Inhibition of weight gain caused by unbalanced diet and related degradation of muscle structure, function and performance

Abstract

The present disclosure relates to compositions comprising thiazolium-based AGE disruptors (advanced glycosylation end product disruptors) for use in methods of inhibiting weight gain and related muscle structure, function and performance degradation induced by hyperglycemia. The thiazolium-based AGE breaker can be an ALT-711 (Alpha Transferase Type 711).

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application Serial No. 63 / 512,317, filed July 7, 2023, the entire contents of which, including any drawings, tables or figures, are incorporated herein by reference. Background Technology

[0002] Diabetes is one of the most serious health problems that modern society needs to address. Its rising prevalence is due to a sedentary lifestyle and an unbalanced diet. It is estimated that by 2045, the global diabetic population will increase by another 46%, reaching 783 million people [1]. For long-term diabetic patients, their exercise capacity will decline and their quality of life will decrease, which creates a vicious cycle and further deteriorates glucose mobilization. Skeletal muscle has always been considered the main defect site in the development of hyperglycemia, and it has already shown insulin resistance before blood glucose changes [2]. In addition, exercise is one of the most effective strategies for preventing hyperglycemia in routine clinical practice. However, there are currently no drugs available in clinical practice that target skeletal muscle to inhibit or treat hyperglycemia.

[0003] Therefore, the industry needs a new treatment method that targets skeletal muscle to inhibit and / or treat hyperglycemia. Summary of the Invention

[0004] This disclosure relates to compositions comprising a thiazolyl-based AGE disruptor (advanced glycation end product disruptor) in methods for inhibiting weight gain and muscle structural, functional, and performance deterioration associated with hyperglycemia. This disclosure also relates to methods for treating diabetes. In a preferred embodiment, the diabetes is prediabetes or type 2 diabetes. In some embodiments, the compositions of this disclosure comprise a thiazolyl-based AGE disruptor, such as ALT-711. In some embodiments, the thiazolyl-based AGE disruptor can inhibit weight gain; alleviate hyperglycemia; reduce food intake; improve feed conversion ratio; inhibit the muscle deterioration effects of weight gain and hyperglycemia; inhibit and improve diet-related intramuscular AGE, fibronectin, and collagen accumulation; inhibit diet-related skeletal muscle stiffening; inhibit and improve diet-related skeletal muscle contraction and relaxation abnormalities; inhibit and improve diet-related skeletal muscle fatigue recovery rate disturbances; inhibit and improve skeletal muscle force output under isolated stimulation; improve age-related intramuscular fibronectin and collagen accumulation; or any combination thereof. Attached Figure Description

[0005] Figure 1Dietary plans for the control, prevention, and treatment groups. A repetitive high-fat diet was administered to the control, prevention, and treatment groups of the animals.

[0006] Figures 2A-2D ALT-711 inhibited weight gain, reduced hyperglycemia, decreased food intake, and improved feed conversion ratio. Between the control and prevention groups, at the end of Phase 1, the animals exhibited (…). Figure 2A Weight gain or loss, ( Figure 2B The severity of high blood sugar has decreased. Figure 2C Reduced food intake, and ( Figure 2D Improved feed conversion ratio. Feed conversion ratio: food intake / weight gain over a specified time period. Statistical analysis was performed using the Student's t-test (T-test). p < 0.05.

[0007] Figures 3A-3B ALT-711 prevented weight gain and worsening of hyperglycemia after the second high-fat diet intake. In the control group, weight gain and further worsening of hyperglycemia were observed at week 16 (W16). However, the weight gain in both the prevention and treatment groups was significantly lower. Figure 3A ) and blood sugar levels ( Figure 3B All values ​​were comparable to those of the control group at week 5 (W5). Statistical analysis was performed using two-way ANOVA, p < 0.05, ‡: compared with the control group at the same time point, +: compared with the control group at week 5 (W5).

[0008] Figures 4A-4F ALT-711 prevents and improves the accumulation of diet-related intramuscular AGEs, fibronectin, and collagen. Comparisons between healthy and control groups showed accumulation of AGEs, Fn1, and OH-Pro (collagen) at week 16 (W16). AGEs (…) are shown here. Figure 4A ), Fn1 ( Figure 4C ) and OH-Pro ( Figure 4E Representative images of [the disease / organization]. Furthermore, the expression levels in the prevention and treatment groups were significantly lower than those in the control group ([the control group]). Figure 4B , Figure 4D , Figure 4F Statistical analysis was performed using two-way ANOVA, p < 0.05, ∠: compared with the healthy group at the same time point, ‡: compared with the control group at the same time point.

[0009] Figures 5A-5BALT-711 prevents diet-related skeletal muscle stiffening. Hardness and ultimate strength significantly increased between the control group's week 0 (W0) and week 16 (W16) time points. Results show that in the prevention group, muscle hardness ( Figure 5A ) and ultimate strength ( Figure 5B ) were comparable to the control group's week 0 (W0) time point. Statistical analysis was performed using two-way ANOVA, p<0.05, #: compared to week 0 (W0), ‡: compared to the control group at the same time point.

[0010] Figures 6A-6D ALT-711 prevents and improves diet-related skeletal muscle contraction and relaxation abnormalities. According to the results, both the prevention and treatment groups showed improvements in maximum contraction rate compared to age-matched controls ( Figure 6A ); the treatment group showed improvements in the downregulation of time to maximum force compared to age-matched controls ( Figure 6B ); both the prevention and treatment groups showed improvements in maximum relaxation time compared to age-matched controls ( Figure 6C ); and the treatment group showed improvements in half relaxation time compared to age-matched controls ( Figure 6D ). Statistical analysis was performed using two-way ANOVA, p<0.05, #: compared to week 0 (W0), ‡: compared to the control group at the same time point.

[0011] Figures 7A-7B ALT-711 prevents and improves diet-related skeletal muscle fatigue recovery rate disturbances. In the control group, the 10-minute fatigue recovery rate significantly decreased. Results show that both the prevention and treatment groups showed significant improvements in fatigue recovery rate at 5 minutes ( Figure 7A ) and 10 minutes ( Figure 7B ). Statistical analysis was performed using two-way ANOVA, p<0.05, #: compared to week 0 (W0), ‡: compared to the control group at the same time point.

[0012] Figures 8A-8B ALT-711 prevents and improves skeletal muscle force output under in vitro stimulation. The control group showed a significant decrease in twitch force at the week 16 (W16) time point. However, the prevention and treatment groups were statistically comparable to the control group's week 0 (W0) time point ( Figure 8A ). The prevention and treatment groups showed significant improvements in isometric force output ( Figure 8B ). Statistical analysis was performed using two-way ANOVA, p<0.05, #: compared to week 0 (W0), ‡: compared to the control group at the same time point.

[0013] Figures 9A-9BALT-711 prevents and improves diet-related grip strength reduction. Relative grip strength was normalized by body weight. At the 11th week (W11) time point, animals were comparable in body weight and the control group showed a reduction in strength compared to the 0th week (W0) time point; however, the prevention and treatment groups showed prevention and improvement in diet-related strength reduction ( Figure 9A ). At the 16th week (W16) time point, body weight was higher than the 0th week (W0) time point; however, the prevention and treatment groups showed a reduction in the degree of grip strength reduction ( Figure 9B ). Statistical analysis was performed using two-way ANOVA, p<0.05, #: compared to the 0th week (W0), ‡: compared to the control group at the same time point.

[0014] Figure 10 Diet plan for the old group and the treatment group. The treatment group received AGE-breaker treatment for one month at 24 months of age.

[0015] Figures 11A-11C ALT-711 improves age-related hyperglycemia and reduces food intake. After one month of treatment with ALT-711 in animals. Old animals showed a reduction in ( Figure 11A ) intraperitoneal glucose tolerance test - area under the curve (IPGT-AUC), ( Figure 11B ) fasting blood glucose, and ( Figure 11C ) food intake. Statistical analysis was performed using T-test, p values are shown in the figure.

