US 20160374979A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0374979 A1 Yamamoto et al. (43) Pub. Date: Dec. 29, 2016

(54) METHOD OF TREATMENT OF ALOPECIA A6IR 8/37 (2006.01) WITH MONOTERPENOIDS A63L/II (2006.01) A61O 13/00 (2006.01) (71) Applicant: CELLMID LIMITED, Sydney, New A63L/045 (2006.01) South Wales (AU) A6IR 8/34 (2006.01) A6II 3L/22 (2006.01) (72) Inventors: Masakuni Yamamoto, Chiba (JP); A6IR 8/35 (2006.01) Masato Namekata, Chiba (JP); Koichi A61O 7/00 (2006.01) Matsumoto, Chiba (JP); Darren Ross (52) U.S. Cl. Jones, Avalon Beach (AU); Maria CPC ...... A61K 31/22 (2013.01); A61O 700 Halasz, Sydney (AU) (2013.01); A61K 9/0014 (2013.01); A61K 8/37 (2013.01); A61 K3I/II (2013.01); A61K 8/33 (21) Appl. No.: 15/102,502 (2013.01); A61 K3I/045 (2013.01); A61K 8/34 (22) PCT Filed: Dec. 12, 2014 (2013.01); A61K 31/122 (2013.01); A61K 8/35 (2013.01); A61O 13/00 (2013.01); A61 K (86). PCT No.: PCT/AU2014/OSO421 2800/74 (2013.01) S 371 (c)(1), (2) Date: Jun. 7, 2016 (57) ABSTRACT (30) Foreign Application Priority Data The present application generally relates to topical formu lations comprising monoterpenoid compounds which are Dec. 12, 2013 (AU) ...... 2O139.04859 effective inhibitors of FGF-5-dependent signalling in follicles or parts thereof, the manufacture of such topical Publication Classification formulations, and their use to reduce, delay or prevent loss (51) Int. Cl. of caused by FGF-5 signalling in the hair A6 IK 3L/22 (2006.01) follicle, such as in Subjects Suffering from, or having a A6K 9/00 (2006.01) propensity to develop, alopecia Patent Application Publication Dec. 29, 2016 Sheet 1 of 19 US 2016/0374979 A1

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METHOD OF TREATMENT OF ALOPECA to 72 hours, faster than any other cells in the body. The WITH MONOTERPENOIDS follicle is surrounded by an inner root sheath and an outer root sheath. These two sheaths protect and mould the RELATED APPLICATION DATA growing bait shaft. The inner root sheath follows the hair shaft and ends below the opening of a sebaceous (oil) gland, 0001. This application claims priority from Australian which produces sebum, and sometimes an apocrine (scent) Provisional Application No. 2013904859 filed on 12 Dec. gland. The outer root sheath continues all the way up to the 2013, the full contents of which is incorporated by reference sebaceous gland. An erector pili muscle attaches below the herein in its entirety. sebaceous gland to a fibrous layer around the outer sheath. FIELD OF THE INVENTION When this muscle contracts, it causes the hair to stand up. 0007 Human skin comprises two types of hair: vellus 0002 The present application relates to the field of hair hair and terminal hair. is short, fine, “peach fuzz' loss and/or hair growth, Such as the production and use of . It is a very soft, generally pale, and that cosmetics for prevention or treatment of or the grows in most places on the human body in both sexes. promotion or enhancement of hair growth, and the produc Vellus hair is generally less than two centimetres in length, tion and use of medicaments for therapy of allopecia. and the follicles from which vellus hair grows are not connected to sebaceous glands. It is observed most easily in BACKGROUND TO THE INVENTION those having less terminal hair to obscure it, such as women 0003 Hair and Hair Development and children. It is also found in pre-adolescents and in males 0004 Hair is integral to our body image and can have a exhibiting male-pattern baldness. Terminal or "androgenic’ profound influence on out self-esteem and self-confidence. hair is developed hair, which is generally longer, coarser, The appearance altering effects of hair loss and/or hair thicker and darker than vellus hair. Phases of growth for thinning can have a significant impact on an individuals terminal hair are also more apparent than for Vellus hair, by psychological well-being and quality of life. In this regard, virtue of a generally-longer anagen phase. Terminal hair has alopecia, and particularly androgenic alopecia, is a source of associated Sebaceous glands. In puberty, some Vellus hair low self-esteem and anxiety for many sufferers. Hair is an may develop into terminal hair. Under other conditions. Such important facet of the human appearance that is commonly as male pattern baldness, terminal hair may revert to a used for recognition and is one determinant of physical Vellus-like state. attractiveness. In both Western and Asian cultures, Volumi 0008. The hair growth cycle in mammals is composed of nous thick hair is a symbol of health, youthfulness and three sequential phases: anagen, catagen and telogen. Virility. As a consequence, the loss of one's hair can diminish 0009 Anagen is the active growth phase of the cycle body image satisfaction and have deleterious effects on during which time cells in the root of the hair are dividing self-esteem e.g., Cash T F. British Journal of Dermatology, rapidly, follicles grow, hair synthesis takes place and skin 141: 398-405, 1999, Those suffering from hair loss often thickness increases. Anagen can be further divided into six experience embarrassment and fear being ridiculed by others short Subphases i.e., anagen I-VI. During the anagen phase, because they look different. In some subjects, alopecia may are anchored deeply into the Subcutaneous fat and lead to depression. These factors, coupled with society's therefore cannot be pulled out easily. As new hair is syn current emphasis on youthfulness, have only served to thesized, the club hair is pushed up the follicle, and even strengthen the value of abundant hair, and, as a result, tually out from the skin. During this phase active growth products and services promoting hair growth, replacement phase, the hair grows at a rate of about 1 cm every 28 days. or fuller appearance of hair have proliferated. Scalp hair stays in this active phase of growth for approxi 0005. The hair of non-human mammals is commonly mately 2-6 years. Human subjects that have difficulty grow referred to as “fur”. Unless specifically stated otherwise, or ing their hair beyond a certain length may have a shortened the context requires otherwise, the term “hair as used herein anagen phase, whereas those having an ability to grow shall be taken to include “fur. The term "hair shall also be longer hair quickly may have a longer anagen phase. In taken to include hair on any part of a mammalian body, humans, the hair on the arms, legs, , and including the , edge of the eyelid, armpit, and inside