access to the visit-related HRQL survey is removed upon completion of the visit-related physical exam eCRF.

[0210] The Canine Frailty Index (CFI) is a veterinary assessment consisting of 33 questions that focus on the dog's health and clinical data. These responses are recorded on the CFI eCRF associated with the visit within the eDC. It needs to be initiated by the investigator or examining veterinarian on the day of PE and completed after receiving and reviewing the dog's clinicopathological results.

[0211] The first CFI will begin at the screening visit / first study visit and be completed at or before the second study visit. This assessment will then begin at the fourth–sixth study visits and be completed after reviewing blood test results for the duration of the study.

[0212] A complete medical history for all dogs will be obtained at the screening visit / first study visit and each subsequent study visit (except the third study visit) to document any changes or adverse events (AEs). To differentiate between pre-existing or ongoing medical conditions and potential adverse events (AEs) occurring during the study, a thorough review of the dogs' health status and any changes since the last visit and the last physical examination (PE) is required. Reports will include a brief description of each medical condition, the date of diagnosis (if known), the date of resolution (if resolved), or the ongoing status (if experiencing). All medical history, including ongoing and unresolved medical conditions, will be recorded in the Medical History Log.

[0213] Physical examination (PE) will be performed at each study visit (except for the second and third study visits), starting from the screening visit / first study visit. PE will involve a subjective assessment of overall appearance, posture, ears, eyes, oral / mucous membrane color, respiration, cardiovascular, gastrointestinal, neurological, musculoskeletal, skin, and genitourinary systems. PE should include recording of body temperature (℉), heart rate (heart beats per minute), respiratory rate (respiratory rates per minute), and mucous membrane (MM) color. The results of PE will be recorded on the physical examination eCRF associated with each dog's performance as the visit is examined. All abnormalities will be recorded in the physical examination eCRF, and any information regarding pre-existing, ongoing, and new symptoms will be recorded in the medical history log. Abnormalities discovered after the start of medication at the second study visit will be recorded as AEs or SAEs (according to Section 15) in the Adverse Event (AE) log or serious adverse event (SAE) form and the medical history log.

[0214] As part of the physical examination (PE), the dog's weight will be measured on a calibrated balance, rounded to the nearest decimal place, and recorded in kilograms (kg) or pounds (lbs). The dog's initial weight will be recorded in the first visit physical examination eCRF, and the Study Drug: Subject Log will be automatically populated to provide the appropriate dose of the investigational veterinary product / control product (IVP / CP). The IVP / CP dose will remain constant throughout the study, even if the dog's weight changes.

[0215] A Body Condition Score (BCS) will be measured as part of the Physical Examination (PE). The Nestlé PURINA Body Condition System will be used to assess the BCS. The BCS uses visual examination and palpation to assess the dog's overall shape and the amount of fat coverage on the ribs, spine, and hips. This BCS is graded on a scale of 1-9; 9 is a significantly overweight dog, and 1 is an extremely underweight dog. The BCS will be recorded on the physical examination eCRF, using supplementary BCS guidelines if necessary.

[0216] Muscle condition score (MCS) will also be measured as part of the physical examination (PE). The MCS will be assessed using instruments conforming to the World Small Animal Veterinary Association (WSAVA). The MCS will be assessed using visual examination and palpation of the spine, scapula, skull, and iliac wing. Muscle condition will be graded as normal, mild loss, moderate loss, or severe loss. If necessary, the MCS will be recorded on the physical examination eCRF using supplementary MCS guidelines.

[0217] Starting from the screening visit / first study visit, blood samples will be collected from the dogs via venipuncture at each study visit (except for the second and third study visits) for hematological and biochemical analysis. The maximum amount of blood collected will not exceed the safety limit for the smallest dogs eligible for enrollment in the study.

[0218] All collected samples and related sample collection information will be recorded in the Clinical Pathology eCRF and IDEXX Lab Forms associated with the visit. Care should be taken to minimize hemolysis during intravenous puncture.

[0219] Starting with the screening visit / first study visit, urine will also be collected for analysis at each study visit (except for the second and third study visits). The method of urine collection may be free capture, bladder puncture, or catheterization, as determined by the veterinarian. Owners may also collect their dog's urine sample and bring it to the study site if collection is required within 2 hours of the scheduled time. The collection method will be recorded on the IDEXX Lab Form. Similarly, failure to collect a urine sample will be recorded as a protocol deviation in the Protocol Deviation: Subject Level Form.

