Methods of reducing hair growth ii

Abstract

The invention relates to methods of inhibiting hair growth in a subject. Also provided herein are compositions for inhibiting hair growth and methods of screening for inhibitors of hair growth, wherein the composition comprises an inhibitor of lactate dehydrogenase (LDH).

Description

[0001] METHODS OF REDUCING HAIR GROWTH II

[0002] Field of Invention

[0003] The invention relates to methods of inhibiting hair growth in a subject. Also provided herein are compositions for inhibiting hair growth and methods of screening for inhibitors of hair growth.

[0004] Background

[0005] There is currently an unmet consumer need to prevent the appearance of excessive or unwanted hair in both men and women for cosmetic, cultural or therapeutic reasons. The appearance of excessive or unwanted hair can be due to hirsutism or hypertrichosis. Current means to remove unwanted hair include shaving, laser hair removal, electrolysis, depilatories, and waxing. These methods all require repetitive treatments, and none ensure complete and lasting hair removal.

[0006] Currently, there is one FDA approved medication that slows hair growth: a topical ornithine decarboxylase inhibitor Eflornithine (Vaniqa®) that shows significant efficacy in only a limited proportion of women with unwanted facial hair and has not been FDA approved to be safe to use on other, larger body surface areas. There are several systemic agents that slow the transition of vellus to terminal hair growth or cause some miniaturization of terminal hair in women with hirsutism, and these agents include systemic antiandrogens (such as spironolactone, fiutamide, and cyproterone acetate) and 5a-rcductasc inhibitors (such as finasteride or dutastcridc). However, these agents do not cause total removal of the unwanted hair, nor are they FDA approved for this indication. Furthermore, they may cause unwanted side effects such as pain or pigmentation.

[0007] It would be desirable to overcome or ameliorate at least one of the above-described problems, or at least to provide a useful alternative. Summary

[0008] Disclosed herein is a method of inhibiting hair growth in a subject, the method comprising administering an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivate or prodrug thereof, to the subject.

[0009] Disclosed herein is a method of treating a subject suffering from a condition associated with excessive or unwanted hair growth, the method comprising administering an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivative or prodrug thereof, to the subject.

[0010] Disclosed herein is an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivate or prodrug thereof, for use in treating a subject suffering from a condition associated with excessive or unwanted hair growth.

[0011] Disclosed herein is the use of an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivative or prodrug thereof, in the manufacture of medicament for treating a subject suffering from a condition associated with excessive or unwanted hair growth.

[0012] Disclosed herein is a composition comprising an inhibitor of lactate dehydrogenase (LDH), salt, solvate, derivative or prodrug thereof.

[0013] Disclosed herein is a method of screening for an inhibitor of hair growth in a subject, the method comprising: a) contacting a hair follicle keratinocyte with an inhibitor of lactate dehydrogenase (LDH); and b)i) detecting a reduction of ATP production through lactic acid fermentation (LAF) as compared when the hair follicle keratinocyte is not contacted with the inhibitor of LDH; wherein the reduction of ATP production via LAF indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject; ii) detecting a reduction in extracellular acidification (ECAR) as compared to when the hair follicle keratinocyte is not contacted with the inhibitor of LDH; wherein the reduction of ECAR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject; or iii) detecting an increase in oxygen consumption rate (OCR) as compared to when the hair follicle keratinocytes is not contacted with the inhibitor of LDH; wherein the increase of OCR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject.

[0014] Brief Description of Drawings

[0015] Embodiments of the present invention are hereafter described, by way of non-limiting example only, with reference to the accompanying drawings in which:

[0016] Figure 1. Metabolic profile of HFKs treated for 24h with the LAF inhibitors, compared to the untreated. (a,b) The rate of ATP produced through LAF (glyco) is shown in dark grey and mitochondrial respiration (mito) is shown in light grey. Statistical test used was one-way anova; *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Mean + / - Standard deviation is represented.

[0017] Figure 2: Ex-vivo human HFs treated with LDH inhibitors, (a, d) Plot of change in HFs shaft length over time, with and without treatment (see legend), (b, e) Representative images of untreated HFs. (c, f) Representative images of treated HFs (see legend).

[0018] Detailed Description

[0019] The present specification teaches a method of inhibiting hair growth in a subject, the method comprising administering an inhibitor of lactate dehydrogenase (LDH), salt, solvate, derivative or prodrug thereof, to the subject.

[0020] In one embodiment, the inhibitor of lactate dehydrogenase (LDH) inhibits the Lactic Acid Fermentation (LAF) pathway.

[0021] The inhibitor may be an oxamate (such as sodium oxamate or potassium oxamte), an oxalate (such as sodium oxalate or potassium oxalate), an oxalic acid or an oxamic acid ester. The inhibitor may also be a derivative of oxamate or oxalate. In one embodiment, the inhibitor is a derivative of oxamate as described in EP0898956B1. Without being bound by theory, the inhibitor of lactate dehydrogenase (LDH) is capable of inhibiting the action of LDH to convert pyruvic acid to lactic acid during the lactic acid fermentation pathway in the cellular respiration process. Generally, the lactic acid fermentation pathway is part of the cellular respiration process to produce energy in the form of adenosine triphosphate (ATP) from glucose. The lactic acid fermentation pathway occurs in an animal cell after glycolysis in the cellular respiration process. After the glycolysis wherein glucose molecules are converted into pyruvic acid, the pyruvic acid is then converted to lactic acid, in the absence or limited presence of oxygen molecules, by the LDH in the lactic acid fermentation pathway.

[0022] In some embodiments, the inhibitor of lactate dehydrogenase inhibits lactate dehydrogenase isoform A and / or lactate dehydrogenase isoform B. Examples of lactate dehydrogenase include is not limited to oxamic acid sodium, oxamic acid, GSK2837808A, FX-11, (R)-GNE-140, (S)-GNE-140, GNE- 140 racemate, Bisadinrone A, ZG-2492, Galloflavin, AXKO-0046, Lathostcrol, LDHA-IN-3, AZ-33, CAY10594, LDH-IN-1, Nedosiran (DCR-PHXC), Nedosiran (DCR-PHXC) sodium, AXKO-0046 dihydrochloridc, Rchmanniosidc A, Linalyl acetate, NHI-2, 3',4',7-Trihydroxyflavonc, Glomeratose A, 3-Dehydrotrametenolic acid, MEDS433, LDCA, PfDHODH-IN-1, RS6212, NCATS-SM1441, WQQ-345, LDH-IN-3, LDHA-IN-5, LDHA-IN-6, LDHA- IN-7, LDHA-IN-8, LDHA-IN-9, LDHA-IN-10, LDH-IN-5, Anticancer agent 121, Anticancer agent 122, AK-135 hydrochloride, Linalyl acetate-d6, Antibiofilm agent-5 (compound 6c), 3-Acetylpyridine adenine dinucleotide, 95% (3-APAD, 95%), Nifurtimox, Nifurtimox-d4, AChE-TN-85 (Compound 7k), NCI-006, LM-021 , lathosterol-d?, Galloflavin potassium, and BMS-191095 hydrochloride.