generally has a short anagen compared to head or scalp hair. of the , unless the context requires otherwise. Thus, 0010. The catagen phase is a transitional stage that lasts hair may include head hair, eyebrow hair, , cilia, or for about 2-3 weeks in humans, during which time growth other body hair. stops, thereby forming “club' hair, follicles regress and skin 0006 Each hair comprises two structures: the shaft and thickness decreases. the follicle. The primary component of the hair shaft is 0011 Telogen is the final phase of the hair growth cycle keratin. The hair shaft contains three layers of keratin, during which both follicles and skin are at rest, lasting for however the inner layer i.e., the medulla, may not be present. about 100 days for scalp hair and much longer for other body The middle layer i.e., the cortex, makes up the majority of hair. During telogen, the is at rest, the club hair the hair shaft. The outer layer i.e., the cuticle, is formed by is formed, and compared to hair in anagen, the hair in tightly-packed scales in an overlapping structure. Pigment telogen is located higher in the skin and can be pulled out cells are distributed throughout the cortex and medulla more readily. The root of telogen hair comprises a visible giving the hair its characteristic colour. The follicle contains solid, hard, dry, and white material. Shedding of hair in the several layers. At the base of the follicle is a projection telogen phase is normal, and up to 75 hairs in telogen are called a papilla, which contains capillaries, or tiny blood shed from a normal human scalp daily. However, hairs are vessels, that feed the cells. The living part of the hair, the typically replaced at a rate similar to that at which they are area Surrounding the papilla called the bulb, is the only part shed, because about the same number of follicles enter the fed by the capillaries. The cells in the bulb divide every 23 anagen phase daily. At any given time, approximately 80% US 2016/0374979 A1 Dec. 29, 2016

to 90% of follicles in a normal scalp are in the anagen phase, hair produced from normal hair follicles and therefore about 1% to 3% are in the catagen phase i.e., undergoing provides less complete scalp coverage. involution, and about 5% to 10% are in the telogen phase. 0018. In contrast, androgen stimulation of facial dermal 0012. The hair growth cycle is known to he regulated by papillae cells produces insulin-like growth factor-2 (IGF-2), a variety of mediators, including several members of the resulting in cyclical enlargement of the entire hair follicle. fibroblast growth factor (FGF) family. Of the 22 known As a consequence, hair produced from follicles that have members of the FGF gene family, FGF-1, FGF-2. FGF-7, undergone cyclical enlargement is generally longer and FGF-13. FGF-18 and FGF-22 are expressed in the epithe thicker compared to hair produced from normal hair follicles lium of the hair follicle and are thought to be involved in the and provides more complete facial skin coverage. hair growth cycle. For example, FGF-1, FGF-2 and FGF-7 are reported to be involved in cell proliferation in the hair 0019 Acute alopecia is hair loss associated with an acute follicle and agonists of these molecules have been proposed event, such as pregnancy, severe illness, treatment e.g., Such for used in hair growth products. as by chemotherapy, stress, severe malnutrition, iron defi ciency, hormonal disorders, AIDS, or acute irradiation. For 0013 Conditions of Hair Loss and/or Reduced Hair example, treatment with chemotherapeutic agents, radio Growth therapeutic agents, and other medicinal products may induce 0014. As used herein, the term “alopecia’ refers to a necrosis or apoptosis of the follicle as a side-effect of the medical condition or pathology in which hair loss or hair therapy, thereby preventing the follicle from entering ana thinning occurs by virtue of a reduced ability to replace shed gen. Examples of agents which are known to induce tem hairs or as a result of a medical condition or pathology that porary or permanent alopecia include alkylating agents e.g., results in enhanced hair shedding without concomitant or temozolomide, buSulfan, ifosamide, melphalan hydrochlo Subsequent replacement thereof e.g., brittle hair growth, thin ride, carmustine, lomustine or cyclophosphamide, and anti hair growth, short hair growth, sparse hair growth, alopecia, metabolites e.g., 5-fluorouracil, capecitabine, gemcitabine, or hair de-pigmentation. For example, the hair cycle can floXuridine, decitabine, mercaptopurine, pemetrexed diso become uncontrolled leading to accelerated hair loss, which dium, methotrexate or dacarbazine, and natural products may be temporary or permanent. e.g., Vincristine, vinblastine, Vinorelbine tartrate, paclitaxel, 0.015 Alopecia can have various causes, including andro docetaxel, ixabepilone, daunorubicin, epirubicin, doxorubi genic alopecia (also referred to as male or female pattern cin, idarubicin, mitoxantrone, mitomycin, dactinomycin, hair loss), acute alopecia, and including irinotecan, topotecan, etoposide, teniposide, etoposide phos and . phate, or bleomycin sulfate, and biologies e.g., filgrastim, 0016. Androgenic alopecia is the most common form of pegfilgristim, bevacizunab, SargramoStim or panitumumab, alopecia. Androgenic alopecia is a hereditary hair-loss con and hormones or hormone-related agents e.g., megestrol dition affecting men and women of for example, Caucasian acetate, fluoxymesterone, leuprolide, octreotide acetate, or Asian descent. Androgenic alopecia is characterised by a tamoxifen citrate or fluxymesterone, and other therapeutic progressive decrease in hair Volume, or even baldness. agents e.g., Sorafenib, erlotinib, oxaliplatin, dexraZoxane, Without treatment, the number of hairs on a sufferer of anagrelide, isotretinoin, beXarotene, Vorinostat, adriamycin, androgenic alopecia will decrease at a rate of approximately cytoxan, taxol, leucovorin, oxaliplatin, and combinations of 5% per year after onset e.g., Ellis et al. Expert Reviews in the foregoing agents. Molecular Medicine, 4: 1-11, 2002. Androgenic alopecia is so common it is reported to affect up to 70% of the general 0020. Alopecia areata is a common cause of non-scarring population, with an estimated 30% of men developing alopecia that occurs in a patchy, confluent or diffuse pattern androgenic alopecia by the age of 30, and 50% of men on one or more sites of the body. Alopecia areata is thought affected by the age of 50. In fact, it is reported