Pentadecanoylcarnitine for the treatment of conditions related to the quality of aging and longevity

Abstract

Aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety and anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric diseases and conditions, metabolic disorders, migraine, nasal and sinus congestion, nausea, neuropathic pain associated with multiple sclerosis and multiple sclerosis. Administration of pentadecanoylcarnitine or pentadecanoic acid is provided for the prevention, management or treatment of symptoms of chronic kidney disease, neurological and neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavior problems associated with Tourette's syndrome, as well as to support appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, social and metabolic, hematology, renal, and weight loss.

Description

[Technical field]

[0001] STATEMENT ON FEDERALLY SUPPORTED R&D The U.S. Government has certain rights in this invention under ONR SBIR Agreement No. N00014-21-9-0002.

[0002] Administration of pentadecanoylcarnitine or pentadecanoic acid has been shown to be effective in treating aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety and anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric diseases and conditions, metabolic disorders, migraine, and nasal and sinus congestion. , nausea, neuropathic pain and symptoms associated with multiple sclerosis, neurological and neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavior problems associated with Tourette's syndrome; and for assistance with appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, social and metabolic, hematology, renal, and weight loss. [Background technology]

[0003] Carnitine is an amino acid present in food, primarily of animal origin, but it can also be made endogenously. L-carnitine is the bioavailable and bioactive isomer. Carnitine is found almost entirely within cells, where it can shuttle long-chain fatty acids as long-chain acylcarnitines to mitochondria, thereby enabling beta-oxidation-generated energy for cellular activity. Summary of the Invention [Problem to be solved by the invention]

[0004] Aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety and anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial rash associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric diseases and conditions, metabolic disorders, migraine, nasal and sinus congestion, nausea, neurological disorders associated with multiple sclerosis Compositions and methods are provided for the prevention, management or treatment of chronic pain and symptoms of multiple sclerosis, neurological and neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcer, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavior problems associated with Tourette's syndrome; and for the support of appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, social and metabolic, hematology, kidney, and weight loss.These compositions include pentadecanoylcarnitine or pentadecanoic acid, or salts thereof, which can be administered in combination with other medicaments or as part of various treatment regimens described herein.The compositions provided are effective in modulating the markers described herein.Methods are provided for administering the compositions. [Means for solving the problem]

[0005] Thus, in a first aspect which is generally applicable (i.e. which can be combined independently with any of the aspects or embodiments identified herein), there is provided a pharmaceutical composition comprising: pentadecanoylcarnitine or pentadecanoic acid; and a pharma- ceutically acceptable carrier.

[0006] In one embodiment of the first aspect (ie, which can be combined independently with any of the aspects or embodiments specified herein), the composition is in unit dosage form.

[0007] In one embodiment of the first aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the pharmaceutical composition is configured to administer to a patient between 2.5 mg and 50 mg of pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutical acceptable salt thereof, per kg of body weight.

[0008] In one embodiment of the first aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the pharmaceutical composition is configured for administration once daily.

[0009] In one embodiment of the first aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the pharmaceutical composition comprises 0.01 mg to 10,000 mg of pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt thereof.

[0010] In a second aspect of general applicability (i.e. which can be combined independently with any of the aspects or embodiments specified herein), there is provided the use of a pharmaceutical composition of the first aspect, or any embodiment thereof, in the manufacture of a medicament for the treatment or prevention of a condition as described herein.

[0011] In one embodiment of the second aspect (i.e. which can be combined independently with any of the aspects or embodiments identified herein), the use is in the manufacture of a medicament for the treatment or prophylaxis of a condition described herein.

[0012] In one embodiment of the second aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the pharmaceutical composition is configured to modulate a marker of an age-associated condition described herein or a symptom of a condition described herein.

[0013] In one embodiment of the second aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the marker for a condition related to the indication herein is selected from the group consisting of serum or plasma pentadecanoylcarnitine concentration, erythrocyte index (i.e., hemoglobin, red blood cells), serum or plasma cholesterol, triglycerides, insulin, glucose, gamma-glutamyl peptidyltransferase, ferritin, or iron.

[0014] In a third aspect of general applicability (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the pharmaceutical composition is configured to increase serum, red blood cell, or tissue concentrations of pentadecanoylcarnitine to between 0.2 μM and 20 μM.

[0015] In one embodiment of the third aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), pentadecanoylcarnitine or a pharma- ceutically acceptable salt thereof is provided as a pharmaceutical composition in unit dosage form.

[0016] In one embodiment of the third aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the unit dosage form contains 0.01 mg to 10,000 mg of pentadecanoylcarnitine.

[0017] In one embodiment of the third aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the pharmaceutical composition further comprises a plurality of different small molecule metabolites as described herein.

[0018] In one embodiment of the third aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), 2.5 mg to 50 mg of pentadecanoylcarnitine or a pharma- ceutically acceptable salt thereof is administered to a patient per kg of body weight per day.

[0019] In one embodiment of the third aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), pentadecanoylcarnitine or a pharma- ceutically acceptable salt thereof is administered to the patient once daily.

[0020] In one embodiment of the third aspect (i.e., which can be independently combined with any of the aspects or embodiments identified herein), the serum, tissue, or red blood cell membrane concentration of pentadecanoylcarnitine is increased to between 1.25 and 6-fold above the patient's baseline level, thereby achieving a concentration of between 0.5 μM and 20 μM.

[0021] In a fourth aspect of general applicability (i.e., which can be combined independently with any of the aspects or embodiments identified herein), the present invention provides a method for the treatment of a variety of conditions, including but not limited to aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety and anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric diseases and conditions, metabolic disorders, Uses of pentadecanoylcarnitine or pentadecanoic acid are provided to prevent, manage or treat migraine headaches, nasal and sinus congestion, nausea, neuropathic pain and symptoms associated with multiple sclerosis, neurological and neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavioral problems associated with Tourette's syndrome; and to support appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, social and metabolic, hematology, kidneys, and weight loss.

[0022] In a fifth aspect of general applicability (i.e. which can be combined independently with any of the aspects or embodiments specified herein), there is provided a composition substantially as described herein.

[0023] In a sixth aspect of general applicability (i.e. which can be combined independently with any of the aspects or embodiments specified herein), there is provided a composition substantially as described herein.

[0024] In a seventh aspect of general applicability (i.e. which can be combined independently with any of the aspects or embodiments specified herein), there is provided a use substantially as described herein. [Brief description of the drawings]

[0025] [Figure 1A] FIG. 1A shows that serum pentadecanoic acid (C15:0) concentrations increased within one month of the modified fish diet maintained for six months.

[0026] [Figure 1B] FIG. 1B shows increased pentadecanoylcarnitine concentrations within one month in modified fish diets maintained for six months. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Compositions comprising pentadecanoylcarnitine or pentadecanoic acid and methods for treating aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety and anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, high blood pressure, impulsivity, inflammation, psychiatric diseases and conditions, metabolic disorders, migraine headaches, nasal and sinus sacs Treatment of conditions including blood clots, nausea, neuropathic pain and symptoms associated with multiple sclerosis, neurological and neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavioral problems associated with Tourette's syndrome; and related methods for supporting appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, social and metabolic, hematology, renal, and weight loss are provided.

[0028] Aging is accompanied by chronic, low-grade inflammation characterized by increased circulating levels of proinflammatory cytokines, neutrophils, and increasingly activated macrophages. This proinflammatory state is a significant risk factor for older people, both for morbidity and mortality (Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol Ser A 69:S4-S9). People living at least 100 years are unlikely to have developed age-related proinflammatory states, further supporting that chronic, low-grade inflammation impairs quality and persistence of life (Vasto S, Candore G, Balistreri M, Colonna-Romano G, Grimaldi MP, Listi F et al. (2007) Inflammatory networks in ageing, age-related diseases, and longevity. Mech Ageing and Dev 128:83-91). Thus, it has been proposed that therapeutic interventions to reduce age-related inflammation could concomitantly treat multiple age-related diseases, resulting in improved quality of life and extended lifespan.

[0029] As people age, the prevalence of anemia can increase dramatically. A comparison of populations aged 40, 60, 80, 90, and 100 years (total n=1,980) had the following prevalence of anemia: 16.1%, 19.1%, 41.1%, 46.2%, and 57.1% (Zhai Y, Yin ZX, Xu JW, Liu YZ, Shi XM (2010) Anemia status and its relevant factors among elderly people aged above 80 years old in longevity areas in China. Chinese J of Prev Med 44:115-118). The presence of anemia and low hemoglobin concentration increased the risk of 3-year mortality by 25% and reduced life expectancy among older people (Lyu Y, Yin Z, Luo J, Shi X, Zeng Y (2015) Zhonghua Liuxingbingxue Zazhi, 36:682-686). Measures to prevent and treat anemia in aging are expected to improve quality of life and extend life expectancy.

[0030] Elevated cholesterol with aging can have a negative impact on quality of life or longevity (Kriesberg RA and Kasim S (1987) Cholesterol metabolism and aging, Am J Med, 82:54-60). Elevated cholesterol, especially elevated low-density lipoprotein (LDL) cholesterol, has been identified as an underlying cause or contributor to cardiovascular diseases, including atherosclerosis, which also increase in prevalence with age. Lower cholesterol levels, especially for people under 50 years of age, are associated with improved longevity (Anderson KM, Castelli WP, Levy D (1987) Cholesterol and mortality: 30 years of follow-up from the Framingham Study JAMA, 257:2176-2180). Similarly, triglyceride levels can be a major factor for predicting human longevity, with lower triglyceride levels present in longer-lived families compared to controls (Vaarhorst AAM, Beekman M, Suchiman EHD, van Heemst DV, Houwing-Duistermaat JJ, Westerndorp RG, et al. (2010) Lipid metabolism in long-lived families: the Leiden Longevity Study. AGE, 33:219-227). It is emphasized that prevention and treatment of dyslipidemia are important for improving quality of life and extending life span.

[0031] Prediabetic and diabetic conditions, including hyperglycemia and insulin resistance, result in loss of quality and years of life. From 1999 to 2011, the average number of years lost due to diabetes increased by 46% in men and 44% in women (Gregg EW, Zhuo X, Cheng YJ, Albright AL, Narayan KMV, Thompson TJ (2014) Trends in lifetime risk and years of life lost due to diabetes in the USA, 1985-2011: A modelling study. Lancet Diab Endocrinol 2:867-874). Insulin resistance increases with age, and centenarians have lower insulin resistance compared to younger people (Paolisso G, Barbieri M, Rizzo MR, Carella C, Rotondi M, Bonafe M et al. (2001) Low insulin resistance and preserved β-cell function contribute to human longevity but are not associated with TH-INS genes. Exp Gerontol, 37:147-156). Treatments including metformin, which have been used for many years to treat type 2 diabetes, have been demonstrated to extend lifespan (Novelle MG, Ali A, Dieguez C, Bernier M, de Cabo R (2016) Metformin: A hopeful promise in aging research. CSH Perspectives, 6:a025932), and there are active efforts to discover other compounds that may help treat hyperglycemia and insulin resistance and extend lifespan.

[0032] The prevalence of chronic liver disease and associated cirrhosis and hepatocellular carcinoma has been increasing at an alarming rate, especially in developed countries. This increase is mainly due to nonalcoholic fatty liver disease (NAFLD) associated with the worldwide rise in obesity and metabolic syndrome (including elevated glucose, dyslipidemia, and insulin resistance). Chronic liver disease is a cause of morbidity and mortality, and therapeutic agents against liver disease can improve quality of life and extend lifespan by targeting to reduce liver failure, transplantation, and cancer (Lim YS, Kim WR (2008) The global impact of hepatic fibrosis and end-stage liver disease. Clinics in Liver Dis, 12:733-746).

[0033] Aging-related iron overload and hyperferritinemia may have a negative impact on quality of life or longevity. With age, iron accumulates in tissues, including the brain (Hirose W, Ikematsu K, and Tsuda R (2003) Age-associated increases in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Legal Med 5:S360-366). Because iron induces oxidative damage to tissues and leads to age-related diseases, such as Alzheimer's disease, compounds that reduce iron overload and hyperferritinemia have been proposed as therapeutic targets for age-related diseases (Bartzokis G, Tishler TA, Lu PH, Villablanca P, Altshuler LL, Carter M et al. (2007) Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Neurobiol Aging 28:414-423).

[0034] Skin aging and poor wound healing can negatively impact quality of life. Aging skin has structural and functional changes that interfere with its integrity and healing ability (Farage MA, Miller KW, Elsner P, Maiba ch HI (2013) Characteristics of the aging skin. Adv Wound Care 2: doi:10.1089). Compounds that prevent or correct the intrinsic age-related changes that affect skin integrity and repair can help improve quality of life.

[0035] With regard to aging and pain, more than half of people over the age of 65 report having bothersome pain, most of whom have pain in multiple locations and at least two chronic medical conditions, such as arthritis, cardiometabolic disease, and obesity (Patel KV et al. (2013) Prevalence and impact of pain among older adults in the United States: Findings from the 2011 National Health and Aging Trends Study. Pain 154:2649-2657). Thus, anti-inflammatory agents, analgesics, and compounds that attenuate cardiometabolic disease may help relieve pain, including pain associated with aging. As one example, compounds that reduce prostaglandin E2 (PGE2) can help reduce inflammation, pain, and fever, including pain caused by osteoarthritis (Lee AS et al. (2013), A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527:440-447). Other compounds that reduce inflammation associated with autoimmune diseases, such as rheumatoid arthritis, can attenuate joint inflammation and pain. As an example, interleukin-17A (IL-17a) is an important factor in autoimmune diseases, including multiple sclerosis and rheumatoid arthritis, and compounds that reduce IL-17A can help relieve pain from rheumatoid arthritis (Iwakura Y et al. (2008), The roles of IL-17A inflammatory immune responses and host defense against pathogens. Immunol Rev 226:). In addition, compounds that reduce chronic systemic inflammation associated with aging and cardiometabolic diseases can attenuate these diseases and the pain associated with them.

[0036] With regard to aging and allergies, allergies are one of the fastest growing health problems in people over 15 years of age, with 5%-10% of allergies affecting older people (Martinis MD et al. (2017), Allergy and aging: an old / new emerging health issue. Aging and Dis 8:162-175). Older people may be at higher risk for allergies due to aging, co-occurring diseases, multiple drug therapies, and physiological changes in systems including skin, gastrointestinal, and respiratory disorders. Interleukin-17A (IL-17a) is an important factor in allergic responses, including systemic and skin hypersensitivity and allergic airway inflammation (Iwakura Y et al. (2008) The roles of IL-17A inflammatory immune responses and host defense against pathogens. Immunol Rev 226). Thus, compounds that reduce allergic responses, including reducing IL-17A, can improve the quality of life for people, including older people.

[0037] Regarding aging and sleep disorders, sleep problems have been reported that affect up to 40% of the elderly population (Vitiello MV (1997) Sleep disorders and aging: understanding the causes. J Gerontol 52A: M189-M191). This high prevalence is due, in part, to physiological changes due to aging, and to the presence of chronic diseases. Control of chronic conditions, e.g., pain, has been demonstrated to improve sleep quality and resolve insomnia (Monjan A and Foley D (1996) Incidence of chronic insomnia associated with medical and psychosocial factors: an epidemiologic study among older persons. Sleep Res 25: 108). Despite growing concerns about the use of benzodiazepines and other sedatives, especially among the elderly, people over 60 years of age are more likely to receive prescriptions for sedatives compared to those aged 40-59 (Baum C et al. (1986) Drug utilization in the US-1985: Seventh annual review. Rockville, MD: Food and Drug Administration, Center for Drugs and Biologies). Thus, the use of natural compounds that can help alleviate underlying medical conditions that affect sleep can be used as a first-line means of improving sleep and quality of life. As a potential alternative to sedatives, PGE2 inhibitors (which can be used to reduce inflammation, pain and fever) can also help stave off the role of PGE2 in stimulating the wakefulness center near the posterior hypothalamus (Hayaishi O (1991) Molecular mechanisms of sleep-wake regulation: roles of prostaglandins D2 and E2. FASEB J 5: pp. 2575-2581).

[0038] With regard to aging and gastrointestinal and / or digestive disorders, aging affects normal digestion, resulting in disorders associated with sensation, inflammation, poor swallowing, imbalanced microbiome, malabsorption, and malnutrition (Shamburek RD and Farrar JT (1990), Disorders of the digestive system in the elderly. New Engl J Med, 322:438-443). People over 65 years of age represent 25% of all inflammatory bowel disease hospitalizations, and older age is a significant risk factor for increased mortality and more severe gastrointestinal disease compared to younger patients (Ananthakrishnan AN et al. (2009), Inflammatory bowel disease in the elderly is associated with worse outcomes: a national study of hospitalizations. Inflamm Bowel Dis, 15:182-289). Compounds that reduce gastrointestinal inflammation, restore a balanced microbiome, and / or improve proper absorption of nutrients may help alleviate digestive disorders. Interleukin-17A (IL-17A) is a factor in chronic intestinal inflammation, and reducing IL-17A secretion may help alleviate digestive disorders (Coccia M et al. (2012) IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J Exp Med, 209:1595).