[0220] The following blood and urine tests will be performed and analyzed at the central laboratory (IDEXX): Hematology, Comprehensive Blood Cell Count (CBC). Absolute reticulocytes, anisocytosis, neutrophils (% and count), basophils (% and count), eosinophils (% and count), hematocrit (HCT), Heinz bodies, hemoglobin (HGB), lymphocytes (% and count), mean cytohemoglobin (MCH), mean cytohemoglobin concentration (MCHC), mean cytogenetic volume (MCV), promyelocytes (% and count), monocytes (% and count), metamyelocytes (% and count), neutrophils (% and count), nucleated red blood cells (RBC), platelet count, platelet estimate, atypical red blood cells, polychromatic erythrocytes, promyelocytes (% and count), red blood cells (RBC), reticulocytes, undifferentiated, white blood cells (WBC).

[0221] Biochemistry, General Chemistry. Albumin / globulin (ALB / GLOB) ratio, albumin, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), bicarbonate, conjugated bilirubin, non-conjugated bilirubin, blood urea nitrogen (BUN), BUN / creatinine ratio, calcium, chloride, cholesterol, creatine kinase, creatinine, gamma-glutamyl transferase (GGT), globulin, glucose, hemolysis index, lactate dehydrogenase (LDH), lipemia index, Na / K ratio, phosphorus, potassium, sodium, total bilirubin, total protein, triglycerides, LDL, HDL.

[0222] Fasting insulin. Dogs should be fasted for 12 hours before blood collection to determine fasting insulin levels. If the dog is not fasted before blood collection, protocol deviation: subject-level eCRF must be performed.

[0223] Total T4-urine analysis strips, evaluation of microdeposits. Bacteria, bilirubin, blood, casts, transparency, color, crystals, epithelial cells, glucose, ketones, mucus, pH, protein, RBC, urine specific gravity, urobilinogen, volume, WBC. Upon receiving clinicopathological results from the eDC system, the investigator or examining veterinarian will promptly review and evaluate the results. They will assess the clinical significance of abnormal or out-of-range values ​​as clinically significant (CS) or not clinically significant (NCS). CS results will be recorded in the eDC, and any pre-existing or ongoing CS laboratory parameters or corresponding diseases / symptoms should be added to the medical history log and adverse event (AE) log (if the CS parameter was discovered after the initiation of IVP / CP administration on day 0).

[0224] Plasma is collected for storage. Starting from the screening visit / first study visit, a single green top tube will be collected at each study visit (except for the second and third study visits) and submitted to IDEXX for storage.

[0225] PAXgene mRNA collection vials. PAXgene blood vials will be included in the provided laboratory supplies. These will be collected at each study visit (except for the second and third study visits), starting from the screening visit / first study visit. These blood samples will not be used to evaluate exploratory biomarkers in this study. These samples will be labeled and sent to IDEXX along with other blood vials.

[0226] At the screening visit / first study visit, whole blood DNA will be collected only from the same EDTA violet top tube used for CBC samples. These blood samples will not be used in this study but will be stored for use by the sponsor in future DNA projects. These samples will be labeled and sent to IDEXX along with other blood tubes.

[0227] DNA Collection - Saliva Swabs / Cheek Swabs. Saliva or cheek swabs for DNA sampling will be collected only during the screening visit / first study visit using the PERFORMAgene PG-100 non-invasive swab kit, following the manufacturer's instructions. Study subjects must not eat for at least 30 minutes or drink water for at least 10 minutes prior to saliva swab collection. Care should be taken to prevent the collection sponge from scratching the gums or being bitten by the subject.

[0228] After collection, the swabs will be stored at room temperature in a safe location with no significant temperature fluctuations at the research site. The sponsor-designated Clinical Research Associate (CRA) will transport or assist with transport to the storage facility. The saliva swabs will be used by the sponsor in future DNA projects.

[0229] Unplanned visits. Throughout the study, enrolled dogs may report any new clinical signs to the investigators or the study site. These appointments or visits occur between study visits and are not part of this study. Any unplanned visits during the study must be recorded using the eCRF under “Unplanned Visits” in the eDC system (Unplanned Visits: Physical Examination eCRF, Unplanned Visits: Clinical Pathology eCRF, and IDEXX Laboratory Forms). Each new diagnosis or new clinical sign presented by a dog will be recorded in the medical history log and, if applicable, recorded as an AE in the adverse event (AE) log. All AEs will be managed as described in Section 15.

[0230] After completing the Physical Examination (PE) and Out-of-Schedule Visit: Physical Examination eCRF, any diagnosis is made at the investigator's discretion. Any diagnoses performed must be recorded in the dog's medical record and on the Out-of-Schedule Visit: Physical Examination eCRF. The medical history log and concomitant medications log should also be updated for any changes or new prescriptions.