that fewer to be T-cell mediated autoimmune condition and has a than 15% of the male population have little or no baldness reported incidence of 0.1-0.2% in the general population by the age of 70 e.g., Sinclair R, JMHG, 1(4): 319-327, with a lifetime risk of 1.7% in both men and women alike 2004; Lee and Lee, Ann. Dermatol., 24(3): 243-252, 2012. e.g., Amin SS and Sachdeva S.JSSDDS, 17(2): 37–45, 2013. As many as 10% of pre-menopausal women are reported to In approximately 1-2% of cases, the condition can spread to exhibit some evidence of androgenic alopecia (also referred the entire scalp (Alopecia totalis) or to the entire epidermis to as female ), and the incidence of andro (Alopecia universalis). genic alopecia in women increases significantly as women 0021 Mechanistically, in all forms of alopecia, hair loss enter menopause. For instance, as many as 50-75% of is directly-related to a reduced ability, slowing or failure of women aged 65 years or older are or will be affected by the follicle to enter the anagen phase, or a failure to maintain androgenic alopecia e.g., Norwood O T. Dermatol Surg., the follicle in the anagen phase. Such that formation of a hair 27(1): 53-4, 2001. shaft reduces, is slowed or ceases altogether. Hair may move 0017 Whilst the onset and physical manifestation of into the catagen phase before Sufficient growth is achieved androgenic alopecia varies quite significantly among indi in the anagen phase, thus becoming in a Sustained manner viduals, at least in males, its pathogenesis is thought to short and thin (i.e. “hair thinning). Chemotherapeutic commence after puberty when there are sufficient circulating agents, radiotherapeutic agents, and other medicinal prod androgens. For example, dihydrotestosterone (DHT) is pro ucts may induce necrosis or apoptosis of the follicle as a duced by the action of 5C-reductase on testosterone, and side-effect of the therapy, also preventing the follicle from binds to androgen receptors (AR) in the dermal papilla of entering anagen. For example, alkylating agents, antime sensitive hair follicle of the scalp inducing growth factor tabolites, natural products, biologics, hormones or hormone beta (TGF-3), and results in cyclical miniaturization (shrink related agents, other therapeutic agents, and combinations age) of the entire hair follicle. Hair produced from minia thereof are known to induce temporary or permanent acute turized hair follicles is generally short and fine compared to alopecia. US 2016/0374979 A1 Dec. 29, 2016

0022 Animal Models of Alopecia used to study the efficacy of current treatments of allopecia 0023 There are several models of allopecia in humans areata, to study the effectiveness and safety profile of new that have been acknowledged in the art for use in testing treatment forms in established alopecia areata, and to assess efficacy of allopecia remedies and other hair growth-promot the influence of various factors on the development of ing therapies. alopecia areata in order to prevent the onset of the disease. 0024 For example, the Stumptailed macaque possesses hereditary balding characteristics similar in many respects to (0027 Paus et al. Am. J. Pathol. 144, 719-734 (1994) that of androgenic alopecia in humans, is used to obtain a disclose a rodent model of acute alopecia. In this model, morphometric assessment of the rate of cyclic change of the alopecia is induced by a single intraperitoneal injection of hair follicle, including rates of cyclic progression (resting to cyclophosphamide to C57BL/6 mice. In depilated C57 regrowing phase, and regrowing to late anagen phase) and BL/6 mice, the hair follicles are synchronized to anagen. By overall changes in follicular size. These primates are also day 9 after depilation, all follicles are mature anagen VI reasonably good predictors of compound efficacy, and for follicles, and the skin is characterized by grey-to-black example, have been employed to test efficacy of minoxidil colored hair shafts. Histologically, macroscopically, and on androgenic alopecia. Cessation of topical minoxidil treat functionally, depilation-induced anagen VI follicles are ment resulted in a renewal of the balding process, with indistinguishable from spontaneously-developing anagen folliculograms demonstrating increases in the proportion of follicles. Around day 16 after depilation, follicle regression resting follicles. This withdrawal from treatment apparently occurs without loss of hair shafts in the depilated animals, had no effect on hair regrowth during Subsequent reappli and skin color converts from black to pink, indicating both cations of minoxidil. Such treatment resulted in regrowth induction of catagen and cessation of melanogenesis. The similar to that in the first treatment phase. Continuous development of catagen follicles is indicated macroscopi treatment of topical minoxidil for 4 years has not resulted in cally by a change in skin color from black to lightgrey, and systemic or local side effects in these animals. See e.g., occurs in large appearing in the neck region first and Brigham it al., Clin. Dermatol. 6, 177-187, 1998; Sundberg then the flanks and tail regions. At day 20 after depilation, et al., Exp Mot. Pathol 67, 118-130 (1999), the contents of all follicles enter telogen again, characterized by change in which are incorporated herein by reference in their entirety). skin color from grey to pink. When cyclophosphamide is 0025. In addition to the stumptailed macaque, Crabtree administered to C57BL/6 mice on day 9 after depilation, the and colleagues recently reported the first rodent model of animals show rapid and reproducible visible signs of acute androgenic alopecia e.g., Crabtree et al., Endocrinology, alopecia dose-dependent, including significant loss of fur 151(5): 2373-2380, 2010. In this study, transgenic mice and premature termination of anagen characterized by overexpressing human AR in the skin under control of the depigmentation leading to a grey skin appearance by day keratin 5 promoter were exposed to high levels of 5-alpha 12-14. Thus, follicles of the neck region are generally in dihydrotestosterone and showed delayed hair regeneration, catagen 3-5 days after cyclophosphamide treatment. Hair mimicking the androgenic alopecia Scalp. Crabtree and shafts on the backs of animals are also removed easily by colleagues also demonstrated that the androgenic alopecia of rubbing at days 12-14, and by day 15, as much as 60% of the the scalp wars androgen receptor (AR) mediated, because dorsal Surface