[0023] In some embodiments, the inhibitor of lactate dehydrogenase is provided at a concentration of about 1 mM to about 50 mM. In one embodiment, the inhibitor of lactic acid fermentation is provided at a concentration of about 1 mM, about 1.25 mM, about 1.5 mM, about 2 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, or about 50mM.

[0024] The method may be a non-therapeutic or cosmetic method. The term “subject” as used throughout the specification is to be understood to mean a human or may be a domestic or companion animal. While it is particularly contemplated that the methods of the invention are for treatment of humans, they are also applicable to veterinary treatments, including treatment of companion animals such as dogs and cats, and domestic animals such as horses, cattle and sheep, or zoo animals such as primates, felids, canids, bovids, and ungulates. The “subject” may be a mammalian subject. The “subject” may include a person, a patient or individual, and may be of any age or gender.

[0025] “Mammalian hair” as referenced herein, includes hair on any part of the body of a mammal, and can include but is not limited to facial, cranial, or body hair. For instance, it can include hair on the scalp, head, neck, beard, moustache, eyebrows and sidebums hair.

[0026] The ability of an inhibitor of lactate dehydrogenase to inhibit hair growth may be assessed with reference to a suitable control. A skilled person will be able to determine a suitable control for the inhibitor without difficulty.

[0027] Inhibition of hair growth may be assessed with reference to the elongation of the hair shaft. It will be appreciated that an agent that reduces elongation of a hair shaft as compared to a suitable control demonstrates the ability to inhibit hair growth. Inhibition of hair growth may be assessed with reference to hair of human or non-human animals.

[0028] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Non-limiting examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic. malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and galacturonic acid.

[0029] The ability of an inhibitor of lactate dehydrogenase to inhibit hair growth may also be assessed using a suitable ex vivo model. For instance, the ability to inhibit hair growth may be assessed with reference to the ability of the inhibitor to inhibit elongation of hair shafts of isolated hair follicles maintained in culture. Hair follicles may be incubated with the agent in question for a period of time (for example, around six days in a suitable model), and elongation of the hair shaft assessed during and / or at the end of this period. Suitable hair follicles may be obtained from surgical procedures such as hair transplantation.

[0030] Another suitable ex vivo model may make use of hair follicle-containing skin biopsies from human or non-human animals. Such biopsies, which may, for example, be derived from human scalp, may be treated with a test agent for a period of time (for example, around six days in a suitable model), and elongation of the hair shaft assessed during and / or at the end of this period. Hair follicle-containing skin biopsies may be maintained in organ culture during the test period. Suitably the inhibitors may be able to bring about a 20% inhibition of hair growth. In a suitable embodiment, an inhibitor of the invention may be able to bring about a 25%, 30%, 35%, 40%, 45%, or 50% inhibition of hair growth. The requisite extent of inhibition may be demonstrated in any of the experimental models of hair growth considered above.

[0031] In a suitable embodiment, the hair growth to be inhibited is regrowth of hair after hair removal. The inhibitors of the invention may be used to prolong the effects of hair removal. This may allow greater time to elapse between incidences of hair removal. In a suitable embodiment, an inhibitor of the invention may be able to increase the time elapsing between incidences of hair removal by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or more. The increase in the time between incidences of hair removal achieved may be determined with reference to suitable controls. Suitably hair removal may be achieved by a variety of known methods. For example, hair removal may be achieved by mechanical methods, such as those selected from the group consisting of plucking, waxing, shaving (whether using razors, electrical shavers, or clippers or the like). Alternatively, hair removal may be achieved using chemical methods such as those making use of agents (such as calcium thioglycolate or potassium thioglycolate) that weaken constituents of the hair, thus facilitating its removal. Other methods by which hair may be removed include electrology (in which electrical current is applied to hair follicles), and laser hair removal. The inhibitors of lactate dehydrogenase (LDH) may be of utility in inhibiting hair growth after any such methods of removal.

[0032] The hair growth to be inhibited may be regrowth of hair after depilation or epilation. For the purposes of the present invention, depilation may be considered to be the removal of that portion of the hair shaft that normally extends above the skin. Depilation may typically occur as a result of shaving or the use of clippers. For the purposes of the present invention, epilation may be considered to be the removal of the entire hair shaft. Merely by way of example, epilation may occur as a result of plucking or waxing.

[0033] Suitably the inhibition of hair growth may be localized inhibition. For present purposes, localized inhibition may be taken as being inhibition of hair growth that is substantially restricted to certain sites upon a subject's body. Suitably, localized inhibition of hair growth may be achieved by local administration of an inhibitor of lactate dehydrogenase (LDH), with inhibition substantially restricted to the area to which the agent has been administered. Topical compositions for the administration of the inhibitor may be of use in embodiments of this sort.

[0034] Suitably an agent that comprises an inhibitor of lactate dehydrogenase (LDH) may be used to inhibit hair growth on any body part where hair growth inhibition may be desired. Merely by way of example a suitable body part can include those selected from the group consisting of: the head, face, legs, arms, back and chest. However, the various aspects of the invention may also be of use in achieving global inhibition of hair growth. For present purposes global inhibition of hair growth may be taken as being inhibition occurring at a range of sites upon a subject's body. In particular, global inhibition of hair growth may be taken as being inhibition occurring over substantially the entirety of a subject's body. Suitably global inhibition of hair growth may be achieved by provision of an inhibitor of lactate dehydrogenase (LDH), at all sites where it is desired to inhibit hair growth.

[0035] In some embodiment, an inhibitor of lactate dehydrogenase (LDH) can be applied and leave on the skin of the subject for at least 1, 2, 3, 4, 5, 6, 7, or 8 hours or more without removing or washing off the inhibitor. In some embodiment, the inhibitor can be reapplied on the skin of the subject every 8 hours with or without washing off the inhibitor present on the skin of the subject.

[0036] In a suitable embodiment, an inhibitor of lactate dehydrogenase (LDH) may be used for inhibiting the lactic acid fermentation in the hair follicle at all stages of hair growth cycle, namely, anagen phase, catagen phase and telogen phase. The inhibitor of lactic acid fermentation may be used at any stage of the hair growth cycle to arrest or slow hair growth.