[0231] One-week dosing telephone follow-up. This study does not require dog owners to complete daily dosing logs. However, dosing during the first week is crucial for achieving the desired effect of the IVP used in this study. To ensure no doses are missed during the first week, site staff are required to conduct a telephone follow-up (3rd study visit) 5–7 days after the start of dosing. Site staff will use the One Week Dosing Check-In eCRF to record the results of their contact with owners.

[0232] During the first week, the host who reports a missed dose must report how many doses were missed, and site staff will add this information, along with any other comments, to the weekly dosing review eCRF. Site staff will also complete the Protocol Deviation: Subject-Level Form.

[0233] Palatability Questionnaire. During the 3rd–6th study visits, site staff will ask the host to answer three yes-or-no questions about the palatability of the investigational drug. These answers will be recorded on the Palatability Questionnaire eCRF.

[0234] Research Design This study will be a multisite, field pilot study. The design is a randomized, blinded, placebo-controlled study conducted in customer-owned dogs. The study will include two treatment groups randomly assigned in a 3:1 ratio as shown in Table 10 below.

[0235] Table 10. Randomization of Treatment Groups

[0236] Once subjects are deemed eligible for randomization, research site staff will use the integrated Prelude Just-in-Time (JIT) randomization module on the Randomization eCRF to assign each subject to a randomly selected treatment group. The JIT randomization module will adaptively randomize subjects to treatment groups. If a subject is incorrectly given the wrong treatment, the randomization module will be able to correct the treatment code assignment and update the treatment code to the one applied.

[0237] The JIT randomization module will assign an IVP:CP allocation ratio of 3:1. This will result in four treatment blocks. The four blocks will be stratified by site, such that each site will have its own block drawn during randomization. At the second study visit, randomization will be performed according to the presentation order within each site. For example, the first dog randomly assigned at site one (1) will be randomly assigned to a treatment group, and the unique bottle number available at said site will be automatically filled (depending on the dose based on its screening visit weight). Then, the second dog appearing at the same site will be randomly assigned to a treatment group based on the remaining treatment groups in the four blocks unique to said site, and so on.

[0238] Research Procedures Table 11 below provides a description of the animals used in this study. Table 11. Animal Descriptions

[0239] This study will enroll an estimated 60 dogs across all study sites. Approximately 45 dogs will be treated with IVP, and approximately 15 dogs will be treated with CP. Additional dogs may be enrolled if the initial attrition rate exceeds the expected level. Similarly, fewer dogs may be enrolled if the study ends before full enrollment.

[0240] Inclusion / Exclusion Criteria. Dogs screened, enrolled, and randomly assigned to the treatment group at the first study visit must meet all eligibility requirements. Initial eligibility will be confirmed by completing PE, medical history, and concomitant medications. Age verification and results from clinicopathology collected at the first study visit will be finalized at or before the second study visit. Investigators must review CBC, biochemical profile, and T4 to verify eligibility and complete the Eligibility Form. Subjects who are ineligible for enrollment may be contacted and notified, and therefore do not need to attend the second study visit. Eligible subjects will be randomly assigned at the second study visit.

[0241] Inclusion criteria . The following dogs may be included: ● Multiple dogs from the same family ● Dogs that meet the criteria described above ● Dogs with a heart murmur but no other clinical signs of heart disease ● Dogs with stage B1 myxomatous mitral valve degeneration (MMVD) ● Dogs with benign prostatic hyperplasia ● Dogs with clinicopathological abnormalities that the investigators believe are not clinically significant or do not meet any of the following exclusion criteria. Exclusion criteria. The following dogs will be excluded from the study: ● Dogs not expected to survive six (6) months ● Dogs diagnosed with adrenocortical insufficiency or adrenocortical hyperfunction ● Dogs diagnosed or suspected of having malignant tumors ● Dog diagnosed with diabetes ● Diagnosed with liver disease (through functional tests such as bile acid tests). ● Diagnosed with dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC / Boxer cardiomyopathy), or congestive heart failure (CHF). ● Diagnosed with an autoimmune disease requiring immunosuppression ●Medicine ● Dogs with hematocrit < 30 and anemia ●The temperament they exhibit makes it impossible for the dogs to perform research procedures. ● Dogs that have been given prohibited medications or conditionally permitted medications other than those indicated for their condition. Age Verification. The dog's age must be verified by confirming and uploading the following approval documents during the screening visit / first study visit, or at or before the second study visit: ● Breeding records or registration documents showing the accurate date of birth ● Records documenting any examinations or treatments performed on the dog by a veterinarian when the dog was estimated to be one (1) year old or younger. ● Shelter adoption records of dogs that were puppies (less than six (6) months) at the time of adoption. ●The shelter’s veterinary records show that the dog was spayed / neutered and was one (1) year old or younger at the time of surgery. The dog's date of birth (set to the first day of each month, or an estimated date) and the verification source provided by the owner will be recorded in the Demographics eCRF. This source document will be copied, scanned, and uploaded to the document upload form in the eDC.