may be exhibit alopecia. The color change treatment of the mice with the AR antagonist hydroxyflu and alopecia induced by cyclophosphamide reflect the tamide inhibited the effect of dihydrotestosterone on hair induction of dystrophic forms of anagen and catagen in growth. antigen VI follicles. In cyclophosphamide-treated animals, 0026 Collectively, the findings obtained from studies on follicles also progress to telogen rapidly, as evidenced by mouse models Support the concept of allopecia areata as an pink skin, and rapid loss of fur due to damage of the hair autoimmune disease, and several rodent models with spon follicle. Telogen is shortened following cyclophosphamide taneous and induced alopecia areata have been identified. treatment, and normal telogen hair follicles enter the next For example, the Dundee Experimental Bald Rat (DEBR) hair cycle, so that animals develop new hair shafts on days was the first rodent model validated that developed sponta 16-20 i.e., within about 7-10 days following treatment. neous alopecia areata and is utilized to identify candidate These new hair shafts are often de-pigmented due to the alopecia areata susceptibility gene loci (Michie et al., Br J presence of dystrophic anagen follicles that have not had Derrnatol., 125, 94-100, 1991, incorporated herein by ref time to produce new, normally-pigmented hair shafts. Later, erence). The most extensively-characterized and readily pigmented hair shafts develop. accessible alopecia areata model is the C3H/He mouse (0028. Therapy for Alopecia model (Sundberg et al., J Invest Dermatol., 102, 847-56, 0029 Products that claim to be useful for treating hair 1994, incorporated herein by reference). Aging C3H/He loss target a steadily growing, multi-billion dollar market mice (females at 3-5 months of age or older and males at worldwide. Existing therapies for alopecia include topical more than 6 months of age) develop histopathological and minoxidil and derivatives thereof e.g., U.S. Pat. Nos. 4,139. immunohistochemical features of human alopecia areata. 619 and 4,596,812, and European Pat. Nos. EP-0353123, Alopecia develops diffusely or in circular areas on the dorsal EP-0356271, EP-0408442, EP-0522964, EP-0420707, Surface of Sufficiently-aged animals. Histologically, the EP-0459890 and EP-0519819 spironolactone, cyproterone changes in this non-scarring alopecia appear limited to acetate, flutamide, finasteride, progesterone or estrogen. antigen follicles Surrounded by mononuclear cells composed However, none of those agents are broadly applicable for all primarily of cytotoxic or cytostatic (CD8+) and helper forms of allopecia, nor are they uniformly dependable for all (CD4+) T cells, this is associated with follicular and hair patients. shaft dystrophy. Pedigree tracing of affected C3H/He mice 0030 Based on the fact that androgenic alopecia is the Suggests that this non-scarring alopecia may be an inherited most commonly reported form of hair loss, there have been and complex polygenic disease with a female predominance many attempts to discover effective agents for treatment of at younger ages. C3H/He mice with alopecia areata can be this condition. Notwithstanding the large number of adver US 2016/0374979 A1 Dec. 29, 2016 tised anti-hair loss agents on the market, convincing evi at least daily. For example, prostaglandin analogues, which dence-based medicine is still the exception rather than the are have been used to treat eyelash hypotrichosis with some rule in this field, and currently, only monoxidil and finas Success, have been proposed for treating alopecia. However, teride are known to be effective for treating androgenic topical applications of prostaglandins have not proved effi alopecia, and only topical monoxidil and oral finasteride cacious e.g., Atanaskova et al., Dermatologic Clinics, 31(1): formulations (for males only) have been approved by the 119-127, 2013. Botulinum toxins have also been introduced United States Food and Drug Association (FDA). However, for treatment of hair loss with some Success, resulting in even these agents have their own shortcomings. reduced hair loss, and in Some cases, increased hair growth. 0031 Minoxidil is a vasodilator which was originally However, little data on the effectiveness of these emerging used to treat hypertension. However, following observations agents in treating hair loss are currently available. that patients treated with minoxidil showed increased hair 0035. Herbal cosmetics are also finding increasing popu growth, a topical formulation was developed for treatment larity, and approximately 1000 types of plant extracts are of hair loss. Although a mechanism of action of minoxidil is reported to have been examined with respect to hair growth not fully understood, minoxidil has is postulated to (i) arrest e.g., Rathi et al., Pharmacognosy Reviews, 2:185-187, 2008. hair loss by prolonging the anagen growth phase of terminal For example, procantbocyanidins extracted from grape hair leading to a decrease in hair shedding, and (ii) Stimulate seeds have been reported to induce hair growth e.g., Taka hair growth by increasing cutaneous blood flow to the scalp hashi et al., Acta Dermato-Venereologica, 7£1:428-432, e.g., Kwack et al., Journal of Dermatological Science, 1998. 62(3): 154-159, 2011; Buhl et al., The Journal of investiga 0036. There is a need for cosmetic and medical products tive Dermatology, 92(3):315-320, 1989. treatment and prevention of loss and for the treatment of 0032. Whilst minoxidil has demonstrated some efficacy pathological conditions of hair loss Such as alopecia. in promoting hair growth, it does not inhibit the biological 0037. The following publications provide conventional process of hair loss, and upon cessation of topical minoxidil techniques of molecular biology. Such procedures are treatment, hair shedding rapidly resumes, including the loss described, for example, in the following texts that are of any minoxidil-stimulated hair. For this reason, patients incorporated by reference: treated with topical minoxidil require frequent dosing to 0038 1. Remington’s Pharmaceutical Sciences, 21th Ed. achieve an effective outcome e.g., twice-daily at 2% con Philadelphia, Pa...: Lippincott Williams & Wilkins, 2005 centration. Minoxidil is also considered to be effective in less than 60% of patients, and there is currently no indication SUMMARY OF THE INVENTION as to which patients are most likely to respond. Minoxidil also has a number of undesirable side-effects. For example, 0039. In