Vitamin B supplement for treating pituitary intermediate dysfunction (PPID) of equine animals

Abstract

Provided herein are compositions comprising nicotinic acid, a vitamin B3-related nicotinamide adenine dinucleotide precursor, or a combination thereof for use as a medicament, a food supplement, or the like. These compositions are provided to treat and prevent the progression of pituitary intermediate dysfunction (PPID) in non-human animals, such as equine animals.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority of U.S. Patent Application Serial No. 63 / 387,585, filed on December 15, 2022, which is incorporated herein by reference in its entirety. Technical field

[0003] The subject matter of the present disclosure relates to dietary supplements having nicotinic acid and nicotinamide adenine dinucleotide (NAD+) precursors related to vitamin B3, to maintain the health of equids suffering from pars intermedia dysfunction (PPID), slow the progression of PPID, reduce the circulating concentration of adrenocorticotropic hormone (ACTH), and maintain neuronal health in equids. Background art

[0004] Domesticated ponies and horses (Equus caballus) 15 years of age or older are classified as geriatric, and they represent a substantial and apparently increasing proportion of the equine population (Jarvis et al., 2019). As with all animals, equids are at increased risk of certain disorders with aging (Jarvis et al., 2019). The most common endocrine disorder in geriatric equids is pars intermedia dysfunction (PPID) (Tatum et al., 2021).

[0005] PPID is characterized by hyperplasia, hypertrophy, and adenoma or microadenoma formation in the pars intermedia (PI) (McFarlane & Holbrook, 2008; Tatum et al., 2021). The chronic, progressive nature of PPID means that increasing age is a risk factor for its development, and the prevalence has been reported to exceed 20% in horses over 15 years of age (Ireland and McGowan, 2018) and over 25% in horses over 20 years of age (Ballou et al., 2020). In a later study, PPID was the second most common disorder in geriatric horses, second only to osteoarthritis. The reported clinical signs of PPID are diverse and include hypertrichosis / hirsutism, weight loss, abnormal fat redistribution, muscle wasting / atrophy, lethargy and depression, polyuria / polydipsia, and concurrent infectious diseases (Horn et al., 2019, Gallinelli et al., 2022). Laminitis, a painful and often euthanasia - requiring condition, is also frequently reported in cases of PPID. Laminitis is thought to occur primarily in PPID cases with insulin dysregulation (ID) (Tadro et al., 2019).

[0006] Measurement of baseline plasma adrenocorticotropic hormone (ACTH) concentration is the most commonly used method for diagnosing PPID worldwide (Horn & Bertin 2019). However, the thyrotropin-releasing hormone (TRH) stimulation test is a dynamic test that has been shown to be more sensitive for the diagnosis of PPID, particularly in the early stages of the disease when clinical signs are not obvious or when baseline ACTH concentrations are still within the reference range.

[0007] The pituitary gland consists of four distinct regions with different functions: the pars distalis, pars intermedia (PI), pars tuberalis (adenohypophysis), and pars nervosa (neurohypophysis). The PI contains endocrine cells (melanotrophs) that produce polypeptide derivatives of the prohormone protein pro-opiomelanocortin (POMC). After extensive tissue-specific cleavage, these substances specifically produce α-melanocyte-stimulating hormone (α-MSH), β-endorphin (β-end), corticotropin-like intermediate lobe peptide (CLIP), and a small amount of adrenocorticotropic hormone (ACTH) (Horn et al., 2019). These melanotroph endocrine cells are stimulated by the nerve endings of hypothalamic dopaminergic neurons, resulting in the secretion of dopamine, which inhibits POMC transcription and the release of POMC peptides through a negative feedback system (Hart et al., 2020). The pathophysiology of PPID is associated with the progressive degeneration of hypothalamic dopaminergic neurons, leading to the loss of tonic inhibitory control of melanotrophs in the pars intermedia of the pituitary gland (Van Der Kolk et al., 2004; and McFarlane, 2011). Oxidative stress has been shown to be involved in the pathophysiology (Tatum et al., 2020). In healthy equids, ACTH is mainly produced in the pars distalis; however, in equids with PPID, ACTH is overproduced in the PI, along with a variety of other small POMC molecules, which makes the PI unique to equids.

[0008] Currently, the main pharmacological treatment for PPID is the administration of pergolide mesylate, which is a dopamine receptor agonist previously used to treat Parkinson's disease and has been shown to result in clinical improvement (Schott et al., 2019; Tatum et al., 2020; and Van Camp et al., 2004). Mitochondrial dysfunction and oxidative damage have been proposed as key mechanisms in many neurodegenerative diseases, including Parkinson's disease (Schondorg et al., 2018) and PPID (Clover et al., 2009; and Tatum, 2020). Studies have shown that supplementing nicotinamide adenine dinucleotide (NAD+) precursors can be a viable clinical approach to explore Parkinson's disease (Schondorg et al., 2018). Although some recent studies using proteasome inhibitors and lactacystin-induced Parkinson's disease models have suggested possible short-term benefits, in the long term, at least nicotinamide ribose supplementation may downregulate dopamine production (Turconi et al., 2021).

[0009] NAD+ is an essential cofactor involved in many cellular processes, including energy metabolism and aging. Longevity proteins (SIRT) and poly ADP-ribose polymerases (PARP) are NAD+-dependent proteins and enzymes that consume NAD+ in various reactions, thus depleting the cellular NAD+ pool. Therefore, continuous replenishment of NAD+ reserves is required to maintain the normal operation of these processes within the cell. NAD+ is synthesized by various methods: the metabolism of dietary niacin in the Preiss-Handler pathway; the conversion of the amino acid tryptophan through de novo synthesis; and the recycling of nicotinamide (NAM).