[0037] The anagen phase in the hair growth cycle is the rapid growth phase of the hair follicle, wherein the keratinocytes proliferate in the follicular epithelium. In the catagen phase, the hair follicle undergoes involution due to cell apoptosis. Next, the hair follicle enters the telogen phase, wherein the hair follicle is ready to shed the hair. The hair follicle subsequently re-enters the anagen phase and new hair is produced from the hair follicle.

[0038] In a suitable embodiment, an inhibitor of lactate dehydrogenase (LDH) may also inhibit the hair follicle from re-entering anagen phase from the telogen phase, and allow the hair follicle to enter into kenogen phase from telogen phase, resulting in permanent hair loss. An individual may wish to inhibit hair growth after depilation or epilation, by topical application of an inhibitor of lactate dehydrogenase (LDH) prior and post the hair removal procedure.

[0039] In some embodiments, a subject may be a healthy individual with nonnal hair growth. The subject may wish to inhibit hair growth by administration of an inhibitor of lactate dehydrogenase. In some embodiments, the normal hair growth may be hair growth on the face, neck, chest, tummy, lower back, upper back, buttocks, thighs, or any part of the body of an individual.

[0040] In some embodiments, a subject may be suffering from a condition associated with excessive or unwanted hair growth.

[0041] As used herein, the terms “excessive” or “unwanted” may be used interchangeably, and referring to excessive or unwanted hair growth in areas that is not desired by the subject. In some embodiments, the subject may have higher than normal rate of hair growth, hair growth in areas that normally have hair growth, hair growth in areas that normally do not have hair growth or any normal hair growth that are not desired by the subject.

[0042] In a suitable embodiment, an individual wishing to inhibit hair growth may suffer from excess hair growth, such as a result of disorders such as hirsutism, or hypertrichosis. In another embodiment, the invention may be used to treat chemotherapy-induced or related hair growth, and radiation-induced or related hair growth. Treating any of these types of increased hair growth includes arresting hair growth, suppressing hair growth rate, or preventing regrowth after hair removal.

[0043] In some embodiments, the hypertrichosis in the subject may be congenital (genetically- linked) or acquired. In some embodiments, the congenital hypertrichosis includes but not limited to congenital hypertrichosis lanuginosa, congenital hypertrichosis terminalis, and naevoid hypertrichosis. In some embodiments, the acquired hypertrichosis includes but not limited drug-induced hypertrichosis. In some embodiments, the hypertrichosis is generalized hypertrichosis or localized hypertrichosis.

[0044] In some embodiments, the unwanted hair growth may be hair growth on the face, neck, chest, tummy, lower back, upper back, buttocks, thighs, or any part of the body of an individual.

[0045] In some embodiments, an inhibitor of lactic acid fermentation is to be administered to treat a condition of unwanted hair growth in a subject. In some embodiments, the condition is hirsutism or hypertrichosis.

[0046] In some embodiments, the cause of unwanted hair growth may be an increased androgen level, polycystic ovary syndrome (PCOS), side effects of medication, hormonal conditions (such as Cushing’s syndrome, acromegaly, and menopause), metabolic conditions, or a tumor growth affecting the hormone levels in the subject.

[0047] In some embodiments, the subject may also have other metabolic conditions, including but not limited to anorexia, hormone imbalance, hyperthyroidism and side effects of certain drugs.

[0048] Disclosed herein is a composition comprising an inhibitor of lactate dehydrogenase (LDH), salt, solvate, derivative or prodrug thereof.

[0049] Compositions of the invention may take many different forms, depending upon the way in which it is intended that they are to be used. Merely by way of example, a composition of the invention may take the form of a composition for topical administration. A composition of the invention in accordance with this embodiment may be used to provide localized administration of an effective amount of an inhibitor of lactate dehydrogenase (LDH) thereof to a site where it is desired to inhibit hair growth.

[0050] The composition may be applied directly to the hair or skin by any suitable means, including, by hand, with a spatula, scoop or spoon, spraying, dusting, painting and pouring. The composition is preferably massaged into the hair or skin. While some oils, such as rosehip, jojoba, argan, olive, coconut, and sunflower oils, are rapidly absorbed into the hair (about 2-4 hours), others, such as avocado, castor, evening primrose and macadamia nut oils, are absorbed more slowly, (about 6-8 hours). Thus, while some benefit may be obtained while the oil-based compositions are left on for 2- 4 hours, oil-based compositions are preferably left on for at least about 6-8 hours, or longer, such as 8-12 hours, and may conveniently be left on overnight before washing out. Compositions comprising solid components may be mixed with a suitable cosmetically acceptable carrier, in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Some examples of a suitable carrier include water, oils, waxes, and butters extracted from seeds, such as cocoa butter, shea butter and mango butter and mixtures thereof. The solid components may be mixed with a suitable carrier before applying to the hair or skin, and then massaged in. Such compositions may be left in for any suitable period of time, and in some embodiments, are preferably left on for about 10-40 minutes, such as about 15-30 minutes, before washing or rinsing out. A treatment process may be performed as a one- off treatment or may be used on a regular basis over a period of time, for example, the composition may be applied daily, once or twice weekly, fortnightly or monthly.

[0051] The composition of the invention may be in any pharmaceutical form normally used for topical application, in particular in the form of an aqueous, aqueous-alcoholic or oily solution, an oil-in-water or water-in-oil or multiple emulsion, an aqueous or oily gel, a liquid, pasty or solid anhydrous product, a dispersion of oil in an aqueous phase with the aid of spherules, these spherules possibly being polymeric nanoparticles such as nanospheres and nanocapsules or better still lipid vesicles of ionic and / or non-ionic type. This composition may be relatively fluid and have the appearance of a white, clear, or colored cream, an ointment, a milk, a lotion, a serum, a cream, a paste, a foam, a gel, an oil or a spray. It may optionally be applied to the skin or to the hair in aerosol form. It may also be in solid form and, for example, in the form of a stick. It can be used as a care product and / or as a make-up product. It can also be in the form of a shampoo or a conditioner. A composition of the invention may comprise an inhibitor of lactate dehydrogenase (LDH), in combination with an acceptable carrier such as polyethylene glycol (PEG). Typical carriers for an inhibitor of lactate dehydrogenase (LDH) in the topical compositions include water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, combinations thereof, and the like. Preferred carriers include propylene glycol, dimethyl isosorbide, and water.

[0052] In some embodiments, an inhibitor of lactate dehydrogenase (LDH) can be supplemented with any of the additives discussed below and can be incorporated into creams, lotions, salves, liniments, ointments, gels, pastes, tonics, tinctures, unguents, soaps, shampoos, orals, pills, tablets, capsules, and lip balms discussed below. Thus, the form of the compositions of the invention is not limited.