[0242] Owner Informed Consent Form. Owner consent must be obtained from each owner using the OIC form before any research-related procedures are performed on the subject. This form will be completed during the screening visit / first research visit.

[0243] The study will be blinded. The host, researchers, research site staff, and sponsors will remain in the dark about the treatment group. Research site staff distributing IVP / CP should not speculate about or discuss the treatment group with the host.

[0244] Research Facilities. Research sites will be clinical veterinary facilities whose personnel, facilities, equipment, record keeping, and expected adherence to the research procedures outlined in the protocol will facilitate impartial research evaluation. Qualifications for all research sites will be verified as outlined. Site researchers will be registered Doctor of Veterinary Medicine (DVM or VMD). Other research site personnel must include at least one registered veterinary technician (LVT) or veterinary assistant. It is estimated that approximately three research sites will be recruited to conduct this study. Site recruitment may continue until three or more research sites are secured.

[0245] Research Equipment. Scales used at the research site to obtain participant weights must have been calibrated by a certified technician within one (1) year prior to their first use in this study. A copy of the site calibration record will be uploaded to the Clinical Trial Management System (CTMS) and retained in the electronic Trial Master File (eTMF). The calibration period is one (1) year, and the research site will require certified technicians to calibrate the scales annually as needed.

[0246] All enrolled dogs will remain in their normal living environment with their owners. There are no special dietary requirements for participation in this study; owners should continue to feed their dogs their normal diet. The normal diet includes any prescription diets previously prescribed or prescribed during the study. At each relevant study visit, the participants' diet and feeding plan will be documented as part of the physical examination eCRF. Prescription diets will be recorded in the accompanying medication log.

[0247] Drug administration. Starting from the second study visit, IVP / CP will be administered to the subjects once daily by the host throughout the study duration. The routes of administration for IVP and CP are oral (PO).

[0248] Owners will not need to complete a dosing log. Missed doses will be checked when owners return their study vials, and unadministered doses will be calculated monthly when they pick up their IVP / CP refills. Returned vials, missed doses, incorrectly administered doses, associated missed or incorrect dosing dates, and refills will be recorded monthly in the Study Drugs: Subject Log. If an owner administers an incorrect dose or misses an average of more than 8 doses per month, it will be recorded as a protocol deviation in the Protocol Deviation: Subject Level table, but the dog will not be removed from the study. Unadministered tablets will be allocated and accounted for during drug dispensing.

[0249] During the first week of this study, owners must not miss any doses, as this may affect the initial levels of the drug that affect the pharmacodynamics of the dog's biomarkers. Missed doses during the first week will be recorded in the Week 1 Dosing Review (eCRF) and documented as protocol deviations in the Protocol Deviations: Subject Level table.

[0250] Removal Criteria. The study completion date for each enrolled dog is the date of study evaluation and treatment cessation. Study completion may be due to the removal of a subject from the study (see Section 8.7 if the removal criteria are met). Upon completion of the study, the researcher must complete a Study Exit Form to record the date and, if applicable, the reason for removing the dog from the study.

[0251] Dogs to be removed from the study. The following dogs will be removed from the study and must complete the study exit form: ●HCT < 30 indicates anemia ● Dogs diagnosed with diabetes ● Dogs suspected or confirmed to have bladder cancer ● Dogs that experience a sudden or unexpected worsening of edema / fluid retention or CHF ● Dogs diagnosed with hyperadrenocorticism or hypoadrenocorticism ● Dogs incorrectly grouped ● Dogs that need to discontinue medication ● Dogs exhibiting SAE requiring exposure or discontinuation of treatment ● Dogs whose owners do not follow the research procedures (including dogs that miss research visits or miss too many research doses within the permitted timeframes). ●The dog whose owner chose to remove it from the research. ● Dogs that become uncooperative during research procedures Dogs that have been removed. In some cases, follow-up is necessary for clinicopathological abnormalities, adverse events (AEs), and subarachnoid hemorrhages (SAEs). This follow-up is crucial for determining the clinical significance of the abnormality, AE, or SAE and understanding its relationship to in vitro veno-pornography (IVP).