[0010] Increasing the NAD+ precursor pool and thus the potential concentration of NAD+ helps to restore mitochondrial dysfunction in horses, reduce oxidative stress and age-related dopamine neuron loss, thereby improving clinical symptoms associated with PPID, reducing circulating ACTH symptoms and potentially slowing the disease progression in animals presenting early symptoms of PPID. Achieving this goal through nutritional means, without the need for expensive pharmacological treatments associated with side effects such as anorexia, lethargy and diarrhea in approximately one-third of cases (Tatum et al., 2020) or as an adjunct to such treatments, would be very beneficial in reducing costs and the risk of side effects at lower doses.

[0011] Tryptophan supplementation is associated with excitatory and sedative effects in horses, and high doses can result in symptoms of hemolytic anemia and respiratory distress (Davis et al., 2017). Therefore, tryptophan supplementation is not a suitable route to increase NAD+ precursors in horses.

[0012] Equine feeds contain varying amounts of naturally occurring niacin, but in grains for example, most of the niacin is in an unavailable bound form. The niacin content in green grass has been reported as 37 mg (13 mg / kg dry matter to 57 mg / kg dry matter), although this can vary widely depending on environmental stress, and levels in timothy grass have been reported as 24 mg / kg. Horses that are fed mainly green forage can ingest up to 1.5 g / day / 500 kg horse (assuming maximum intake of about 5% BW / day, highest levels and 100% availability), but can ingest less than 100 mg if forage intake is restricted. Currently, NRC 2007 does not have a recommended daily niacin intake for horses, while INRA 1990 recommends a dietary requirement of 0.4 mg / kg Bw / day (i.e., 200 mg / day) for intensively working horses, and a daily requirement of usually 12 mg niacin / kg dry matter dietary intake (i.e., about 120 mg / day) for adult horses (NRC 2007; and INRA 1990).

[0013] Due to reported side effects, niacin (NA) has been shown to be more tolerable than nicotinamide (NRC 2007). In other species, adverse effects of NA on fatty acid mobilization (Parker et al., 1997) as well as flushing have been reported, meaning that NA is not considered a good potential therapeutic target for Parkinson's disease in humans (Brady et al., 2020).

[0014] In horses, the potential role of niacin as a putative supplement has been evaluated (Parker et al., 1997). However, in exercising horses, feeding 3 g / day to adult thoroughbreds of approximately 500 kg for 6 weeks showed no obvious benefits and no adverse effects were measured (Parker et al., 1997). The niacin status measured by the ratio of NAD:NADP in red blood cells was not affected by this supplement level. However, this may reflect the sampling time after feeding (approximately 12 hours) and the dose used not being optimal (Pollard et al., 2021, 2022). Additionally, this could indicate that under normal circumstances, basal dietary sources and production via hindgut fermentation (NRC 2007) are sufficient to maintain the ratio of NAD:NADP in red blood cells. Of course, when using higher doses (5 g / day) in horses (Pollard et al., 2021), an increase in the concentration of NAD+ precursors in plasma and urine was observed, but the levels of potential metabolites were low, indicating some hepatotoxicity, and thus lower doses than this should be considered. Pollard's recent work showed that feeding mares a lower dose (3 g / day: average BW of approximately 500 kg) of NA supplement increased the bioavailability of NAD+ precursors in mare follicular fluid, although plasma concentrations did not increase significantly (Pollard et al., 2022). NA would need to cross the blood-brain barrier to reach the PI. In other species besides horses, exogenous NA has been shown to increase intracellular NAD+ levels in brain cells (Brady et al., 2020).

[0015] Currently, appropriate nutritional and management support is very valuable for PPID (Gallinelli et al., 2022), but these address the consequences of the disorder, not the cause. Although there are no specific vitamin requirements for PPID, it is recommended to provide advice based on age and activity level (Jarvis et al., 2019; and Gallinelli et al., 2022). There are structural changes in the microbiome associated with aging in horses (i.e., changes in diversity) (Dougal et al., 2014), and the microbiota of older animals may be disrupted, reducing the production and absorption of vitamin B. A strong negative correlation between PPID and vitamin B12 in horses has been reported (Siard-Altman et al., 2020), indicating some disruption in vitamin B production in PPID animals. Horses do not naturally ingest vitamin B12 - it is formed through microbial activity in the gastrointestinal tract. The status of vitamin B3 was not evaluated in this study, but the results may reflect a reduced status of vitamin B in older horses, especially PPID horses. Additionally, vitamin B12 supplements have been reported to be beneficial for demented humans with concurrent vitamin B12 deficiency (Ueno et al., 2022). PPID horses often exhibit depression and lethargy, so vitamin B12 supplements could provide additional benefits.

[0016] There is still a need in the art to maintain the health of equines suffering from pars intermedia dysfunction (PPID), slow the progression of PPID, reduce the circulating concentration of adrenocorticotropic hormone (ACTH), and maintain neuronal health in equines. The present disclosure addresses this need by discovering that sufficient additional supplementation with vitamin B3, alone or in combination with other nutritional support including additional vitamin B12, natural and synthetic antioxidants (to reduce any accompanying oxidative stress), and key amino acids, helps combat muscle mass loss commonly associated with PPID (Erdody et al., 2023), and can thus be beneficial to the health and welfare of geriatric and PPID-affected equines. Summary of the Invention

[0017] The objects and advantages of the disclosed subject matter will be set forth in the description which follows and become apparent from the description, as well as will be learned by practice of the disclosed subject matter.