[0016] Figure 12 ALT-711 improves age-related grip strength reduction. Relative grip strength was normalized by body weight. After one month of treatment with ALT-711 in animals. Grip strength was significantly increased compared to age-matched control animals. Statistical analysis was performed using T-test, p values are shown in the figure.

[0017] Figures 13A-13D ALT-711 improves age-related accumulation of intramuscular fibronectin and collagen. After one month of treatment with ALT-711 in animals. The treatment group showed a reduction in Fn1 and OH-Pro (collagen) accumulation. Representative images of OH-Pro ( Figure 13A ) and Fn1 ( Figure 13C ) are shown here. Also, the expression levels of the prevention and treatment groups were significantly lower than those of the old group ( Figure 13B , Figure 13D ). Statistical analysis was performed using T-test, p values are shown in the figure. DETAILED DESCRIPTION

[0018] SPECIFIC DEFINITIONS As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Further, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains" and "containing" are intended to be open-ended terms that do not preclude the presence of other elements or steps than the list of elements or steps recited. The term "comprising" is used herein to mean that the compositions and methods include the recited steps or elements, but do not exclude others. The transitional terms / phrase "comprising", "comprises", "comprise", "consisting essentially of", "consists essentially of", "consisting of", and "consists of" can be used interchangeably.

[0019] The phrase "consisting essentially of" or "consisting of means that the claim encompasses embodiments containing the specified materials or steps and those that do not affect the basic and novel characteristic(s) of the claimed subject matter.

[0020] The term "about" means an acceptable error range determined by one of ordinary skill in the art to the particular value set forth, which varies from the stated value by no more than 10% of the measured value, i.e., the limitations of the measurement system. When the term "about" is used in the context of a composition containing an amount of a component, the composition contains the component in the stated amount with a variation (error range) of 0-10% of the value (X ± 10%). In other contexts, the term "about" provides a variation (error range) of 0-10% of the stated value (X ± 10%). It is readily apparent that such a variation represents a range that is up to 10% higher or lower than the stated value, e.g., X ± 1%, X ± 2%, X ± 3%, X ± 4%, X ± 5%, X ± 6%, X ± 7%, X ± 8%, X ± 9%, or X ± 10%.

[0021] In the present disclosure, to avoid having to set forth and describe every value within a range, ranges are stated in shorthand form. Any appropriate value within a range can be selected as the upper limit value, lower limit value, or endpoint of a range, as appropriate. For example, a range of 0.1-1.0 represents the endpoint values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges contained within 0.1-1.0, e.g., 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. Values having at least two significant digits within a range are contemplated, e.g., a range of 5-10 represents all values between 5.0 and 10.0, as well as between 5.00 and 10.00, including the endpoint values. Combinations and subcombinations of ranges (e.g., subranges within a disclosed range) and specific embodiments therein are expressly included within the scope of the present disclosure when ranges are used herein.

[0022] As used herein, "treatment," "treating," "palliating," and "ameliorating" (and grammatical variations thereof) are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit. Therapeutic benefit is achieved with the eradication or amelioration of one or more signs or symptoms of an underlying disease or its symptoms, whether or not a patient is actually afflicted with the disease.

[0023] As used herein, the terms "diabetes" or "mellitus diabetes" refer to a group of diseases characterized by high levels of glucose in the blood (i.e., hyperglycemia). Diabetes can include chronic diabetes, such as type 1 diabetes or type 2 diabetes. Diabetes can also include prediabetes and gestational diabetes.

[0024] As used herein, the term "hyperglycemia" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0025] As used herein, the term "muscle structural deterioration associated with hyperglycemia" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0026] As used herein, the term "muscle or functional deterioration associated with hyperglycemia" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0027] As used herein, the term "weight gain" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western-style diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0028] As used herein, the term "muscle structure deterioration associated with weight gain" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western-style diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0029] As used herein, the term "muscle function deterioration associated with weight gain" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western-style diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0030] As used herein, the term "skeletal muscle performance deterioration" refers to a condition associated with one or more of the following: high fat diet, high carbohydrate diet, Western-style diet, overnutrition, sedentary lifestyle, inactivity, and aging.

[0031] As used herein, the term "deterioration" refers to the occurrence or progression of clinical and subclinical symptoms, disorders, or conditions.

[0032] "Pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure that is pharmaceutically acceptable, as well as the parent compound. In particular, such nontoxic salts can be inorganic or organic acid addition salts and base addition salts.

[0033] "Pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, or vehicle with which a compound of the disclosure is administered. "Pharmaceutically acceptable carrier" means a material that is not toxic to the subject to whom it is administered, is biologically compatible, and is otherwise suitable for administration to the subject, e.g., an inert substance added to a pharmacological composition or otherwise used to facilitate administration of a formulation and that is compatible with the formulation. Examples of carriers include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0034] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound described herein that is sufficient to affect the intended application including, but not limited to, the treatment of a disease. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response, e.g., enhance the function of skeletal muscle. The specific dose will depend on the particular compounds chosen, the dosing regimen to be followed, whether it is to be administered in combination with other compounds, timing of administration, the tissue to which it is to be administered, and the physical delivery system in which it is carried.

[0035] In some embodiments of the present disclosure, the method comprises multiple administrations of the composition of the present disclosure. The method can comprise administering 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of the composition of the present disclosure described herein. In some embodiments, the doses are administered over the course of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 30 days, or more than 30 days. Further, treatment of a subject with a therapeutically effective amount of the composition of the present disclosure can comprise a single treatment or can comprise a series of treatments. It is also to be understood that the effective dose of the composition for treatment can increase or decrease during a particular course of treatment. Changes in dosages can result from, and become apparent upon, results from diagnostic assays or imaging techniques, e.g., for detecting blood glucose concentration, which are well known in the art. In some embodiments of the present disclosure, the method comprises multiple administrations of the composition per day, including but not limited to 2 times per day, 3 times per day, and 4 times per day.

[0036] The term "subject" herein refers to an animal in need of or desiring the benefits provided by a therapeutic composition. The animal can be a primate or a rodent. The animal can be, for example, a human, a pig, a horse, a goat, a cat, a mouse, a rat, a dog, an ape, a fish, a chimpanzee, a gorilla, a guinea pig, a hamster, a cow, a sheep, a bird, a chicken, and any other vertebrate or invertebrate. The benefits can include, but are not limited to, treatment of a health condition, disease, or disorder; prevention of a health condition, disease, or disorder; immunization; enhancement of function of enamel, an organ, a tissue, or a system in the body. The subject can be of any age or stage of development, including an infant, a toddler, an adolescent, a teenager, an adult, or an elderly person. The terms "subject" and "patient" can be used interchangeably.

[0037] "Decrease" means at least a 1%, 5%, 10%, 25%, 50%, 75%, or 100% negative change.

[0038] "increasing" means at least a 1%, 5%, 10%, 25%, 50%, 75%, or 100% positive change.

[0039] Any reference to a list of chemical groups for a variable herein includes the definition of that variable as any single group or combination of listed groups. Any reference to an embodiment of a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0040] Any composition or method provided herein can be combined with one or more of any other composition and method provided herein.

[0041] Other features and advantages of the present disclosure will be apparent from the following description of the preferred embodiments thereof, and from the claims. All references cited herein are incorporated by reference in their entirety.

[0042] Compositions In certain embodiments, the compositions and methods according to the present disclosure utilize a thiazolium-based AGE breaker, the core structure of which is shown in Formula (I): Formula (I) wherein R1is phenyl or benzyl; R2is methyl or hydrogen; and R3is methyl or hydrogen; the methyl group in R2.