[0039] With regard to ageing and skin conditions and / or wound healing, being older may impair wound healing (Sgnoc R and Gruber J (2013). Age-related aspects of cutaneous wound healing: a mini review. Gerontol, 59:159-164). This impairment may be due to a chronic inflammatory state that appears with age, including increases in cytokines such as IL-6, and chemokines such as CXCL8 (also called interleukin 8 (IL-8)), which is elevated in psoriasis. There are some differences in wound healing in fetuses and elderly people, which may be beneficial. For example, fetal and elderly wounds heal with no to little scarring, respectively. This scarless repair may be due to lower levels of decorin and IL-8, extracellular matrix proteoglycans and chemokines, respectively, observed in fetal tissues (Beanes SR et al. (2001) Down-regulation of decorin, a transforming growth factor-beta modulator, is associated with scarless fetal wound healing. J Pediatr Surg 36:1666-71; Liechty KW (1997) Diminished interleukin-8 (IL-8) production in the fetal wound healing response. J Surg Res 77:80-84). Thus, lower levels of IL-6, IL-8, and decorin may help stave off the inflammation associated with chronic, non-healing wounds, allowing this healing to occur with minimal scarring.

[0040] Carnitine is an amino acid that is present in foods, primarily foods of animal origin, but carnitine can also be made endogenously (Kendler BS. Carnitine: an overview of its role in preventive medicine. Prev Med, 15:373-390 (1986)). L-carnitine is the bioavailable and bioactive isomer (Rebouche C J. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann NY Acad Sci, 1033:30-41 (2004)) and L-carnitine supplementation has demonstrated health benefits related to neurological disorders, cardiovascular disease, and obesity (Flanagan, JL, Simmons, PA, Vehige, J., Wilcox, MDP, Garrett, Q. Role of carnitine in disease. Nutr Metabol, 7:30 (2010); Indiveri, C., Iacobazzi, V., Tonazzi, A., Giangregorio, N., Infantino, V., Convertini, P. et al. The mitochondrial carnitine / acylcarnitine metabolism. carrier:function, structureandphysiopathology.Mol Asp Med 32:223~233 (2011)).

[0041] Carnitine is found almost universally within cells, where it can shuttle long-chain fatty acids as long-chain acylcarnitines to mitochondria, thereby enabling beta-oxidation-generated energy for cellular activity (Flanagan, JL, Simmons, PA, Vehige, J., Wilcox, MDP, Garrett, Q., Role of carnitine in disease. Nutr Metabol 7:30 (2010)).Higher circulating concentrations of long-chain acylcarnitines are associated with a higher risk of age-related diseases, including inflammation, mitochondrial dysfunction, cardiovascular disease, type 2 diabetes, and osteoarthritis (Jarrell, ZR, Smith, MR, Hu, X., Orr, M., Liu, KH, Quyyumi, AA, et al., Plasma acylcarnitine levels increase with healthy aging. Aging 12:13555-13570 (2020); Kalim, S., Clish, CB, Wenger, J., Elmariah, S., Yeh, RW, et al., A plasma long-chain acylcarnitine predicts cardiovascular morality in incident dialysis patients. J Am Heart Assoc 2:e000542 (2013); Koh, A.S., Gao, F., Liu, J., Fridianto, KT, Ching, J., Tan, R.S., et al., Metabolomic profile of arterial stiffness in aged adults.Diab Vasc Dis Res, 15:74~80 pages (2018), Kendler BS.Carnitine:an overview of its role in preventive medicine.Prev Med, 15:373~390 pages (1986), Bouchouirab et al. Plasma Palmitoyl-Carnitine(AC16:0), Is a Marker of Increased Postprandial Nonesterified Incomplete Fatty Acid Oxidation Rate in Adults With Type 2 Diabetes, Can J Diabetes, August 2018;42(4):382–388.e1.doi:10.1016 / j.jcjd.2017.09.002.Epub November 9, 2017 Tootsi, K., Kals, J., Zilmer, M., Paapstel, K., Ottas, A., Martson, A., Medium- and long-chain acylcarnitines are associated with osteoarthritis severity and arterial stiffness in End-stage osteoarthritis patients: a case-control study. Int J Rheum Dis, 21:1211–1218 (2018)).

[0042] While long-chain acylcarnitines have been shown to increase with age, short- and odd-medium-chain acylcarnitines, particularly those containing C5:0, C7:0, and C9:0, decrease with age; this decrease with age was not noted for the odd-long-chain acylcarnitines, e.g., C15:0 and C17:0 (Jarrell et al., Plasma acylcarnitine levels increase with healthy aging, Aging (Albany NY). 2020 July 15;12(13):13555-13570).

[0043] Pentadecanoic acid (C15:0) is an odd-chain saturated fatty acid present at trace levels in dairy fats, as well as in some types of plants and fish (Jenkins, B. et al., A review of odd-chain fatty acid metabolism and the role of pentadecanoic acid(C15:0) and heptadecanoic acid(C17:0) in health and disease. Molecules, 20:2425-2444 (2015)). Large, prospective cohort studies have repeatedly shown that higher blood levels of pentadecanoic acid are associated with a lower risk of developing chronic diseases, including type 2 diabetes, cardiovascular disease, and heart failure (Forouhi, N. G. et al., Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: the EPIC-InterAct case-cohort study. Lancet Diab Endocrinol 14:70146-9 (2014); Trieu, K. et al., Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis. PLoS Med 18:e1003763 (2021); Djousse, L. et al., Serum individual nonesterified fatty acids and risk of heart failure in older adults. Cardiology, 146:351-358 (2021)).Higher dietary intake and circulating concentrations of pentadecanoic acid are also associated with lower mortality and longer life spans (Zhuang, P., Cheng, L., Wang, J. & Zhang Y., Saturated fatty acid intake is associated with total mortality in a nationwide cohortstudy. J Nutrition, 149:68-77 (2019); Trieu et al., 2021, Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis, PLOS Medicine, Published: September 21, 2021, https: / / doi.org / 10.1371 / journal.pmed.1003763; Manca, C., Carta, G, Murru, E., Abolghasemi A, et al., Circulating fatty acids and endocannabiniodome-related mediator profiles associated to human longevity. GeroSci https: / / doi.org / 10.1007 / s11357-021-00342-0(2021)).

[0044] Pentadecanoic acid is a dual, partial peroxisome proliferator-activated receptor (PPAR) α / δ agonist and AMP-activated protein kinase (AMPK) activator with demonstrated ability to restore mitochondrial function, improve red blood cell membrane stability, and reduce breast cancer cell proliferation (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep, 10:8161 (2020); Fu, WC et al., Pentadecanoic acid promotes sbasal and insulin-stimulated glucose uptake in C2C12 myotubes. Food Nutr Res 65:10.29219 / fnr. Volume 65, page 4527 (2021); To, NB, Nguyen, YT, Moon, JY, Ediriweera, MK, Cho, SK, Pentadecanoic acid, an odd-chain fatty acid, suppresses the stemness of MCF-7 / SC human breast cancer stem-like cells through JAK2 / STAT3 signaling. Nutrients 12:1663 (2020)). In human cell lines mimicking various pathologies, pentadecanoic acid has both anti-inflammatory and anti-fibrotic properties (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep, 10:8161 (2020)).Additionally, diet-induced obese mice modeling type 2 diabetes were supplemented with oral pentadecanoic acid daily for approximately 12 weeks and demonstrated lower glucose, cholesterol, weight gain, and proinflammatory cytokines compared to non-supplemented controls (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep, 10:8161 (2020)).

[0045] In an in vivo model of nonalcoholic fatty liver disease, daily pentadecanoic acid supplementation for 11 weeks also lowered inflammation, cholesterol, and triglycerides and attenuated anemia and liver fibrosis (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep 10:8161 (2020)). Pentadecanoic acid has been proposed as an essential fatty acid because 1) it is an established dietary fatty acid that is not readily produced in the body, 2) its reduced bodily levels are repeatedly associated with poor cardiometabolic and liver health, and 3) it has demonstrated beneficial and pleiotropic activities directly related to cardiometabolic and liver health (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep 10:8161 (2020)).

[0046] Bottlenose dolphins (Tursiops truncatus) are long-lived, large-brained mammals that develop similar chronic, age-related conditions as humans, including metabolic syndrome, chronic inflammation, nonalcoholic fatty liver disease, and Alzheimer's disease (Gunn-Moore, D., Kaidanovich-Beilin, O., Iradi, M. C. G., Gunn-Moore, F., Lovestone, S., Alzheimer's disease in humans and other animals: A consequence of post reproductive life span and longevity rather than aging. Alz Dementia 14: pp. 195-204 (2018); Venn-Watson, S., Smith, C. R., Gomez, F., Jensen, E. D., Physiology of aging among healthy, older bottlenose dolphins (Tursiops truncatus): comparisons with aging humans. J Comp Physiol 181:667-680 (2011), Venn-Watson, S., Benham, C., Carlin, K., DeRienzo, D., St. Leger, J., Hemochromatosis and fatty liver disease: building evidence for insulin resistance in bottlenose dolphins (Tursiops truncatus). J Zoo Wildlf Med 43:10.1638 pages (2012), Venn-Watson, S., Smith, CR, Stevenson, S., Parry, C., Daniels, R., Jensen, E. et al. Blood-based indicators of insulin resistance and metabolic syndrome in bottlenose dolphins (Tursiops truncatus). Front Endocrinol:10.3389 pages (2013)).Similar to humans, dolphins with higher circulating concentrations of odd-chain saturated fatty acids are at lower risk of metabolic syndrome and liver disease. Feeding dolphins a diet modified with fish containing higher levels of odd-chain saturated fats, including C15:0 and C17:0, resulted in a shift in the serum metabolome, lower insulin and cholesterol, and attenuation of anemia (Venn-Watson, S., Baird, M., Novick, B., Parry, C., Jensen, E. D., Modified fish diet shifted serum metabolome and alleviated chronic anemia in bottlenose dolphins (Tursiops truncatus): Potential role of odd-chain saturated fatty acids. PLoS ONE doi10.1371 / journal.pone.0230769 (2020)).

[0047] A particular object of the embodiments is to provide a composition comprising pentadecanoylcarnitine or pentadecanoic acid for use in achieving a pentadecanoylcarnitine body concentration of about 1 μM to 20 μM in a subject. Body concentration can include, but is not limited to, any in vivo concentration, including blood concentration, plasma concentration, or other body fluid concentration. Certain aspects of the embodiments are directed to the treatment of aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety and anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric diseases and conditions, metabolic disorders, migraine headaches, nasal and sinus congestion, nausea, neuropathic pain associated with multiple sclerosis and symptoms of multiple sclerosis. , neurological and neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavior problems associated with Tourette's syndrome; and compositions comprising pentadecanoylcarnitine or pentadecanoic acid for use in the treatment of one or more conditions selected from the group consisting of cerebrovascular disease, chronic encephalopathy, rheumatoid arthritis, and cerebrovascular disorders, neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics and behavior problems associated with Tourette's syndrome; and for supporting appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, social and metabolic, hematology, kidney, and weight loss.

[0048] A particular object of the embodiment is to provide a method for detecting protective and risk factors against the conditions provided herein, including, but not limited to, inflammation, anemia, hyperglycemia, dyslipidemia, hyperinsulinemia, liver disease, iron overload, loss of skin integrity, wound healing, scarring, pain, allergies, sleep disorders and problems, and gastrointestinal disorders and problems, and other related conditions, in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for treating conditions, including, but not limited to, conditions associated with aging that affect quality or life span, in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for detecting conditions, including, but not limited to, conditions associated with aging that affect quality or life span, in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for increasing serum, plasma, or red blood cell membrane levels of pentadecanoylcarnitine in mammalian subjects, such as companion animals and humans. A particular object of the embodiments is to provide a pentadecanoylcarnitine or pentadecanoic acid supplement or treatment prescription for treating or preventing conditions, including but not limited to those disclosed herein. A particular object of the embodiments is to provide a method for detecting and / or treating the conditions disclosed herein in mammalian subjects, such as companion animals and humans, which is easily accomplished in a cost-effective manner.

[0049] Certain objects of the embodiments are to provide methods for modulating markers of conditions disclosed herein in mammalian subjects, such as companion animals and humans. Certain objects of the embodiments are to provide methods for detecting conditions disclosed herein in mammalian subjects, such as companion animals and humans. Certain objects of the embodiments are to provide methods for treating conditions disclosed herein in mammalian subjects, such as companion animals and humans. Certain objects of the embodiments are to provide methods for preventing conditions disclosed herein in mammalian subjects, such as companion animals and humans. Certain objects of the embodiments are to provide methods for preventing certain conditions provided herein in mammalian subjects, such as companion animals and humans.

[0050] A particular object of the embodiment is to provide a method for increasing pentadecanoylcarnitine in serum, plasma, or red blood cell membrane of mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for detecting or treating the conditions disclosed herein in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a pentadecanoylcarnitine supplement that is substantially free of other small molecule metabolites in mammalian subjects, such as companion animals and humans.

[0051] A particular object of the embodiment is to provide a method for detecting and treating the conditions disclosed herein in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide pentadecanoylcarnitine or pentadecanoic acid for treating the conditions disclosed herein in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for the prophylaxis of the conditions disclosed herein in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for detecting or treating the conditions disclosed herein in mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide pentadecanoylcarnitine as a supplement for treating the conditions disclosed herein in, for example, companion animals and humans.

[0052] A particular object of the embodiment is to provide pentadecanoylcarnitine or pentadecanoic acid in a bioavailable form to mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide pentadecanoylcarnitine or pentadecanoic acid to mammalian subjects, such as companion animals and humans, together with one or more other small biochemicals as described herein.A particular object of the embodiment is to provide a method for increasing small pentadecanoylcarnitine or pentadecanoic acid in the serum of mammalian subjects, such as companion animals and humans.A particular object of the embodiment is to provide a method for changing the concentration of pentadecanoylcarnitine or pentadecanoic acid as described herein in the serum, plasma, or red blood cell membrane of mammalian subjects, such as companion animals and humans.

[0053] One or more of the above objectives are provided or achieved by the various compositions, methods, and uses described herein. definition

[0054] The term "alcohol," as used herein, is used broadly and is to be given its ordinary and customary meaning to those of skill in the art (and is not to be limited to any special or customized meaning) and refers, without limitation, to any compound described herein that incorporates one or more hydroxy groups or that has been substituted or functionalized to contain one or more hydroxy groups.

[0055] The term "short chain fatty acid," as used herein, is used broadly and is to be given its ordinary and customary meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to fatty acids having from 2 to 6 carbon atoms.

[0056] The term "medium chain fatty acid," as used herein, is used broadly and is to be given its ordinary and accustomed meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to fatty acids having between 7 and 12 carbon atoms.

[0057] The term "long chain fatty acid," as used herein, is used broadly and is to be given its ordinary and customary meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to fatty acids having from 13 to 22 carbon atoms.

[0058] The term "very long chain fatty acid," as used herein, is used broadly and is intended to be given its ordinary and customary meaning to those of skill in the art (and is not intended to be limited to any special or customized meaning), and refers, without limitation, to fatty acids having 23 or more carbon atoms.

[0059] The term "derivative", as used herein, is used broadly and is to be given its ordinary and customary meaning to those of skill in the art (not limited to any special or customized meaning) and refers, without limitation, to any compound described herein that incorporates or has been substituted or functionalized to include one or more derivative groups. Derivatives include, but are not limited to, esters, amides, anhydrides, acid halides, thioesters, phosphates, triphosphates, and beta-sulfenyl derivatives.

[0060] The term "hydrocarbon," as used herein, is used in the broad sense and is to be given its ordinary and customary meaning to those of skill in the art (not limited to any special or customized meaning), and refers, without limitation, to any moiety that contains only carbon and hydrogen atoms. A functionalized or substituted hydrocarbon moiety has one or more substituents as described elsewhere herein.

[0061] The term "lipid", as used herein, is used in a broad sense and is to be given its ordinary and customary meaning to those of skill in the art (and is not to be limited to any special or customized meaning), and refers to, among others, without limitation, saturated and unsaturated oils and waxes, derivatives, amides, glycerides, small molecule metabolites, fatty alcohols, sterols and sterol derivatives, phospholipids, ceramides, sphingolipids, tocopherols, and carotenoids.

[0062] The term "pharmacologically acceptable," as used herein, is used broadly and is to be given its ordinary and accustomed meaning by those of skill in the art (and is not to be limited to any special or customized meaning), and refers, without limitation, to such compounds, materials, compositions, and / or dosage forms that are suitable for contact with the tissues of human beings and animals and / or suitable for consumption by human beings and animals, within the scope of sound medical judgment and balanced against a reasonable ratio of risk / benefit without excessive toxicity, irritation, allergic response, or other undesirable complications.

[0063] The terms "pharmaceutically acceptable salts" and "the pharmaceutically acceptable salts thereof" as used herein are used in the broad sense and are to be given their ordinary and customary meanings by those skilled in the art (not limited to any special or customized meanings), and refer, without limitation, to salts prepared from pharmaceutically acceptable, non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metal salts, such as aluminum, zinc salts, alkali metal salts, such as lithium, sodium, and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts; organic acid salts, such as lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris salts; free acid and base salts; inorganic salts, such as sulfates, hydrochlorides, and hydrobromides; and other salts currently widely and pharmaceutically used and well known to those skilled in the art, such as those listed in sources such as The Merck Index. Any suitable components can be selected to make the salt of the therapeutic agent discussed herein, provided that the components are non-toxic and do not substantially interfere with the desired activity.In addition to salts, pharmaceutically acceptable precursors and derivatives of the compounds can be used.Pharmaceutically acceptable amides, lower alkyl derivatives, and protected derivatives can also be suitable for use in the compositions and methods of preferred embodiments.Although it may be possible to administer the compounds of preferred embodiments in the form of pharmaceutically acceptable salts, it is generally preferred to administer the compounds in neutral form.