[0018] To achieve these and other advantages, and in accordance with the purpose of the disclosed subject matter, as embodied and broadly described herein, the disclosed subject matter relates to the use of niacin to maintain or support neuronal health in equines suffering from PPID and / or geriatric equines.

[0019] The disclosed subject matter provides a composition comprising niacin, a vitamin B3-related nicotinamide adenine dinucleotide precursor, or a combination thereof, for use as a medicament.

[0020] In certain embodiments, the composition comprises niacin for the treatment of pars intermedia dysfunction (PPID). In a specific embodiment, the use is applicable to the treatment of non-human animals. In certain embodiments, the non-human animal is an equine. In a specific embodiment, the equine is a horse, pony, or donkey.

[0021] In certain embodiments, the equine weighs from about 350 kg to about 650 kg. In a specific embodiment, the non-human animal is a geriatric animal. In certain embodiments, the non-human animal is about 15 years of age or older.

[0022] In certain embodiments, the composition is a supplement to the non-human animal's primary diet. In a specific embodiment, the supplement is in powder, or crumble, or solid form such as tablets, granules, or liquid. In a specific embodiment, the niacin is isolated from its original food source.

[0023] In a specific embodiment, the composition may further comprise vitamin B12. In certain embodiments, the vitamin B12 is isolated from its original food source.

[0024] In certain embodiments, the dose of niacin is from about 1 mg / kg of non-human animal body weight per day to less than about 10 mg / kg of non-human animal body weight per day. In specific embodiments, the dose of vitamin B12 is from about 0.001 mg / kg of non-human animal body weight per day to about 0.1 mg / kg of non-human animal body weight per day.

[0025] In certain embodiments, the composition further comprises an amino acid. In specific embodiments, the amino acid is one or more amino acids selected from lysine, methionine, threonine, and any branched-chain amino acids such as leucine, valine, and isoleucine. In certain embodiments, the amino acid is lysine, and the amount of lysine present in the composition is from about 2 g to about 10 g per day. In specific embodiments, the amino acid is methionine, and the amount of methionine present in the composition is from about 1 g dose to about 6 g dose per day. In certain embodiments, the amino acid is lysine, and the amount of lysine present in the composition is from about 1 g dose to about 6 g dose per day. In specific embodiments, the amino acid is a branched-chain amino acid or a mixture of branched-chain amino acids, and the amount of branched-chain amino acids present is from about 5 g to about 25 g per day. In certain embodiments, the branched-chain amino acids are provided in the form of whey protein, and preferably the whey protein is provided in an amount of from about 2 g to about 15 g per day.

[0026] In specific embodiments, the composition further comprises one or more antioxidants. In certain embodiments, the one or more antioxidants are natural or synthetic. In specific embodiments, the antioxidant is vitamin E. In certain embodiments, the amount of vitamin E present is from about 50 units to about 2000 units per day. In specific embodiments, the antioxidant is an antioxidant flavonoid, preferably quercetin. In certain embodiments, the quercetin is provided in the form of grape seed concentrate, and preferably the amount of grape seed concentrate present is from about 0.25 g to about 10 g per day.

[0027] In a specific embodiment, the composition further comprises one or more components selected from binders, flavoring agents, carriers, wheat feed, rapeseed oil, pharmaceutically acceptable excipients, stabilizers, anti-caking agents, emulsifying agents, and combinations thereof. In certain embodiments, the flavoring agent is a spearmint flavor or a rosemary extract. In a specific embodiment, the range of the spearmint flavor is from about 1 mg per day to about 100 mg per day. In certain embodiments, the rosemary extract is present in a range of from about 5 mg per day to about 100 mg per day. In a specific embodiment, the carrier is calcium carbonate, which is present in a range of from about 1 mg per day to about 50 g per day. In certain embodiments, the wheat feed is present in a range of from about 100 mg per day dose to about 30 g per day dose. In a specific embodiment, the rapeseed oil is present in a range of from about 150 mg per day dose to about 100 g per day dose.

[0028] In a specific embodiment, the dose decreases proportionally with the alleviation of the severity of PPID symptoms over time. In certain embodiments, the dose increases with the increase in the age of the animal.

[0029] The subject matter of the present disclosure also provides a composition comprising niacin, a nicotinamide adenine dinucleotide precursor related to vitamin B3, or a combination thereof, in a dose of from about 1 mg / kg of non-human animal body weight per day to less than about 10 mg / kg of non-human animal body weight per day.

[0030] In certain embodiments, the composition is a supplement to the main diet of the non-human animal. In a specific embodiment, the supplement is in the form of a powder, or crumbs, or a solid form such as tablets, granules, or a liquid.

[0031] In certain embodiments, the niacin is isolated from its original food source.

[0032] In a specific embodiment, the composition further comprises vitamin B12. In certain embodiments, vitamin B12 is isolated from its original food source. In a specific embodiment, the dose of vitamin B12 is from about 0.001 mg / kg of non-human animal body weight per day to about 0.1 mg / kg of non-human animal body weight per day.

[0033] In certain embodiments, the composition further comprises an amino acid. In a specific embodiment, the amino acid is one or more amino acids selected from lysine, methionine, threonine, and any branched-chain amino acids such as leucine, valine, and isoleucine and combinations thereof. In certain embodiments, the amino acid is lysine, and the amount of lysine present in the composition is from about 2 g per day to about 10 g per day. In a specific embodiment, the amino acid is methionine, and the amount of methionine present in the composition is from about 1 g per day to about 6 g per day. In certain embodiments, the amino acid is lysine, and the amount of lysine present in the composition is from about 1 g per day to about 6 g per day. In a specific embodiment, the amino acid is a branched-chain amino acid or a mixture of branched-chain amino acids, and the amount of branched-chain amino acids present is from about 5 g per day to about 25 g per day. In a specific embodiment, the branched-chain amino acids are provided in the form of whey protein, and the whey protein is provided in an amount from about 2 g per day to about 15 g per day.