[0043] In a preferred embodiment, R1is phenyl and R2and R3are methyl.

[0044] In a preferred embodiment, R1is phenyl and R2and R3are hydrogen.

[0045] In a preferred embodiment, R1is benzyl, R2is methyl, and R3is hydrogen.

[0046] In certain embodiments, such a thiazolium-based AGE breaker is ALT-711, which is according to Formula (II): Formula (II) .

[0047] In certain embodiments, the composition further comprises metformin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (RA), a dipeptidyl peptidase-4 (DPP-4) inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

[0048] In certain embodiments, metformin can be administered in an amount of about 500 to about 2000 mg / day.

[0049] In certain embodiments, the SGLT-2 inhibitor can be administered in an amount of about 5 to about 25 mg / day. In certain embodiments, the SGLT-2 inhibitor is Bexagliflozin, Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin, Sergliflozin, Sotagliflozin, Tofogliflozin, or any combination thereof.

[0050] In certain embodiments, the GLP-1 receptor agonist and GIP receptor agonist can be administered in an amount of about 0.25 to about 1 mg / week. In certain embodiments, the GIP-1 RA or GLP-1 RA is Liraglutide, Semaglutide, Dulaglutide, Tirzepatide, Exenatide, Albiglutide, Lixisenatide, or any combination thereof.

[0051] In certain embodiments, the DPP-4 inhibitor can be administered in an amount of about 5 to about 100 mg / day. In certain embodiments, the DPP-4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, or any combination thereof.

[0052] In certain embodiments, the thiazolidinedione can be administered in an amount of about 15 to about 45 mg / day. In certain embodiments, the thiazolidinedione is Rosiglitazone, Pioglitazone, or a combination thereof.

[0053] In certain embodiments, the sulfonylurea can be administered in an amount of about 1 to about 10 mg / day. In certain embodiments, the sulfonylurea is Acetohexamide, Carbutamide, Chlorpropamide, Glycyclamide, Metahexamide, Tolazamide, Tolbutamide, Glibenclamide, Glibornuride, Gliclazide, Glipizide, Gliquidone, Glisoxepide, Glyclopyramide, Glimepiride, or any combination thereof.

[0054] In certain embodiments, the insulin can be administered in an amount of about 10 to about 100 units / day. In certain embodiments, an international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 micrograms of pure crystalline insulin.

[0055] In some embodiments, the present disclosure provides pharmaceutically acceptable salts, solvates, or hydrates of the compounds described herein. In certain embodiments, the compositions of the present disclosure can be dissolved in water, alcohol, or other polar solvents.

[0056] The pharmaceutically acceptable salts can be salts with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid; with organic acids such as trifluoroacetic acid (TFA), formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid; or salts with bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines, and substituted ethanol amines.

[0057] Further, pharmaceutically acceptable salts include: (1) acid addition salts, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, and the like; and, where the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. Hydrate refers to a compound of the disclosure, or a salt thereof, which further includes stoichiometric or non-stoichiometric water combined through non-covalent intermolecular forces.

[0058] Solvate refers to a solvate formed by one or more solvent molecules in association with a compound of the disclosure. "Solvate" includes hydrates (e.g., monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

[0059] Certain embodiments provide amorphous forms of the salts of the compounds disclosed herein. Such amorphous forms are advantageous for oral, pulmonary, buccal, intravaginal, or suppository delivery. In preferred embodiments, the compounds of the disclosure are administered orally.

[0060] In one embodiment, the compositions of the present disclosure are formulated into orally available products, such as foodstuffs, capsules, pills, or drinkable liquids. Orally deliverable drugs are any physiologically active substances that are delivered by initial absorption through the gastrointestinal tract or oral mucosa. In one embodiment, the compositions of the present disclosure are formulated into orally consumable products, such as foodstuffs, capsules, pills, or drinkable liquids. The subject compositions can also be formulated into solutions that can be administered by, for example, injection, which includes intravenous, intraperitoneal, intramuscular, intrathecal, intracerebroventricular, or subcutaneous injection. In other embodiments, the compositions of the present disclosure are formulated for administration through a patch via the skin, or directly onto the skin to produce a local or systemic effect. These compositions can be administered sublingually, buccally, rectally, or vaginally. In addition, these compositions can be sprayed into the nasal cavity for absorption through the nasal mucosa, nebulized for inhalation through the mouth or nose, or administered in the eye or ear.

[0061] Orally available products according to the present disclosure are any formulation or composition suitable for consumption, nutrition, oral hygiene, or pleasure, and are products intended to be introduced into the mouth of a human or animal, to stay there for some time, and then to be swallowed (e.g., ready-to-eat foodstuffs or pills) or to be removed from the mouth again (e.g., chewing gum or oral hygiene products or medicinal mouthwash). While orally deliverable drugs can be formulated into orally available products, and orally available products can include orally deliverable drugs, the two terms are not intended to be used interchangeably herein. The subject compositions can also be formulated into solutions that can be administered by, for example, injection, which includes intravenous, intraperitoneal, intramuscular, subcutaneous, or local injection.

[0062] Orally available products include all substances or products intended to be ingested by a human or animal in a processed, semi-processed, or unprocessed state. This also includes substances added to orally available products (in particular foodstuffs and pharmaceuticals) during their production, handling, or processing, and intended to be introduced into the mouth of a human or animal.

[0063] Orally available products can also include substances intended to be swallowed by a human or animal and then to be digested in an unmodified, prepared, or processed state. Orally available products according to the present disclosure thus also include casings, coatings, or other enclosures intended to be swallowed together with the product or expected to be swallowed.

[0064] In one embodiment, orally available products are capsules, pills, syrups, emulsions, or liquid suspensions containing the desired orally deliverable substance. In one embodiment, orally available products can include orally deliverable substances in the form of a powder that can be mixed with water or other liquids to produce a drinkable orally available product.

[0065] In some embodiments, orally consumable products according to the present disclosure can include one or more formulations for nutrition or pleasure. These include, among others, baked products (e.g., breads, dry biscuits, cakes, and other pastries), confections (e.g., chocolates, chocolate bar products, other bar products, fruit pastilles, coated tablets, hard caramels, toffees, and caramels, and chewing gums), alcoholic or non-alcoholic beverages (e.g., cocoa, coffee, green tea, black tea, black or green tea beverages enriched with green or black tea extracts, rooibos tea, other herbal teas, fruit-infused lemonades, isotonic beverages, soft drinks, nectars, fruit and vegetable juices, and fruit or vegetable juice preparations), instant beverages (e.g., instant cocoa beverages, instant tea beverages, and instant coffee beverages), meat products (e.g., hams, fresh or raw sausage preparations, and seasoned or cured fresh or salted meat preparations), eggs or egg preparations (e.g., dried whole eggs, egg whites, and egg yolks), cereal products (e.g., breakfast cereals, muesli bars, and pre-cooked instant rice products), dairy products (e.g., whole or reduced or skimmed milk beverages, rice pudding, yogurts, kefir, cream cheese, soft cheese, hard cheese, milk powder, whey, butter, buttermilk, and products containing partially or completely hydrolyzed milk proteins), products from soy protein or other soy components (e.g., soy milk and products prepared therefrom, beverages containing isolated or enzyme-treated soy protein, beverages containing soy flour, preparations containing soy lecithin, fermented products such as tofu or tempeh and products prepared therefrom, and mixtures with fruit preparations and optional flavoring substances), fruit preparations (e.g., fruit jams, fruit ice cream, fruit sauces, and fruit fillings), vegetable preparations (e.g., tomato sauce, sauce, dried vegetables, frozen vegetables, pre-cooked vegetables, and cooked vegetables), snacks (e.g., baked or fried potato chips (crisps) or potato dough products and extruded products based on corn or peanuts), products based on fats and oils or emulsions thereof (e.g., mayonnaise, seasoned mayonnaise, and dressings), other ready-to-eat meals and soups (e.g., dry soups, instant soups, and pre-cooked soups), seasonings (e.g., sprinkling seasonings), sweetener compositions (e.g., tablets, sachets, and other preparations for sweetening or whitening beverages or other foods). Compositions of the present disclosure can also be used as semi-finished products for the production of other compositions for nutrition or pleasure.