[0053] Creams refer to semi- solid emulsions of oil and water in approximately equal proportions. They are divided into two types: oil-in-water (O / W) creams, composed of small droplets of oil dispersed in a continuous phase; and water-in-oil (W / O) creams, composed of small droplets of water dispersed in a continuous oily phase. Creams can provide a barrier to protect the skin. This may be a physical barrier or a chemical barrier as with UV-absorbing compounds. To aid in the retention of moisture (especially water- in-oil creams), creams are usually used for a variety of purposes including cleansing, emollient effects, and as a vehicle for drug substances such as local anesthetics, antiinflammatories (NSAIDs or corticosteroids), hormones, antibiotics, antifungals or counter-irritants.

[0054] The term “carrier” as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting an inhibitor of lactic acid fermentation across a tissue layer such as the stratum comeum or stratum spinosum, and may be delivered to the target site, such as the hah- follicle.

[0055] The carrier of the topical composition may further comprise one or more ingredients selected from the group consisting of emollients, propellants, solvents, humectants, thickeners, powders, fragrances and pH-adjusting additive. The amount of emollient in the topical composition is typically about 5 to about 95%. Non-limiting examples of emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2 -diol, butane- 1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, polydimethylsiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof.

[0056] Oils include cannabidiol oil and various plant derived oils containing cannabidiol, such as, hempseed oil, Echinacea purpurea, Echinacea angustifolia, Acmella oleracea, Hclichrysum umbraculigcrum, Radula marginata, and the like. In some embodiments, cannabidiol isolated from such plants or made synthetically may be formulated with an oil such as, for example, olive oil, grapeseed oil, tea tree oil, almond oil, avocado oil, sesame oil, evening primrose oil, sunflower oil, kukui nut oil, jojoba oil, walnut oil, peanut oil, pecan oil, macadamia nut oil, coconut oil, and the like and combinations thereof.

[0057] The amount of propellant in the topical composition is typically about 5% to about 95%. Non-limiting examples of propellants include propane, butane, iso-butane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.

[0058] The amount of solvent in the topical composition is typically about 5% to about 95%. Non-limiting examples of solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, dicthylcnc glycol monocthyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Preferred solvents include ethyl alcohol.

[0059] The amount of humectant in the topical composition is typically about 5% to about 95%. Non-limiting examples of humectants include glycerin, sorbitol, sodium 2-pyrrolidone- 5 -carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Preferred humectants include glycerin.

[0060] The amount of thickener in the topical composition is typically 0% to about 95%. Nonlimiting examples of thickeners include xanthan gum, guar hum / hydroxypropyl guar, cellulose derivatives (such as hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and carboxymethylcellulose), alginates, pectin, agar, starch derivatives, synthetic polymer thickeners, stearic acid, palmitic acid, waxes, shea butter, cocoa butter, mineral thickeners, hydroxypropyl starch phosphate, PEG- 150 distearate, PEG-150 pentaerythrityl tetrastearate, lauryl glucoside, sodium chloride, sodium sulfate, sodium polystyrene sulfonate, protein-based thickeners (such as collagen, hydrolyzed collagen, and gelatin), and silicone-based thickeners.

[0061] The amount of powder in the topical composition is typically 0% to about 95%. Nonlimiting examples of powders include chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof.

[0062] The amount of fragrance in the topical composition is typically about 0.001% to about 0.5%.

[0063] Ointments are compositions in which oil and water are provided in a ratio of from 7 : 1 to 2: 1, from 5: 1 to 3: 1, or 4: 1. Ointments are generally formulated using oils, waxes, water, alcohols, petroleum products, water, and other agents to prepare compositions with various viscosities and solvent properties. Commonly used compositions include oleaginous base (White Ointment), absorption base, W / O emulsion base (Cold Cream type base), O / W emulsion base (Hydrophilic Ointment), water soluble base, in addition to others. These preparations are used to dissolve or suspend substances or products with medicinal or cosmetic value. Lotions are low- to medium-viscosity topical preparations. Most lotions are oil-in-water emulsions containing an emulsifier such as cetyl alcohol to prevent separation of these two phases. Lotions can include fragrances, glycerol, petroleum jelly, dyes, preservatives, proteins and stabilizing agents.

[0064] In another embodiment, an inhibitor of lactate dehydrogenase (LDH) can be provided to the individual as a composition comprising emulsifying ointment BP, isopropyl myristate, hydroxyethylcellulose, glycerol, phenoxyethanol, propylene glycol and water.

[0065] In another embodiment, an inhibitor of lactate dehydrogenase (LDH) can be formulated with a delivery vehicle. For example, in a suitable embodiment, a composition of the invention may comprise liposomes in which at least some of the inhibitor of lactic acid fermentation, is incorporated.

[0066] By way of further example, suitable delivery vehicles include those selected from the group consisting of: liposomes, amphoteric and cationic liposomes, niosomes, lipophihe formulations, aqueous-alcoholic solutions, hydrophilic formulations, water-in-oil nanoemulsions, nanoparticles of various sizes, microparticles of various sizes, polystyrene microspheres of various sizes, titanium dioxide particles and solid lipid particles.

[0067] Suitably liposomes employed in the compositions or methods of the invention may be ones that have a particular affinity for hair / hair follicles. By way of example suitable liposomes include, amphoteric and cationic liposomes and niosomes.

[0068] In a suitable embodiment a composition of the invention may be formulated for use in combination with a device which enhances transdermal penetration of the composition. The composition may thus be applied to the area requiring hair growth inhibition prior to use of the device, or concurrently with use of the device. Merely by way of example such devices may include devices which produce electrical current such as galvanic devices, lasers, devices which produce vibrations such as ultrasound, and massage devices which enhance blood circulation around the hair follicles. In another embodiment, a composition of the invention may be formulated for use in combination with a device used for the removal of hair by mechanical or chemical methods.

[0069] In some embodiments, an inhibitor of LDH may be delivered to the subject via transdermal delivery mechanism. Non-limiting examples of transdermal delivery mechanisms include microneedles or dissolvable microneedles, and the microneedles may be fabricated into a form of microneedle patch.