[0034] In a specific embodiment, the composition further comprises one or more antioxidants. In certain embodiments, the one or more antioxidants are natural or synthetic. In certain embodiments, the antioxidant is vitamin E. In a specific embodiment, the amount of vitamin E present is from about 5 units per day to about 2000 units per day. In certain embodiments, the antioxidant is an antioxidant flavonoid, preferably quercetin. In certain embodiments, quercetin is provided in the form of grape seed concentrate, and preferably the amount of grape seed concentrate present is from about 0.25 g per day to about 5 g per day.

[0035] In certain embodiments, the composition further comprises one or more components selected from binders, flavoring agents, carriers, wheat feed, rapeseed oil, pharmaceutically acceptable excipients, stabilizers, anti-caking agents, emulsifying agents, and combinations thereof. In certain embodiments, the flavoring agent is spearmint spice or rosemary extract. In certain embodiments, the range of the spearmint spice is from about 1 mg per day to about 100 mg per day. In certain embodiments, the rosemary extract is present in a range from about 5 mg per day to about 100 mg per day. In certain embodiments, the carrier is calcium carbonate, and preferably it is present in a range from about 1 mg per day to about 50 g per day. In certain embodiments, the wheat feed is present in a range from about 100 mg per day to about 30 g per day. In a specific embodiment, the rapeseed oil is present in a range from about 150 mg per day to about 100 g per day.

[0036] The subject matter of the present disclosure also provides the use of the composition disclosed herein for treating PPID in equines.

[0037] The subject matter of the present disclosure also provides a method for treating pars intermedia dysfunction (PPID) in a equine in need thereof, the method comprising administering a composition comprising niacin, a vitamin B3-related nicotinamide adenine dinucleotide precursor, or a combination thereof. In certain embodiments, the equine is a horse, pony, or donkey. In a specific embodiment, the composition is a supplement to the primary diet.

[0038] These and other features, aspects, and advantages of the present disclosure will become apparent by reading the following detailed description. The present invention includes any combination of two, three, four, or more of the above-described embodiments, as well as any combination of any two, three, four, or more features or elements set forth in the present disclosure, whether or not such features or elements are explicitly combined in the specific embodiments described herein. The present disclosure is intended to be read as a whole such that any separable features or elements of the disclosed invention in any one of its aspects and embodiments are considered to be combinable unless the context clearly dictates otherwise. Detailed Description

[0039] The present disclosure is in part based on the discovery that dietary supplements with niacin and / or vitamin B3-related nicotinamide adenine dinucleotide (NAD+) improve the clinical symptoms of equines suffering from pars intermedia dysfunction (PPID). Dietary supplements with niacin and / or vitamin B3-related nicotinamide adenine dinucleotide (NAD+) precursors are capable of maintaining the health of equines suffering from PPID, slowing the progression of PPID, reducing the circulating concentration of adrenocorticotropic hormone (ACTH), and maintaining neuronal health in equines.

[0040] For clarity, but not by way of limitation, the detailed description of the subject matter of the present disclosure is divided into the following subsections:

[0041] Definitions;

[0042] Equines;

[0043] Niacin-based compositions; and

[0044] Treatment methods.

[0045] I. Definition

[0046] The terms used in this specification generally have their ordinary meanings in the art, in the context of the present disclosure, and in the particular context in which each term is used. Certain terms are discussed below or elsewhere in the specification to provide additional guidance to the practitioner in describing the compositions and methods of the present disclosure and how to make and use them.

[0047] For the purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural and vice versa. In the event of any conflict between any of the definitions set forth below and any document incorporated by reference herein, the definitions set forth below will control.

[0048] As used herein, when used in connection with the term "comprising" in the claims and / or the specification, the words "a" or "an" can mean "one", but they are also consistent with the meaning of "one or more", "at least one", and "one or more than one".

[0049] As used herein, the terms "comprising", "including", "having", "has", "may", "containing" and variations thereof are intended to be open transitional phrases, terms or words and do not exclude additional acts or structures. The present disclosure also contemplates other embodiments that "comprise" the embodiments or elements presented herein, "consist of" the embodiments or elements presented herein, and "consist essentially of" the embodiments or elements presented herein, whether or not explicitly set forth.

[0050] As used herein, the term "about" or "approximately" means within an acceptable error range of a particular value as determined by a person of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, in accordance with the practice in the art, "about" can mean within or above three standard deviations. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value.

[0051] The terms "embodiment", "an embodiment", "one embodiment", "in various embodiments", "certain embodiments", "some embodiments", "other embodiments", "certain other embodiments", etc. mean that the described embodiments may include a particular feature, structure or characteristic, but each embodiment need not include that particular feature, structure or characteristic. In addition, these phrases do not necessarily refer to the same embodiment. Further, when a particular feature, structure or characteristic is described in connection with an embodiment, it should be assumed that a person of ordinary skill in the art knows how to combine that feature, structure or characteristic with any other embodiment, whether or not explicitly described.

[0052] As used in accordance with the present disclosure, the term "animal" refers to equids, including horses, ponies and donkeys.