[0066] Compositions of the present disclosure can further include one or more pharmaceutically acceptable carriers and / or excipients, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, aerosols, bars, wafers, films, pellets, cachets, lozenges, troches, dispersions, aqueous solutions, non-aqueous solutions, oil-in-water emulsions, or water-in-oil liquid emulsions.

[0067] The term "pharmaceutically acceptable" as used herein means compatible with the other ingredients of a pharmaceutical composition and not injurious to the recipient.

[0068] The carriers and / or excipients according to the present disclosure can include any and all solvents, diluents, buffers (e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate, or phosphate buffers), oil-in-water or water-in-oil emulsions, aqueous compositions including or excluding organic co-solvents suitable for, e.g., intravenous use, solubilizers (e.g., polysorbate 65, polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavorings, aromatics, thickening agents (e.g., carbomer, gelatin, or sodium alginate), coatings, preservatives (e.g., thimerosal, benzyl alcohol, polyquatemium salts), antioxidants (e.g., ascorbic acid, sodium metabisulfite), tonicity adjusters, absorption delaying agents, adjuvants, fillers (e.g., lactose, mannitol), and the like. The use of carriers and / or excipients in the field of pharmaceuticals and supplements is well known. Carriers or excipients can be considered for use in the compositions of the present disclosure, except for any conventional medium or agent that is incompatible with the subject health-promoting substance or with the composition.

[0069] In one embodiment, the compositions of the present disclosure can be formulated as an aerosol formulation, so that, for example, it can be nebulized or inhaled. Suitable pharmaceutical formulations for administration in an aerosol or spray form, for example, are powders, granules, solutions, suspensions, or emulsions. Formulations for oral or nasal aerosol or inhalation administration can also be formulated with a carrier, including, for example, saline, polyethylene glycol or glycols, dipalmitoyl phosphatidyl choline (DPPC), methyl cellulose, or mixed with powdered dispersants or fluorocarbons. Aerosol formulations can be placed in a pressurized propellant, such as dichlorodifluoromethane, propane, nitrogen, fluorocarbons, and / or other solubilizers or dispersants known in the art. By way of illustration, delivery can be by use of a disposable delivery device, a nebulizer, a breath-activated dry powder inhaler, a metered dose inhaler (MDI), or any other of the numerous nebulization delivery devices available in the art. In addition, a mist tent or direct administration through an endotracheal tube can also be used.

[0070] In an embodiment, the compositions of the present disclosure can be formulated for administration by injection, e.g., as a solution or suspension. The solution or suspension can include a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, or isotonic sodium chloride solution, or a suitable dispersing or wetting agent and suspending agent, such as a sterile, fixed oil, including synthetic mono-or digylcerides, and fatty acids, including oleic acid. Examples of carriers for intravenous use include a mixture of 10% USP ethanol, 40% USP propylene glycol, or polyethylene glycol 600, with the balance being USP water for injection (WFI). Other exemplary carriers for intravenous use include 10% USP ethanol and USP WFI; 0.01-0.1% triethanolamine in USP WFI; or 0.01-0.2% dipalmitoyl di-phosphatidyl choline in USP WFI; and 1-10% squalene or oil-in-water emulsion of parenteral vegetable oil. Water or saline solutions and aqueous dextrose and glycerol solutions can be preferably used as carriers, particularly for injectable solutions. Examples of carriers for subcutaneous or intramuscular use include phosphate buffered saline (PBS) solution, 5% dextrose in WFI, and 0.01-0.1% triethanolamine in 5% dextrose or 0.9% sodium chloride USP WFI, or 10% USP ethanol, 40% propylene glycol in a 1 to 2 or 1 to 4 mixture with the balance being an acceptable isotonic solution such as 5% dextrose or 0.9% sodium chloride; or 0.01-0.2% dipalmitoyl di-phosphatidyl choline in USP WFI, and 1 to 10% squalene or oil-in-water emulsion of parenteral vegetable oil. In an embodiment, the compositions of the present disclosure can be formulated for administration by topical application through the skin, e.g., as a topical composition, including a rinse, spray, or drop, lotion, gel, ointment, cream, foam, powder, solid, sponge, tape, vapor, paste, tincture, or using a transdermal patch. Suitable formulations for topical application can include, in addition to any pharmaceutically active carrier, for example, an emollient such as carnauba wax, cetyl alcohol, cetyl esters wax, emulsifying wax, hydrophilic lanolin, lanolin, lanolin alcohols, microcrystalline wax, paraffin wax, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white beeswax, or yellow beeswax. In addition, these compositions can contain a humectant such as glycerin, propylene glycol, polyethylene glycol, sorbitol solution, and 1,2,6-hexanetriol, or a penetration enhancer such as ethanol, isopropyl alcohol, or oleic acid.

[0071] The present disclosure also relates to kits comprising at least 1, 2, 3, or more compounds of the present disclosure in one or more containers. The kits of the present disclosure can also include one or more compounds, biomolecules, or drugs. In one embodiment, the kits of the present disclosure include a compound of the present disclosure. In certain embodiments, the present disclosure also relates to kits comprising a compound of the present disclosure, a composition comprising a compound of the present disclosure, and, optionally, other compounds, including, for example, insulin effective in treating symptoms of diabetes. In preferred embodiments, such diabetes is prediabetes or type 2 diabetes.

[0072] The present disclosure also provides kits comprising a compound of the present disclosure and a pharmaceutical formulation packaged in a suitable packaging material, optionally in combination with instructions for using the kit components, e.g., instructions for performing a method of the present disclosure. In one embodiment, the kit comprises an amount of a compound of the present disclosure, and instructions on the label or package insert for administering the compound of the present disclosure to a subject in need of treatment. In a further embodiment, the kit comprises an article of manufacture for delivering a compound of the present disclosure locally, regionally, or systemically into a subject.

[0073] Herein, "packaging material" refers to the physical structure that contains the kit components. The packaging material can preserve the sterility of the components and can be made of material commonly used for this purpose, e.g., paper, corrugated fiber, glass, plastic, foil, ampule, etc. The label or package insert can include appropriate written instructions, e.g., for performing a method of the present disclosure, e.g., treating diabetes, an assay for identifying a subject having hyperglycemia, etc. Thus, in other embodiments, the kit includes a label or package insert including instructions for performing a method of the present disclosure in solution, in vitro, in vivo, or ex vivo. In preferred embodiments, such diabetes is prediabetes or type 2 diabetes.

[0074] Thus, the instructions can include instructions for performing any of the methods of the present disclosure described herein. For example, a pharmaceutical composition can be included in a container, pack, or dispenser together with instructions for administration to a subject. The instructions can additionally include appropriate routes of administration, dosage information, indications of satisfactory clinical endpoints or any adverse symptoms that can occur, storage information, expiration date, or any information required by regulatory agencies such as the U.S. Food and Drug Administration or the European Medicines Agency for human subjects.

[0075] The instructions can be on "printed matter" such as paper or cardboard within the kit, on a label affixed to the kit or packaging material, or attached to a vial or tube containing a kit component. The instructions can include an audio or video cassette, and can additionally be included on a computer readable medium such as a magnetic disk (floppy disk or hard drive), optical disk such as CD- or DVD-ROM / RAM, magnetic tape, electrical storage media such as RAM and ROM, and hybrids of these such as magnetooptical storage media.