work leading up to the present invention, the irritation of the scalp, including dryness, Scaling, itching, inventor sought to identify compounds e.g., for topical and redness, is reported to occur in approximately 7% of administration to a subject, capable of reducing FGF-5- patients using the 2% solution and in more of those using the dependent signalling in a hair follicle or part thereof, and/or 5% solution because of its higher content of propylene which are capable of preventing and/or reducing and/or glycol. Minoxidil may also cause allergic contact dermatitis inhibiting FGF-5 binding to its cognate receptor, FGFR1. or photoallergic contact dermatitis. is another The inventors hypothesized that such compounds would be dermatologic adverse effect reported in Subjects using useful for reducing and/or preventing loss or thinning of minoxidil which is thought to be caused by increase cuta terminal hair associated with FGF-5 signalling in the hair neous blood flow thereby increasing nutrients, blood and follicle. This work was based on the recognition by the oxygen to the follicles e.g., Price V H, New England Journal inventors that FGF-5 is important for transition of a hair of Medicine, 341 (131:964-973, 1999; Rossie et al., Recent follicle from anagen to catagen during the normal growth Patents on Inflammation & Allergy Drug Discovery, 6(2): cycle and that FGF-5-signalling in the hair follicle can cause 130-136, 2012. hair loss or hair thinning by decreasing proliferation of outer 0033 Finasteride is a selective inhibitor of 5-alpha reduc root sheath cells, Suppressing dermal papillae cell activation tase of type II, which reduces conversion of testosterone into during anagen and inducing onset of catagen. DHT. Notwithstanding that finasteride provides an advance 0040. The inventors reasoned that compounds identified over minoxidil in being deliverable orally, approximately as being capable of reducing FGF-5-dependent signalling in 35% or more of balding male recipients show poor or no a hair follicle or part thereof and/or which are capable of response to finasteride treatment. Furthermore, because fin preventing and/or reducing and/or inhibiting FGF-5 binding asteride is used for systemic therapy in males, DHT pro to its cognate receptor, FGFR1, could be administered as duction is reduced systematically in tissues and serum. As a part of a topical formulation to a reduce, delay or prevent consequence, systemic inhibition of 5-alpha reductase dur loss of terminal hair caused by FGF-5 signalling in the hair ing finasteride treatment can produce significant side-effects follicle, such as in Subjects Suffering from, or having a in some users, including erectile dysfunction, impotence, propensity to, develop alopecia. low libido, or gynecomestica after using that drug e.g., Price 0041. The inventors screened synthetic and naturally V H, New England Journal of Medicine, 341 (13):964-973, occurring compounds using a FR-Ba/F3 cell-based screen 1999. In those males suffering such side-effects, the side ing assay, e.g., Ito et al., Journal of Cellular Physiology, effects may not disappear after ceasing finasteride. Finas 197:273-283, 2003. The inventors also used a dermal papilla teride is also costly to produce. Alkaline Phosphatase (DP-ALP) cell-based screening assay 0034. Other experimental agents, including various pros as disclosed in WO20131105417 to validate the FGF-5- taglandin analogs, have also been disclosed for use in inhibitory activity of monoterpenoids identified in the pri treatment of allopecia e.g., travoprost and voprostol. How mary FR-Ba/F3 cell-based screening assay as inhibiting ever, most of these drug require frequent administration e.g., FGF-5-dependent signalling. US 2016/0374979 A1 Dec. 29, 2016

0042. The data provided herein show that certain 0054 By “topical formulation' is meant that the formu monoterpenoid compounds derived from plant extracts lation is capable of being applied externally to the dermis of exhibit an inhibitory activity on proliferation and/or viability a mammal e.g., a human, or is applied to the dermis. of FGF-5-dependent FR-BaF3 cells cultured in the presence 0055 As used herein, the term “FGF5-dependent signal of FGF-5. Because FR-BaF3 cells are dependent on FGF-5 ling shall be understood to mean any signalling within for viability and proliferation, the observed reduction in cell and/or between cells in a signal transduction pathway that is proliferation and viability indicates the ability of the dependent, either directly or indirectly, on the presence of monoterpenoid compound(s) to inhibit and/or prevent and/ FGF-5 and/or the presence of an amount of FOP-5 above a or reduce FGF-5 dependent signalling in those cells. The specific threshold. data provided herein also show that a subset of monoterpe 0056. As used herein, the term "C. C. alkyl” refers to noid compounds that modulate FGF-5-dependent signalling monovalent straight chain or branched hydrocarbon groups, the FR-BaF3 cell assay are also capable of increasing or having 2 to 5 carbon atoms. It is to be understood that the enhancing alkaline phosphatase (ALP) activity in dermal term "C-C alkyl includes an alkyl chain having 2, 3, 4 papilla (DP) cells treated with FGF-5. Collectively, these or 5 carbon atoms. Suitable alkyl groups include, but are not data Support the conclusion that monoterpenoid compounds limited to, ethyl, propyl, isopropyl. n-butyl, sec-butyl, tert of the invention are effective inhibitors of FGF-5-dependent butyl, n-pentyl or 2.2-dimethylpropyl. The C-C alkyl signalling in hair follicles or parts thereof, and useful to may be optionally substituted with one or more substituents. reduce and/or delay and/or inhibit hair loss or hair thinning The Substituents may be in any position of the carbon chain. caused by FGF-5 signalling in the hair follicle. Hydroxyl groups of the C. C. alkyl may be esterified with 0043. The monoterpenoids compounds are formulated a lower alkyl carboxylic acid, Such as for example, acetic for topical application to the skin. Such topical formulations acid, propionic acid or formic acid. are administered topically to subjects to reduce FGF5 0057 The topical formulation of the present invention dependent signalling in a hair follicle cell or part thereof may comprise a Co-monoterpenoid which is monohydroxy and/or delay FGF5-dependent signalling in a hair follicle lated or non-hydroxylated. In one example, the Co cell or part thereof and/or prevent FGF5-dependent signal monoterpenoid is