[0070] In some embodiments, the compositions may include one or more bioenhancers. Bioenhancers include any compound or composition that aids in the transport of another compound across epithelial membranes. Bioenhancers include P-glycoprotein inhibitors, compounds that reverse P-glycoprotein-mediated efflux, limit metabolism of active agents, increase gastric emptying time and intestinal motility, reduce degradation of the active agent by hydrochloric acid, modify cell membrane permeability, produce a cholagoguc effect, modify the bioenergetics and thermogenic properties of the active agent, suppress first pass metabolism, and inhibit metabolizing enzymes, stimulate gamma glutamyl transpeptidase, enhance the uptake of amino acids, and the like and combinations thereof. In some embodiments, the bioenhancers may be herbal or neutraceutical bioenhancers. Examples of bioenhancers encompassed by the invention include pipeline, quercetin, genistein, naringin, sinomenine, glycyrrhizin, nitrile glycosides cuminum cyminum, zingiver officinale, lysergol, allium sativum, aloe vera, and the like and combinations thereof. In some embodiments, the bioenhancers may be liposomes, microspheres, nanoparticles, transferosomes, ethosomes, nanoemulsions, microemulsions, lipid-based systems, polymeric micelle formulations, ketoprofen- loaded solid lipid nanoparticles, and the like, which can be made from beeswax, carnauba wax, or other natural waxes and solid lipids, and combinations thereof. In some embodiments, the bioenhancers may be liposomal enhancers such as, for example, ginkgo biloba lipid-based systems, silybin lipid-based systems, ginseng lipid-based systems, hawthorn lipid-based systems, quercetin lipid-based systems, curcumin lipid- based systems, and the like and combinations thereof. In further embodiments, the bioenhancers may be capsaicin transferosomes, colchicine tranferosomes, vincristine tranferosomes, and the like and combinations thereof, which may find particular use as natural skin penetration agents. The amount of bioenhancer in the compositions may be from about 0.05 % to about 20% (w / w), relative to the total amount of the composition or in some embodiments, from about 0.1% to about 10% (w / w), relative to the total weight of the composition, from about 0.1% to about 5% (w / w), relative to the total amount of the composition, from about 0.1% to about 2% (w / w), relative to the total amount of the composition, or any range or individual concentration encompassed by these example ranges.

[0071] When the compositions of the invention are to be employed in the inhibition of hair regrowth after hair removal they may be used before and / or after the hair removal has taken place. The inhibitors may be used for the prophylactic inhibit of hair regrowth after hair removal, in which case they may be used prior to hah' removal (and optionally further used after hair removal has occurred).

[0072] In some embodiments, the compositions may further include hydrocortisone or any steroid within Groups I to VII in the US classification system to prevent inflammation during or after an inhibitor of lactic acid fermentation is administered to the subject. Group 1 steroids include, but are not limited to, clobetasol propionate, betamethasone dipropionate, halobetasol, and diflorasone diacetate. Group II steroids include, but are not limited to, fluocinonide, halcinonide, amcinonide, and desoximetasone. Group III steroids include, but are not limited to, triamcinolone acetonide, mometasone furoate, fluticasone propionate, betamethasone dipropionate, and halometasone. Group IV steroids include, but are not limited to, fluocinolone acetonide, hydrocortisone valerate, hydrocortisone butyrate, flurandrenolide, triamcinolone acetonide, and mometasone furoate. Group V steroids include, but are not limited to, fluticasone propionate, desonide, fluocinolone acetonide, and hydrocortisone valerate. Group VI steroids include, but are not limited to, alclometasone dipropionate, triamcinolone acetonide, fluocinolone acetonide, and desonide. Group VII steroids include, but are not limited to, hydrocortisone (2.5%) and hydrocortisone (1%). The amount of hydrocortisone or steroid in the compositions may be from about 0.01% to about 5% (w / w), relative to the total amount of the composition or in some embodiments, from about 0.1% to about 1% (w / w), relative to the total amount of the composition, or any range or individual concentration encompassed in these example ranges. In some embodiments, the compositions may further include an anti-inflammatory compound such as methotrexate, tofacitinib, 6-mercaptopurine, azathioprine sulphasalazine, mesalazine, olsalazine chloroquinine / hydroxychloroquinine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, cochicine, corticosteroids (oral, inhaled, and local injection), a beta-2 adrenoreceptor agonist (salbutamol, terbutaline, salmeteral), xanthine (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, an NSATD (e.g. ibuprofen), a corticosteroid (e. g. prednisolone), a phosphodiesterase inhibitor, an adensosine agonist, an antithrombotic agent, a complement inhibitor, an adrenergic agent, an agent that interferes with signalling by proinflammatory cytokines such as TNF or IL-1 (e.g., a NIK, IKK, p38 or MAP kinase inhibitor), an IL-1 converting enzyme inhibitor, a T-cell signalling inhibitor (e.g. a kinase inhibitor), a metalloproteinase inhibitor, sulfasalazine, a 6-mcrcaptopurinc, an angiotensin converting enzyme inhibitor, a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRigG (etanercept) and p55TNFRigG (Lenercept), siL-lRI, siL-lRII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL- 11 , IL- 13 and TGF), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, certolizumab, tocilizumab, abatacept, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone acetonide, propoxyphene napsylate / apap, folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium, oxaprozin, oxycodone HC1, hydrocodone bitartrate / apap, diclofenac sodium / misoprostol, fentanyl, anakinra, tramadol HC1, salsalate, sulindac, cyanocobalamin / fa / pyridoxine, acetaminophen, alendronate sodium, prednisolone, cortisone, betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulf / chondroitin, amitriptyline HCL sulfadiazine, oxycodone HCV acetaminophen, olopatadine HC1 misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-ILIS, BIRB-796, SCIO-469, VX-702, AMG- 548, VX-740, Roflumilast, IC-485, CDC-801, S1PI agonists (such as FTY720), a PKC family inhibitor (e.g. Ruboxistaurin or AEB-071 ) or Mesopram, budenoside; epidermal growth factor; a corticosteroid; cyclosporin, sulfasalazine; an aminosalicylate; 6- mercaptopurine; azathioprine; metronidazole; a lipoxygenase inhibitor; mesalamine; olsalazine; balsalazide; an antioxidant; a thromboxane inhibitor; an IL-1 receptor antagonist; an anti-IL-1 monoclonal antibody; an anti-IL-6 monoclonal antibody; a growth factor; an elastase inhibitor; a pyridinyl-imidazole compound; an antibody to or antagonist of other human cytokines or growth factors (e.g. TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF); a cell surface molecule (e.g. CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, or CD90 or their ligands); methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide; an NSAID (e.g. ibuprofen); a corticosteroid (e.g. prednisolone); a phosphodiesterase inhibitor; an adenosine agonist; an antithrombotic agent; a complement inhibitor; an adrenergic agent; an agent that interferes with signalling by proinflammatory cytokines such as TNF 5 or IL-1 (e.g. a NIK, IKK, or MAP kinase inhibitor); an IL-1 converting enzyme inhibitor; a TNF converting enzyme inhibitor; a T-cell signalling inhibitor such as kinase inhibitors; a metalloproteinase inhibitor; sulfasalazine; azathioprine; a 6-mcrcaptopurinc; an angiotensin converting enzyme inhibitor; a soluble cytokine receptor (e.g. soluble p55 or p75 TNF receptors, siL-lRI, siL-lRII, siL-6R), an antiinflammatory cytokine (e.g. IL-4, IL-1 0, IL- 11, IL- 13 or TGF), therapeutic agents that target an intrinsic checkpoint blockade, such as, for example, the gene encoding Cytokine-inducible SH2-containing protein (CISH), antibody BGB-A317, Nivolumab, or Pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, and the like and combinations thereof. The amount of antiinflammatory in the composition may be from about 0.01% to about 5% (w / w), relative to the total amount of the composition, or in some embodiments, from about 0.1% to about 1% (w / w), relative to the total amount of the composition, or any range or individual concentration encompassed by these example ranges.