[0076] The kit can additionally include buffers, preservatives, or reagents for stabilizing the compounds of the disclosure. The kit can also include control components for assaying for the presence of blood glucose, such as control samples or standards. Each component of the kit can be packaged in a separate container or in admixture, and all of the different containers can be located in a single or multiple packages.

[0077] Methods of using the compositions of the disclosure The present disclosure relates to methods and compositions for treating hyperglycemia in a subject, muscle structure or function deterioration associated with hyperglycemia in a mammal, weight gain in a mammal, muscle structure or function deterioration associated with weight gain in a mammal, or for treating a subject with deteriorating skeletal muscle performance by administering an effective amount of a thiazolium-based AGE breaker (advanced glycation end product breaker). These methods and compositions have the advantage of ease of administration and improved patient compliance.

[0078] In certain embodiments, a thiazolium-based AGE breaker can be administered to a subject. Any mode of administration that can be used is contemplated in the methods of the present disclosure, including, for example, oral, intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0079] In certain embodiments, a thiazolium-based AGE breaker administered orally is absorbed through the oral mucosa. In certain embodiments, the oral mucosa is selected from one or more of the following: sublingual mucosa, buccal mucosa, and labial mucosa. In certain embodiments, a thiazolium-based AGE breaker administered orally is absorbed through the gut. In certain embodiments, the present disclosure provides a method of administering a composition of the present disclosure in an oral dispersal dose.

[0080] In certain embodiments, the method further comprises administering a dose of the thiazolium-based AGE breaker in a range of about 0.1 mg to 50 mg per kg of body weight of the subject. In certain embodiments, the dose of the thiazolium-based AGE breaker is about 20 mg per kg of body weight.

[0081] In certain embodiments, the method further comprises administering a dose of the thiazolium-based AGE breaker at least every about 7 days, at least every day, or at least twice every day. In certain embodiments, a dose of the thiazolium-based AGE breaker is administered every day.

[0082] In certain embodiments, the method further comprises administering a dose of the thiazolium-based AGE breaker in a form selected from the group consisting of a strip, a wafer, a film, a pellet, a sachet, a tablet, a lozenge, a pastille, a dispersion, a powder, a granule, an aqueous solution, a non-aqueous solution, an oil-in-water emulsion, or a water-in-oil emulsion.

[0083] In certain embodiments, the method further comprises administering a lifestyle intervention, such as a dietary adjustment, a time-restricted diet, caloric restriction, endurance training, weight training, or any combination thereof.

[0084] In certain embodiments, the method further comprises administering one or more blood glucose lowering drugs selected from the group consisting of metformin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, a glucagon-like peptide-1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

[0085] In certain embodiments, metformin can reduce intestinal glucose absorption, increase muscle glucose uptake, reduce hepatic glucose production. In certain embodiments, SGLT-2 inhibitors can reduce glucose reabsorption. In certain embodiments, GIP receptor agonists can affect the incretin system. In certain embodiments, GLP-1 receptor agonists can affect the incretin system. In certain embodiments, DPP-4 inhibitors can affect the incretin system. In certain embodiments, thiazolidinediones can inhibit Pparg signaling. In certain embodiments, sulfonylureas can promote insulin secretion.

[0086] In certain embodiments, the method further comprises inhibiting muscle structural deterioration in skeletal muscle mechanical performance, intramuscular extracellular matrix (ECM), intramuscular AGE, or any combination thereof.

[0087] In certain embodiments, muscle structural deterioration is measured by histology, immunoassay, ultrasound, photoacoustic effect, fluorescence, or any combination thereof.

[0088] In certain embodiments, muscle structural deterioration is determined by a change of at least 5% in skeletal muscle mechanical performance, intramuscular extracellular matrix (ECM), intramuscular AGE, or any combination thereof, in a diseased subject compared to the mean value of a healthy subject thereof.

[0089] In certain embodiments, the method further inhibits skeletal muscle function deterioration by measuring muscle contraction and muscle relaxation capacity.

[0090] In certain embodiments, muscle contraction and muscle relaxation deterioration is determined by at least a 5% change in time to peak force, peak contraction rate, half relaxation time, and peak relaxation rate, or any combination thereof, of a diseased subject compared to the mean of healthy subjects of the same sex and age group.

[0091] In certain embodiments, the method further inhibits skeletal muscle performance deterioration, which can be determined using ex vivo muscle performance tests, clinical muscle performance tests, or a combination thereof.

[0092] In certain embodiments, skeletal muscle ex vivo performance deterioration is determined by at least a 5% change in 5-minute fatigue recovery, 10-minute fatigue recovery, specific twitch force, specific tetanic force, or any combination thereof, of a diseased subject compared to the mean of healthy subjects.

[0093] In certain embodiments, skeletal muscle clinical muscle performance deterioration is determined by at least a 1 standard deviation decrease in performance of a timed up and go test, chair stand test, gait speed test, grip strength test, isokinetic muscle function test, single repetition maximum weight test, maximum isometric force test, muscle power test, or any combination thereof, of a diseased subject compared to the mean of healthy subjects in the same sex and age group.

[0094] In certain embodiments, the method further comprises inhibiting hyperglycemia, which can be measured using fasting blood glucose, 2-hour blood glucose after an oral glucose tolerance test (OGTT), 2-hour blood glucose after an intraperitoneal glucose tolerance test (IPGTT), area under the curve (AUC) of OGTT, IPGTT AUC, glycosylated hemoglobin (HbAlc), or any combination thereof.

[0095] In certain embodiments, hyperglycemia is determined by at least a 10% change in fasting blood glucose, 2-hour blood glucose after OGTT, 2-hour blood glucose after IPGTT, OGTT AUC, IPGTT AUC, or any combination thereof, of a diseased subject compared to the mean of healthy subjects.

[0096] In certain embodiments, hyperglycemia is determined by fasting blood glucose > 100 mg / dL, 2-hour blood glucose after OGTT > 140 mg / dL, HbAlc > 5.7%, or any combination thereof.

[0097] In certain embodiments, the method further comprises inhibiting weight gain by, for example, reducing or stabilizing body weight, reducing food intake, increasing feed conversion, or any combination thereof.

[0098] In certain embodiments, the weight gain is determined by an average change in body weight of at least 5% compared to the average body weight of a diseased subject to a healthy subject, or by a body mass index (BMI) > 25.

[0099] In certain embodiments, the present disclosure provides a composition for oral administration for treating hyperglycemia in a mammal, muscle structure or function deterioration associated with hyperglycemia in a mammal, weight gain in a mammal, muscle structure or function deterioration associated with weight gain in a mammal, or skeletal muscle performance deterioration in a mammal, the composition comprising administering (i) a thiazolium-based AGE breaker in a range of about 0.1 mg to 50 mg per kg of body weight; or (ii) a thiazolium-based AGE breaker at a concentration of about 20 mg per kg of body weight.

[0100] In certain embodiments, the composition further comprises one or more of the following: dietary adjustments, time-restricted diet, caloric restriction, endurance training, and weight training.

[0101] In certain embodiments, the compounds of the present disclosure can be administered prior to a subject being diagnosed with diabetes (e.g., prediabetes), or for treating a subject diagnosed with diabetes. In preferred embodiments, such diabetes is prediabetes or type 2 diabetes. In certain embodiments, the compounds of the present disclosure can be administered in combination with a hypoglycemic drug, e.g., insulin. In certain embodiments, the dose of insulin can be about 10 to 100 units per day. In certain embodiments, the compounds of the present disclosure or compositions thereof can be administered simultaneously with the hypoglycemic drug, prior to administration of the hypoglycemic drug to the subject, or after administration of the hypoglycemic drug. In certain embodiments, the administration of the hypoglycemic drug occurs less than or about 15 minutes prior to or after administration of the composition. In preferred embodiments, the compounds of the present disclosure or compositions thereof can be administered simultaneously with the hypoglycemic drug.