[0064] The term "pharmaceutical composition", as used herein, is used in a broad sense and is to be given its ordinary and customary meaning by those skilled in the art (not limited to any special or customized meaning), and refers, without limitation, to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid or base. Pharmaceutical compositions are generally tailored to a specific intended route of administration.

[0065] The term "carrier" as used herein is used in a broad sense and is to be given its ordinary and customary meaning by those skilled in the art (not limited to any special or customized meaning), and refers to, without limitation, a compound that facilitates the incorporation of a compound into cells or tissues.For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into cells or tissues of a subject.Water, saline, ethanol, and mineral oil are also carriers used in certain pharmaceutical compositions.

[0066] The term "diluent", as used herein, is used in a broad sense and is to be given its ordinary and customary meaning by those skilled in the art (not limited to any special or customized meaning), and refers, without limitation, to an ingredient in a pharmaceutical composition that is not pharmacologically active but may be pharmacologic necessary or desirable. For example, a diluent can be used to increase the bulk of a potent drug whose mass is too small for manufacture and / or administration. A diluent can also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, without limitation, phosphate buffered saline, which mimics the composition of human blood.

[0067] The term "excipient", as used herein, is used broadly and is to be given its ordinary and customary meaning by those of skill in the art (and is not to be limited to any special or customized meaning) and refers, without limitation, to substances added to a pharmaceutical composition to provide the composition with mass, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient.

[0068] The term "subject", as used herein, is used in a broad sense and is to be given its ordinary and customary meaning by those skilled in the art (not limited to any special or customized meaning), and refers, without limitation, to an animal that is the subject of treatment, observation or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and especially mammals. "Mammals" includes, without limitation, dolphins, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and especially humans. In some embodiments, the subject is a human.

[0069] The terms "treat", "treatment", "therapeutic" or "therapy" as used herein are intended to be used in a broad sense and to be given their ordinary and customary meaning (not limited to a special or customized meaning), and do not necessarily mean, without limitation, a complete cure or abolition of a disease or condition. Any prevention of any undesirable marker of a disease or condition, any undesirable sign of a disease or condition, or any undesirable symptom of a disease or condition, to any extent, can be considered a treatment and / or therapy. Any alleviation, reduction, lowering, or mitigation of any undesirable marker of a disease or condition, any undesirable sign of a disease or condition, or any undesirable symptom of a disease or condition, to any extent, can be considered a treatment and / or therapy. Any promotion, support, enhancement, strengthening, improvement, or improvement of any desired marker, desired physical condition, desired physical condition, desired mental condition, desired mental condition, health condition, or health condition, by itself or in relation to a disease or condition, to any extent, can be considered a treatment and / or therapy. Any modulation of any marker of disease or condition, sign of disease or condition, symptom of disease or condition, physical condition, physical condition, mental condition, mental condition, health condition, health condition, aging condition, or aging condition, can be considered as treatment and / or therapy, to any extent, by itself or in relation to disease or condition.Modulation can include, but is not limited to, shifting the marker, value, level, or other indicator of physical, mental, health, or aging condition or condition from one that indicates a relatively unhealthy condition or condition to one that indicates a relatively healthier condition or condition; or shifting the marker, value, level, or other indicator of physical, mental, health, or aging condition from one that is associated with a certain risk of disease or condition to one that indicates a relatively lower risk of disease or condition; or causing a desired reduction in the variability of the marker, value, level, or other indicator of physical, mental, health, or aging condition or condition.Furthermore, treatment can include an effect that can worsen the patient's general well-being or appearance.

[0070] The terms "therapeutically effective amount" and "effective amount", as used herein, are used broadly and shall be given their ordinary and customary meanings to those skilled in the art (not limited to special or customized meanings), and are used without limitation to indicate the amount of active compound or pharmaceutical agent that elicits the indicated biological or pharmaceutical response. For example, a therapeutically effective amount of a compound can be the amount required to prevent, alleviate or improve a marker or symptom of a condition, or to prolong the survival of the subject being treated. This response can occur in a tissue, system, animal or human, and includes alleviating the signs or symptoms of the disease being treated. Determination of a therapeutically effective amount is well within the capabilities of one of ordinary skill in the art in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose depends on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosage can be set to achieve the desired effect, but depends on factors such as body weight, diet, concurrent drug therapy, and other factors recognized by those skilled in the art.

[0071] The term "solvent", as used herein, is used in a broad sense and is to be given its ordinary and customary meaning to those skilled in the art (not limited to any special or customized meaning) and refers to a compound that can be, without limitation, polar or non-polar, straight-chain or branched, cyclic or aliphatic, aromatic, naphthenic, and has some characteristic of dissolving power for other compounds or means, including, but not limited to, alcohols, derivatives, diesters, ketones, acetates, terpenes, sulfoxides, glycols, paraffins, hydrocarbons, anhydrides, heterocycles, among others.

[0072] All percentages, ratios or other amounts referred to herein are on a weight basis unless otherwise indicated. Small molecule metabolites

[0073] In addition to pentadecanoylcarnitine or pentadecanoic acid, other small molecule metabolites may be present in the composition or administered to the subject. Small molecule metabolites may include, but are not limited to, amino acids, peptides, carbohydrates, cofactors and vitamins, xenobiotics, or lipids (including monohydroxy fatty acids, medium chain fatty acids, long chain fatty acids, very long chain fatty acids, dicarboxyl fatty acids, phosphatidylcholines, phosphatidylethanolamines, lysophospholipids, plasmalogens, lysoplasmalogens, monoacylglycerols, diacylglycerols, sphingomyelins, or ceramides) that are low molecular weight (usually less than 900 daltons, but sometimes higher) and can be identified and measured in the body and as provided herein. Small molecule metabolites may result from ingestion from food or other oral products, or may be produced endogenously. Small molecule metabolites are referred to and described using conventional nomenclature as used by those skilled in the art.

[0074] When specific compounds or classes of compounds are referred to herein, these compounds or classes of compounds may be produced by metabolic processes (e.g., by administration of a prodrug or by endogenous production) or may be provided to the patient in the form of a pharmaceutical composition. The term "metabolite" is not intended to necessarily require the production of the compound by metabolic processes in the patient to be treated. Instead, compounds identified as "metabolites" may be administered directly to the patient in the form of a pharmaceutical composition rather than in a prodrug form that produces the compound as a metabolite in vivo. The term "metabolite" is used in a broad sense and is not intended to limit the compounds administered to the patient to those produced by a particular synthetic method (produced in vivo from a prodrug as opposed to ex vivo).

[0075] Small molecule metabolites may be referred to by various names, for example, 2-methylserine may also be called 2-amino-3-hydroxy-2-methylpropanoic acid.

[0076] In some embodiments, the small molecule metabolites can be amino acids, peptides, carbohydrates, cofactors and vitamins, xenobiotics, or lipids, as provided herein. In further embodiments, the one or more small molecule metabolites can include at least one amino acid, peptide, carbohydrate, cofactor and vitamin, xenobiotic, or lipid, as provided herein.

[0077] Ideal candidate small molecule metabolites, both as biomarkers and as therapeutic agents, are those that have low molecular weights (<900 Daltons) and are successfully detected in serum at high nanomolar or micromolar levels that satisfy the Lipinski rule 5. All metabolites provided herein meet these criteria.

[0078] In some embodiments, the small molecule metabolite can be an amino acid, including, but not limited to, 2-methylserine, 4-hydroxyglutamate, N-acetyl-aspartyl-glutamate, 2-pyrrolidinone, trans-urocanate, imidazole proprionate, 1-ribosyl-imidazole acetate, 5-imidazole acetate, N-acetylhistamine, hydantoin 5-prorionic acid, 5-hydroxylysine, 5-aminovalerate, 2-oxoadipate, xanthurenate, methionine sulfone, homocitrulline, trans-4-hydroxyproline, prolyl-hydroxyproline, or guanidinosuccinate. Derivatives can be synthesized by published methods.

[0079] In some embodiments, the small molecule metabolite can be a peptide, including but not limited to, gamma-glutamylglutamine, or gamma-glutamylglycine; a carbohydrate, including but not limited to, N6-carboxymethyllysine; a cofactor or vitamin, including, but not limited to, N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide; or a xenobiotic, including but not limited to, 2,3-dihydroxyisovalerate. Derivatives can be synthesized by published methods.

[0080] In some embodiments, the small molecule metabolite can be a monohyroxy fatty acid, including but not limited to 2-hydroxyoctanoate, 2-hydroxydecanoate, 8-hydroxyoctanoate, 2-hydroxymyristate, or 16-hydroxypalmitate. Derivatives can be synthesized by published methods.

[0081] In some embodiments, the small molecule metabolites are medium chain fatty acids, including, but not limited to, those containing the following groups: heptanoate (C7:0, e.g., heptanoic acid), caprylate (C8:0, e.g., caprylic acid), pelargonate (C9:0, e.g., pelargonic acid), undecanoate (C11:0, e.g., undecanoic acid), or 10-undecanoate (C11:1n1, e.g., 10-undecanoic acid); long chain fatty acids, including, but not limited to, pentadecanoate (C15:0, e.g., pentadecanoic acid), margarate (C17:0, e.g., margaric acid), 10-heptadecanoate (C17:1n7, e.g., 10-heptadecanoic acid), 10-nonadecanoate (C17:1n7, e.g., 10-non ... can be canoate (19:1n9, e.g., 10-nonadecanoic acid), C20:0 fatty acid, or C20:2 fatty acid; very long chain fatty acid, including but not limited to: C24:0 fatty acid or C24:1 fatty acid; branched chain fatty acid, including but not limited to: 15-methyl palmitate (i17:0, e.g., methyl palmitic acid), 17-methyl stearate (i19:0, e.g., 17-methyl stearic acid), or 2-hydroxyphytanate (e.g., 2-hydroxyphytanic acid); or dicarboxylate fatty acid, including but not limited to: dodecadienoate (C12:2, e.g., dodecanedioic acid) or docosadioate (C22-DC, e.g., docosadioic acid). Derivatives can be synthesized by published methods.

[0082] In some embodiments, the small molecule metabolite can be a part or product of fatty acid metabolism, including, but not limited to, propionylglycine, lignoceroylcarnitine (C24), serotoylcarnitine (C26), N-palmitoylglycine, cis-4-decenoylcarnitine (C10:1), behenoylcarnitine (C22), pentadecanoylcarnitine (C15), or arachidonoylcholine. Derivatives can be synthesized by published methods.

[0083] In some embodiments, the small molecule metabolite is a phosphatidylcholine, including but not limited to 1-stearoyl-2-arachidonoyl-GPC(18:0 / 20:4), 1-palmitoyl-2-arachidonoyl-GPC(16:0 / 20:4n6), PC(18:2 / 22:4), PC(20:0 / 14:1), PC(20:0 / 20:3), or PC(20:0 / 22:4); 1-palmitoyl-2-arachidonoyl-GPE(16:0 / 20:4), 1-stearoyl-2-arachidonoyl-GPC(18:0 / 20:4), 1-palmitoyl-2-arachidonoyl-GPC(16:0 / 20:4n6), PC(18:2 / 22:4), PC(20:0 / 14:1), PC(20:0 / 20:3), or PC(20:0 / 22:4); The derivatives may be phosphatidylethanolamines, including but not limited to 1-stearoyl-2-oleoyl-GPS (18:0 / 18:1), phosphatidylserines, including but not limited to 1-arachidonoyl-GPC (20:4n6), 1-lignoceroyl-GPC (24:0), or 1-arachidonoyl-GPE (20:4n6). Derivatives may be synthesized by published methods.

[0084] In some embodiments, the small molecule metabolite can be a plasmalogen, including but not limited to 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE (P-16:0 / 20:4), 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0 / 18:1), 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (P-16:0 / 20:4), or 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (P-18:0 / 20:4); or a lysoplasmalogen, including but not limited to 1-(1-enyl-palmitoyl)-GPC (P-16:0). Derivatives can be synthesized by published methods.

[0085] In some embodiments, the small molecule metabolite can be monoacylglycerol (MAG), including but not limited to MAG(12:0), MAG(17:0), MAG(20:0), MAG(20:2), 1-arachidonylglycerol (20:4) or 1-heptadecenylglycerol (17:1); or diacylglycerol (DAG), including but not limited to DAG(14:1 / 18:1), stearoyl-arachidonoyl-glycerol (18:0 / 20:4)[2], oleoyl-arachidonoyl-glycerol (18:1 / 20:4)[1], or oleoyl-arachidonoyl-glycerol (18:1 / 20:4)[2]. Derivatives can be synthesized by published methods.

[0086] In some embodiments, the small molecule metabolite is selected from the group consisting of stearoyl sphingomyelin (d18:1 / 18:0), behenoyl sphingomyelin (d18:1 / 22:0), tricosanoyl sphingomyelin (d18:1 / 23:0), lignoceroyl sphingomyelin (d18:1 / 24:0), sphingomyelin (d18:2 / 23:1), sphingomyelin (d18:2 / 24:2), sphingomyelin (d17:1 / 14:0, d16:1 / 15:0), sphingomyelin (d17:1 / 16:0, d18:1 / 15:0, d16:1 / 17 ... The derivatives may be sphingomyelins, including but not limited to sphingomyelin (d17:2 / 16:0, d18:2 / 15:0), sphingomyelin (d18:1 / 17:0, d17:1 / 18:0, d19:1 / 16:0), sphingomyelin (d18:1 / 19:0, d19:1 / 18:0), sphingomyelin (d18:1 / 21:0, d17:1 / 22:0, d16:1 / 23:0), sphingomyelin (d18:2 / 21:0, d16:2 / 23:0), or sphingomyelin (d18:2 / 23:0, d18:1 / 23:1, d17:1 / 24:1). Derivatives may be synthesized by published methods.

[0087] In some embodiments, the small molecule metabolite can be a ceramide, including but not limited to CER(14:0), HCER(26:1), or LCER(26:0). Derivatives can be synthesized by published methods.

[0088] In some embodiments, the derivative of the small molecule metabolite can be a beta-sulfenyl derivative. It is believed that beta-sulfenyl derivatives, such as acids or esters, can be resistant to beta-oxidation in the body. The derivatives can be synthesized by published methods.

[0089] In some embodiments, the small molecule metabolites are provided in a bioavailable form. The term "bioavailability" refers to the percentage of an administered dose of an unchanged drug that reaches the systemic circulation, which is one of the main pharmacokinetic properties of a drug. By definition, when a drug therapy is administered intravenously, its bioavailability is 100%. As used herein, the term "bioavailable" refers to a form of a small molecule metabolite that is successfully absorbed by the body when using a method of administration other than intravenous, for example, an oral therapeutic agent. In some embodiments, the small molecule metabolite-based composition can include adaptations that optimize absorption.

[0090] Pure or purified small molecule metabolites can exist in various physical contexts. For example, 4-hydroxyglutamate exists as a white powder that is stable at room temperature. This compound can be purchased in small quantities from several vendors (e.g., from SIGMA-Aldrich Corp., St. Louis, MO) in a form suitable for research purposes. Other small molecule metabolites, or their stereoisomers, or solvates, or esters, or salts, or other derivatives, can exist as oils, solids, crystalline solids, or gases.

[0091] Pentadecanoylcarnitine, pentadecanoic acid, or other small molecule metabolites or pharma- ceutically acceptable salts or derivatives thereof may be provided in a purity of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, at least about 99.9%, at least about 99.99% (e.g., the percentage of the compound in bulk form, or a pharma- ceutically acceptable salt thereof), or substantially pure, which may include, but is not limited to, products having impurities at levels such that no physiological effect due to the presence of the impurities is detectable. The mixture of small molecule metabolites, such as amino acids and / or lipids, or pharma- ceutically acceptable salts or derivatives thereof, may be present at a purity of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, at least about 99.9%, at least about 99.99%, or substantially pure, or in a range including and / or ranging from the above values. Pentadecanoylcarnitine, pentadecanoic acid, or mixtures thereof, or pharma-ceutically acceptable salts thereof, individually or as a group, may be free of other small molecule metabolites. In some embodiments, the pentadecanoylcarnitine, pentadecanoic acid, or mixtures thereof provided herein may be substantially free of other species of lipids not included herein.

[0092] Pentadecanoylcarnitine, pentadecanoic acid, or small molecule metabolites, such as amino acids, peptides, carbohydrates, cofactors, vitamins, xenobiotics, or lipids, or pharmaceutically acceptable salts or derivatives thereof, can be derived from any source.In some embodiments, pentadecanoylcarnitine, pentadecanoic acid, or salts thereof can be present in natural sources, isolated from natural sources, semi-synthetic, synthetic, or a mixture of one or more of these.Pentadecanoylcarnitine, pentadecanoic acid, or salts thereof can be produced in a laboratory, naturally, produced by enzymatic processes, produced by wild-type microorganisms, produced by genetically modified microorganisms, isolated from animal tissues, produced by chemical synthesis, or produced by a combination of these processes.

[0093] Pentadecanoylcarnitine, pentadecanoic acid, or small molecule metabolites may be derived from natural sources, such as fish oil, or may be synthesized by methods known in the art. In some embodiments, pentadecanoylcarnitine, pentadecanoic acid, or small molecule metabolites may be contaminated with undesired components present in natural products that have not been refined or purified. In such situations, it may be desirable to use known separation or purification techniques to remove undesired components or to increase the concentration of desired components.

[0094] All tautomeric forms are also intended to be included in any compound described. Without limitation, all tautomeric forms of a carboxyl group are intended to be included.