[0073] In some embodiments, the compositions may further include an antiseptic compound. The antiseptic compound is not particularly limited, and in some embodiments may include, for example, iodine, manuka honey, octcnidinc dihydrochloridc, phenol, polyhexanide, sodium chloride, sodium hypochlorite, calcium hypochlorite, sodium bicarbonate, methyl paraben, and sodium dehydroacetate. The amount of the antiseptic in the compositions may be from about 0.01 % to about 5% (w / w), relative to the total amount of the composition, or in some embodiments, from about 0.1% to about 1%, relative to the total amount of the composition, or any range or individual concentration encompassed by these example ranges.

[0074] In some embodiments, the compositions may further include an anti-acne compound. The anti-acne agent is not limited and includes, for example, salicylic acid, benzoyl peroxide, and the like and combinations thereof. The amount of the anti-acne compound in the compositions may be from about 0.01% to about 5% (w / w), relative to the total amount of the composition, or in some embodiments, from about 0.1% to about 1% (w / w), relative to the total amount of the composition, or any range or individual concentration encompassed by these example ranges.

[0075] In some embodiments, the compositions may further include analgesic agent. The analgesic agent is not particularly limited and includes, for example, methyl salicylate, codeine, morphine, methadone, pethidine, buprenorphine, hydromorphine, levorphanol, oxycodone, fentanyl, a non-steroidal anti-inflammatory drug, and the like and combinations thereof. The amount of the analgesic agent in the compositions may be from about 0.01% to about 5% (w / w), relative to the total amount of the composition or in some embodiments, from about 0.1% to about 1% (w / w), relative to the total amount of the composition, or any range or individual concentration encompassed by these example ranges.

[0076] In one embodiment, the compositions comprising an inhibitor of lactate dehydrogenase (LDH) may be formulated into a shampoo or other suitable products such as creams, pastes, lotions, serums, ointments, or gels. The formulation of a shampoo or other suitable products may comprise an inhibitor of lactate dehydrogenase (LDH). The formulation of a shampoo or other suitable products may comprise a cleansing agent (such as sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfate, sulfonates, isethionates, sarcosinates, and taurates). The formulation of a shampoo or other suitable products may comprise a surfactant (such as anionic detersive surfactant, zwitterionic detersive surfactant, amphoteric detersive surfactant, cocamidopropyl betaine, decyl glucoside, sodium cocoamphoacetate, amphoacetates, and alkyl polyglucosides). The formulation of a shampoo or other suitable products may comprise a conditioning agent (such as dimethicone, polyquaterniums, natural oils, cetyl alcohol. stearyl alcohol, isopropyl myristate, and organic conditioning oil, including but not limited to hydrocarbon oils, polyolefins, and fatty esters polyolefins, and fatty esters). The formulation of a shampoo or other suitable products may comprise a silicone- containing conditioning agent (such as silicone oils, cationic silicones, silicone gums, high refractive silicones, and silicone resins). The formulation of a shampoo or other suitable products may comprise a humectant (such as polyhydric alcohols, alkoxylated nonionic polymers, glycerin, polyethylene glycol, propylene glycol, and sorbitol). The formulation of a shampoo or other suitable products may comprise a thickener or a suspending agent (such as sodium chloride, Xanthan gum, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, nitrocellulose, sodium cellulose sulfate, crystalline cellulose, cellulose powder, polyvinylpyrrolidone, polyvinyl alcohol, guar gum, hydroxypropyl guar gum, xanthan gum, arabia gum, tragacanth, galactan, carob gum, guar gum, karaya gum, carraghccnin, pectin, agar, quince seed, starch, algae colloids, and microbiological polymers). The formulation of a shampoo or other suitable products may comprise a preservative (such as phenoxyethanol, sodium benzoate, and potassium sorbate). The formulation of a shampoo or other suitable products may comprise a pH adjuster (such as citric acid, and sodium hydroxide). The formulation of a shampoo or other suitable products may comprise a fragrance or a colorant (such as essential oils, synthetic fragrances, dyes, nitroso, monoazo, diazo, carotenoid, triphenyl methane and natural colours). The formulation of a shampoo or other suitable products may comprise an aqueous carrier (such as water, and miscible mixture of water and organic solvent). The formulation of a shampoo or other suitable products may comprise a cationic polymer (such as organic cationic polymer containing nitrogen-containing moieties, cationic protonated amino moieties, polysaccharide polymers, and cationic cellulose polymers). The formulation of a shampoo or other suitable products may comprise a counterion in the presence of cationic polymers (such as halides, sulfate, and methylsulfate). The formulation of a shampoo or other suitable products may comprise an anti-dandruff active (such as pyridincthionc salts, selenium sulfide, particulate sulfur, and zinc pyrithionc). The formulation of a shampoo or other suitable products may comprise an antimicrobial agent (such as piroctone olamine, trichlosan, troclocarban, and zinc pyrithione) and / or other active ingredients (such as salicylic acid, panthenol, niacinamide, allantoin, vitamins, and amino acids). In some embodiments, the formulation may comprise the following composition by way of non-limiting examples. The inhibitor of lactate dehydrogenase (LDH) may be present in the composition from 0.001% to 10% by weight of the composition, e.g. from 0.001% to 5%, 0.005% to 5%, 0.01% to 5%, 0.1% to 5%, 1% to 5%, 0.001% to 1%, 0.001% to 0.1%, 0.001 to 0.01%, or 0.001 to 0.005% by weight of the composition. The aqueous carrier may be present in the composition from about 20% to about 95%, such as from about 50% to about 95%, from about 60% to about 90%, from about 65% to about 85%, or from about 70% to about 80% by weight of the compositions. The surfactant may be present in the composition from about 5% to about 50%, such as from about 8% to about 40%, from about 10% to about 30%, or from about 15% to about 25% by weight of the composition. The cationic polymer may be present in the composition from about 0.05% to about 3%, such as from about 0.075% to about 2.5%, from about 0.1% to about 2%, or from about 0.5% to about 1.5% by weight of the composition. The conditioning agent, including organic conditioning oils, may be present in the composition from about 0.05%) to about 3%;, such as from about 0.08%; to about 1.5%, from about 0.1%; to about 1%, from about 1% to 3%, or from about 2% to about 3% by weight of the composition. The silicone-containing conditioning agent may be present in the composition from about 0.01% to about 10%, such as from about 0.1% to about 8%, from about 0.1% to about 5%, from about 0.2% to about 3%, from about 0.5%o to about 2%, or from about 0.5% to about 1.5% by weight of the composition. The anti-dandruff active may be present in the composition from about 0.1% to about 4%, such as 0.1% to about 3%, from about 0.3% to about 2.5%, from about 0.3% to about 2%, from about 0.5% to about 1.5%, from about 2% to about 4%, or from about 2.5% to about 3.5% by weight of the composition. The humectant may be present in the composition from about 0.1% to about 20%, such as from about 0.5% to about 15%, from about 1% to about 12%, from about 2% to about 10%, from about 3% to about 5%, from about 5% to about 8%, or from about 8% to about 10%.