[0053] As used herein, and as is well known in the art, "treatment" is a method of obtaining a beneficial or desired result, including a clinical result. For the purposes of this subject matter, "treatment" refers to ameliorating an existing medical condition, such as by slowing the progression of a disease, prolonging survival, reducing the risk of death, and / or providing a measurable improvement in disease parameters. "Treatment" can also mean preventing a disease and reducing the likelihood of developing a disease.

[0054] As used herein, in the context of administering a composition to a subject, the term "prevent" refers to preventing or inhibiting the occurrence and / or development of pars intermedia pituitary dysfunction (PPID).

[0055] As used herein, the term "pars intermedia pituitary dysfunction (PPID)" refers to a neurodegenerative endocrine disorder common in geriatric equids (Tatum et al., 2021; and www.ceh.vetmed.ucdavis.edu / health-topics / pituitary-pars-intermedia-dysfunction-ppid).

[0056] As used herein, the term "niacin" generally includes or is alternatively referred to as nicotinic acid, niacinamide, and related derivatives. Niacin is also referred to as vitamin B3 and can encompass vitamin B3-related nicotinamide adenine dinucleotide (NAD+) precursors (see www.ods.od.nih.gov / factsheets / Niacin-HealthProfessional). NAD+ precursors can encompass nicotinamide mononucleotide, nicotinamide riboside, nicotinic acid adenine dinucleotide, nicotinic acid mononucleotide.

[0057] The term "food" refers to a product or composition for equine consumption that provides certain nutritional benefits to the equine. In certain non-limiting embodiments, the equine (Equus caballus) is a member of the Equidae family (e.g., a horse, pony, or donkey). "Food" includes any food, feed, treat, food supplement, liquid, beverage, snack, toy (chewable and / or consumable toy), meal replacement, or dietary substitute.

[0058] Equine

[0059] The subject matter of the present disclosure pertains to animal populations within the genus Equus. This genus is part of the Equidae family and includes many extant and extinct species. Species within the genus Equus include Equus caballus, Equus mulus, hinny, Equus ferus, Equus zebra, Equus africanus, Equus africanus asinus, Equus grevyi, Equus hemionus, Equus kiang, and Equus quagga.

[0060] In certain embodiments, the animal is of the species Equus caballus, which includes horses and ponies. The animals of the species Equus caballus can be of any age, sex, or castration status, and thus the present invention can be used to evaluate (but is not limited to) foals, weanlings, yearlings, colt foals, filly foals, mares, stallions, geldings, or rigs. Any and all animal breeds within the genus Equus can be evaluated using the methods of the present invention, preferably Equus caballus.

[0061] In certain embodiments, the methods of the present disclosure can be applied to non-human animals. In certain embodiments, the non-human animal is an equine. In other specific embodiments, the equine is a horse, pony, or donkey.

[0062] Nicotinic acid-based composition

[0063] As is well known in the art, "niacin" is also known as "vitamin B3", which is a B vitamin naturally obtained from food and used as a dietary supplement or food additive. "Niacin" can also refer to nicotinic acid, niacinamide, and / or their derivatives. Niacin is a water-soluble vitamin that is converted in the body to NAD+ (see www.ods.od.nih.gov / factsheets / Niacin-HealthProfessional). According to the disclosed subject matter, niacin and / or other vitamin B3-related nicotinamide adenine dinucleotide precursors are used herein as a medicament for treating PPID.

[0064] In certain embodiments, niacin is naturally derived from food. In alternative embodiments, niacin is obtained by synthetic means.

[0065] In certain embodiments, niacin is formulated into a composition for oral administration. In certain embodiments, niacin is administered in an amount of from about 0.5 g to less than about 5 g per 500 kg of equine per day. In a specific embodiment, niacin is administered in an amount of from about 0.5 g to about 4 g per 500 kg of equine per day. In certain embodiments, niacin is administered in an amount of from about 1 mg / kg body weight to less than about 10 mg / kg body weight per day, or from about 1 mg / kg body weight to about 8 mg / kg body weight per day.

[0066] In certain embodiments, vitamin B3 is administered alone or in combination with vitamin B12. In a specific embodiment, vitamin B3 is provided alone or in combination with vitamin B12 in an amount of from about 0.5 g to less than about 5 g per 500 kg of equine per day, or from about 0.5 g to about 4 g per 500 kg of equine per day, or from about 1 mg to less than about 10 mg per kg body weight per day, or from about 1 mg to about 8 mg per kg body weight per day, in combination with vitamin B12 in an amount of from about 0.001 mg to about 0.1 mg per kg body weight per day.

[0067] The composition may include a source of amino acids to aid in muscle repair and development. In certain embodiments, the source of amino acids may include one or more of lysine, methionine, threonine, leucine, valine, and / or isoleucine. In certain embodiments, the source of amino acids may be whey protein. The amount of amino acids required per equine depends on the weight of the animal. For example, the average weight of an adult horse is from about 350 kg to about 650 kg. Based on this weight, in certain embodiments, the amount of amino acids that may be included is from about 1 g to about 25 g, or from about 5 g to about 25 g, or from about 2 g to about 15 g, or from about 2 g to about 10 g, or from about 1 g to about 6 g. In certain embodiments, lysine may be present in an amount of from about 2 g to about 10 g. In certain embodiments, methionine may be present in an amount of from about 1 g to about 6 g. In certain embodiments, threonine may be present in an amount of from about 1 g to about 6 g. In certain embodiments, leucine, valine, and / or isoleucine may be present in an amount of from about 5 g to about 25 g. In certain embodiments, whey protein may be present in an amount of from about 2 g to about 15 g. In certain embodiments, the amino acids are branched-chain amino acids or a mixture of branched-chain amino acids, which are present in an amount of from about 5 g to about 25 g per day. The amount of amino acids may be adjusted based on the weight of the animal.