[0095] In any compound described herein that has geometric isomers that produce one or more double bonds that can be defined as E or Z, each double bond can independently be E or Z, or a mixture thereof.

[0096] Where the compounds disclosed herein have incomplete atomic valences, the valences are intended to be filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0097] Pentadecanoylcarnitine, pentadecanoic acid, or small molecule metabolites, such as amino acids, peptides, carbohydrates, cofactors and vitamins, xenobiotics, or lipids described herein, include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of compounds of the same elemental composition), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process with pharma-ceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0098] The compounds described herein can be isotopically labeled. In some circumstances, substitution with an isotope such as deuterium may result in certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements. Isotopic substitution may be beneficial in monitoring a subject's response to administration of a compound, for example, by providing an opportunity to monitor the ultimate fate of atoms in the compound. Each chemical element represented in a compound structure may include any isotope of said element. For example, in a compound structure, hydrogen atoms may be explicitly disclosed or considered to be present in the compound. In any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly dictates otherwise. Compositions containing pentadecanoylcarnitine or pentadecanoic acid

[0099] A formulation comprising pentadecanoylcarnitine or pentadecanoic acid is provided.It is generally preferred to administer the compound of the embodiment in an oral formulation.However, other routes of administration, such as topical, are also envisioned.The formulation is suitable for use as a consumer health and wellness product, including over-the-counter (OTC) products, as well as supplements and food products.

[0100] The compositions of the embodiments may be used in cosmetic, cosmeceutical and general skin care compositions, or may be provided in pharmaceutical compositions.

[0101] The composition of the embodiment can also be used in relation to mucous membranes, such as lips and vaginal mucosa. When applied to vaginal mucosa, vaginal applicators can be used as commercially available. Suitable applicators can be in the form of pre-filled syringes, tubes connected to pre-filled squeeze reservoirs, pre-packaged rods containing a pre-selected amount of the composition, or the most common vaginal applicators that contain perforations along their length to dispense the composition through the perforations.

[0102] Certain compositions may contain additional therapeutic agents, such as locally acting drugs, such as antibacterial drugs, antiprotozoal drugs, antifungal drugs, antiviral drugs, spermicides, prostaglandins, and steroids.Drugs suitable for delivery include bromocriptine, sildenafil, oxytocin, calcitonin, luteinizing hormone releasing hormone and analogs, insulin, human growth hormone, oxybutynin, and steroids used in hormone replacement therapy or for contraception.Antifungal drugs include clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, and amphotericin.Antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole / trimethoprim, amoxicillin / clavulanate, and levofloxacin. Antibiotic classes include penicillins, tetracyclines, cephalosporins, quinolones, lincomycins, macrolides, sulfonamides, glycopeptides, aminoglycosides, and carbapenems. Hormonal classes include 5-alpha-reductase inhibitors, adrenocorticosteroids, corticotropins, glucocorticoids, mineralocorticoids, adrenocorticosteroid inhibitors, antiandrogens, antidiuretic hormones, antigonadotropics, antithyroid agents, inhibitors, calcitonin, estrogen receptor antagonists, gonadotropin releasing hormone antagonists, growth hormone receptor blockers, growth hormone, insulin-like growth factors, parathyroid hormone and analogs, progesterone receptor modulators, prolactin inhibitors, selective estrogen receptor modulators, sex hormones, androgens and anabolic steroids, contraceptives, estrogens, gonadotropin releasing hormones, gonadotropins, progestins, combinations of sex hormones, somatostatin and somatostatin analogs, synthetic ovulation stimulants, and thyroid drugs.Antiviral agents include adamantane antivirals, antiviral boosters, antiviral combinations, antiviral interferons, chemokine receptor antagonists, integrase strand transfer inhibitors, miscellaneous antivirals, neuraminidase inhibitors, NNRTIs, NS5A inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, and purine nucleosides. Medications for treating skin conditions include acne medications (isotretinoin), atopic dermatitis medications (topical steroids), shingles medications (antivirals, e.g., valacyclovir), rashes (antihistamines like loratadine or fexofenadine, omalizumab), sunburn (lidocaine), contact dermatitis (antihistamines, topical steroids), diaper rash (zinc oxide), rosacea (metronidazole, doxycycline, azelaic acid, isotretinoin, beta blockers, estrogen), athlete's foot (antifungals), and medications for basal cell carcinoma (imiquimod, fluorouracil, vismodegib).

[0103] The composition of the embodiment comprises a topical preparation containing at least one excipient.The excipient can comprise non-aqueous or aqueous carrier and one or more agents selected from moisturizing agents, pH adjusters, deodorants, fragrances, chelating agents, preservatives, emulsifiers, thickeners, solubilizers, percutaneous absorption enhancers, anti-irritants, colorants, surfactants, beneficial agents, pharmaceuticals, and other components known in the art to be used in connection with topical preparations for treating skin.The composition can be formulated so that it does not require the use of preservatives.

[0104] To facilitate application, the composition may be provided as an ointment, oil, lotion, paste, powder, gel, or cream.The composition may also include additional ingredients, such as protective agents, emollients, astringents, moisturizers, sunscreens, suntanning agents, UV absorbers, antibiotics, antifungals, antivirals, antiprotozoal agents, antiacne agents, anesthetics, steroidal anti-inflammatory agents, nonsteroidal anti-inflammatory agents, antipruritic agents, additional antioxidants, chemotherapeutic agents, antihistamines, vitamins or multivitamins, hormones, antidandruff agents, anti-wrinkle agents, anti-skin atrophy agents, skin whitening agents, cleansing agents, and combinations thereof.In further embodiments, the composition may avoid animal or cell-based materials to avoid skin irritation.The composition may be applied to the dermis or mucosa.

[0105] Some embodiments include administering pentadecanoylcarnitine or pentadecanoic acid in a topical formulation. However, in addition to oral administration, other routes of administration are also envisioned (e.g., mucosal, subcutaneous, oral, etc.). Envisioned routes of administration include, but are not limited to, topical, mucosal, and subcutaneous. Suitable liquid forms include suspensions, emulsions, solutions, and the like. The unit dosage form can also provide individual packets of pre-measured amounts of the formulation designed to be administered to a body part, for example, on a predetermined schedule before and after treatment. Unit dosage forms designed to be administered two or three times a day are particularly preferred. However, in certain embodiments, it may be desirable to design the unit dosage form for administration once a day, four times a day, or more.

[0106] In some embodiments, topical and other formulations typically contain from about 0.001% or less to about 50% or more by weight of an active ingredient, e.g., pentadecanoylcarnitine or pentadecanoic acid or salts thereof, from about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% by weight to about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45% by weight or ranges including and / or spanning the aforementioned values.

[0107] Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, sprays, liquids, aerosols, and powders. Conventional pharmaceutical carriers, aqueous or oily bases, thickeners, and the like can be used. In certain applications, ointments, lotions, creams, gels, or similar formulations can be provided that can be applied to the skin using a finger. Such formulations are usually provided in squeeze tubes or bottles or pots, or roll-ons, where a ball is fixed at the top of the formulation container, and the ball can be rolled. By rolling the ball over the skin surface, the liquid in the container is transferred to the skin in a controlled manner. Alternative delivery mechanisms include containers with perforated lids, with a mechanism for releasing the extrudable formulation through the lid. In another form, a gel formulation is provided that has sufficient structural integrity to maintain its shape, which is advanced to a tube and applied to the skin (e.g., in the form of a stick). The advantage of the stick form is that only the formulation, not the finger or a portion of the container, contacts the skin during the application process. The liquid or gel may also be deposited using an applicator, such as a wand, sponge, syringe, or other suitable method.

[0108] In some embodiments, pentadecanoylcarnitine or pentadecanoic acid or its salts can be combined or mixed with suitable carriers, diluents, or excipients, and can contain auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, odorants, colorants, etc., depending on the desired route of administration and preparation, etc. The techniques for the formulation and administration of the compounds described herein are known to those skilled in the art. For example, see "Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th Edition (June 1, 2003) and "Remington's Pharmaceutical Sciences", Mack Pub.Co. 18th Edition and 19th Edition (December 1985 and June 1990, respectively). Such preparations may include complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts. Lipids suitable for liposomal formulations include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, bile acids, and the like. The presence of such additional components may affect the physical conditions, solubility, stability, release rate, clearance rate, and penetration of the active ingredient.

[0109] The composition for topical administration comprises pentadecanoylcarnitine or pentadecanoic acid or its salt and a dermatologically acceptable vehicle. The vehicle may be aqueous or non-aqueous. The dermatologically acceptable vehicle used in the topical composition may be in the form of a lotion, gel, ointment, liquid, cream, or emulsion. When the vehicle is an emulsion, the emulsion may have a continuous aqueous phase and a discontinuous non-aqueous or oily phase (oil-in-water emulsion), or a continuous non-aqueous or oily phase and a discontinuous aqueous phase (water-in-oil emulsion). When topically administered in liquid or gel form, a liquid carrier, such as water, petroleum, oil of animal or vegetable origin, such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oil, may be added to the active ingredient. Saline solution, glucose or other sugar solution, or glycol, such as ethylene glycol, propylene glycol, or polyethylene glycol, are also suitable liquid carriers. The pharmaceutical composition can also be in the form of an oil-in-water emulsion.The oil phase can be vegetable oil, such as olive or peanut oil, mineral oil, such as liquid paraffin, or mixtures thereof.Suitable emulsifiers include naturally occurring gums, such as gum arabic and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.The emulsion can also contain colorants and odorants.

[0110] In certain embodiments, silicone elastomers (e.g., dimethicone crosspolymers) are used to increase the delivery and penetration of pentadecanoylcarnitine or pentadecanoic acid or its salts into the skin.The pharmaceutical excipients used in the topical preparation of the composition can be selected from the group consisting of solvents, emollients and / or emulsifiers, oil bases, preservatives, antioxidants, tonicity adjusters, percutaneous absorption enhancers and solubilizers, chelating agents, buffering agents, surfactants, one or more polymers, and combinations thereof.

[0111] Suitable solvents for aqueous or hydrophilic topical formulations include water; ethyl alcohol; isopropyl alcohol; mixtures of water and ethyl and / or isopropyl alcohol; glycerin; ethylene, propylene or butylene glycol; DMSO; and mixtures thereof.Suitable solvents for hydrophobic topical formulations include mineral oil, vegetable oil, and silicone oil.If desired, the composition described herein may be dissolved or dispersed in a hydrophobic oil phase, and the oil phase can then be emulsified into an aqueous phase containing water, alone or in combination with lower alcohol, glycerin, and / or glycol.Anhydrous formulations can also be used.However, it may be acceptable to provide a water-based composition or accept the presence of limited amounts of water in certain embodiments.

[0112] The viscosity of the composition can be maintained at a selected level using a pharma- ceutically acceptable thickening agent. Suitable viscosity enhancing or thickening agents that can be used to prepare viscous gels or creams with aqueous bases include sodium polyacrylate, xanthan gum, polyvinylpyrrolidone, acrylic acid polymers, carrageenan, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxypropyl methyl cellulose, polyethoxylated polyacrylamides, polyethoxylated acrylates, and polyethoxylated alkanethiols. Methyl cellulose is preferred because it is readily and economically available and easy to handle. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, and the like. The preferred concentration of the thickening agent depends on the thickening agent selected. An amount that achieves the selected viscosity is preferably used. Viscous compositions are usually prepared from solutions by adding such thickening agents or by using bases with acceptable levels of viscosity.

[0113] Suitable emollients include hydrocarbon oils and waxes such as mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, squalene, perhydrosqualene, silicone oils, triglyceride esters, acetoglyceride esters such as acetylated monoglycerides; ethoxylated glycerides such as ethoxylated glyceryl monostearate; alkyl esters of fatty acids or dicarboxylic acids.

[0114] Suitable silicone oils for use as emollients include dimethylpolysiloxane, methyl(phenyl)polysiloxane, and water-soluble and alcohol-soluble silicone glycol copolymers.Suitable triglyceride esters for use as emollients include vegetable and animal fats and oils, including castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, and soybean oil.

[0115] Carboxylic or diacid esters suitable for use as emollients include methyl, isopropyl, and butyl esters of fatty acids.Specific examples of alkyl esters include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, dilauryl lactate, myristyl lactate, and cetyl lactate; and alkenyl esters of fatty acids, such as oleyl myristate, oleyl stearate, and oleyl oleate.Specific examples of alkyl esters of diacids include diisopropyl adipate, diisohexyl adipate, bis(hexyldecyl) adipate, and diisopropyl sebacate.

[0116] Other suitable classes of emollients or emulsifiers that can be used in topical formulations include fatty acids, fatty alcohols, fatty alcohol ethers, ethoxylated fatty alcohols, fatty acid esters of ethoxylated fatty alcohols, and waxes.

[0117] Specific examples of fatty acids for use as emollients include pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic, and erucic acids.Specific examples of fatty alcohols for use as emollients include lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleyl, behenyl, and erucyl alcohol, and 2-octyldodecanol.

[0118] Specific examples of waxes suitable for use as emollients include lanolin and its derivatives, including lanolin oil, lanolin wax, lanolin alcohol, lanolin fatty acid, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohol, ethoxylated cholesterol, propoxylated lanolin alcohol, acetylated lanolin, acetylated lanolin alcohol, linoleic lanolin alcohol, ricinoleate lanolin alcohol, acetate ester of lanolin alcohol ricinoleate, acetate ester of lanolin alcohol ricinoleate, acetate ester of ethoxylated alcohol, hydrogenolysis of lanolin, hydrogenated lanolin, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolins. Waxes that can be used include hydrocarbon waxes, ester waxes, and amide waxes. Useful waxes include wax esters such as beeswax, spermaceti, myristyl myristate, and stearyl stearate; beeswax derivatives such as polyoxyethylene sorbitol beeswax; and vegetable waxes including carnauba and candelilla wax.

[0119] Polyhydric alcohols and polyether derivatives can be used as solvents and / or surfactants in topical formulations.Suitable polyhydric alcohols and polyethers include propylene glycol, dipropylene glycol, polypropylene glycol 2000 and 4000, poly(oxyethylene-co-oxypropylene) glycol, glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol 200-6000, methoxypolyethylene glycol 350, 550, 750, 2000 and 5000, poly[ethylene oxide] homopolymer (100,000-5,000,000), polyalkylene glycols and derivatives, hexylene glycol, 2-methyl-2,4-pentanediol, 1,3-butylene glycol, 1,2,6-hexanetriol, 2-ethyl-1,3-hexanediol, vicinal glycols with 15-18 carbon atoms, and polyoxypropylene derivatives of trimethylolpropane.

[0120] Polyhydric alcohol esters can be used as emulsifiers or emollients.Suitable polyhydric alcohol esters include ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters.

[0121] Emulsifiers suitable for use in topical formulations include anionic, cationic, nonionic, and zwitterionic surfactants. Preferred ionic emulsifiers include phospholipids, such as lecithin and derivatives.

[0122] Pentadecanoylcarnitine or pentadecanoic acid or its salts can be formulated as liposomes. Small molecule metabolites can be components of the lipid portion of the liposome or can be encapsulated in the aqueous portion of the liposome. Pentadecanoylcarnitine or pentadecanoic acid or its salts can also be co-formulated with cyclodextrin. The cyclodextrin can be, for example, hydroxypropyl-β-cyclodextrin or sulfobutylether cyclodextrin. Lecithin and other phospholipids can be used to prepare liposomes containing the active ingredients described herein. When phospholipids such as lecithin are placed in water and once sufficient energy is provided, this results in the formation of lipid vesicles when a bilayer or a series of bilayers are formed, each separated by a water molecule. Liposomes can be produced by sonicating phospholipids in water. Low shear rates create multilamellar liposomes. Continued high shear sonication tends to form smaller unilamellar liposomes. Hydrophobic chemicals can be dissolved in phospholipid bilayer membranes. The lipid bilayer of the liposome delivers the compositions described herein.

[0123] Topical formulations may contain micelles or aggregates of surfactant molecules dispersed in an aqueous solution. Micelles can be prepared by dispersing an oil solvent in an aqueous solution containing a surfactant, where the surfactant concentration exceeds the critical micelle concentration. The resulting formulation contains micelles, i.e., spherical oil droplets surrounded by a membrane of polar surfactant molecules dispersed in an aqueous solvent.

[0124] For example, sterols, including cholesterol and cholesterol fatty acid esters, amides, such as fatty acid amides, ethoxylated fatty acid amides, and fatty acid alkanolamides, can also be used as emollients and / or transdermal absorption enhancers.

[0125] Pharmaceutically acceptable preservatives can be used to extend the shelf life of the composition. Other suitable preservatives and / or antioxidants for use in topical formulations include, and can be used, benzalkonium chloride, benzyl alcohol, phenol, urea, parabens, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, thimerosal, chlorobutanol, and the like, and mixtures thereof. When preservatives such as antioxidants are used, the concentration is usually about 0.02% to about 2% by weight of the total composition, although greater or lesser amounts may be desired depending on the agent selected. Reducing agents as described herein can be advantageously used to maintain good shelf life of the formulation. Anhydrous formulations of embodiments have generally been observed to exhibit satisfactory stability such that preservatives may be removed from the formulation.

[0126] Chelating agents suitable for use in the topical formulations include ethylenediaminetetraacetic acid, its alkali metal salts, its alkaline earth metal salts, its ammonium salts, and its tetraalkylammonium salts.