[0252] Dogs found to have elevated liver enzymes but deemed suitable for continued study by the researcher or study veterinarian do not need to be immediately removed from the study. Because elevated liver enzymes are nonspecific and not always clinically significant, researchers are allowed to make their own decisions regarding these cases. If dogs continue to be enrolled, their blood biochemistry profiles (including liver enzymes: AST, ALT, ALP, bilirubin) will be repeated every 30 days (an appropriate retest interval considering the half-life of liver enzymes). If the retested liver enzyme values ​​are equal to or higher than the initially detected elevated values, and the veterinarian deems it an appropriate precaution, the dog may be removed from the study, and the researcher will complete the study exit form.

[0253] Companion medications. Companion medications are defined as any medications or treatments the dog receives during the screening visit / first study visit and at any time after the study period. This includes, but is not limited to, flea and tick preventatives, supplements, prescription diets, and prescription medications. If the dog receives a medication listed under “Conditional Allowance” in Table 4, the researcher or examining veterinarian must ensure the dog meets the criteria under the “Conditional Allowance” column in Table 8 before completing any further study procedures. At each visit, any new or in-use companion medications and related medical history must be recorded in the medical history log and companion medication log.

[0254] Permitted medications are those for which the dogs are not restricted in their intake during the study duration. The use of these medications does not require withdrawal or conditions. For this study, it is important that the dogs included represent a normal canine population, so most medications and supplements are permitted. Conditionally permitted medications are allowed during the study period, but require certain conditions or observation periods. Prohibited medications are those that are not permitted to be used in the study at all, because they would replicate the effects of IVP, or because their use might complicate the addition of IVP.

[0255] Table 12 below details common concomitant medications and their relevance to the inclusion / exclusion criteria for this study.

[0256] Table 12. Accompanying Drugs

[0257] If a dog is found to be receiving a prohibited medication during the screening visit / first study visit, this will be the reason for excluding the dog from the study. The medication and the reason for exclusion will be recorded in the concomitant medication log, eligibility form, and study exit form.

[0258] Dog disposal. Dogs will remain in the care of their owners. Dogs withdrawn or removed from the study early will continue to be in the care of their owners.

[0259] Effects of pioglitazone on dogs This study concluded that, from baseline to day 90, dogs in the control group showed a mean increase in insulin levels of 3.85 μIU / mL (95% CI = 1.37, 9.06). This increase was not statistically significant (p = 0.132). Dogs treated with pioglitazone showed a mean decrease in insulin levels of 2.35 μIU / mL (95% CI = 10.07, 5.36), but this decrease was not statistically significant (p = 0.538). The mean decrease in insulin levels in dogs treated with pioglitazone was generally less than that in the control group (p = 0.171). Due to insufficient support and short duration of this study, statistically significant differences in insulin levels between the groups could not be detected to demonstrate effectiveness.

[0260] However, in the three dogs treated with pioglitazone who had elevated baseline insulin levels, there was a significant effect on insulin levels. This effect necessitates closer observation of these three isolated dogs with abnormally elevated fasting insulin levels and their response to pioglitazone treatment. These case studies not only demonstrate the acute effects of pioglitazone treatment but also provide important safety data for dogs not at their peak metabolic health.

[0261] Subject 001-SAR-007 was a 9-year-old sterile male Yorkshire Terrier. At the screening visit, his insulin level was 76.8 uIU / mL (reference range 5.2–41.5 uIU / mL). In addition, his ALP was elevated to 177 U / L (reference range 5–160 U / L), AST to 182 U / L (reference range 16–55 U / L), ALT to 469 U / L (reference range 18–121 U / L), and TBili to 0.5 mg / dL (reference range 0.0–0.3 mg / dL). Prior to randomization, the study veterinarian measured pre- and post-meal bile acids, which were within the normal range. Less than a month later, after starting pioglitazone, the dog's liver values ​​all returned to normal (ALP 88 U / L, AST 22 U / L, ALT 48 U / L and TBili 0.2 mg / dL), as did its insulin (16.2 uIU / mL).

[0262] Subject 003-BAK-016 was a 7-year-old neutered male Welsh Terrier. At the screening visit, his insulin level was 96.6 uIU / mL (reference range 5.2–41.5 uIU / mL) and his ALP level was 241 U / L (reference range 5–160 U / L). Although his ALP remained elevated, his insulin level gradually decreased to 62.2 uIU / mL at subsequent visits, then to 52.9 uIU / mL, and finally to 42.3 uIU / mL by the 6th visit after 90 days.

[0263] Subject 003-BAK-018 was an 8-year-old spayed female Cocker Spaniel. At the screening visit, her insulin level was 66.3 uIU / mL (reference range 5.2–41.5 uIU / mL) and ALP was 1603 U / L (reference range 5–160 U / L). Concerned about Cushing's disease, the study veterinarian performed a low-dose dexamethasone suppression test, which was normal. After starting pioglitazone, by the fourth visit (approximately day 30), her insulin level had recovered to 15.3 uIU / mL, and her ALP had decreased to 774 U / L.