[0102] The therapeutic or prophylactic applications of the compounds of the present disclosure and compositions comprising these compounds can be accomplished by any suitable therapeutic or prophylactic methods and techniques currently or future known to those skilled in the art. The compounds can be administered by any suitable route known in the art, including, for example, oral, intramuscular, intraspinal, intracranial, nasal, rectal, parenteral, subcutaneous, or intravascular (e.g., intravenous) routes of administration. In preferred embodiments, the compounds or compositions thereof can be administered orally. Administration of the compounds of the present disclosure can be continuous or at explicit intervals, which can be readily determined by those skilled in the art.

[0103] In some embodiments, an amount of a compound can be administered once per day or twice per day for 1, 2, 3, 4, 5, 6, 7, or more days. Treatment can continue for as long as desired, for example, for weeks, months, years.

[0104] In certain embodiments, the inhibition of the deterioration of muscle mechanical performance is determined by comparing skeletal muscle of a subject treated with the present disclosure to a diseased subject using passive stretch method. In certain embodiments, an improvement of at least 10% of the pre-set average deterioration indicates the inhibition of the deterioration of muscle mechanical performance.

[0105] In certain embodiments, the compositions and methods of the present disclosure can inhibit the deterioration of skeletal muscle mechanical performance by inhibiting skeletal muscle stiffening. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an improvement in skeletal muscle stiffening. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an inhibition of the upregulation of skeletal muscle maximal force. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an improvement in the upregulated skeletal muscle maximal force. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an inhibition of the upregulation of skeletal muscle viscoelasticity. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an improvement in the upregulated skeletal muscle viscoelasticity. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an inhibition of the upregulation of skeletal muscle stress-relaxation rate. In certain embodiments, the inhibition of the deterioration of skeletal muscle mechanical performance comprises an improvement in the upregulated skeletal muscle stress-relaxation rate.

[0106] In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration is determined by comparing skeletal muscle between a subject treated with the present disclosure and a diseased subject using immunostaining. In certain embodiments, an improvement of at least 10% in the average degree of deterioration is indicative of the inhibition of intramuscular extracellular matrix (ECM) deterioration. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the inhibition of intramuscular collagen accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the improvement of intramuscular collagen accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the inhibition of intramuscular fibronectin accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the improvement of intramuscular fibronectin accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the inhibition of intramuscular elastin accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the improvement of intramuscular elastin accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the inhibition of intramuscular decorin accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the improvement of intramuscular decorin accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the inhibition of intramuscular hyaluronic acid accumulation. In certain embodiments, the inhibition of intramuscular extracellular matrix (ECM) deterioration comprises the improvement of intramuscular hyaluronic acid accumulation.

[0107] In certain embodiments, the inhibition of intramuscular AGE deterioration is determined by comparing skeletal muscle between a subject treated with the present disclosure and a diseased subject using immunostaining. In certain embodiments, an improvement of at least 10% in the average degree of deterioration is indicative of the inhibition of intramuscular AGE deterioration.

[0108] In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of accumulation of dicarbonyl AGE precursors in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of accumulation of dicarbonyl AGE precursors in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of accumulation of non-crosslinking-nonfluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of accumulation of non-crosslinking-nonfluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of accumulation of non-crosslinking-fluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of accumulation of non-crosslinking-fluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of accumulation of crosslinking-nonfluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of accumulation of crosslinking-nonfluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of accumulation of crosslinking-fluorescent AGEs in muscle. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of accumulation of crosslinking-fluorescent AGEs in muscle.

[0109] In certain embodiments, the inhibition of muscle relaxation deterioration is determined by comparing skeletal muscle between a subject treated with the present disclosure and a diseased subject by providing a series of electrical stimuli to record the response of the skeletal muscle. In certain embodiments, an improvement of at least 10% in the average degree of deterioration is indicative of inhibition of muscle relaxation deterioration.

[0110] In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of downregulation of time to maximal force. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of downregulation of time to maximal force. In certain embodiments, the inhibition of muscle contraction deterioration comprises inhibition of upregulation of maximal contraction rate. In certain embodiments, the inhibition of muscle contraction deterioration comprises improvement of upregulation of maximal contraction rate.

[0111] In certain embodiments, the inhibition of muscle relaxation deterioration is determined by comparing skeletal muscle between a subject treated with the present disclosure and a diseased subject by providing a series of electrical stimuli to record the response of the skeletal muscle. In certain embodiments, an improvement of at least 10% in the average degree of deterioration is indicative of inhibition of muscle relaxation deterioration.

[0112] In certain embodiments, the inhibition of muscle relaxation deterioration comprises inhibition of upregulation of half relaxation time. In certain embodiments, the inhibition of muscle relaxation deterioration comprises improvement of upregulation of half relaxation time. In certain embodiments, the inhibition of muscle relaxation deterioration comprises inhibition of downregulation of maximal relaxation rate. In certain embodiments, the inhibition of muscle relaxation deterioration comprises improvement of downregulation of maximal relaxation rate.

[0113] In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo is determined by providing a series of electrical stimuli to record the response of skeletal muscle to compare skeletal muscle between a subject treated with the present disclosure and a diseased subject. In certain embodiments, an improvement of at least 10% in the pre-set average degree of deterioration indicates inhibition of deterioration of performance of muscle ex vivo.

[0114] In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises inhibition of down-regulated twitch force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises improvement of down-regulated twitch force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises inhibition of down-regulated specific twitch force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises improvement of down-regulated specific twitch force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises inhibition of down-regulated tetanic force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises improvement of down-regulated tetanic force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises inhibition of down-regulated specific tetanic force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises improvement of down-regulated specific tetanic force. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises inhibition of down-regulated fatigue resistance. In certain embodiments, the inhibition of deterioration of performance of muscle ex vivo comprises improvement of down-regulated fatigue resistance.

[0115] In certain embodiments, the inhibition of deterioration of clinical muscle performance is determined by providing a series of electrical stimuli to record the response of skeletal muscle to compare skeletal muscle between a subject treated with the present disclosure and a diseased subject. In certain embodiments, an improvement of at least 10% in the pre-set average degree of deterioration indicates inhibition of deterioration of clinical muscle performance.

[0116] In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a timed up and go test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a timed up and go test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a chair stand test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a chair stand test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a pace test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a pace test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a grip strength test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a grip strength test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in an isokinetic muscle function test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in an isokinetic muscle function test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a single repetition maximum weight test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a single repetition maximum weight test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a maximum isometric strength test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a maximum isometric strength test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes inhibiting the decline in performance in a muscle power test. In certain embodiments, inhibiting the deterioration of clinical muscle performance includes improving the decline in performance in a muscle power test.

[0117] In certain embodiments, the inhibition of hyperglycemia is by comparing the fasting blood glucose, 2 hour blood glucose after an oral glucose tolerance test (OGTT), 2 hour blood glucose after an intraperitoneal glucose tolerance test (IPGTT), area under the curve (AUC) of the OGTT, area under the curve (AUC) of the IPGTT, or glycated hemoglobin (HbAlc) values between a subject treated with the present disclosure and a diseased subject by blood glucose measurement. In certain embodiments, a decrease in fasting blood glucose, 2 hour blood glucose after an OGTT, 2 hour blood glucose after an IPGTT, area under the curve (AUC) of the OGTT, area under the curve (AUC) of the IPGTT, or glycated hemoglobin (HbAlc) values of at least 10% is indicative of the inhibition of hyperglycemia.