[0127] In some embodiments, the carrier can have a pH between about 4.0 and 10.0. In some embodiments, the carrier can have a pH between about 6.8 and about 7.8. The pH can be controlled using a buffer or other pH modifier. Suitable pH modifiers include phosphoric acid and / or phosphate salts, citric acid and / or citrate salts, hydroxide salts (i.e., calcium hydroxide, sodium hydroxide, potassium hydroxide) and amines, such as triethanolamine. Suitable buffers include buffers containing solutions of monopotassium phosphate and dipotassium phosphate that maintain a pH between 5.8 and 8; and buffers containing solutions of monosodium phosphate and disodium phosphate that maintain a pH between 6 and 7.5. Other buffers include citric acid / sodium citrate, and dibasic sodium phosphate / citric acid. The compositions of the embodiments can be isotonic with the blood or other bodily fluids of the recipient. The isotonicity of the composition can be achieved using sodium tartrate, propylene glycol, or other inorganic or organic solutes. Sodium chloride is particularly preferred. For example, buffering agents such as acetic acid and salts, citric acid and salts, boric acid and salts, and phosphoric acid and salts can be used. It may also be desirable to include a reducing agent in the formulation, such as vitamin C, vitamin E, or other reducing agents known in the pharmaceutical art.

[0128] Surfactants can also be used as excipients, for example, anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate, cationic detergents such as benzalkonium chloride or benzethonium chloride, or nonionic detergents such as polyoxyethylene hydrogenated castor oil, glycerol monostearate, polysorbates, sucrose fatty acid esters, methylcellulose, or carboxymethylcellulose.

[0129] When the formulation of the embodiment is administered by subcutaneous injection, it is preferably in the form of a pyrogen-free, parenterally acceptable aqueous or oily suspension, emulsion or solution. The suspension can be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. Preparation of acceptable aqueous or non-aqueous solutions with suitable properties, such as pH, isotonicity, stability, etc., is within the skill of the art. For example, isotonic vehicles such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other vehicles known in the art can be used, or fixed oils, such as synthetic mono- or diglycerides, fatty acids, etc., can be used as conventional solvents or suspension media. The formulation can also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art.

[0130] In certain embodiments, it may be advantageous to include an additional agent that has pharmacological activity. Anti-infective agents include anthelmintics (mebendazole), antibiotics, including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin b, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, micatin, tolnaftate), cephalosporins (cefachlor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, ticarcillin), tetracyclines (doxicillin, cephalosporins ... Antivirals include, but are not limited to, acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine, quinolones (ciprofloxacin, levofloxacin), sulfonamides (sulfadiazine, sulfisoxazole), sulfones (dapsone), furazolidone, metronidazole, pentamidine, sulfanilamida crystalline num, gatifloxacin, and sulfamethoxazole / trimethoprim. Anesthetic agents can include, but are not limited to, ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine, and phenazopyridine.Anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sulindac, and tolmetin; and corticosteroids. and the like.

[0131] In certain embodiments, the addition of emollients, emulsion stabilizers, humectants, excipients, and other compounds can be modified to enhance the sensory properties of the topical composition, including, but not limited to, skin feel (silky feel, lightness, creaminess, etc.), absorbency (the time required for the product to lose its moist feel and no longer be perceived on the skin), consistency, hardness, spreadability (e.g., viscosity, onset of flow, shear rate), stickiness, shape integrity, gloss, hydrophilicity or hydrophobicity, and others.

[0132] In certain embodiments, systemic administration of pentadecanoylcarnitine or pentadecanoic acid may be desired. In such embodiments, pentadecanoylcarnitine or pentadecanoic acid or salts thereof are formulated into a composition suitable for oral administration, although other routes of administration are also envisioned.

[0133] The compositions described herein can be administered to a subject by themselves or in compositions where they are mixed with other active agents, or with carriers, diluents, excipients, or combinations thereof, as in the case of combination therapy. Formulations depend on the route of administration selected. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art (see, for example, "Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th Edition (June 1, 2003) and "Remington's Pharmaceutical Sciences", Mack Pub.Co. 18th Edition and 19th Edition (December 1985 and June 1990, respectively)).

[0134] The compositions disclosed herein can be manufactured into administrable forms by means of processes known per se, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, tabletting, or extraction processes. Many of the compounds used in the pharmaceutical combinations disclosed herein are provided as salts with pharma- ceutically acceptable counterions.

[0135] The techniques of administering pentadecanoylcarnitine or pentadecanoic acid or its salts that exist in the art include, but are not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including, for example, intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intracerebroventricular, intraperitoneal, intranasal and intraocular injection. Any combination of the above or other methods known to those skilled in the art is contemplated herein (see, for example, "Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins; 20th edition (June 1, 2003) and "Remington's Pharmaceutical Sciences", Mack Pub.Co. 18th and 19th editions (December 1985 and June 1990, respectively)).

[0136] In fact, pentadecanoylcarnitine or pentadecanoic acid or its salts can be combined as an active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Pentadecanoylcarnitine or pentadecanoic acid or its salts can be added directly to, for example, gelatin capsules or softgel capsules for consumption by the patient. In other embodiments, a carrier can be used. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration. Thus, the compositions provided herein can be presented as separate units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be presented as oils, powders, granules, liquids, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions, using components similar to the topical formulations described elsewhere herein, but suitable for human consumption. In addition to the common dosage forms provided above, the compositions provided herein can also be administered by controlled release and / or delivery devices. Composition can be prepared by any method of pharmacy.Generally, such method comprises the step of combining active ingredient with carrier that constitutes one or more necessary ingredients.Generally, composition is prepared by uniformly and intimately mixing active ingredient with liquid carrier or finely divided solid carrier or both.Then, product can be conveniently shaped into desired presentation.

[0137] The formulations can also be administered in a local rather than systemic manner, for example, via injection of the composition directly into the target area, for example, in a depot or sustained release formulation. Additionally, targeted drug delivery systems for the compositions can be used, for example, in liposomes coated with tissue-specific antibodies.

[0138] The composition can contain pentadecanoylcarnitine or pentadecanoic acid or a salt thereof in an amount effective for the desired therapeutic effect. In some embodiments, the composition is in a unit dosage form and contains about 0.1 mg or less to about 5000 mg or more of pentadecanoylcarnitine or pentadecanoic acid or a salt thereof per unit dosage form. In further embodiments, the composition contains about 1 to about 500 mg of pentadecanoylcarnitine or pentadecanoic acid or a salt thereof per unit dosage form, or about 500 to 5000 mg per unit dosage form. Such dosage forms can be solid, semisolid, liquid, emulsion, or can be adapted for delivery via aerosol or the like for inhalation administration.

[0139] The carrier used can be, for example, solid, liquid or gas.The examples of solid carrier include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.The examples of liquid carrier include sugar syrup, peanut oil, olive oil, lower alcohol and water.The examples of gas carrier include carbon dioxide and nitrogen.

[0140] The compositions provided herein can be prepared as a solution or suspension of pentadecanoylcarnitine or pentadecanoic acid or its salt in water or non-aqueous liquid.Suitable surfactants can be included, for example, in hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil.Furthermore, preservatives can be included, for example, to prevent harmful growth of microorganisms.

[0141] The compositions provided herein suitable for use in injection include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders for extemporaneous preparation of such injectable sterile solutions or dispersions.The compositions can be stable under the conditions of manufacture and storage.Therefore, they can be preserved against the contaminating action of microorganisms, such as bacteria and fungi.The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0142] In addition to the above-mentioned carrier components, the formulations described above may optionally contain one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to render the formulation isotonic with the blood or other bodily fluids of the intended recipient. The compositions containing the compounds provided herein, or pharma-ceutically acceptable salts or derivatives thereof, may also be prepared in the form of powders or liquid concentrates for dilution.

[0143] Compositions are contemplated herein that include pentadecanoylcarnitine or pentadecanoic acid or a salt thereof as described herein in combination with at least one additional active agent. Pentadecanoylcarnitine or pentadecanoic acid or a salt thereof and at least one additional active agent may be in a single formulation or multiple formulations provided together, or may be unformulated. In some embodiments, pentadecanoylcarnitine or pentadecanoic acid or a salt thereof can be administered together in a single composition with one or more additional agents. For example, pentadecanoylcarnitine or pentadecanoic acid or a salt thereof can be administered in one composition, and at least one of the additional agents can be administered in a second composition. In further embodiments, pentadecanoylcarnitine or pentadecanoic acid or a salt thereof and at least one additional active agent are packaged together as a kit. For example, a drug manufacturer, drug reseller, doctor, compounding store, or pharmacist can provide a kit that includes pentadecanoylcarnitine or pentadecanoic acid or a salt thereof in combination with another product or component for delivery to a patient. Such additional components may include anti-infective agents, anti-inflammatory agents, anesthetic agents, and the like.

[0144] Some embodiments described herein relate to an oral composition of pentadecanoylcarnitine or pentadecanoic acid or a salt thereof, which may comprise a therapeutically effective amount of pentadecanoylcarnitine or pentadecanoic acid or a salt thereof described herein and a pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof. The composition may comprise pentadecanoylcarnitine or pentadecanoic acid or a salt thereof, for example, in an amount of >1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, ≥98% of the composition, or in a range including and / or ranging from the values ​​mentioned above. In some embodiments, the pharmaceutical composition can comprise pentadecanoylcarnitine or pentadecanoic acid or salts thereof and one or more other small molecule metabolites, e.g., one or more of amino acids, peptides, carbohydrates, cofactors, vitamins, xenobiotics, and / or lipids described herein, or salts or derivatives thereof, e.g., >1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%, ≥60%, ≥70%, ≥80%, ≥90%, ≥95%, ≥98% of the composition, or a range including and / or spanning the aforementioned values. Food

[0145] Foodstuffs and other foods containing pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, are provided, and the amount of pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, in the foodstuff is enriched (e.g., enriched or concentrated). Pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, can be added to foodstuffs for consumption by subjects. Pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, can be integrated into one or more ingredients of foodstuffs. Pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, can be prepared as an ingredient or not. Pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, or a preparation containing pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, can be added before, during, or after preparation. Preparation can include, without limitation, cooking, mixing, flavoring, seasoning, blending, boiling, frying, roasting, or other processes known in the art. The fortification is preferably at a level that provides a therapeutic daily dose of pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, as described elsewhere herein, or achieves the body concentration of pentadecanoylcarnitine described herein.However, beneficial effects can also be obtained at amounts less than such doses.Pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, can be administered in unit dosage form as a dietary supplement (tablet, capsule, encapsulated pill, or gelcap pill), or in dispensable form of liquid suspension or solution for oral or injection (spray, aerosol, powder, or granule), or as a dietary supplement, additive, ingredient, or fortifier added to dietary substances (food or beverage).In certain embodiments, pentadecanoylcarnitine or pentadecanoic acid, or its salts, as dietary supplements or food / drink ingredients or additives, can be utilized to promote or support health, for example, promote or support metabolic health, promote or support heart health, promote or support liver health, promote or support red blood cells, promote or support immune health, and / or slow down the rate of aging.Thus, pentadecanoylcarnitine or pentadecanoic acid, or its salts, are suitable for administration in forms and manners known in pharmaceutical and dietary supplement technology, including, but not limited to, dietary supplements, medical foods, food additives, food ingredients, food supplements, beverage additives, beverage ingredients, beverage supplements, fortified foods, fortified beverages, food supplemented with additives, beverage supplemented with additives, and pharmaceuticals in any form, for example, tablets, encapsulated pills, gel cap pills, liquid suspensions, liquid solutions, sprays, or powders.

[0146] The pentadecanoylcarnitine or pentadecanoic acid or salts thereof provided herein can be present as a component in foodstuffs by the action of processes known in nature, for example, by modifying the metabolic processes of plants, animals, bacteria, or fungi. Genetic modification of plants, animals, bacteria, or fungi to increase the concentration of pentadecanoylcarnitine or pentadecanoic acid or salts thereof is contemplated. By way of example, pentadecanoylcarnitine or pentadecanoic acid or salts thereof can be present in the foodstuff at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or higher, e.g., 1%-2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 20%, or 30%, or 40%, 50%, or a range including and / or spanning the aforementioned values. When pentadecanoylcarnitine or pentadecanoic acid or a salt thereof is naturally present in a foodstuff, it can be present in an abundant amount above the amount that naturally occurs in the foodstuff, for example, at a concentration of 10% or more above the average, or at the highest naturally occurring concentration observed, for example, at a concentration of 20% or 30% or 40% or 50% or 100% or 200% or 300% or 400% or 1000% or 2000% or 5000% or more above the average, or at the highest naturally occurring concentration observed. Indications

[0147] Aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety, anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric conditions, metabolic disorders, migraine Compositions and methods are provided for the treatment, management, amelioration, or prevention of a condition selected from the group consisting of: nasal congestion, sinus congestion, nausea, neuropathic pain associated with multiple sclerosis, symptoms of multiple sclerosis, neurological disorders, neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics associated with Tourette's syndrome, and behavioral problems associated with Tourette's syndrome.

[0148] Compositions and methods are provided for supporting appetite, cardiovascular health, hematological health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, sociality, metabolic health, hematological health, renal health, and weight loss.

[0149] Compositions and methods are provided for achieving a body concentration of pentadecanoylcarnitine of 1 μM to 20 μM in a subject.

[0150] In some embodiments, following administration of pentadecanoylcarnitine or pentadecanoic acid or a salt thereof, serum, plasma, or red blood cell membrane pentadecanoylcarnitine levels may be increased.

[0151] In some embodiments, the compositions and methods provided herein are intended to provide a therapeutic effect against a range of conditions, including but not limited to aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety, anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric disorders, mental conditions, metabolic disorders, migraine headaches, nasal congestion, sinus congestion, nausea, hypercalcaemia ... The marker of neuropathic pain associated with progressive sclerosis, symptoms of multiple sclerosis, neurological disorders, neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcer, schizophrenia, sleep disorder, spinal cord injury, tardive dyskinesia, tics associated with Tourette's syndrome, or behavior problems associated with Tourette's syndrome, or the marker of appetite, cardiovascular health, blood system health, memory, metabolic health, mood, long REM sleep, kidney health, sexuality, sociability, metabolic health, hematological health, kidney health, or weight loss.In certain embodiments, the marker is the percentage of pentadecanoylcarnitine in serum, plasma, or red blood cell membrane; the concentration of the pentadecanoylcarnitine contained in the present invention in serum, plasma, or red blood cell membrane; or the total pentadecanoylcarnitine in serum, plasma, or red blood cell membrane. In some embodiments, pentadecanoylcarnitine is measured as a component of glycolipids. In further embodiments, pentadecanoylcarnitine is measured as a component of phospholipids. In yet further embodiments, the marker is the percentage of serum or red blood cell membrane pentadecanoylcarnitine, the serum concentration of pentadecanoylcarnitine, or total serum pentadecanoylcarnitine.

[0152] In some embodiments, the methods provided herein include measuring the concentration of a marker. A person skilled in the art can perform suitable methods for such measurements, including but not limited to those described herein.

[0153] Provided herein are methods for treating comprising administering a dose of pentadecanoylcarnitine or pentadecanoic acid or a salt thereof at predetermined intervals or at intervals left to the discretion of the subject.

[0154] In some embodiments, the compounds and methods provided herein can provide a threshold serum, plasma, or red blood cell membrane percentage of pentadecanoylcarnitine relative to all serum, plasma, or red blood cell membrane small molecule metabolites. For example, the threshold value may be a value of about 0.05% or less to 90% or more, for example, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.0%, at least about 1.1%, at least about 1.2%, at least about 1.3%, at least about 1.4%, at least about 1.5%, at least about 1.6%, at least about 1.7%, at least about 1.8%, at least about 1.9%, at least about 2.1%, at least about 2.2%, at least about 2.3%, at least about 2.4%, at least about 2.5%. , at least about 2.6%, at least about 2.7%, at least about 2.8%, at least about 2.9%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, greater than 90%, or a range including and / or spanning the aforementioned values.

[0155] In some embodiments, the compositions and methods provided herein can provide an increase in serum or plasma concentrations of pentadecanoylcarnitine, or red blood cell membrane concentrations of pentadecanoylcarnitine, above a baseline value (e.g., a pre-treatment value in a patient undergoing treatment, or a typical value observed in a particular patient population). For example, serum or plasma pentadecanoylcarnitine or red blood cell membrane concentrations of pentadecanoylcarnitine can be increased by at least about 1 μg / ml, at least about 2 μg / ml, at least about 3 μg / ml, at least about 4 μg / ml, at least about 5 μg / ml, at least about 6 μg / ml, at least about 7 μg / ml, at least about 8 μg / ml, at least about 9 μg / ml, at least about 10 μg / ml, at least about 15 μg / ml, at least about 20 μg / ml, at least about 25 μg / ml, at least about 30 μg / ml, at least about 35 μg / ml, at least about 40 μg / ml, at least about 45 μg / ml, at least about 50 μg / ml, greater than 50 μg / ml, or a range including and / or ranging from the aforementioned values. In some embodiments, the serum concentration of pentadecanoylcarnitine, or the red blood cell membrane concentration of pentadecanoylcarnitine, is increased to at least about 0.01×10 above a baseline value (e.g., a pre-treatment value in a patient undergoing treatment, or a typical value observed in a particular patient population). -4 M, at least about 0.05 × 10 -4 M, at least about 0.1 × 10 -4 M, at least about 0.2 × 10 -4 M, at least about 0.3 × 10 -4 M, at least about 0.4 × 10 -4 M, at least about 0.5 × 10 -4 M, at least about 0.6 × 10 -4 M, at least about 0.7 × 10 -4 M, at least about 0.8 × 10 -4 M, at least about 0.9 × 10 -4 M, at least about 1 × 10 -4 M, at least about 2 × 10 -4 M, at least about 3 × 10 -4M may be increased or ranged to include and / or extend beyond the values ​​set forth above.