monohydroxylated. In one example, the ling in a hair follicle cell or part thereof, to thereby reduce Co-monoterpenoid is non-hydroxylated. loss of terminal hair and/or reduce thinning of terminal hair and/or prevent loss of terminal hair and/or prevent thinning 0058. In one example, the topical formulation comprises of terminal hair and/or delay loss of terminal hair and/or a Co-monoterpenoid of formula (I) wherein R is hydrogen. delay thinning of terminal hair in a subject e.g., Such as in Alternatively, the topical formulation comprises a Co an aging Subject or a Subject wishing or a subject Suffering monoterpenoid of formula (I) wherein R is oxygen. from alopecia, Such as androgenic alopecia and/or alopecia 0059. In another example, the topical formulation com areata and/or acute alopecia. prises to Co-monoterpenoid of formula (I) wherein X is 0044 Accordingly, the present invention provides a topi CH and Y is CH. Alternatively, the topical formulation cal formulation comprising an amount of an isolated Co comprises a Co-monoterpenoid of formula (I) wherein X is monoterpenoid or isolated enantiomer thereof or an isolated CH-OH and Y is CH. ester thereof with a carboxylic acid in an amount sufficient 0060. In another example, the topical formulation com to reduce fibroblast growth factor 5 (FGF5)-dependent sig prises a Co-monoterpenoid of formula (I) wherein X is nalling in a hair follicle cell, wherein the Co-monoterpenoid CHCH. For example, the topical formulation may com is of formula (I): prise a Co-monoterpenoid of formula (I) wherein X is CHCH and Y is CH. Alternatively, the topical formulation may comprise a Co-monoterpenoid of formula (I) wherein R3 X is CHCH and Y is COH. 0061. In another example, the topical formulation com x1 N prises a Co-monoterpenoid of formula (I) wherein X is CHOHCH. For example, the topical formulation may com prise a Co-monoterpenoid of formula (I) wherein X is CHOHCH and Y is CH. Alternatively, the topical formu Z R. lation may comprise a Co-monoterpenoid of formula (I) 1NR, wherein X is CHOHCH and Y is COH. 0062. In another example, the topical formulation com prises a Co-monoterpenoid of formula (I) wherein R is 0045 wherein: hydrogen. Alternatively, the topical formulation comprises a 0046 R is hydrogen, hydroxyl or oxygen; Co-monoterpenoid of formula (I) wherein R is hydroxyl. 0047 R is absent or hydrogen or hydroxyl: Alternatively, the topical formulation comprises a Co 0048 R is CH: monoterpenoid of formula (I) wherein R is absent. 0049 X is CH or CH-OH, or 0063. In another example, the topical formulation com 0050 X is CHCH, or CHOHCH, and X and Y prises a Co-monoterpenoid of formula (I) wherein Z is a together form a single bond within a 6-membered ring; saturated C alkyl, such as, for example, CCH. Alterna 0051 Y is CH, when X is CH or CH-OH, or tively, the topical formulation comprises a Co-monoterpe 0.052 Y is CH or COH when X is CHCH, or noid of formula (I) wherein Z is an unsaturated C. C. CHOHCH; and alkyl, such as, for example, CCH or CCHCH. In one 0053 Z is a saturated or unsaturated C. Cs alkyl or embodiment, Z is CCH. In another embodiment, Z is alkyl ester. CCHCH. US 2016/0374979 A1 Dec. 29, 2016

0064. In another example, the topical formulation com acid. For example, the carboxylic acid is acetic acid In prises a Co-monoterpenoid of formula (I) wherein Z is an another example, the carboxylic acid is acetic acid and/or the unsaturated C-C alkyl and R is absent. Alternatively, the the Co-monoterpenoid carboxylic acid ester is selected topical formulation comprises a Co-monoterpenoid of for from the group consisting of (2E)-3,7-Dimethyl-2,6-octa mula (I) wherein Z is an unsaturated C-C alkyl and R is dien-1-yl acetate (geranyl acetate), 3,7-Dimethyl-1,6-octa hydroxyl. Alternatively, the topical formulation comprises a dien-3-yl acetate (linallyl acetate): 2-(4-Methyl-3-cyclo Co-monoterpenoid of formula (I) wherein Z is an unsatu hexen-1-yl)-2-propanyl acetate (terpinyl acetate); and rated C-C alkyl and R is hydrogen. 5-Isopropenyl-2-methyl-2-cyclohexen-1-yl acetate (carvyl 0065. In yet another example, the topical formulation acetate). More preferably, the Co-monoterpenoid carbox comprises a Co-monoterpenoid of formula (I) wherein Z is ylic acid ester is (2E)-3,7-Dimethyl-2,6-octadien-1-yl CCHCHOCOCH. In a preferred embodiment, Z is acetate (geranyl acetate) or 3,7-Dimethyl-1,6-octadien-3-yl CCHCHOCOCH, and the Co-monoterpenoid or acetate (linallyl acetate). enantiomer thereof is non-hydroxylated. 0071. In a further example, the topical formulation of the 0066. In a further example, the topical formulation com present invention comprises an isolated enantiomer of a prises a Co-monoterpenoid or enantiomer thereof which is Co-monoterpenoid of formula (I) as described herein, Such monohydroxylated, wherein R is hydrogen, R is hydroxyl, as, for example, an isolated enantiomer selected from the X is CH, Y is CH, and Z is an unsaturated C-C alkyl, group consisting of (R)-1-Isopropyl-4-methyl-3-cyclo such as CCHCH. hexen-1-ol (-)-terpinen-4-ol. (1S)-1-Isopropyl-4-methyl 0067. In another example, the topical formulation com 3-cyclohexen-1-ol (+)-terpinen-4-ol. 2-(1R)-4-Methylcy prises a Co-monoterpenoid or enantiomer thereof which is clohex-3-en-1-yl)propan-2-ol (+)-alpha-terpineol, (6R)-3- monohydroxylated, wherein R is hydrogen or oxygen, R is methyl-6-(propan-2-yl)cyclohex-2-en-1-one syn. (6R)- absent or hydrogen or hydroxyl, X is CHCH or Isopropyl-3-methyl-2-cyclohexen-1-one (-)-piperitone. CHOHCH, Y is CH or COH, and Z is a saturated or (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)-pi unsaturated C alkyl. For example, the topical formulation peritone, (3 S)-3,7-Dimethyl-1,6-octadien-3-ol (+)-Lina may comprise a Co-monoterpenoid of formula (I) wherein lool, (3R)-3,7-Dimethyl-1,6-octadien-3-ol (-)-Linalool, R is oxygen, R is hydrogen or hydroxyl, X is CHCH, Y (1R, 5R)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol is CH, and Z is a saturated C. alkyl, preferably, wherein R (-)-cis-carveol. (1S,5S)-2-Methyl-5-(1-methylethenyl)-2- is hydrogen. Alternatively, the topical formulation may cyclohexen-1-ol (+)-cis-carveol. (1R, 5S)-2-Methyl-5-(1- comprise a Co-monoterpenoid of formula (1) which is methylethenyl)-2-cyclohexen-1-ol (+)-trans-carveol, and monohydroxylated, wherein R is hydrogen, R is hydrogen (1S, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol or hydroxyl, X is CHCH, Y is CH or COH, and Z is a (-)-trans-carveol. In one example, the isolated enantiomer saturated