[0068] In certain embodiments, the composition may comprise natural or synthetic antioxidants. In certain embodiments, the antioxidant may include vitamin E and / or flavonoids. In certain embodiments, the flavonoids may be present in grape seed concentrate containing quercetin. In certain embodiments, for example, for an average adult equine, the antioxidant may be included in an amount of about 5 IU to about 2000 IU or about 0.25 g to about 5 g. Since these amounts are based on the animal's body weight, the amount used can be adjusted accordingly.

[0069] The composition may contain other ingredients used in equine food, such as binders, flavorants, carriers, pharmaceutically acceptable excipients, stabilizers, anti-caking agents, emulsifiers, palatability agents, fiber sources, fat sources, starch sources, and / or fillers. In certain non-limiting embodiments, the flavorant may include one or more of spearmint flavor and / or rosemary extract. In certain non-limiting embodiments, the carrier may include one or more of calcium carbonate, wheat feed, and / or canola oil or other such oils. In certain non-limiting embodiments, molasses and / or a molasses and oil mixture may be included as a binder and / or palatability agent. In certain embodiments, the fiber source may include one or more of grass, beet, soybean hull, and / or oats. In certain embodiments, the fat source may include one or more of corn oil, soybean oil, processed canola oil, coconut oil, palm oil, and / or sunflower oil. In certain embodiments, the starch source is a grain, which may include one or more of corn grain, barley grain, and / or oat grain. In certain embodiments, the filler may include one or more of oat feed and / or wheat feed.

[0070] In a specific embodiment, about 1 mg to about 200 mg, or about 50 mg to about 150 mg, or about 75 mg to about 125 mg of spearmint flavor may be included. In certain embodiments, spearmint is present in an amount of about 100 mg.

[0071] In a specific embodiment, about 5 mg to about 100 mg, or about 5 mg to about 50 mg, or about 10 mg to about 50 mg, or about 15 mg to about 45 mg, or about 20 mg to about 30 mg of rosemary extract may be included. In certain embodiments, rosemary extract is present in an amount of about 25 mg.

[0072] In a specific embodiment, about 50 mg to about 50 g, or about 1 g to about 50 g, or about 5 g to about 20 g of calcium carbonate may be included. In certain embodiments, calcium carbonate is present in an amount of about 12 g.

[0073] In certain embodiments, it may comprise from about 100 mg to about 30 g, or from about 150 mg to about 15 g, or from about 175 mg to about 1 g, or from about 100 mg to about 500 mg, or from about 150 mg to about 300 mg, or from about 200 mg to about 275 mg of wheat feed. In certain embodiments, the wheat feed is present in an amount of from about 230 mg to about 260 mg. In certain embodiments, the wheat feed is present in an amount of about 254 mg.

[0074] In certain embodiments, it may comprise from about 150 mg to about 100 g, or 150 mg to about 1 g, or from about 200 mg to about 10 g, or from about 150 mg to about 350 mg of rapeseed oil. In certain embodiments, the rapeseed oil is present in an amount of about 250 mg.

[0075] Treatment method

[0076] The present disclosure provides methods of supplementing nicotinic acid and / or NAD+ precursors related to vitamin B3 to improve the clinical symptoms of equines suffering from PPID, slow down the progression of PPID, treat / prevent PPID, and reduce the circulating concentration of ACTH.

[0077] The methods of the present disclosure also support the metabolism of geriatric equines vulnerable to hormonal challenges, maintain the health of PPID equines, support the neuronal health of equines, maintain the brain health of equines and geriatric equines, and support the healthy aging of equines. These methods are achieved by administering a medicament comprising a nicotinic acid-based composition as described herein.

[0078] The nicotinic acid-based composition can be administered orally to equines of any age. In certain embodiments, the animal is a geriatric equine. In certain embodiments, the animal is an equine of a horse, pony or donkey and is at least about 15 years old.

[0079] In certain embodiments, the nicotinic acid-based composition is administered to an equine diagnosed with early or advanced PPID. In certain embodiments, the nicotinic acid-based composition is administered to slow down the development of PPID.

[0080] The nicotinic acid-based composition can be administered orally in the form of food, powder, crumbs, solid pellets, granules, tablets or liquid. In certain embodiments, the food can be a food supplement to the main diet, or can be added to the supplementary feed itself. In certain embodiments, the powder can be sprinkled on the food of a horse, pony or donkey. In certain embodiments, the powder or crumbs are in the form of a powder or solid.

[0081] In certain embodiments, the niacin-based composition can be administered daily. The dosage for equines can be based on the weight of the animal. For example, the disclosed subject matter provides non-limiting examples of dosages for an average adult equine weighing from about 350 kg to about 650 kg. A proportionally lower daily dosage can be administered to horses, ponies, or donkeys weighing less than about 350 kg. A proportionally higher daily dosage can be administered to horses, ponies, or donkeys weighing more than about 650 kg.

[0082] In certain embodiments, the niacin-based composition can be administered at an initially higher dosage and then reduced to a lower long-term maintenance dosage, or can be started at a lower dosage and then increased as the equine ages. In certain embodiments, the dosage decreases proportionally over time with the alleviation of the severity of the PPID symptoms.

[0083] Example

[0084] The subject matter of the present disclosure will be better understood by reference to the following examples, which are provided by way of example and not limitation of the subject matter of the present disclosure.

[0085] Example 1: Benefits of a diet with a niacin-based composition

[0086] This example compared the benefits of a diet supplemented with vitamin B3 or vitamin B3 and other ingredients to a normal diet.