[0156] In some embodiments, the compounds and methods provided herein can provide an increase in serum or plasma total pentadecanoylcarnitine and pentadecanoic acid, or red blood cell membrane total pentadecanoylcarnitine and pentadecanoic acid. For example, serum total pentadecanoylcarnitine and pentadecanoic acid, or red blood cell membrane total pentadecanoylcarnitine and pentadecanoic acid, can be increased by at least about 5 μg / ml, at least about 6 μg / ml, at least about 7 μg / ml, at least about 8 μg / ml, at least about 9 μg / ml, at least about 10 μg / ml, at least about 15 μg / ml, at least about 20 μg / ml, at least about 25 μg / ml, at least about 30 μg / ml, or at least about 40 μg / ml, or at least about 50 μg / ml, or at least about 60 μg / ml, or at least about 70 μg / ml, or at least about 80 μg / ml, or at least about 90 μg / ml, or at least about 100 μg / ml, or at least about 150 μg / ml, or at least about 200 μg / ml, or at least about 300 μg / ml, or at least about 400 μg / ml, or at least about 500 μg / ml, or at least about 600 μg / ml, or at least about 700 μg / ml, or at least about 800 μg / ml, or at least about 900 μg / ml, or at least about 1000 μg / ml, or at least about 1500 μg / ml, or at least about 2000 μg / ml, or at least about 3000 μg / ml, or at least about 4000 μg / ml, or at least about 5000 μg / ml, or at least about 5000 μg / ml, or at In some embodiments, the increase may be at least about 35 μg / ml, at least about 40 μg / ml, at least about 45 μg / ml, at least about 50 μg / ml, at least about 60 μg / ml, at least about 70 μg / ml, at least about 80 μg / ml, at least about 90 μg / ml, at least about 100 μg / ml, at least about 150 μg / ml, at least about 200 μg / ml, at least about 250 μg / ml, at least about 300 μg / ml, at least about 350 μg / ml, at least about 400 μg / ml, at least about 450 μg / ml, at least about 500 μg / ml, or greater than 500 μg / ml.

[0157] In some embodiments, the compounds and methods provided herein can provide an increase above baseline levels of serum, plasma, or red blood cell membrane pentadecanoylcarnitine (e.g., pre-treatment levels in patients undergoing treatment, or typical levels observed in a particular patient population) for all serum or red blood cell membrane small molecule metabolites, respectively. For example, serum, plasma, or red blood cell membrane pentadecanoylcarnitine can be increased by at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 1.1%, at least about 1.2%, at least about 1.3%, at least about 1.4%, at least about 1.5%, at least about 1.6%, at least about 1.7%, at least about 1.8%, at least about 1.9%, at least about 2.0%, at least about 2.1%, at least about 2.2%, at least about 2.3%, at least about 2.4%, at least about 2.5%, at least about 2.6%, at least about 2.7%, at least about 2.8%, at least about 2.9%, at least about 3.0%, at least about 3.1%, at least about 3.2%, at least about 3.3%, at least about 3.4%, at least about 3.5%, at least about 3.6%, at least about 3.7%, at least about 3.8%, at least about 3.9%, at least about 3.1%, at least about 3.2 ... The increase may be at least about 1.4%, at least about 1.5%, at least about 1.6%, at least about 1.7%, at least about 1.8%, at least about 1.9%, at least about 2%, at least about 2.1%, at least about 2.2%, at least about 2.3%, at least about 2.4%, at least about 2.5%, at least about 2.6%, at least about 2.7%, at least about 2.8%, at least about 2.9%, at least about 3%, at least about 3.5%, at least about 4%, at least about 4.5%, at least about 5%, more than 5%, or a range including and / or ranging from the values ​​recited above.

[0158] In some embodiments, pentadecanoylcarnitine or pentadecanoic acid or a salt thereof is administered to maintain the total percentage of serum or plasma pentadecanoylcarnitine above a predefined threshold. In further variations, pentadecanoylcarnitine or pentadecanoic acid or a salt thereof is administered to maintain the serum phospholipid percentage of pentadecanoylcarnitine at about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.2%, about 1.4%, about 1.6%, about 1.8%, about 2%, about 2.2%, about 2.4%, about 2.6% or more, or in a range including and / or ranging from the above values.

[0159] In some embodiments, the compounds and methods provided herein can provide a threshold serum, plasma, or red blood cell membrane percentage of pentadecanoylcarnitine relative to all serum or red blood cell membrane small molecule metabolites, respectively. For example, the threshold value may be a value from less than about 0.05% to 90% or more, e.g., at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1.0%, at least about 1.1%, at least about 1.2%, at least about 1.3%, at least about 1.4%, at least about 1.5%, at least about 1.6%, at least about 1.7%, at least about 1.8%, at least about 1.9%, at least about 2.1%, at least about 2.2%, at least about 2.3%, at least about 2.4%, at least about 2.5%. , at least about 2.6%, at least about 2.7%, at least about 2.8%, at least about 2.9%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, greater than 90%, or a range including and / or spanning the aforementioned values.

[0160] In some embodiments, the compounds and methods provided herein can provide an increase in serum or plasma concentrations of pentadecanoylcarnitine, or red blood cell membrane concentrations of pentadecanoylcarnitine above a baseline value (e.g., a pre-treatment value in a patient undergoing treatment, or a typical value observed in a particular patient population). For example, serum pentadecanoylcarnitine or red blood cell membrane concentrations of pentadecanoylcarnitine can be increased by at least about 0.01 μg / ml, at least about 0.05 μg / ml, at least about 0.1 μg / ml, at least about 0.4 μg / ml, 1 μg / ml, at least about 2 μg / ml, at least about 3 μg / ml, at least about 4 μg / ml, at least about 5 μg / ml, at least about 6 μg / ml, at least about 7 μg / ml, at least about 8 μg / ml, at least about 9 μg / ml, at least about 10 μg / ml, at least about 15 μg / ml, at least about 20 μg / ml, at least about 25 μg / ml, at least about 30 μg / ml, at least about 35 μg / ml, at least about 40 μg / ml, at least about 45 μg / ml, at least about 50 μg / ml, by more than 50 μg / ml, or by a range including and / or spanning the aforementioned values. In some embodiments, the serum concentration of pentadecanoylcarnitine, or the red blood cell membrane concentration of pentadecanoylcarnitine, is at least about 0.001×10 higher than a baseline value (e.g., a pre-treatment value in a patient undergoing treatment, or a typical value observed in a particular patient population). -4 M, at least about 0.005 × 10 -4 M, at least about 0.05 × 10 -4 M, at least about 0.01 × 10 -4 M, at least about 0.05 × 10 -4 M, at least about 0.1 × 10 -4 M, at least about 0.2 × 10 -4 M, at least about 0.3 × 10 -4 M, at least about 0.4 × 10 -4 M, at least about 0.5 × 10 -4 M, at least about 0.6 × 10 -4 M, at least about 0.7 × 10 -4 M, at least about 0.8 × 10-4 M, at least about 0.9 × 10 -4 M, at least about 1 × 10 -4 M, at least about 2 × 10 -4 M, at least about 3 × 10 -4 M may be increased by any number above or within a range including and / or spanning the values ​​set forth above.

[0161] In some embodiments, the compounds and methods provided herein may provide an increase in serum or plasma total pentadecanoylcarnitine and pentadecanoic acid or salts thereof, or red blood cell membrane total pentadecanoylcarnitine and pentadecanoic acid or salts thereof. For example, serum total pentadecanoylcarnitine and pentadecanoic acid or salts thereof, or red blood cell membrane total pentadecanoylcarnitine and pentadecanoic acid or salts thereof, is at least about 0.05 μg / ml, at least about 0.1 μg / ml, at least about 0.5 μg / ml, at least about 1 μg / ml, at least about 5 μg / ml, at least about 6 μg / ml, at least about 7 μg / ml, at least about 8 μg / ml, at least about 9 μg / ml, at least about 10 μg / ml, at least about 15 μg / ml, at least about 20 μg / ml, at least about 25 μg / ml, at least about 30 μg / ml, at least about 40 μg / ml, at least about 50 μg / ml, at least about 60 μg / ml, at least about 70 μg / ml, at least about 80 μg / ml, at least about 90 μg / ml, at least about 100 μg / ml, at least about 150 μg / ml, at least about 200 μg / ml, at least about 300 μg / ml, at least about 400 μg / ml, at least about 500 μg / ml, at least about 600 μg / ml, at least about 700 μg / ml, at least about 800 μg / ml, at least about 900 μg / ml, at least about 1000 μg / ml, at least about 1500 μg / ml, at least about 2000 μg / ml, at least about 3000 μg / ml, at least about / ml, at least about 30 μg / ml, at least about 35 μg / ml, at least about 40 μg / ml, at least about 45 μg / ml, at least about 50 μg / ml, at least about 60 μg / ml, at least about 70 μg / ml, at least about 80 μg / ml, at least about 90 μg / ml, at least about 100 μg / ml, at least about 150 μg / ml, at least about 200 μg / ml, at least about 250 μg / ml, at least about 300 μg / ml, at least about 350 μg / ml, at least about 400 μg / ml, at least about 450 μg / ml, at least about 500 μg / ml, by more than 500 μg / ml or by a range including and / or spanning the aforementioned values. Combination therapy

[0162] In some embodiments, pentadecanoylcarnitine or pentadecanoic acid or its salt can be used in combination with one or more additional active agents.Examples of the additional active agents that can be used in combination include small molecule metabolites, or their salts or derivatives, or compositions that contain small molecule metabolite compounds, or their salts or derivatives, including, but not limited to, drugs currently used to treat the conditions provided herein, and other drugs known in medicine.

[0163] In some embodiments, pentadecanoylcarnitine or pentadecanoic acid or its salts can be used with one, two, three or more additional active agents described herein. Such agents include, but are not limited to, small molecule metabolites, or salts or derivatives thereof.

[0164] In some embodiments, pentadecanoylcarnitine or pentadecanoic acid or a salt thereof can be used (e.g., administered or taken) in combination with another agent(s) for the treatment, prevention, maintenance, or prophylaxis of the conditions provided herein.

[0165] Additionally, pentadecanoylcarnitine or pentadecanoic acid or salts thereof are used in the treatment of various conditions, including but not limited to Altoprev (lovastatin), Crestor (rosuvastatin), Lescol (fluvastatin), Lipitor (atorvastatin), Livalo (pitavastatin), Pravachol (pravastatin), Zocor (simvastatin), antiplatelet agents, beta blockers, ACE inhibitors, calcium channel blockers, diuretics, anticoagulants, aspirin, bile acid sequestrants, ezetimibe, fibrates, glycoprotein IIb / IIIa receptor inhibitors, niacin (nicotinic acid), nitrates, platelet inhibitors, thrombolytic agents, oral lisinopril, oral atenolol, oral Bystolic, oral Diovan, oral hydrochlorothiazide, oral metoprolol succinate, oral amlodipine, oral Norvasc, oral Toprol XL, Oral Benicar, Oral Metoprolol Tartrate, Oral Losartan, Oral Lisinopril-Hydrochlorothiazide, Oral Clonidine HCl, Oral Diovan HCT, Oral Cozaar, Oral Propranolol, Oral Spironolactone, Oral Azor, Oral Carvedilol, Oral Coreg, Oral Benicar HCT, Oral Exforge, Oral Avapro, Oral Lotrel, Oral Verapamil, Oral Furosemide, Oral Lasix, Oral Hyzaar, Oral Tekturna, Oral Enalapril Maleate, Oral Micardis, Oral Losartan-Hydrochlorothiazide, Oral Ramipril, Oral Lopressor, Oral Altace, Oral Micardis HCT, Oral Avalide, Oral Diltiazem, Oral Triamterene-Hydrochlorothiazide, Oral Labetalol, Oral Terazosin, Oral Amlodipine-Benazepril, Oral Hydralazine, Oral Atacand, Oral Benazepril, Oral Tribenzor, Oral Triamterene, Oral Doxazosin, Oral Nifedipine, Oral Ziac, Oral Aldacton, Oral Maxzide, Oral Cartia XT, Oral Prazosin, Oral Cardizem CD, Oral Zestril, Oral Dyazide, Oral Bisoprolol Fumarate, Oral Tenex, Oral Tenormin, Oral CoregCR, Oral Prinivil, Oral Valsartan, Oral Atenolol-Chlorthalidone, Oral Edarbyclor, Oral Benazepril-Hydrochlorothiazide, Oral Ferrous Sulfate, Intravenous Ferrlecit, Intravenous Ferahem, Oral Feosol, Infed Injection, Oral Integra, Oral Ferrex 150 Forte, Oral Tandem Dual Action, Oral Ferrex 150, Oral Ferrous Gluconate, Oral Corvitate 150, Oral Integra F, Oral NovaFerrum, Oral Iron (Ferrous Sulfate), Oral Vitron-C, Folic Acid, Corticosteroids, Rituximab, IVIG, Prednisone, Oral Methylprednisolone, Kenalog Injection, Oral Medrol (Pak), Oral Medrol, Oral Dexamethasone, Depo-Medrol Injection, Oral Prednisolone, Oral DexPak 13 Day, intravenous Solu-Medrol, oral hydrocortisone, oral Cortef, oral Deltasone, triamcinolone acetonide injection, oral cortisone, cholinesterase inhibitors such as Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne), Memantine, Aricept, Namenda, Namenda XR, Razadyne ER, AlphaE, Vitamin E, Hydergine, Namzaric, Dopamine agonists such as Pramipexole (Mirapex), Ropinirole (Requip), Rotigotine (Neupro patch) and Apomorphine (Apokyn), Anticholinergics such as Benztropine (Cogentin) and Trihexyphenidyl, MAO-B inhibitors such as (Eldepryl, Zelapar) and Rasagiline (Azilect), COMT inhibitors such as Entacapone (Comtan), Carbidopa / Levodopa (Sinemet®), Amantadine, Tetrabenazine (Xenazine), Haloperidol (Haldol ), chlorpromazine, risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac, diclofenac sodium, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, lornoxicam, cinnoxicam, sudoxicam, and tenoxicam.

[0166] Additionally, pentadecanoylcarnitine or pentadecanoic acid or salts thereof may be used in combination with one or more agents selected from iron dextran, iron sumalate, polysaccharide iron, ferrus fumarate, carbonyl iron, ferrous aspartoglycinate, and heme iron polypeptides may sometimes be indicated, as well as other medications such as ferrus bisglycinate, e.g., androgenic hormones, e.g., erythropoietin, folic acid, vitamin B12, vitamin C, succinic acid, niacin, pyridoxine, riboflavin, biotin, thiamine, calcium formate, Aminoxin, Anadrol-50, Chromagen Forte, Epoetin alfa, Epogen, FeC Tab Plus, FeRiva, FeRivaFA, Ferocon, Ferotrin, Ferralet 90, Ferrex 28, Ferrogels Forte, FoliTab 500, Fumatinic, Hematogen Forte, Hemetab, Integra Plus, Irospan 42 / 6, Lenalidomide, Maxaron Forte, Myferon 150 Forte, MyKidz Iron, NovaFerrum, Oxymetholone, Procrit, Proferrin-Forte, Pyridoxine, Repliva 21 / 7, Revlimid, and Tricon can also be administered. dosage

[0167] As those skilled in the art can easily understand, the useful in vivo dosage and specific administration mode to be administered vary according to the age, weight, severity of condition, and species of mammals to be treated, the specific form of compound to be used, and the specific use for which these compounds are used.Determining effective dosage level (the dosage level required to achieve desired results) can be achieved by those skilled in the art using routine methods, for example, in vivo experiments.For example, see "Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers", US Food and Drug Administration, June 2005.

[0168] In some embodiments, the methods provided herein can include administering a therapeutically effective amount of a composition provided herein. In some embodiments, the therapeutically effective amount can be determined with reference to modulation of a marker of a condition provided herein. In some embodiments, the therapeutically effective amount can be determined with reference to modulation of a symptom of a condition provided herein. In still other embodiments, established guidelines for the conditions described herein can be referenced, including but not limited to, guidelines for the treatment of conditions provided herein, including inflammation.

[0169] Dosages may vary widely depending on the desired effect and indication of treatment, e.g., marker levels. Alternatively, dosages may be calculated based on the surface area or weight of the patient, as understood by those skilled in the art. The exact dosage is determined on a case-by-case basis, or, in some cases, at the informed discretion of the subject. A daily dosage regimen for an adult human patient may be, for example, oral administration of about 0.01 mg to about 10,000 mg, about 1 mg to about 5,000 mg, about 5 mg to about 2,000 mg, about 10 mg to about 1,000 mg, about 50 mg to about 500 mg, or about 100 mg to about 200 mg of pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, or a mixture of pentadecanoylcarnitine and pentadecanoic acid, or a salt thereof. A single dose, e.g., a minimum dose, can include about 0.01 mg, about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 900 mg, about 1000 mg, about 2000 mg, about 5000 mg, or more, or a range including and / or spanning the recited values. The dosage can be adjusted according to the subject's body mass, for example, the dosage, e.g., a minimum dosage, can be about 0.001 mg / kg, about 0.01 mg / kg, about 0.1 mg / kg, 0.3 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, or higher, or a range including and / or spanning the aforementioned values. For example, dosages may be from about 0.001 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 5 mg / kg, from about 0.3 mg / kg to about 3 mg / kg, or from about 1 mg / kg to about 3 mg / kg. Dosages may be a single administration, or a series of two or more administrations over the course of one or more days, as appropriate for the individual subject.In some embodiments, pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, is administered for a period of continuous therapy, for example, about one week or more (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or more), several weeks, about one month or more (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more), about one year or more, or multiple years. In some embodiments, pentadecanoylcarnitine or pentadecanoic acid, or a salt thereof, can be administered or taken once a day, twice a day, three times a day, or more.