[0264] These three cases confirmed the acute effects of improved metabolic function and reduced fasting insulin. In terms of clinicopathology, these dogs also experienced various additional improvements, including decreased liver enzymes (all three dogs), reduced or normalized triglycerides, and elimination of total lipemia in blood samples submitted to IDEXX (001-SAR-007 and 003-BAK-018).

[0265] Example 7. Safety of pioglitazone in dogs The safety of pioglitazone in dogs has been evaluated in numerous laboratory studies and a recent clinical trial.

[0266]

[0267] Example 8. Preparation of pioglitazone Pioglitazone or its salts can be formulated into any of the tablet forms described in Table 13 below.

[0268] Table 13: Preparation of pioglitazone in 18 mg, 54 mg and 81 mg tablets

[0269] Example 9. Preparation of pioglitazone Pioglitazone or its salts can be formulated into any of the tablet forms described in Table 14 below.

[0270] Table 14: Formulation of pioglitazone by % wt / wt

[0271] Example 10. Preparation of pioglitazone Pioglitazone or its salts can be formulated into any of the tablet forms described in Table 15 below.

[0272] Table 15: Formulation of pioglitazone by % wt / wt

[0273] Example 11. Preparation of pioglitazone Pioglitazone or its salts can be formulated into any of the tablet forms described in Table 16 below.

[0274] Table 16: Formulation of pioglitazone by % wt / wt

[0275] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used to practice the invention. The appended claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A method for alleviating or reversing age-induced insulin resistance in a mammal in need, the method comprising administering to a companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

2. A method for alleviating or reversing insulin resistance in a mammal in need, the method comprising administering to a companion animal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

3. A method for mitigating or reversing age-induced elevation of circulating lipids in a desired mammal, the circulating lipids comprising fatty acids, triglycerides, or cholesterol, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

4. A method for maintaining or restoring healthy function of adipose tissue in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a formulation comprising a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

5. The method according to any one of claims 1 to 4, wherein the method does not reduce the glucose level of the companion animal.

6. The method according to any one of claims 1 to 5, wherein the method does not increase the glucose level of the companion animal.

7. The method according to any one of claims 1 to 6, wherein the method comprises reducing the insulin level of the companion animal.

8. The method of claim 7, wherein the reduction in insulin level is a reduction of at least 5%.

9. The method of claim 8, wherein the reduction in insulin level is a reduction of at least 10%, at least 15%, or at least 20%.

10. The method according to any one of claims 1 to 9, wherein the method improves insulin sensitivity.

11. The method of claim 10, wherein the insulin sensitivity is measured by an oral glucose tolerance test.

12. The method of claim 10, wherein the insulin sensitivity is measured by a high insulin positive glucose clamp test.

13. The method of claim 10, wherein the insulin sensitivity is measured using fasting insulin blood levels.

14. The method according to any one of claims 3 or 5 to 13, wherein the lipid is an aggregated free fatty acid, saturated fatty acid, palmitic acid, linoleic acid, or oleic acid, or any combination thereof.

15. The method of claim 14, wherein the fatty acid is a saturated fatty acid.

16. The method of claim 14, wherein the fatty acid is palmitic acid.

17. The method according to any one of claims 1 to 16, wherein the method reduces the triglyceride level of the mammal.

18. The method according to any one of claims 1 to 17, wherein the method increases the adiponectin level of the mammal.

19. The method according to any one of claims 1 to 17, wherein the method reduces the cholesterol level of the mammal.

20. The method according to any one of claims 1 to 19, wherein the mammal is a dog or a cat.

21. The method of claim 20, wherein the mammal is a dog.

22. The method of claim 20, wherein the mammal is a cat.

23. The method according to any one of claims 1 to 22, wherein the mammal is at least 7 years old.

24. The method according to any one of claims 1 to 23, wherein the mammal is at least 10 years old.

25. The method according to any one of claims 1 to 24, wherein the formulation comprises about 3% to about 35% of the PPARγ agonist.

26. The method according to any one of claims 1 to 25, wherein the formulation comprises about 10% to about 20% of the PPARγ agonist.

27. The method according to any one of claims 1 to 26, wherein the formulation comprises about 1 mg to about 100 mg of the PPARγ agonist.

28. The method according to any one of claims 1 to 27, wherein the formulation comprises about 4 mg to about 85 mg of the PPARγ agonist.