[0087] Methods:

[0088] Horses were fed a diet containing a niacin-based composition at 1 mg / kg body weight to 8 mg / kg body weight per day for four weeks. NAD+ precursors and metabolites in blood and urine were measured to determine the optimal dosage.

[0089] Two to twenty-four horses with PPID were used to measure the effect of the optimal dosage. The horses were divided into two groups, or preferably three groups. One group was fed a normal diet, one group was fed a normal diet supplemented with vitamin B3, and / or one group was fed a normal diet supplemented with a mixture of vitamin B3 and co-ingredients, the ingredients including one or more ingredients such as antioxidants, other B vitamins such as vitamin B12, and amino acids. The horses were fed this diet for 1 to 12 months.

[0090] Data collection:

[0091] Horses were tested for TRH stimulation and their blood and optionally urine were collected before the start of the study, periodically during the study, and at the end of the study. Blood samples were used to measure ACTH and liver enzymes and optionally NAD+ precursors, dopamine, prolactin, and / or other POMCs, such as α-MSH. Urine samples were used to selectively measure NAD+ precursors, including indications of possible liver toxicity. Optionally, clinical assessments were used to monitor muscle atrophy scores, behavioral scores, spontaneous blink rate, and / or body condition scores.

[0092] ***

[0093] Although the subject matter disclosed currently and its advantages have been described in detail, it should be understood that various changes, substitutions and modifications can be made herein without departing from the spirit and scope of the disclosed subject matter. In addition, the scope of the present application is not intended to be limited to the specific embodiments of the processes, machines, manufactures and material compositions, methods and processes described in the specification. It will be easily understood by those of ordinary skill in the art from the subject matter disclosed herein that the process, machine, manufacture, material composition, method or step of performing the functions substantially the same as the corresponding embodiments described herein or achieving substantially the same results can be utilized according to the subject matter disclosed herein. Therefore, the appended claims are intended to include these processes, machines, manufactures, material compositions, methods or steps within their scope.

[0094] Throughout this application, various patents, patent applications, publications, product descriptions, protocols, and sequence accession numbers are cited, which are hereby incorporated by reference in their entirety for all purposes.

[0095] Reference

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Claims

1. A composition comprising nicotinic acid, a nicotinamide adenine dinucleotide precursor related to vitamin B3, or a combination thereof, which is used as a medicine.

2. The composition comprising nicotinic acid according to claim 1, which is used for treating pars intermedia dysfunction (PPID).

3. The composition according to any one of the preceding claims, wherein the use is applicable to treating non-human animals.

4. The composition according to any one of the preceding claims, wherein the non-human animal is a member of the Equidae family.

5. The composition according to claim 4, wherein the member of the Equidae family is a horse, a pony or a donkey.

6. The composition according to any one of claims 4 or 5, wherein the weight of the member of the Equidae family is about 350 kg to about 650 kg.

7. The composition according to any one of the preceding claims, wherein the non-human animal is an elderly animal.

8. The composition according to any one of the preceding claims, wherein the age of the non-human animal is 15 years or older.

9. The composition according to any one of the preceding claims, wherein the composition is a supplement to the main diet of the non-human animal.

10. The composition according to claim 9, wherein the supplement is in the form of a powder, or a crumb, or a solid such as a tablet, a granule or a liquid.

11. The composition according to any one of the preceding claims, wherein the nicotinic acid is isolated from its original food source.

12. The composition according to any one of the preceding claims, the composition further comprises vitamin B12.

13. The composition according to claim 12, wherein the vitamin B12 is isolated from its original food source.

14. The composition according to any one of the preceding claims, wherein the dose of nicotinic acid is from about 1 mg / kg of the body weight of the non-human animal per day to less than about 10 mg / kg of the body weight of the non-human animal per day.

15. The composition according to any one of claims 12 or 13, wherein the dose of vitamin B12 is from about 0.001 mg / kg of the body weight of the non-human animal per day to about 0.1 mg / kg of the body weight of the non-human animal per day.

16. The composition according to any one of the preceding claims, the composition further comprises an amino acid.

17. The composition according to claim 16, wherein the amino acid is one or more amino acids selected from the group consisting of lysine, methionine, threonine and any branched-chain amino acids such as leucine, valine and isoleucine.

18. The composition according to claim 17, wherein when the amino acid is lysine, the amount of lysine present in the composition is from about 2 g per day to about 10 g per day.

19. The composition according to any one of claims 16 to 17, wherein when the amino acid is methionine, the amount of methionine present in the composition is a dose of 1 g per day to about 6 g per day.

20. The composition according to any one of claims 16 to 17, wherein when the amino acid is threonine, the amount of threonine present in the composition is from about 1 g per day to about 6 g per day.

21. The composition according to any one of claims 16 to 17, wherein when the amino acid is a branched-chain amino acid or a mixture of branched-chain amino acids, the amount of the branched-chain amino acid present is from about 5 g per day to about 25 g per day.

22. The composition according to claim 21, wherein the branched-chain amino acid is provided in the form of whey protein, preferably wherein the whey protein is provided in an amount from about 2 g per day to about 15 g per day.

23. The composition according to any one of the preceding claims, the composition further comprising one or more antioxidants.

24. The composition according to claim 23, wherein the one or more antioxidants are natural or synthetic.

25. The composition according to claims 23 to 24, wherein the antioxidant is vitamin E.

26. The composition according to claim 25, wherein the amount of vitamin E present is from about 50 units per day to about 2000 units per day.

27. The composition according to claim 16, wherein the antioxidant is an antioxidant flavonoid compound, preferably quercetin.