[0170] As will be appreciated by those of skill in the art, in certain circumstances it may be necessary to administer the compounds disclosed herein in amounts outside the preferred dosage ranges, as set forth above, to effectively treat a subject.

[0171] The unit dosage form may also be provided, for example, in individual packages with a pre-measured amount of the composition designed to be administered on a predetermined schedule. A unit dosage form designed to be administered 1-3 times a day is preferred. However, in certain embodiments, it may be desirable to design the unit dosage form to be administered more than 3 times a day or less than once a day.

[0172] Dosage and interval can be adjusted for each subject to obtain sufficient plasma levels of active moiety to maintain a predetermined parameter, indicator, or marker value, or minimum effective concentration (MEC).The dosage required to achieve the desired result depends on individual characteristics and route of administration.However, serum concentration can be determined using assays, such as HPLC assays or bioassays.

[0173] In some embodiments, the compounds and methods provided herein are directed to compounds that are disclosed in, for example, U.S. Pat. Nos. 7,651,845; 8,251,904; 4,985,015; 8,827,957; 4,252,159; 5,318,521; 4,718,430; 9,713,600; 9,707,199; 9,687,461; 9,662,306; 9,561,206; U.S. Publication No. 2011 / 0190; 702; US Publication No. 2017 / 0266144, US Publication No. 2016 / 0324814, US Publication No. 2016 / 0195559, US Publication No. 2016 / 0195558, US Publication No. 2016 / 0193172, US Publication No. 2016 / 0193171, US Publication No. 2016 / 0193170, WO2016 / 111843, DE2615061, and can be used in conjunction with the device and method of using the device as provided in, for example, US Publication No. 2012 / 0072236. The contents of each of the aforementioned patent documents are incorporated herein by reference in their entirety. Diagnostics and Monitoring

[0174] Provided herein are methods for diagnosing and monitoring the conditions provided herein.

[0175] In some embodiments, the method of diagnosis or monitoring can include measuring the percentage of pentadecanoylcarnitine described herein in a fluid in the body. In some embodiments, the method of diagnosis or monitoring can include measuring a marker of a condition provided herein in a subject. In some embodiments, a correlation between one marker and another marker can prove instructive. In some embodiments, the condition provided herein can be diagnosed with reference to a threshold level of a marker of the condition, such as serum pentadecanoylcarnitine percentage, serum concentration of pentadecanoylcarnitine, serum total pentadecanoylcarnitine and pentadecanoic acid, or the ratio between pentadecanoylcarnitine and pentadecanoic acid. For example, the threshold can be determined with reference to a symptom or marker of the condition provided herein.

[0176] The percentage of pentadecanoylcarnitine or the condition markers provided herein in a subject can be monitored by any means.The sample for analysis can be obtained from any fluid or tissue of the subject.For example, it can be obtained from serum, plasma, red blood cell membrane, urine and feces. EXAMPLES

[0177] Example 1 A series of experiments were conducted to identify additional serum-based compounds associated with lower risk of chronic disease index in dolphins in addition to pentadecanoic acid. Promising compounds were then tested at various concentrations for direct, clinically relevant activity known to prevent, manage, treat or cure the chronic condition.

[0178] We hypothesized that downstream C15:0 metabolites may contribute to the health benefits observed in this case-control study in bottlenose dolphins fed a modified fish diet containing higher concentrations of C15:0 (Venn-Watson, S., Baird, M., Novick, B., Parry, C., Jensen, E. D., Modified fish diet shifted serum metabolome and alleviated chronic anemia in bottlenose dolphins (Tursiops truncatus): Potential role of odd-chain saturated fatty acids. PLoS ONE doi10.1371 / journal.pone.0230769 (2020)). To test this hypothesis, we assessed changes in the dolphin serum metabolome over the course of 0, 1, 3, and 6 months and compared them between baseline and modified fish-fed dolphins. method

[0179] Methods for this modified diet experiment, including metabolomics, were previously described (Venn-Watson, S., Baird, M., Novick, B., Parry, C., Jensen, E. D., Modified fish diet shifted serum metabolome and alleviated chronic anemia in bottlenose dolphins (Tursiops truncatus): Potential role of odd-chain saturated fatty acids. PLoS ONE doi10.1371 / journal.pone.0230769 (2020)) and included bioinformatics, principal component analysis, hierarchical clustering, and random forest regression to identify metabolites that best predicted dolphins fed the modified diets versus the baseline diet. Bioinformatics

[0180] The informatics system consisted of four main components: a Laboratory Information Management System (LIMS), data extraction and peak identification software, data processing tools for QC and compound identification, and a set of information interpretation and visualization tools for use by data analysts. The hardware and software foundation for these informatics components was a LAN backbone and a database server running Oracle 10.2.0.1 Enterprise Edition. Peaks were quantified using area under the curve. For experiments spanning multiple days, a data normalization step was performed to correct for variability resulting from instrument day-to-day tuning differences. Essentially, each compound was corrected in a block of operating days by registering the mean equal to one (1.00), and each data point was normalized by proportion (referred to as "block correction"). For experiments that did not require analysis for more than one day, no normalization was necessary other than for data visualization purposes. In certain cases, biochemical data may be normalized to additional factors (e.g., cell number, total protein as determined by Bradford assay, osmolality, etc.) that account for differences in metabolite levels due to differences in the amount of material present in each sample. A two-way ANOVA main effects model, including experimental group, month, and sex, was used to determine the main drivers of differences in the metabolome. Principal Component Analysis and Hierarchical Clustering

[0181] Each principal component was a linear combination of all metabolites, and the principal components were uncorrelated. The number of principal components was equal to the number of observations. The first principal component was calculated by determining the coefficients of the metabolites with the highest variance of the linear combination. The second component was found to have the highest variance coefficient, provided that the second component was orthogonal to the first. The third component was orthogonal to the first two components. The total variance was defined as the sum of the variance of the predicted values ​​of each component (variance is the square of the standard deviation), and for each component, the percentage of the total variance was calculated. Hierarchical clustering to cluster the data was used as unsupervised learning to show any large differences. Complete clustering using Euclidean distance was applied, where each sample was a vector with the values ​​of all metabolites. Random Forest Regression

[0182] Random forests, a supervised classification technique based on an ensemble of decision trees, were used to obtain rank orderings of the "importance" of serum biochemicals that were altered by the modified diet. A random subset of the data with information identifying the true class was selected to create a tree (the "bootstrap sample" or "training set"), and the remaining data "out-of-bag" (OOB) variables were then passed down the tree to obtain class predictions for each sample. This process was repeated thousands of times to generate the forest. The final classification of each sample was determined by calculating class prediction frequencies ("votes") for OOB variables across the forest. The method was unbiased, since predictions for each sample were based on trees constructed from a subset of samples that did not contain that sample. Once the entire forest was grown, the class predictions were compared to the true classes to generate an "OOB error rate" as a measure of prediction accuracy. Prediction accuracy was thus an unbiased prediction of how well the sample classes could be predicted in a new data set. To determine which biochemicals contributed most to the classification, a "variable importance" measure was calculated. "Diminished Prediction Accuracy" (MDA) was used as this metric. MDA was determined by randomly permuting the order of variables, running the observed values ​​through the tree, and then re-evaluating the predictive accuracy. result

[0183] Within one month of feeding the modified fish diet (which was sustained through 6 months), FIG. 1A shows an increase in serum pentadecanoic acid (C15:0) and FIG. 1B shows an increase in pentadecanoylcarnitine concentrations. Using ANOVA contrast models, there were no significant differences in serum C15:0 or pentadecanoylcarnitine concentrations between cases and controls at baseline (month 0) (p=0.81 for C15:0 and p=0.86 for pentadecanoylcarnitine), but both serum C15:0 and pentadecanoylcarnitine concentrations were higher in cases compared to controls at month 1 (p<0.0001 for C15:0 and p<0.0001 for pentadecanoylcarnitine), month 3 (p<0.0001 for C15:0 and p<0.0001 for pentadecanoylcarnitine), and month 6 (p<0.0001 for C15:0 and p<0.0001 for pentadecanoylcarnitine). As outlined in Table 1, both C15:0 (pentadecanoic acid) and pentadecanoylcarnitine were ranked within the top 30 important biochemical predictors in dolphins fed the modified fish diet by month 1. Furthermore, as the experiment progressed from month 1 to month 6, pentadecanoylcarnitine's ranking increased to become the most important biochemical in dolphins fed the modified diet. [Table 1]

[0184] Example 2 Given that increased circulating concentrations of pentadecanoylcarnitine were observed in dolphins fed the modified fish diet, it was hypothesized that higher serum pentadecanoylcarnitine concentrations would correlate with changes in clinically relevant indicators. method

[0185] Methods for this correlation experiment have been described previously (Venn-Watson, S., Baird, M., Novick, B., Parry, C., Jensen, E. D., Modified fish diet shifted serum metabolome and alleviated chronic anemia in bottlenose dolphins (Tursiops truncatus): Potential role of odd-chain saturated fatty acids. PLoS ONE doi10.1371 / journal.pone.0230769 (2020)) and included Pearson's correlation to assess correlations between serum pentadecanoylcarnitine concentrations and relative changes in log-transformed cholesterol, glucose, hemoglobin, red blood cell count, and platelets, as well as Spearman's correlations for glomerular filtration rate and insulin. result

[0186] Table 2 shows that the increased serum pentadecanoylcarnitine concentrations observed in the modified diet study correlated with lower cholesterol and lower insulin. Increased serum pentadecanoylcarnitine concentrations correlated with higher hemoglobin, red blood cell count, platelets, and glomerular filtration rate. These data support that increased serum pentadecanoylcarnitine concentrations can play a role in improving chronic conditions, including hypercholesterolemia, hyperinsulinemia, anemia, thrombocytopenia, and renal disease. [Table 2]

[0187] Example 3 Given our previous demonstration of biologically relevant activity of C15:0 in human cell lines mimicking various chronic disease conditions, including reduced inflammation and fibrosis (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep 10:8161 (2020)), it was hypothesized that pentadecanoylcarnitine would have similar biologically relevant activity. method

[0188] The method for this human primary cell phenotypic profiling experiment was that described previously (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep 10:8161 (2020)). Significant activity of pentadecanoylcarnitine was equal to or greater than 0.1|log10| at 6.7 μM. Biomarkers with significant changes caused by pentadecanoylcarnitine were compared to results from the same experiment using pentadecanoic acid (C15:0). result

[0189] Table 3 demonstrates clear differences in primary cell-based activities between pentadecanoylcarnitine and pentadecanoic acid. Of the 24 identified biological activities elicited by pentadecanoylcarnitine, no specific biomarkers were significantly altered in the same direction as pentadecanoic acid.

[0190] This experiment confirms that pentadecanoylcarnitine has biological activity relevant to preventing, managing or treating autoimmune diseases, allergies, asthma, chronic inflammation, cardiovascular disease, oncology, chronic obstructive pulmonary disease, pulmonary inflammation, restenosis, fibrosis, dermatitis, psoriasis, and wound healing, which is surprisingly distinct from pentadecanoic acid. [Table 3]

[0191] Example 4 Given that pentadecanoylcarnitine has been demonstrated as a biologically active compound in human cell systems mimicking various pathological conditions, it was hypothesized that pentadecanoylcarnitine may have receptor-based pharmacological activity. method

[0192] The method for this experiment has been described previously (Venn-Watson, S., Lumpkin, R., Dennis, EA, Efficacy of dietary odd-chain saturated fatty acid pentadecanoic acid parallels broad associated health benefits in humans: could it be essential? Sci Rep 10:8161 (2020)). Significant activity of pentadecanoylcarnitine was activity labeled as having 70% or greater maximal pharmacological activity equal to that of the internal control at concentrations between 1 and 20 μM. Significant pharmacological activity caused by pentadecanoylcarnitine was compared to results obtained from the same assay using pentadecanoic acid (C15:0). result

[0193] Table 4 shows several pharmacological activities of pentadecanoylcarnitine at RC50 concentrations between approximately 3 and 10 μM, which are almost in agreement with the maximum activity of the positive control.

[0194] Pentadecanoylcarnitine is a cannabinoid receptor 1 and receptor 2 agonist at approximately 1-20 μM, further supporting its role in preventing, managing and treating cardiovascular disease, cancer, inflammation, arthritis and cholestatic pruritus (as shown at 6.7 μM in Example 3). Compounds with these activities have also been used or proposed to be used to prevent, combat, or treat nausea, obesity, neuropathic pain associated with multiple sclerosis, pain, gastrointestinal disorders, atherosclerosis, symptoms of multiple sclerosis, spinal cord injury, Alzheimer's disease, and amyotrophic lateral sclerosis, tics and behavior problems associated with Tourette's syndrome, anxiety disorders, attention deficit hyperactivity disorder, depression, brain injury, tardive dyskinesia, glaucoma, and cough (Pertwee, R. G., Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 156:397-411 (2009); Bryk, M. and Starowicz, K., Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain: an updated review. Pharmacol Rep 73:681-699 (2021).

[0195] The two most potent endocannabinoids (also called endogenous cannabinoids) are anandamide and 2-arachidonoylglyerol (Battista, N., Tommaso, MD, Bari, M., Maccarrone, M., The endocannabinoid system: a review. Front Behav Neurosci doi 10.3389 / fnbeh.2012.00009 (2012)).

[0196] Bouchouriab, FZ, Fortin, M., Noll, C., Dube, J., Carpentier, A.C., Plasma palmitoyl-carnitine (AC16:0) is a marker of increased postprandial nonesterified incomplete fatty acid oxidation rate in adults with type 2 diabetes. Can J Diabetes 42:382-388.e1 (2018). These compounds bind to and activate both cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors, as well as peroxisome proliferator-activated receptors (PPARs), which are found throughout the body. Through these mechanisms, endocannabinoids that occur naturally in the body have demonstrated a wide array of health benefits, including those related to modulating memory, cancer, appetite, fertility, pain, obesity, nausea, osteoarthritis, cardiovascular disease, metabolic disorders, liver disease, inflammation, and neurological and neuropsychiatric disorders (Ligresti, A., Petrosino, S., Di Marzo, V., From endocannabinoid profiling to 'endocannabinoid therapeutics'. Curr Opin Chem Biol, 13:21-31 (2009)).

[0197] Pentadecanoylcarnitine is a histamine H1 and H2 receptor antagonist at approximately 1-20 μM, further supporting its role in preventing, managing and treating allergies, asthma and dermatitis (as shown in Example 3 at 6.7 μM). Compounds with these activities are also used to manage or treat other hypersensitivity disorders and peptic ulcers.

[0198] Pentadecanoylcarnitine is a dopamine receptor D1 antagonist at approximately 1-20 μM. Compounds with these activities have been used or proposed to be used to prevent, manage, or treat neurological disorders, including Parkinson's disease, as well as psychiatric disorders, schizophrenia, cocaine abuse, obesity, pathological gambling, and Tourette's syndrome.

[0199] Pentadecanoylcarnitine is an α2A adrenergic receptor agonist at approximately 1-20 μM, further supporting its role in preventing, managing and treating allergic reactions, asthma, nasal and sinus congestion, allergic rhinitis and facial rash associated with rosacea (as shown in Example 3 at 6.7 μM). Compounds with these activities have been used or proposed to be used to aid in weight loss.

[0200] Pentadecanoylcarnitine is a cholinergic receptor muscarinic 1 antagonist at about 1-20 μM, further supporting its role in preventing, managing and treating allergies, chronic obstructive pulmonary disease (COPD) and asthma (as shown in Example 3 at 6.7 μM). Compounds with these activities have been used or proposed to be used to prevent, manage or treat movement disorders including Parkinson's disease, sleep disorders, nausea, inflammatory bowel syndrome spasticity, psychiatric disorders, peptic ulcers, overactive bladder and depression.

[0201] Pentadecanoylcarnitine is a SERT blocker at approximately 1-20 μM. Compounds with these activities have been used or proposed to be used to prevent, manage, or treat depression and obsessive-compulsive disorder.

[0202] Pentadecanoylcarnitine is a 5-HT1A receptor agonist at approximately 1-20 μM. Compounds with these activities have been used or proposed to be used to regulate mood, sleep, nausea, sexuality and appetite, including, for example, increasing sociability, reducing impulsivity, promoting sexual drive and arousal, attenuating food intake, and prolonged REM sleep. Compounds that activate this receptor have also been used as a means to prevent, manage, and treat depression, migraine, bipolar disorder, anxiety, hypertension, pain, schizophrenia, Parkinson's disease, aggression, drug-seeking behavior, and opioid-induced respiratory depression.

[0203] Pentadecanoylcarnitine is a 5-HT1B receptor agonist at approximately 1-20 μM. Compounds with these activities have been used or proposed to be used to manage depression and anxiety, and to reduce aggression and impulsivity.