29. The method according to any one of claims 1 to 28, wherein the PPARγ agonist is administered at about 3 mg / kg / day.

30. The method according to any one of claims 1 to 28, wherein the PPARγ agonist is administered at about 5 mg / kg / day.

31. The method according to any one of claims 1 to 28, wherein the PPARγ agonist is administered at about 10 mg / kg / day.

32. The method according to any one of claims 1 to 31, wherein the formulation is administered for at least about 4 weeks.

33. The method according to any one of claims 1 to 32, wherein the formulation is administered for at least about 12 weeks.

34. The method according to any one of claims 1 to 33, wherein the formulation is applied for at least about 6 months.

35. The method according to any one of claims 1 to 34, wherein the formulation is applied for at least about one year.

36. The method according to any one of claims 1 to 35, wherein the formulation is applied daily.

37. The method according to any one of claims 1 to 36, wherein the PPARγ agonist is pioglitazone or a salt or prodrug thereof.

38. The method of claim 37, wherein the pioglitazone is administered at 1 mg / kg / day.

39. The method of claim 37, wherein the pioglitazone is administered at a dose of 2 mg / kg / day to 3 mg / kg / day.

40. The method according to any one of claims 1 to 39, wherein the PPARγ agonist is rosiglitazone or a salt or prodrug thereof.

41. The method according to any one of claims 1 to 40, wherein the formulation is a pharmaceutical formulation.

42. The method according to any one of claims 1 to 40, wherein the formulation is a nutritional formulation.

43. The method according to any one of claims 1 to 42, wherein the formulation is in a solid dosage form (e.g., tablets or capsules).

44. The method of claim 43, wherein the solid dosage form comprises hydrolyzed chicken product.

45. The method of claim 43 or 44, wherein the solid dosage form comprises 18 mg, 54 mg or 81 mg of the PPARγ agonist.

46. ​​The method according to any one of claims 43 to 45, wherein the solid dosage form further comprises at least one filler.

47. The method according to any one of claims 46, wherein the filler is lactose monohydrate.

48. The method of claim 47, wherein the amount of lactose monohydrate is from about 10% w / w to about 40% w / w.

49. The method of claim 48, wherein the amount of lactose monohydrate is about 22% w / w.

50. The method according to any one of claims 43 to 49, wherein the solid dosage form further comprises carboxymethyl cellulose Na.

51. The method of claim 50, wherein the amount of carboxymethyl cellulose Na is about 2% w / w to about 10% w / w.

52. The method according to claim 51, wherein the amount of carboxymethyl cellulose Na is about 4% w / w.

53. The method according to any one of claims 43 to 52, wherein the solid dosage form further comprises a flavoring agent (e.g., FlavorPAL X1212).

54. The method of claim 53, wherein the amount of the flavoring agent is from about 10% w / w to about 40% w / w.

55. The method of claim 54, wherein the amount of the flavoring agent is about 20% w / w.

56. The method according to any one of claims 43 to 55, wherein the solid dosage form further comprises magnesium stearate.

57. The method of claim 56, wherein the amount of magnesium stearate is from about 0.25% w / w to about 3% w / w.

58. The method according to any one of claims 43 to 57, wherein the solid dosage form is a tablet.

59. A method for reducing or delaying death from age-related diseases in a mammal in need, the method comprising administering to the mammal a therapeutically effective amount of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

60. A method for treating age-related decline in quality of life, the method comprising administering to the mammal a therapeutically effective amount of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

61. A method for treating age-related increased frailty, the method comprising administering to the mammal a therapeutically effective amount of a PPARγ agonist or a pharmaceutically acceptable salt or prodrug thereof.

62. The method of claim 59, wherein the method further comprises increasing lifespan, wherein the increased lifespan comprises an increase of at least 5% relative to the expected or median lifespan of companion animals of similar species, strains or varieties.

63. The method of claim 62, wherein increasing the lifetime comprises increasing the lifetime by at least 10%, at least 15%, at least 20%, or at least 25%.

64. The method according to any one of claims 59 to 63, wherein the method comprises reducing or reversing insulin resistance in the mammal.

65. The method of claim 64, wherein the insulin resistance occurs during aging.

66. The method according to any one of claims 59 to 65, wherein the method comprises reducing or reversing fatty acid elevation.

67. The method of claim 66, wherein the elevated fatty acid levels are associated with age-related disease states.

68. The method of claim 67, wherein the age-related disease state is metabolic syndrome, insulin resistance, obesity, type II diabetes, cardiovascular disease, or sarcopenia.