C. alkyl, preferably wherein Y is CH and/or R is of the Co-monoterpenoid is (R)-1-Isopropyl-4-methyl-3- hydroxyl. Alternatively, the topical formulation may com cyclohexen-1-ol (-)-terpinen-4-ol. In one example, the prise a Co-monoterpenoid of formula (I) which is mono isolated enantiomer of the Co-monoterpenoid is (1S)-1- hydroxylated, wherein R is hydrogen, R is hydrogen or Isopropyl-4-methyl-3-cyclohexen-1-ol (+)-terpinen-4-ol. hydroxyl, X is CHCH, Y is CH or COH, and Z is a In one example, the isolated enantiomer of the Co-monoter saturated C. alkyl, preferably wherein Y is COH and/or R penoid is 2-[(1R)-4-Methylcyclohex-3-en-1-yl)propan-2-ol is hydrogen. Alternatively, the topical formulation com (+)-alpha-terpineol. In one example, the isolated prises a Co-monoterpenoid or enantiomer thereof which is enantiomer of the Co-monoterpenoid is (6R)-3-methyl-6- monohydroxylated, wherein R is hydrogen or oxygen, R is (propan-2-yl)cyclohex-2-en-1-one syn. (6R)-Isopropyl-3- absent, X is CHOHCH, Y is CH, and Z is an unsaturated C. methyl-2-cyclohexen-1-one (-)-piperitone. In one alkyl. example, the isolated enantiomer of the Co-monoterpenoid 0068. In another example, the topical formulation com is (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)- prises a Co-monoterpenoid or enantiomer thereof which is piperitone. In one example, the isolated enantiomer of the non-hydroxylated, and wherein R is hydrogen, R is absent, Co-monoterpenoid is (3S)-3,7-Dimethyl-1,6-octadien-3-ol X is CH, Y is CH, and Z is CCHCHOCOCH. (+)-Linalool. In one example, the isolated enantiomer of 0069. In one example, the Co-monoterpenoid is selected the Co-monoterpenoid is (3R)-3,7-Dimethyl-1,6-octadien from the group consisting of 3-Methyl-6-(propan-2-yl)cy 3-ol (-)-Linalool. In one example, the isolated enantiomer clohex-2-en-1-one (piperitone), 1-Isopropyl-4-methyl-3-cy of the Co-monoterpenoid is (1R, 5R)-2-Methyl-5-methyle clohexen-1-ol (terpinen-4-ol), 2-(4-Methyl-3-cyclohexen-1- thenyl)-2-cyclohexen-1-ol (-)-cis-carveol. In one yl)-2-propanol (alpha-terpineol), 2-Methyl-5-(1- example, the isolated enantiomer of the Co-monoterpenoid methylethenyl)-2-cyclohexen-1-ol (carveol), 6-Isopropyl-3- is (1S, 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- methyl-2-cyclohexen-1-one (3-carvomenthenone), and 3.7- ol (+)-cis-carveol. In one example, the isolated enantiomer Dimethyl-1,6-octadien-3-ol (linalool). Preferably, the Co of the Co-monoterpenoid is (1R,5S)-2-Methyl-5-(1-methy monoterpenoid is 3-Methyl-6-(propan-2-yl)cyclohex-2-en lethenyl)-2-cyclohexen-1-ol (+)-trans-carveol. In one 1-one (piperitone) or 1-Isopropyl-4-methyl-3-cyclohexen-1- example, the isolated enantiomer of the Co-monoterpenoid ol (terpinen-4-ol). More preferably, the Co-monoterpenoid is (1S, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- is 3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (piperi ol (-)-trans-carveol. Preferably, the isolated enantiomer of tone). the Co-monoterpenoid is selected from the group consisting 0070. In another example, the topical formulation com of (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol (-)-ter prises a carboxylic acid monoester of a Co-monoterpenoid pinen-4-ol. (IS)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol of formula (I) as described herein. For example, the carbox (+)-terpinen-4-ol, (6R)-3-methyl-6-(propan-2-yl)cyclo ylic acid monoester may be a monoester with a carboxylic hex-2-en-1-one or (6R)-Isopropyl-3-methyl-2-cyclohexen acid selected from acetic acid, propionic acid and formic 1-one (-)-piperitone, (6S)-3-Methyl-6-(propan-2-yl)cy US 2016/0374979 A1 Dec. 29, 2016 clohex-2-en-1-one (+)-piperitone, (1S,5S)-2-Methyl-5-(1- 0076. In a preferred example, the topical formulation of methylethenyl)-2-cyclohexen-1-ol (+)-cis-carveol, and the invention consists of or comprises a fragrance oil or (1R, 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol perfume oil or essential oil or combination thereof or a (+)-trans-carveol. Preferably, an isolated enantiomer of the perfume derived from a fragrance oil or perfume oil or Co-monoterpenoid is (R)-1-Isopropyl-4-m ethyl-3-cyclo essential oil or combination thereof, wherein the fragrance hexen-1-ol (-)-terpinen-4-ol. oil or perfume oil or essential oil or perfume comprises an 0072 Alternatively, or in addition, an isolated amount of at least one monoterpenoid or enantiomer or enantiomer of the Co-monoterpenoid is (-)-piperitone or carboxylic acid derivative thereof is in an amount sufficient (+)-piperitone. For example, a topical formulation of the to reduce binding of FGF-5 to FGFR1 or to treat or prevent present invention comprises isolated piperitone or hair loss in a subject in need thereof, especially in treatment enantiomer thereof Such as (-)-piperitone or (+)-piperitone or prevention of allopecia, as described in any example in combination with terpinen-4-ol or enantiomer thereof hereof. Such as (-)-terpinen-4-ol. (0077. As used herein the term “fragrance oil” or “per fume oil shall be taken to refer to an extract such as a 0073. A further particularly preferred embodiment of the Solution comprising alcohol, e.g., ethanol, comprising one or present invention provides a topical formulation comprising more synthetic monoterpenoids of the invention, whether or a combination of (i) isolated piperitone or an isolated not the extract also comprises a natural compound. enantiomer or carboxylic acid ester thereof and (ii) isolated terpinen-4-ol or an isolated enantiomer or carboxylic acid 0078. As used herein, the term “essential oil shall be ester thereof in the preparation of a topical medicament for taken to mean a concentrated hydrophobic liquid derived by the treatment and/or prevention of allopecia in a subject in distillation or cold pressing of plant material and comprising need thereof. This combination includes a combination one or more natural monoterpenoids of the. An oil is termed selected from the following: (i) piperitone and terpinene-4- “essential” because it carries a distinctive scent or essence of ol; (ii) piperitone and (-)-terpinene-4-ol; (iii) piperitone and the plant from which it derives. (+)-terpinen-4-ol; (iv) (-)-piperitone and terpinene-4-ol; (v) 007.9 For example, the topical formulation of the present (-)-piperitone and (-)-terpinen-4-ol; (vi) (-)-piperitone and invention may comprise the isolated Co-monoterpenoid or (+)-terpinen-4-ol; (vii) (+)-piperitone and terpinene-4-ol; ester or enantiomer thereof in the form of an essential oil, (viii) (+)-piperitone