[0118] In certain embodiments, inhibiting hyperglycemia comprises inhibiting increased fasting blood glucose. In certain embodiments, inhibiting hyperglycemia comprises ameliorating increased fasting blood glucose. In certain embodiments, inhibiting hyperglycemia comprises inhibiting increased blood glucose at 2 hours post OGTT. In certain embodiments, inhibiting hyperglycemia comprises ameliorating increased blood glucose at 2 hours post OGTT. In certain embodiments, inhibiting hyperglycemia comprises inhibiting increased area under the curve (AUC) of OGTT. In certain embodiments, inhibiting hyperglycemia comprises ameliorating increased area under the curve (AUC) of OGTT. In certain embodiments, inhibiting hyperglycemia comprises inhibiting increased area under the curve (AUC) of IPGTT. In certain embodiments, inhibiting hyperglycemia comprises ameliorating increased area under the curve (AUC) of IPGTT. In certain embodiments, inhibiting hyperglycemia comprises inhibiting increased glycated hemoglobin (HbAlc). In certain embodiments, inhibiting hyperglycemia comprises ameliorating increased glycated hemoglobin (HbAlc).

[0119] In certain embodiments, the inhibition of weight gain is determined by comparing the weight of a subject treated with the present disclosure to a diseased subject by weight measurement. In certain embodiments, a decrease in BMI of at least 5% indicates inhibition of weight gain.

[0120] In certain embodiments, inhibiting weight gain comprises inhibiting increased body weight. In certain embodiments, inhibiting weight gain comprises ameliorating increased body weight. In certain embodiments, inhibiting weight gain comprises inhibiting increased food intake. In certain embodiments, inhibiting weight gain comprises ameliorating increased food intake. In certain embodiments, inhibiting weight gain comprises inhibiting decreased feed conversion ratio. In certain embodiments, inhibiting weight gain comprises ameliorating decreased feed conversion ratio.

[0121] Materials and Methods Animals: Twelve-week-old male C57BL / 6J mice were purchased from the Laboratory Animal Services Centre, Chinese University of Hong Kong. The animals were housed in a temperature- and humidity-controlled room with a 12-hour light cycle and free access to food and water. The animals were randomly assigned to receive either a control diet (14.8% of calories from fat, 3002906, purchased from LabDiet) or a high-fat diet (60% of calories from fat, D12492, purchased from Research Diet) according to a dietary plan.

[0122] Intraperitoneal glucose tolerance test (IPGTT): Animals were fasted for 16 hours. A sterile 20 wt% glucose solution was injected intraperitoneally at 1% of body weight. Blood glucose levels were measured using a commercial glucometer at 0 minutes post-injection (fasting blood glucose level before injection) and 15, 30, 60, and 120 minutes. The blood glucose values were plotted against time and the total area under the curve (AUC) was measured.

[0123] Forelimb grip strength test: Animals were allowed to grip the handle of a grip strength meter and then their tails were held horizontally and pulled gently backwards. The maximum tension at which the animals released the handle was recorded as the grip strength and this value was normalized to body weight.

[0124] Ex vivo muscle function test: The active contractile capacity and passive mechanical properties of muscles were measured using an ex vivo muscle test system (1200A; Aurora Scientific Inc.) and analyzed using dynamic muscle control and analysis software (DMC v5.4; DMA v3.2; Aurora Scientific Inc.). The animals were sacrificed and the extensor digitorum longus (EDL) was isolated for a 6-step passive stretch protocol to measure the passive mechanical properties of the muscle. The gastrocnemius (GA) was isolated for active contractile capacity testing. The raw data were normalized to cross-sectional area before further analysis. The passive mechanical properties of the EDL were measured using a 6-step stretch protocol that lengthened the muscle at a rate of 2 cm / sec in increments of 10% of optimal length with 1.5 seconds of stabilization between stretches until 160% of optimal length was reached. The active contractile capacity of the GA was assessed by measuring the response to multiple 150 Hz stimuli to calculate contractile and relaxation parameters such as maximum contraction time, time to maximum force, maximum relaxation time, ½ relaxation time, specific twitch force, specific tetanic force, 5-minute fatigue recovery rate, and 10-minute fatigue recovery rate.

[0125] Immunostaining: Freshly isolated GA muscles were snap-frozen in isopentane pre-cooled with liquid nitrogen and stored at -80°C for later processing. The frozen muscles were embedded in embedding medium and sectioned at 7 microns and stored at -80°C for later staining. The frozen section samples were blocked with 2% horse serum for 1 hour at room temperature, followed by incubation with hydroxyproline, AGE, or Fn1 antibodies for 1 hour at room temperature. After washing with PBS, the samples were incubated with secondary antibodies for 1 hour at room temperature and with DAPI for 5 minutes. Image processing was performed using ImageJ software.

[0126] All patents, patent applications, provisional applications, and publications referenced or mentioned in this document are incorporated herein by reference in their entirety, to the extent not conflicting with the explicit teachings of this specification, including all drawings and tables.

[0127] The following are examples illustrating procedures for practicing the present disclosure. These examples should not be construed as limiting. Unless otherwise indicated, all percentages are by weight percent, and all solvent mixture proportions are by volume proportion.

[0128] Example 1 - Prevention of diet-related muscle structural deterioration using a thiazolium-based AGE breaker An ALT-711 solution in water was prepared in phosphate buffered saline at a concentration of 20 mg per kg body weight.

[0129] As shown in Figure 1 The animal model was fed by an intermittent high-fat diet feeding regimen.

[0130] In Phase 1, to investigate the effect of ALT-711 on diet-related muscle structural deterioration, hyperglycemia-related muscle structural deterioration, and weight gain-related muscle structural deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage.

[0131] Muscle structural changes were measured using histological staining and passive mechanics at the Week 5 (W5) and Week 16 (W16) time points.

[0132] Example 2 - Improvement of diet-related muscle functional deterioration using a thiazolium-based AGE breaker An ALT-711 solution in water was prepared in phosphate buffered saline at a concentration of 20 mg per kg body weight.

[0133] As shown in Figure 1 The animal model was fed by an intermittent high-fat diet feeding regimen.

[0134] In Phase 2, to investigate the effect of ALT-711 on diet-related muscle functional deterioration, hyperglycemia-related muscle functional deterioration, and weight gain-related muscle functional deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage.

[0135] Muscle functional changes were measured using muscle contraction and relaxation parameters at the Week 5 (W5) and Week 16 (W16) time points.

[0136] Example 3 - Improvement of diet-related muscle performance deterioration using a thiazolium-based AGE breaker An ALT-711 solution in water was prepared in phosphate buffered saline at a concentration of 20 mg per kg body weight.

[0137] As Figure 1 shown, the animal model was fed by an intermittent high-fat feeding regimen.

[0138] In Phase 1 or Phase 2, to investigate the effect of ALT-711 on diet- associated muscle performance deterioration, high blood glucose associated muscle performance deterioration, and body weight gain associated muscle performance deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage.

[0139] At week 5 (W5), week 11 (W11), and week 16 (W16) time points, muscle performance was measured using grip strength, power output, and fatigue recovery rate.

[0140] Example 4 - Reducing the extent of diet-associated body weight gain and high blood glucose using a thiazolium-based AGE breaker An ALT-711 aqueous solution was prepared in phosphate buffered saline at a concentration of 20 milligrams per kilogram of body weight.

[0141] As Figure 1 shown, the animal model was 24 months of age.

[0142] To investigate the effect of ALT-711 on age-associated muscle structural deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage for one month.

[0143] At 25 months of age time point, muscle structural changes were measured using histological staining.

[0144] Example 5 - Improving age-associated muscle structural deterioration using a thiazolium-based AGE breaker An ALT-711 aqueous solution was prepared in phosphate buffered saline at a concentration of 20 milligrams per kilogram of body weight.

[0145] As Figure 10 shown, the animal model was 24 months of age.

[0146] To investigate the effect of ALT-711 on age-associated muscle structural deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage for one month.

[0147] At 25 months of age time point, muscle structural changes were measured using histological staining.