69. The method according to any one of claims 59 to 68, wherein the mammal has reached maturity.

70. The method according to any one of claims 59 to 69, wherein the mammal is at least 7 years old.

71. The method according to any one of claims 59 to 70, wherein the mammal is at least 10 years old.

72. The method according to any one of claims 59 to 71, wherein the mammal has reached old age.

73. The method according to any one of claims 59 to 72, wherein the mammal is at least 14 pounds.

74. The method according to any one of claims 59 to 73, wherein the mammal is a dog or a cat.

75. The method of claim 74, wherein the mammal is a dog.

76. The method of claim 74, wherein the mammal is a cat.

77. The method according to any one of claims 59 to 76, wherein the method comprises about 5% to about 35% of the PPARγ agonist.

78. The method according to any one of claims 59 to 77, wherein the method comprises about 10% to about 20% of the PPARγ agonist.

79. The method according to any one of claims 59 to 78, wherein the method comprises about 1 mg to about 100 mg of the PPARγ agonist.

80. The method according to any one of claims 59 to 79, wherein the method comprises about 4 mg to about 85 mg of the PPARγ agonist.

81. The method according to any one of claims 59 to 80, wherein the PPARγ agonist is administered at about 3 mg / kg / day.

82. The method according to any one of claims 59 to 80, wherein the PPARγ agonist is administered at about 5 mg / kg / day.

83. The method according to any one of claims 59 to 80, wherein the PPARγ agonist is administered at about 10 mg / kg / day.

84. The method according to any one of claims 59 to 83, wherein the PPARγ agonist is administered for at least about 4 weeks.

85. The method according to any one of claims 59 to 84, wherein the PPARγ agonist is administered for at least about 12 weeks.

86. The method according to any one of claims 59 to 85, wherein the PPARγ agonist is administered for at least about 6 months.

87. The method according to any one of claims 59 to 86, wherein the PPARγ agonist is administered for at least about one year.

88. The method according to any one of 59 to 87, wherein the PPARγ agonist is administered daily.

89. The method according to any one of claims 59 to 88, wherein the PPARγ agonist is pioglitazone or a salt thereof.

90. The method of claim 89, wherein the pioglitazone is administered at 1 mg / kg / day.

91. The method of claim 89, wherein the pioglitazone is administered at a dose of 2 mg / kg / day to 3 mg / kg / day.

92. The method according to any one of claims 59 to 88, wherein the PPARγ agonist is rosiglitazone or a salt thereof.

93. The method according to any one of claims 59 to 92, wherein the PPARγ agonist is in a pharmaceutical formulation.

94. The method according to any one of claims 59 to 92, wherein the PPARγ agonist is in a nutritional formulation.

95. The method according to any one of claims 59 to 94, wherein the PPARγ agonist is in a solid dosage form (e.g., tablets or capsules).

96. The method of claim 95, wherein the solid dosage form comprises hydrolyzed chicken product or chicken seasoning.

97. The method according to claim 95 or 96, wherein the solid dosage form comprises 18 mg, 54 mg or 81 mg of the PPARγ agonist.

98. The method according to any one of claims 95 to 97, wherein the solid dosage form further comprises at least one filler.

99. The method of claim 98, wherein the filler comprises lactose monohydrate, and the amount of lactose monohydrate is from about 10% w / w to about 40% w / w.

100. The method of claim 99, wherein the amount of lactose monohydrate is about 22% w / w.

101. The method according to any one of claims 95 to 100, wherein the solid dosage form further comprises carboxymethyl cellulose Na.

102. The method of claim 101, wherein the amount of carboxymethyl cellulose Na is about 2% w / w to about 10% w / w.

103. The method according to claim 102, wherein the amount of carboxymethyl cellulose Na is about 4% w / w.

104. The method according to any one of claims 95 to 103, wherein the solid dosage form further comprises a flavoring agent (e.g., FlavorPAL X1212).

105. The method of claim 104, wherein the amount of the flavoring agent is from about 10% w / w to about 40% w / w.

106. The method of claim 105, wherein the amount of the flavoring agent is about 20% w / w.

107. The method according to any one of claims 95 to 106, wherein the solid dosage form further comprises magnesium stearate.

108. The method of claim 107, wherein the amount of magnesium stearate is from about 0.25% w / w to about 3% w / w.

109. The method according to any one of claims 95 to 108, wherein the solid dosage form is a tablet.

110. A pharmaceutical formulation in solid dosage form, the pharmaceutical formulation comprising: (a) pioglitazone or a salt thereof, (b) one or more fillers (e.g., lactose monohydrate, hydroxypropyl cellulose, sodium carboxymethyl cellulose or combinations thereof), (c) a lubricant (e.g., magnesium stearate), and (d) a flavoring agent.

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