28. The composition according to claim 27, wherein the quercetin is provided in the form of grape seed concentrate, preferably wherein the grape seed concentrate is present in an amount from about 0.25 g per day to about 10 g per day.

29. The composition according to any one of the preceding claims, the composition further comprising one or more components selected from the group consisting of binders, flavoring agents, carriers, wheat feed, rapeseed oil, pharmaceutically acceptable excipients, stabilizers, anti-caking agents, emulsifying agents, and combinations thereof.

30. The composition according to claim 29, wherein the flavoring agent is spearmint spice or rosemary extract.

31. The composition according to claim 30, wherein the range of the spearmint spice is from about 1 mg per day to about 100 mg per day.

32. The composition according to claim 30, wherein the rosemary extract is present in a range from about 5 mg per day to about 100 mg per day.

33. The composition according to claim 29, wherein the carrier is calcium carbonate, which is present in a range from about 1 mg per day to about 50 g per day.

34. The composition according to claim 29, wherein the wheat feed is present in a range from a dose of about 100 mg per day to a dose of about 30 g per day.

35. The composition according to claim 29, wherein the rapeseed oil is present in a range from a dose of about 150 mg per day to a dose of about 100 g per day.

36. The composition according to any one of the preceding claims, wherein the dose decreases proportionally over time with the alleviation of the severity of the PPID symptoms.

37. The composition according to the preceding claims, wherein the dose increases with the increasing age of the animal.

38. A composition comprising niacin, a nicotinamide adenine dinucleotide precursor related to vitamin B3, or a combination thereof, in a dose from about 1 mg / kg non-human animal body weight per day to less than about 10 mg / kg non-human animal body weight per day.

39. The composition according to claim 38, wherein the composition is a supplement to the main diet of a non-human animal.

40. The composition according to claim 39, wherein the supplement is in the form of a powder, or a crumb, or a solid form such as a tablet, granule or a liquid.

41. The composition according to any one of claims 38 to 40, wherein the niacin is isolated from its original food source.

42. The composition according to any one of claims 38 to 41, the composition further comprising vitamin B12.

43. The composition according to claim 42, wherein the vitamin B12 is isolated from its original food source.

44. The composition according to any one of claims 42 or 43, wherein the dose of vitamin B12 is from about 0.001 mg / kg of non-human animal body weight per day to about 0.1 mg / kg of non-human animal body weight per day.

45. The composition according to any one of claims 38 to 44, the composition further comprising an amino acid.

46. The composition according to claim 45, wherein the amino acid is one or more amino acids selected from the group consisting of lysine, methionine, threonine and any branched-chain amino acids such as leucine, valine and isoleucine, and combinations thereof.

47. The composition according to claim 46, wherein the amino acid is lysine, and the amount of lysine present in the composition is from about 2 g per day to about 10 g per day.

48. The composition according to claim 46, wherein the amino acid is methionine, and the amount of methionine present in the composition is from about 1 g per day to about 6 g per day.

49. The composition according to claim 46, wherein when the amino acid is lysine, the amount of lysine present in the composition is from about 1 g per day to about 6 g per day.

50. The composition according to claim 46, wherein when the amino acid is a branched-chain amino acid or a mixture of branched-chain amino acids, the amount of branched-chain amino acids present is from about 5 g per day to about 25 g per day.

51. The composition according to claim 46, wherein the branched-chain amino acids are provided in the form of whey protein, and wherein the whey protein is provided in an amount of from about 2 g per day to about 15 g per day.

52. The composition according to any one of claims 38 to 51, the composition further comprising one or more antioxidants.

53. The composition according to claim 52, wherein the one or more antioxidants are natural or synthetic.

54. The composition according to claims 52 to 53, wherein the antioxidant is vitamin E.

55. The composition according to claim 54, wherein the amount of vitamin E present is from about 5 units per day to about 2000 units per day.

56. The composition according to claim 52 or 53, wherein the antioxidant is an antioxidant flavonoid compound, preferably quercetin.

57. The composition according to claim 56, wherein the quercetin is provided in the form of grape seed concentrate, preferably in an amount of from about 0.25 g per day to about 5 g per day of the grape seed concentrate.

58. The composition according to any one of claims 38 to 57, wherein the composition further comprises one or more components selected from the group consisting of a binder, a flavoring agent, a carrier, wheat feed, rapeseed oil, a pharmaceutically acceptable excipient, a stabilizer, an anti-caking agent, an emulsifier, and combinations thereof.

59. The composition according to claim 58, wherein the flavoring agent is a spearmint spice or a rosemary extract.

60. The composition according to claim 59, wherein the spearmint spice ranges from about 1 mg per day to about 100 mg per day.

61. The composition according to claim 59, wherein the rosemary extract is present in the range of about 5 mg per day to about 100 mg per day.

62. The composition according to claim 58, wherein the carrier is calcium carbonate, preferably present in the range of about 1 mg per day to about 50 g per day.

63. The composition according to claim 58, wherein the wheat feed is present in the range of about 100 mg per day to about 30 g per day.

64. The composition according to claim 58, wherein the rapeseed oil is present in the range of about 150 mg per day to about 100 g per day.

65. Use of the composition according to any one of the preceding claims for the treatment of PPID in equines.

66. A method for treating pituitary pars intermedia dysfunction (PPID) in an equine in need thereof, the method comprising administering a composition comprising nicotinic acid, a nicotinamide adenine dinucleotide precursor related to vitamin B3, or a combination thereof.

67. The method according to claim 66, wherein the equine is a horse, a pony, or a donkey.

68. The method according to claims 66 to 67, wherein the composition is a supplement to the main diet.