[0204] In summary, this experiment identifies pentadecenoyl carnitine as a newly discovered endocannabinoid that fully activates both cannabinoid 1 and 2 receptors at concentrations between 1 and 20 μM. [Table 4]

[0205] Various literature references contain teachings related to fatty acid supplementation, including: Greenberg JA, Bell SJ, Ausdal WV. Omega-3 Fatty Acid supplementation during pregnancy. Reviews in obstetrics & gynecology 2008, 1:162-169; Mihalik, SJ, Goodpaster, BH, Kelley, DE, Chace, DH, Vockley, J., Toledo, FGS, et al., Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity 18:1695-1700 (2010); Venn-Watson, S., Parry, C., Baird, M., Stevenson, S., Carlin, K., Daniels, R, et al., Increased dietary intake of saturated fatty acid heptadecanoic acid(C17:0)associated with decreasing ferritin and alleviated metabolic syndrome in dolphins.PLoS ONE doi10.1371(2015);Venn-Watson, S., Smith, CR, Stevenson, S., Parry, C., Daniels, R., Jensen, E. et al., Blood-based indicators of insulin resistance and metabolic syndrome in bottlenose dolphins(Tursiops truncatus).Front Endocrinol:10.3389(2013);Venn-Watson, S., Benham, C., Carlin, K., DeRienzo, D., St. Leger, J., Hemochromatosis and fatty liver disease: building evidence for insulin resistance in bottlenose dolphins (Tursiops truncatus). J Zoo Wildlf Med 43:10. 1638 pages (2012); Venn-Watson, S., Smith, CR, Gomez, F., Jensen, ED, Physiology of aging among healthy, older bottlenose dolphins (Tursiops truncatus): comparisons with aging humans. J Comp Physiol 181: 667-680 pages (2011). Exemplary Compositions, Uses, and Methods

[0206] Composition 1: Aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety, anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric disorders, mental conditions, metabolic disorders, migraine, nasal congestion, sinus congestion, nausea, neurological disorders associated with multiple sclerosis 1. A composition for the treatment, management, amelioration, or prevention of a condition selected from the group consisting of crippling pain, symptoms of multiple sclerosis, neurological disorders, neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics associated with Tourette's syndrome, and behavior problems associated with Tourette's syndrome, comprising pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0207] Composition 2: A composition for supporting appetite, cardiovascular health, hematological health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, sociability, metabolic health, hematological health, renal health, and weight loss, comprising pentadecanoylcarnitine or pentadecanoic acid or a pharma-ceutically acceptable salt, solvate, or stereoisomer thereof.

[0208] Composition 3: Composition 1 or 2 containing pentadecanoylcarnitine.

[0209] Composition 4: Composition 1 or 2 containing pentadecanoic acid.

[0210] Composition 5: Composition 1 or 2 comprising pentadecanoylcarnitine and pentadecanoic acid.

[0211] Composition 6: Any one of Compositions 1-5, designed to administer 0.1 mg to 50 mg per kg of body weight, optionally 0.3 mg to 5 mg per kg of body weight, of pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.

[0212] Composition 7: Any one of compositions 1 to 6, designed to be administered once daily.

[0213] Composition 8: Any one of compositions 1 to 7, in a unit dosage form comprising 0.01 mg to 10,000 mg, optionally 10 mg to 200 mg, of pentadecanoylcarnitine or pentadecanoic acid or a pharma- ceutically acceptable salt, solvate, stereoisomer, or ester thereof.

[0214] Composition 9: Any one of Compositions 1-7, in a form selected from the group consisting of a food product, a dietary supplement, a unit dosage form, a prescription drug, or a pharmaceutical.

[0215] Composition 10: Any one of Compositions 1 to 7, in a form selected from the group consisting of nutritional supplements, medical foods, food additives, food fortifiers, beverage additives, beverage fortifiers, fortified foods, fortified beverages, foods with additives added, and beverages with additives added.

[0216] Use 11: Use of any one of compositions 1 to 10 in the manufacture of a medicament for achieving a body concentration of pentadecanoylcarnitine of 1 μM to 20 μM.

[0217] Method 12: Aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety, anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric disorders, mental conditions, metabolic disorders, migraine, nasal congestion, sinus congestion, nausea, neuropathic pain associated with multiple sclerosis, multiple sclerosis 20. A method for the treatment, management, amelioration, or prevention of a condition selected from the group consisting of symptoms of chronic kidney disease, neurological disorders, neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcers, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics associated with Tourette's syndrome, and behavior problems associated with Tourette's syndrome, comprising the step of administering to a subject in need thereof an effective amount of pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0218] Method 13: A method for assisting with appetite, cardiovascular health, hematological health, memory, metabolic health, mood, long REM sleep, renal health, sexuality, sociability, metabolic health, hematological health, renal health, and weight loss, the composition comprising administering to a subject in need thereof an effective amount of pentadecanoylcarnitine or pentadecanoic acid or a pharma-ceutically acceptable salt, solvate, or stereoisomer thereof.

[0219] Method 14: Method 12 or 13, wherein a systemic concentration of pentadecanoylcarnitine of 1 μM to 20 μM is achieved in the subject.

[0220] Method 15: Methods 12-14, wherein pentadecanoylcarnitine is administered.

[0221] Method 16: Methods 12-14, wherein pentadecanoic acid is administered.

[0222] Method 17: Methods 12-14, wherein pentadecanoylcarnitine and pentadecanoic acid are administered.

[0223] Method 18: Methods 12-17, wherein 0.1 mg to 50 mg per kg of body weight, optionally 0.3 mg to 5 mg per kg of body weight of pentadecanoylcarnitine or pentadecanoic acid or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof is administered.

[0224] Method 19: Methods 12-18, wherein pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered once daily.

[0225] Method 20: Methods 12-19, wherein the pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is a unit dosage form comprising 0.01 mg to 10,000 mg, optionally 10 mg to 200 mg of pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, stereoisomer, or ester thereof.

[0226] Method 21: Methods 12-20, wherein pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered in a form selected from the group consisting of a food product, a dietary supplement, a unit dosage form, a prescription drug, or a pharmaceutical.

[0227] Method 22: Methods 12-20, wherein pentadecanoylcarnitine or pentadecanoic acid, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is administered in a form selected from the group consisting of a dietary supplement, a medical food, a food additive, a food fortifier, a beverage additive, a beverage fortifier, an enriched food, an enriched beverage, an additive-added food, and an additive-added beverage.

[0228] Dietary Supplement 23: A dietary supplement comprising pentadecanoylcarnitine, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0229] Dietary supplement 24: A dietary supplement 23 configured to administer at least 0.1 mg per kg of body weight, optionally at least 0.3 mg per kg of body weight, and optionally at least 1 mg per kg of body weight of pentadecanoylcarnitine, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, to a subject in need thereof.

[0230] Dietary Supplement 25: Any one of Dietary Supplements 23-24, configured to administer to a subject in need thereof 0.1 mg to 50 mg per kg of body weight, and optionally 0.3 mg to 5 mg per kg of body weight, of pentadecanoylcarnitine, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0231] Dietary Supplement 26: Any one of Dietary Supplements 23 to 25, configured to be administered once daily.

[0232] Dietary Supplement 27: Any one of Dietary Supplements 23 to 26, which is a unit dosage form containing 0.01 mg to 10,000 mg, optionally 1 mg to 1,000 mg, optionally 10 mg to 200 mg of pentadecanoylcarnitine, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0233] Dietary Supplement 28: Any one of Dietary Supplements 23 to 27 in the form of a pharmaceutical or prescription drug.

[0234] Dietary supplement 29: Any one of dietary supplements 23 to 27, in a form selected from the group consisting of food products, medical foods, food additives, food fortifiers, beverage additives, beverage fortifiers, fortified foods, fortified beverages, foods with additives added, and beverages with additives added.

[0235] Dietary Supplement 30: Any one of Dietary Supplements 23 to 27 in the form of a food product.

[0236] Dietary supplement 31: Any one of dietary supplements 23 to 27 in the form of a medical food.

[0237] Dietary supplement 32: Any one of dietary supplements 23 to 27 in the form of a food additive.

[0238] Dietary Supplement 33: Any one of Dietary Supplements 23 to 27 in the form of a food fortifier.

[0239] Dietary Supplement 34: Any one of Dietary Supplements 23 to 27 in the form of a beverage additive.

[0240] Dietary Supplement 35: Any one of Dietary Supplements 23 to 27 in the form of a beverage enhancer.

[0241] Dietary Supplement 36: Any one of Dietary Supplements 23 to 27 in the form of a fortified food.

[0242] Dietary Supplement 37: Any one of Dietary Supplements 23 to 27 in the form of a fortified beverage.

[0243] Dietary Supplement 38: Any one of Dietary Supplements 23 to 27 in the form of a food to which additives have been added.

[0244] Dietary Supplement 39: Any one of Dietary Supplements 23 to 27 in the form of a beverage to which additives have been added.

[0245] Dietary Supplement 40: Any one of Dietary Supplements 23 to 39, for veterinary use.

[0246] Dietary Supplement 41: Any one of Dietary Supplements 23 to 39, for human use.

[0247] Composition 42: A composition substantially as described herein.

[0248] Method 43: A method substantially as described herein.

[0249] Use 44: A use substantially as described herein.

[0250] While the present disclosure has been illustrated and described in detail in the drawings and the foregoing description, such illustration and description are considered to be illustrative or exemplary and not restrictive. The present disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the drawings, the disclosure, and the appended claims.

[0251] All references cited herein are incorporated herein by reference in their entirety. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the specification is intended to supersede and / or precede any such conflicting material.

[0252] Unless otherwise defined, all terms (including technical and scientific terms) shall be given their ordinary and customary meanings to those skilled in the art and shall not be limited to any special or customized meaning unless expressly defined as such herein. It should be noted that when a particular terminology is used in describing a particular feature or embodiment of the present disclosure, it should not be taken to mean that the terminology is redefined herein to be limited to including any particular feature of the feature or embodiment of the disclosure to which the terminology is attached. Terms and phrases used in this application, and in particular in the appended claims, and variations thereof, unless expressly stated otherwise, should be construed as open-ended as opposed to limiting. As an example of the foregoing, the term "including" should be read to mean "including, without limitation," "including but not limited to," and the like. The term "comprising," as used herein, has the same meaning as "including," "containing," or "characterized by," and is inclusive or open-ended, and does not exclude additional, unmentioned elements or method steps. The term "having" should be interpreted as "having at least." The term "includes" should be interpreted as "includes but is not limited to." The term "example" is used to provide illustrative instances of the item under discussion, not an exhaustive or limiting list thereof.Adjectives such as "known," "normal," "standard," and terms of similar import should not be construed as being limited to the items described for a given time frame or available at a given time, but instead should be read to encompass known, normal, or standard technology that may be available or known at any time now or in the future. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood to imply that a particular feature is critical, essential, or even important to the structure or function of the invention, but instead are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Similarly, a group of items joined by the conjunction "and" should not be read as requiring that every single one of the items be present in the group, but rather as "and / or," unless expressly stated otherwise. Similarly, a group of items joined by the conjunction "or" should not be read as requiring mutual exclusivity among the group, but rather as "and / or" unless expressly stated otherwise.

[0253] As used in the claims that follow and throughout this disclosure, the phrase "consisting essentially of" is meant to include any elements recited after the phrase, limited to other elements that do not interfere with or contribute to the activity or function specified in this disclosure for the recited elements. Thus, the phrase "consisting essentially of" suggests that the recited elements are required or mandatory, but that other elements are optional and may or may not be present depending on whether they affect the activity or function of the recited elements.

[0254] Where a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of the range, are encompassed within an embodiment.

[0255] With respect to the use of virtually any plural and / or singular term herein, one of ordinary skill in the art can translate from plural to singular and / or from singular to plural, where appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for purposes of clarity. The indefinite article "a" or "an" does not exclude a plurality. A single quantifier or other unit may fulfill the function of several items recited in a claim. The mere fact that certain measurements are recited in mutually different dependent claims does not suggest that a combination of these measurements cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0256] Those skilled in the art further understand that if a specific number of recitations of introduced claims are intended, such intention is explicitly recited in the scope of the claim, and that in the absence of such recitation, no such intention exists. For example, to aid in understanding, the following appended claims may contain the use of the introductory phrases "at least one" and "one or more" to introduce the recitation of claims. However, even if the same claim contains the introductory phrases "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be normally interpreted to mean "at least one" or "one or more"), the use of such phrases should not be interpreted as meaning that the introduction of the recitation of claims with the indefinite article "a" or "an" limits any particular claim containing such an introduced recitation of claims to an embodiment containing only one such recitation. The same applies to the use of definite articles used to introduce the recitation of claims. In addition, even if a particular number introduced in a recitation of a claim is explicitly recited, those skilled in the art will recognize that such recitation should generally be interpreted to mean at least the recited number (e.g., a minimum recitation of "two recitations" without other qualifiers generally means at least two recitations, or more than two recitations). Furthermore, in instances where a conventional expression similar to "at least one of A, B, and C, etc." is used, such a structure generally intends the conventional expression to have the meaning as understood by those skilled in the art (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together).In instances where a conventional expression similar to "at least one of A, B, or C, etc." is used, such construction generally intends the conventional expression to have the meaning as understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A only, B only, C only, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). One of ordinary skill in the art will further appreciate that substantially any disjunctive word and / or disjunctive phrase expressing two or more alternative terms, whether in the description, claims, or drawings, should be considered to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0257] All numbers expressing quantities of ingredients, reaction conditions, and the like used in the specification are to be understood in all instances to be modified by the term "about." Accordingly, unless specifically indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0258] Moreover, although the foregoing description has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced. Thus, the description and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but should be construed as covering all modifications and alternative forms that come with the true scope and spirit of the invention.

Claims

1. Aggression, allergies, allergic rhinitis, Alzheimer's disease, anxiety, anxiety disorders, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, attention deficit hyperactivity disorder, bipolar disorder, brain injury, cancer, cardiovascular disease, cholestatic pruritus, depression, chronic obstructive pulmonary disease (COPD), cocaine abuse, cough, dermatitis, depression, drug-seeking behavior, gastrointestinal disorders, facial erythema associated with rosacea, glaucoma, liver disease, overactive bladder, hypersensitivity disorders, hypertension, impulsivity, inflammation, psychiatric disorders, mental conditions, metabolic disorders , migraine, nasal congestion, sinus congestion, nausea, neuropathic pain associated with multiple sclerosis, symptoms of multiple sclerosis, neurological disorders, neuropsychiatric disorders, obesity, obsessive-compulsive disorder, opioid-induced respiratory depression, osteoarthritis, pain, Parkinson's disease, pathological gambling, peptic ulcer disease, schizophrenia, sleep disorders, spinal cord injury, tardive dyskinesia, tics associated with Tourette's syndrome, behavioral problems associated with Tourette's syndrome, A composition comprising pentadecanoylcarnitine or pentadecanoic acid or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. 1. A composition for supporting appetite, cardiovascular health, hematological health, memory, metabolic health, mood, long REM sleep, kidney health, sexuality, sociability, metabolic health, hematological health, kidney health, and weight loss, comprising: A composition comprising pentadecanoylcarnitine or pentadecanoic acid or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. 3. The composition of claim 1, comprising pentadecanoylcarnitine.

4. 3. The composition of claim 1, further comprising pentadecanoic acid.

5. 3. The composition of claim 1, comprising pentadecanoylcarnitine and pentadecanoic acid.

6. 3. The composition of claim 1 or 2, configured to administer 0.1 mg to 50 mg of pentadecanoylcarnitine or pentadecanoic acid, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, per kg of body weight to a subject in need thereof.

7. 3. The composition of claim 1 or 2, adapted for once-daily administration.

8. 3. The composition of claim 1 or 2, in unit dosage form, comprising 0.01 mg to 10,000 mg of the pentadecanoylcarnitine or pentadecanoic acid, or a pharmaceutically acceptable salt, solvate, stereoisomer, or ester thereof.

9. 3. The composition of claim 1 or 2, in a form selected from the group consisting of a foodstuff, a dietary supplement, a unit dosage form, a prescription drug, or a pharmaceutical.

10. 3. The composition of claim 1 or 2, in a form selected from the group consisting of nutritional supplements, medical foods, food additives, food fortifiers, beverage additives, beverage fortifiers, fortified foods, fortified beverages, foods with added additives, and beverages with added additives.

11. 3. Use of the composition according to claim 1 or 2 in the manufacture of a medicament for achieving a body concentration of pentadecanoylcarnitine of 1 μM to 20 μM.

12. A dietary supplement comprising pentadecanoylcarnitine, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

13. 13. The dietary supplement of claim 12, configured to administer at least 0.1 mg of said pentadecanoylcarnitine, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, per kg of body weight to a subject in need thereof.

14. 13. The dietary supplement of claim 12, configured to administer 0.1 mg to 50 mg of said pentadecanoylcarnitine, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, per kg of body weight to a subject in need thereof.

15. 13. The dietary supplement of claim 12, adapted for once-daily administration.

16. 13. The dietary supplement of claim 12, in a unit dosage form containing 0.01 mg to 10,000 mg of said pentadecanoylcarnitine, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

17. 13. The dietary supplement of claim 12 in the form of a pharmaceutical or prescription drug.

18. 13. The nutritional supplement of claim 12, in a form selected from the group consisting of foodstuffs, medical foods, food additives, food fortifiers, beverage additives, beverage fortifiers, fortified foods, fortified beverages, food with added additives, and beverage with added additives.

19. 19. A dietary supplement according to any one of claims 12 to 18 for veterinary use.

20. 19. A dietary supplement according to any one of claims 12 to 18 for human use.

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