[0077] In some embodiments, the formulation may include an inhibitor of lactate dehydrogenase (LDH), and compositions described in patent application PCT / US2003 / 004977, which is incorporated herein in its entirety by reference. In one embodiment, the inhibitor of lactic acid fermentation may be present in a range ranging from 0.001% to 10%, e.g. from 0.001% to 5%, 0.005% to 5%, 0.01% to 5%, 0.1% to 5%, 1% to 5%, 0.001%; to 1%, 0.001% to 0.1%, 0.001 to 0.01%, or 0.001 to 0.005% by weight of the composition.

[0078] As used herein, the term “solvate” refers to an aggregate of a solute ion or molecule with one or more solvent molecules (such as a hydrate). In some embodiments, the inhibitor may form a solvate by incorporating a suitable solvent such forming solvate with water molecules.

[0079] As used herein, the term “derivative” refers to a chemical compound that is derived from an inhibitor of lactate dehydrogenase, comprising substitution and / or removal of a functional group through a chemical reaction. The inhibitor may be an oxamate or oxalate. In some embodiments, the inhibitor is a derivative of oxamatc or oxalate. In some embodiments, the inhibitor is dimethyl oxalate or oxalic acid diethyl ester. In one embodiment, the inhibitor is a derivative of oxamatc as described in EP0898956B1.

[0080] As used herein, the term “prodrug” refers to an inhibitor of lactate dehydrogenase in a form that requires activation, such as through enzymatic and / or biotransformation, before the inhibitor can have a significant therapeutic effect on the subject in which the inhibitor is administered to. The biotransformation process includes metabolism process of the subject that the inhibitor is administered to.

[0081] The inhibitors as referred to herein can be present in the composition in an amount ranging from 0.001% to 10%, e.g. from 0.001% to 5%, 0.005% to 5%, 0.01% to 5%, 0.1% to 5%, 1% to 5%, 0.001% to 1%, 0.001%) to 0.1%, 0.001 to 0.01%, or 0.001 to 0.005% of the total weight of the composition.

[0082] As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and / or condition. The term “administering” refers to contacting, applying, or providing an inhibitor of lactate dehydrogenase (LDH) to a subject.

[0083] By “effective amount”, in the context of treating or preventing a condition is meant the administration of an amount of an inhibitor of lactate dehydrogenase (LDH) to an individual in need of such treatment or prophylaxis, either in a single dose or as part of a series, that is effective for the prevention of incurring a symptom, holding in check such symptoms, and / or treating existing symptoms, of that condition. The effective amount will vary depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.

[0084] Provided herein is a method of screening for an inhibitor of hair growth in a subject, the method comprising: a) contacting a hair follicle keratinocyte with an inhibitor of lactate dehydrogenase (LDH); and b) i) detecting a reduction of ATP production through lactic acid fermentation (LAF) as compared when the hair follicle keratinocyte is not contacted with the inhibitor of LDH; wherein the reduction of ATP production via LAF indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject; ii) detecting a reduction in extracellular acidification (ECAR) as compared to when the hair follicle keratinocyte is not contacted with the inhibitor of LDH; wherein the reduction of ECAR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject; or iii) detecting an increase in oxygen consumption rate (OCR) as compared to when the hair follicle keratinocytes is not contacted with the inhibitor of LDH; wherein the increase of OCR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject.

[0085] In some embodiments, the hair follicle keratinocyte that is not contacted with an inhibitor of LDF is used as a reference for comparison.

[0086] In some embodiments, the hair follicle keratinocyte is cultured in a suitable culture media under a suitable condition. In one embodiment, the hair follicle keratinocyte is cultured in KGM ® Gold Keratinocyte Growth Medium (Lonza), at 37 degrees Celsius and 5% CO2.

[0087] In some embodiments, the inhibitor may be prepared, dissolved, and / or diluted in a suitable vehicle or solvent, such as dimethyl sulfoxide (DMSO), water, dichloromethane, ethyl acetate, ethanol and dimethylformamide, prior to testing on the hair follicle keratinocyte in culture.

[0088] In some embodiments, the culture is a hair follicle keratinocyte cell culture.

[0089] In some embodiments, a candidate compound of an inhibitor of lactic acid fermentation may be present in the culture prior to and / or during the screening.

[0090] In some embodiments, the method of screening may be a metabolic assay platform may comprise a measuring the ATP production level, extracellular acidification (ECAR), and oxygen consumption rate (OCR) of a hair follicle keratinocyte using a Seahorse XF Real-Time ATP Rate Assay Kit comprising different types of compounds, with a Seahorse XF Analyzer platform. The compounds may be oligomycin, FCCP, antimycin A, and Rotenone in suitable concentrations.

[0091] The metabolic assay platform allows the skilled person to measure the basal respiration, ATP-linked respiration, proton leak, maximal respiratory capacity, non-mitochondrial oxygen consumption and reserve capacity of a cell subjected to testing. The cells are cultured in a dedicated cell culture plate for the metabolic assay. The platform allows the addition of the different compounds at a pre-determined timepoint and a predetermined volume. From the screening output of the different parameters, it will be appreciated that the skilled person is able to derive, calculate, and compare the ATP production, extracellular' acidification (ECAR), and oxygen consumption rate (OCAR) under different conditions (such as with or without a candidate compound) without undue burden.