[0148] Example 6 - Improvement of age-related muscle performance deterioration using a thiazolium-based AGE breaker An ALT-711 aqueous solution was prepared in phosphate buffered saline at a concentration of 20 mg per kg of body weight.

[0149] As shown in Figure 10 , the animal model was 24 months of age.

[0150] To study the effect of ALT-711 on age-related muscle performance deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage for one month.

[0151] At the 25-month time point, muscle performance was measured using grip strength.

[0152] Example 7 - Improvement of age-related hyperglycemia using a thiazolium-based AGE breaker An ALT-711 aqueous solution was prepared in phosphate buffered saline at a concentration of 20 mg per kg of body weight.

[0153] As shown in Figure 10 , the animal model was 24 months of age.

[0154] To study the effect of ALT-711 on age-related muscle performance deterioration, the animals were provided with this concentration of ALT-711 solution daily by oral gavage for one month.

[0155] At the 25-month time point, the degree of hyperglycemia and weight gain was measured. At the 25-month time point, food intake was measured.

[0156] It is to be understood that the embodiments and implementations described herein are for illustrative purposes only and that various modifications or changes in light thereof will be apparent to persons skilled in the art and are to be included within the purview of this application and the scope of the appended claims. Further, any and every element or limitation of any disclosure herein or of any implementation thereof can be combined with any and / or all other elements or limitations of any other disclosure herein or of any implementation thereof, and all such combinations are contemplated to be within the scope of the present disclosure and the following claims. In addition, some practice of the present disclosure can include hardware and software components.

[0157] References 1. Magliano, D.J., E.J. Boyko, and I.D.F.D.A.t.e.s. committee, IDF Diabetes Atlas, in Idf diabetes atlas. 2021, International Diabetes Federation© International Diabetes Federation, 2021.: Brussels. 2. DeFronzo, R.A. and D. Tripathy, Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care, 2009. 32 Suppl 2 (Suppl 2): p. S157-63.

Claims

1. A composition, characterized in that, include: Thiazolium-based AGE disruptors (advanced glycosylation product disruptors).

2. The composition according to claim 1, characterized in that, in, The thiazolyl-based AGE destructor has formula (I): Formula (I) Wherein, R1 is phenyl or benzyl alcohol; R2 is either methyl or hydrogen; and R3 is a methyl or hydrogen group.

3. The composition according to claim 2, characterized in that, in: R1 is phenyl, R2 is methyl, and R3 is methyl; R1 is a phenyl group, R2 is a hydrogen group, and R3 is a hydrogen group; or R1 is benzyl alcohol, R2 is methyl, and R3 is hydrogen.

4. The composition according to claim 2, characterized in that, in, The thiazolyl-based AGE destructor is ALT-711, which is based on formula (II): Equation (II) 。 5. The composition according to claim 1, characterized in that, in, The concentration of the thiazolyl-based AGE destroyer is from about 0.1 mg / kg body weight to 50 mg / kg body weight.

6. The composition according to claim 1, characterized in that, Also includes: At least one carrier or excipient.

7. The composition according to claim 6, characterized in that, in, The carrier or excipient is phosphate-buffered saline.

8. The composition according to claim 1, characterized in that, Also includes: Metformin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, GLP-1 analogs, gastric inhibitory peptide (GIP), dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones, sulfonylureas, insulin, or any combination thereof.

9. A method for treating muscle structural or functional deterioration in a subject, characterized in that, Includes: a composition comprising an effective dose of a thiazolyl-based AGE destroyer.

10. The method according to claim 9, characterized in that, in, The thiazolyl-based AGE destructor has formula (I): Formula (I) Wherein, R1 is phenyl or benzyl alcohol; R2 is either methyl or hydrogen; and R3 is a methyl or hydrogen group.

11. The method according to claim 10, characterized in that, in: R1 is phenyl, R2 is methyl, and R3 is methyl; R1 is a phenyl group, R2 is a hydrogen group, and R3 is a hydrogen group; or R1 is benzyl alcohol, R2 is methyl, and R3 is hydrogen.

12. The method according to claim 10, characterized in that, in, The thiazolyl-based AGE destructor is ALT-711, which is based on formula (II): Equation (II) 。 13. The method according to claim 9, characterized in that, in, The concentration of the thiazolyl-based AGE destroyer is from about 0.1 mg / kg body weight to 50 mg / kg body weight.

14. The method according to claim 9, characterized in that, in, The composition further includes at least one carrier or excipient.

15. The method according to claim 14, characterized in that, in, The carrier or excipient is phosphate-buffered saline.

16. The method according to claim 9, characterized in that, in, The composition further includes metformin, SGLT-2 inhibitors, GLP-1 receptor agonists, GLP-1 analogs, GIP, DPP-4 inhibitors, thiazolidinediones, sulfonylureas, insulin, or any combination thereof.

17. The method according to claim 9, characterized in that, in, The deterioration of muscle structure or function was associated with hyperglycemia or weight gain in the subject.

18. The method according to claim 9, characterized in that, in, The aforementioned deterioration of muscle structure or function refers to deterioration of skeletal muscle structure or function.

19. The method as described in claim 9, characterized in that, in, The composition is applied at least once every 7 days.

20. The method according to claim 19, characterized in that, in, The composition is applied at least once a day.

21. The method according to claim 9, characterized in that, in, The subjects were primates or rodents.

22. The method according to claim 9, characterized in that, Also includes: The methods include reducing the subject's calorie intake, subjecting the subject to timed eating, subjecting the subject to endurance training, subjecting the subject to weight training, improving the subject's feed conversion ratio, or any combination thereof.

23. The method according to claim 9, characterized in that, Also includes: Administer metformin, SGLT-2 inhibitors, GLP-1 receptor agonists, GLP-1 analogs, GIP, DPP-4 inhibitors, thiazolidinediones, sulfonylureas, insulin, or any combination thereof.

24. The method according to claim 9, characterized in that, in, Treatment of the subject's muscle structure or functional deterioration includes: inhibiting skeletal muscle stiffness, inhibiting the upregulation of skeletal muscle ultimate strength, inhibiting the upregulation of skeletal muscle viscoelasticity, inhibiting the upregulation of skeletal muscle stress-relaxation rate, inhibiting intramuscular collagen accumulation, inhibiting intramuscular fibronectin accumulation, inhibiting intramuscular elastin accumulation, inhibiting intramuscular core proteoglycan accumulation, inhibiting intramuscular hyaluronic acid accumulation, inhibiting intramuscular dialdehyde AGE precursor accumulation, inhibiting intramuscular non-crosslinked-nonfluorescent AGE accumulation, inhibiting intramuscular non-crosslinked-fluorescent AGE accumulation, inhibiting intramuscular crosslinked-nonfluorescent AGE accumulation, inhibiting intramuscular crosslinked-fluorescent AGE accumulation, or any combination thereof.

25. The method according to claim 17, characterized in that, in, Treatment of skeletal muscle performance deterioration induced by hyperglycemia or weight gain includes: inhibiting downregulation of time to reach maximum strength, inhibiting upregulation of maximum contraction rate, inhibiting upregulation of half-relaxation time, inhibiting downregulation of maximum relaxation rate, inhibiting downregulation of twitching force, inhibiting downregulation of specific twitching force, inhibiting downregulation of tetanic contraction force, inhibiting downregulation of specific twitching force, inhibiting decrease in fatigue resistance, inhibiting decrease in performance in timed stand-up walking tests, inhibiting decrease in performance in chair stand tests, inhibiting decrease in performance in gait tests, inhibiting decrease in performance in grip strength tests, inhibiting decrease in performance in isokinetic muscle function tests, inhibiting decrease in performance in single-repetition maximum weight tests, inhibiting decrease in performance in maximum isometric strength tests, inhibiting decrease in performance in muscle power tests, or any combination thereof.

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