[0092] The inhibitor of LDH may inhibit the ATP production through lactic acid fermentation in the hair follicle keratinocyte when compared to the hair keratinocyte that is not contacted with the inhibitor of LDH. The inhibitor of LDH may lead to a decrease in ATP production. The reduction of ATP production via LAF indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject. The decrease may be, for example, a decrease of 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 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% or up to and including a 100% decrease or any decrease between 5-100% as compared to a reference level.

[0093] The inhibitor of LDH may inhibit the carbon dioxide production of the hair keratinocyte into the ex trace I hi I ar environment (such as into the cell culture media) when compared to the hair keratinocyte in is not contacted with the inhibitor of LDH. The production of carbon dioxide into the extracellular environment leads to extracellular acidification. The reduction of ECAR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject. The decrease or reduction may be, for example, a decrease of 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 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% or up to and including a 100% decrease or any decrease between 5-100% as compared to a reference level.

[0094] The inhibitor of LDH may increase the oxygen consumption rate (OCR) as compared to when the hair follicle keratinocytes are not contacted with the inhibitor of LDH. The increase of OCR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject. The increase may be, for example, an increase of 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 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% or up to and including a 100% increase or any increase between 5-100% as compared to a reference level. The terms “detecting”, “determining”, “measuring”, “evaluating”, “assessing” and “assaying” are used interchangeably herein to refer to any form of measurement, and include determining if an element is present or not. These terms include both quantitative and / or qualitative determinations. Assessing may be relative or absolute. The methods defined herein may comprise measuring the ATP production level, extracellular acidification (ECAR), and oxygen consumption rate (OCR).

[0095] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (or).

[0096] As used in this application, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "an agent" includes a plurality of agents, including mixtures thereof.

[0097] Throughout this specification and the statements which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0098] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavor to which this specification relates.

[0099] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications, which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0100] Certain embodiments of the invention will now be described with reference to the following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.

[0101] EXAMPLES

[0102] This disclosure represents the use of inhibitors of the lactic acid fermentation (LAF) pathway, specifically lactate dehydrogenase (LDH) inhibitors, to slow human hair growth. Human hair requires a large amount of energy to grow. There are about 100,000 terminal scalp hair follicles on a healthy adult’s scalp and each hair follicle (HF) produces hair at 0.3 mm / day, at about 1-2 metres of hair per hour. Due to their rapid growth, HFs preferentially produce the required ATP via LAF rather than via mitochondria respiration, even in the presence of oxygen. This is markedly different from majority of other cell types that primarily generate ATP via mitochondria respiration. In addition, comparison of healthy HFs (isolated from occipital region of donor) to miniaturized HFs (isolated from balding region) showed that miniaturized follicles undergo metabolic reprogramming to a more OXPHOS state, expressing more genes and proteins associated with mitochondrial respiration (unpublished TD Lab data). Hence, it is postulated that compounds which induce the same metabolic reprogramming in HF kcratinocytcs (HFK) will be able to switch the HF to a ‘balding- like’ state, inhibiting hair growth.

[0103] Based on this hypothesis, inhibitors of lactate dehydrogenase (LDH), a key enzyme in LAF pathway, were tested for their ability to attenuate ATP-production via LAF. Briefly, HFKs were treated with LDH inhibitors, sodium oxamate and sodium oxalate. Thereafter, their live metabolic profile was obtained using commercially available Seahorse XF Real-Time ATP Rate Assay Kit with a Seahorse XF Analyzer, which simultaneously measures the real-time extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of the treated and untreated cells. The rate of ATP produced through LAF and mitochondrial respiration could then be derived from the ECAR and OCR respectively, using the Seahorse XF Analyzer software (or by manual calculation using standard ATP production biochemical equations). Untreated HFKs were found to produce majority of then- ATP through LAF, consistent with what is known about hair follicle metabolism. (Figure 1). As expected, sodium oxamate and sodium oxalate were able to reduce ATP production via LAF, shifting cellular metabolism towards OXPHOS.

[0104] Sodium oxamate’ s and sodium oxalate’ s ability to inhibit hair growth was then validated in ex vivo whole HF cultures. Briefly, human HFs were treated with each compound and their rate of growth compared with that of untreated HFs, at various days post treatment. It was consistently found that the follicles treated with these LDH inhibitors had reduced hair growth rate compared with the untreated control (Figure 2).

[0105] Table 1:

Claims

CLAIMS1. A method of inhibiting hair growth in a subject, the method comprising administering an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivate or prodrug thereof, to the subject.

2. The method of claim 1, wherein the inhibitor of lactate dehydrogenase (LDH) inhibits the Lactic Acid Fermentation (LAF) pathway.

3. The method of claims 1 or 2, wherein the inhibitor is an oxamate, an oxalate, an oxalic acid ester or an oxamic acid ester.

4. The method of any one of claims 1 to 3, wherein the subject is a human subject.

5. The method of any one of claims 1 to 4, wherein the subject is suffering from a condition associated with excessive or unwanted hair growth.

6. The method of claim 5, wherein the condition is hirsutism or hypertrichosis.

7. The method of any one of claims 1 to 6, wherein the inhibitor is administered topically or transdermally to the subject.

8. The method of any one of claims 1 to 7, wherein the method is a non-therapeutic or cosmetic method.

9. A method of treating a subject suffering from a condition associated with excessive or unwanted hair growth, the method comprising administering an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivative or prodrug thereof, to the subject.

10. An inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivate or prodrug thereof, for use in treating a subject suffering from a condition associated with excessive or unwanted hair growth.

11. Use of an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivative or prodrug thereof, in the manufacture of medicament for treating a subject suffering from a condition associated with excessive or unwanted hair growth.

12. A composition comprising an inhibitor of lactate dehydrogenase (LDH), or a salt, solvate, derivative or prodrug thereof.

13. A method of screening for an inhibitor of hair growth in a subject, the method comprising: a) contacting a hair follicle keratinocyte with an inhibitor of lactate dehydrogenase (LDH); and b) i) detecting a reduction of ATP production through lactic acid fermentation (LAF) as compared when the hair follicle keratinocyte is not contacted with the inhibitor of LDH; wherein the reduction of ATP production via LAF indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject; ii) detecting a reduction in extracellular acidification (ECAR) as compared to when the hair follicle keratinocyte is not contacted with the inhibitor of LDH; wherein the reduction of ECAR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject; or iii) detecting an increase in oxygen consumption rate (OCR) as compared to when the hair follicle kcratinocytcs is not contacted with the inhibitor of LDH; wherein the increase of OCR indicates that the inhibitor of LDH is an inhibitor of hair growth in the subject.

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