and (-)-terpinen-4-ol; and (ix) (+)- Such as an essential oil from Eucalyptus dives. An essential piperitone and (+)-terpinen-4-ol. In one example, the com oil from E. dives may comprise piperitone or enantiomer bination is piperitone and terpinene-4-ol. In one example, thereof such as (-)-piperitone or (+)-piperitone and/or ter the combination is piperitone and (-)-terpinene-4-ol. In one pinen-4-ol or enantiomer thereof Such as (-)-terpinen-4-ol. example, the combination is piperitone and (+)-terpinen-4- 0080. As used herein, the term “perfume' shall be taken ol. In one example, the combination is (-)-piperitone and to mean an oil e.g., a perfume oil or essential oil or terpinene-4-ol. In one example, the combination is (-)- combination thereofas defined herein wherein the oil com piperitone and (-)-terpinen-4-ol. In one example, the com prises up to about 25% of the essential oil or perfume oil or bination is (-)-piperitone and (+)-terpinen-4-ol. In one combination thereof, generally diluted in ethanol and/or example, the combination is (+)-piperitone and terpinene water or other diluent known in the art. 4-ol. In one example, the combination is (+)-piperitone and I0081. It is to be understood that an oil or perfume need (-)-terpinen-4-ol. In one example, the combination is (+)- only have a sufficient concentration of a monoterpenoid piperitone and (+)-terpinen-4-ol. Of these combinations, the described herein to perform the invention. Notwithstanding combination of piperitone and (-)-terpinene-4-ol is particu that an oil or perfume is generally used in liquid form, larly preferred. quantitation of the active compound e.g., monoterpenoid or carboxylic acid ester or enantiomer thereof, may be deter 0074 The total amount of the Co-monoterpenoid or ester mined employing the liquid or a powder prepared therefrom. or enantiomer thereof in the topical formulation is an The skilled artisan will be aware various methods known in amount sufficient to reduce or inhibit FGF-5 activity in the the art for quantifying Such active compounds. For example, hair follicle or part thereof. For example, the total amount of a powder may be prepared from a predetermined Volume of the Co-monoterpenoid or ester or enantiomer thereof is an oil or perfume, resuspending the powder in a suitable solvent amount sufficient to reduce or inhibit FGF-5 binding to a to produce a sample solution, and Subjecting the sample cognate fibroblast growth factor receptor (FGFR) e.g., Solution to one or more gas chromatography (GC) and/or FGFR1, in the hair follicle or part thereof. mass spectrometry (MS) processes to thereby determine an 0075. It is to be understood that isolated Co-monoterpe amount of monoterpenoid in the powder. Exemplary means noids or esters or enantiomers thereof comprised in the for drying an oil or perfume include drying over anhydrous topical formulation(s) of the present invention may be Sodium Sulphate. Exemplary solvents for dissolving pow isolated from various sources. For example, the Co ders comprising monoterpenoids include any solvent Suit monoterpenoids or esters or enantiomers thereof may be a able for GS-MS, e.g., diethyl ether. Exemplary GS-MS natural product or isolated from a natural product or natural systems for quantitation of monterpenoids include fast-GC Source e.g., Such as from plants, plant parts and/or essential and/or fast-GC-qMSs and/or enantioselective GC and/or oils by conventional procedures. Alternatively, the isolated multidimensional GC and/or GC-isotopic ratio mass spec Co-monoterpenoids or esters or enantiomers thereof may be trometry (GC-IRMS) and/or gas chromatography with flame synthetic compounds. Alternatively, the monoterpenoids ionization detection (GC-FID). Thus, based on the concen may be produced recombinantly, such as by expression of tration of monoterpenoid in a powder prepared from a genes required for monoterpenoid production in yeast cells. known sample Volume of oil or perfume, the amount of the Preferably, the compound is isolated as an essential oil, active compound in any other Volume of the oil or perfume perfume oil, or perfume. may be determined without undue effort. Similarly, if such US 2016/0374979 A1 Dec. 29, 2016

quantitation is performed on a liquid aliquot of the oil or dil, Sanguisorba officinalis root extract, Rosa multiflora perfume, the amount of the active compound in any other extract, Brown algae extract, loquat leaf extract, Pecan shell volume of the oil or perfume may be determined without extract, Squill extract, sodium phytate, Fucus vesiculosus undue effort. Similarly, quantitation of formulations of the extract, phytic acid, nominal, and Lipidure-C. Combinations invention other than oils or perfumes e.g., a tonic or sham of the monoterpenoids of the invention are not excluded from poo or lotion, may be determined readily based on the such adjunctive formulations. percentage volume of oil or perfume (v/v) in the formula tion. I0088. The topical formulations of the invention as 0082) Exemplary concentrations of monoterpenoids in described in any example hereof are useful for delaying essential oils are set forth in Table 1 hereof, and amounts of and/or reducing loss of terminal hair in a Subject. Such the monoterpenoids in any fragrance oils may be determined utility may be non-therapeutic or therapeutic. By “non readily based on the known amount of the active compound therapeutic' is meant that the subject to whom the formu (s). lation is administered does not suffer from a pre-existing 0083. It is within the ken of a skilled formulation chemist medical condition that causes hair loss or hair thinning, e.g., to produce an oil or perfume or other formulation of the alopecia, however may be predisposed to Such a condition. invention having a reproducible amount of a given monoter Accordingly, a non-therapeutic use may be a cosmetic penoid or carboxylic acid ester or enantiomer thereof. In treatment or a prophylactic treatment in the present context. general, a suitable concentration of such active compound(s) Such cosmetic treatments include treatment of hair loss that is prepared readily by evaporation of an oil or perfume is of non-medical aetiology e.g., as a consequence of age comprising one or more non-volatile active compounds, or and/or sex of the Subject. In contrast, a therapeutic use is for by dilution of an oil or perfume comprising the active treatment of a pre-existing medical condition that causes compound(s) described herein, e.g., using ethanol or other hair loss or hair thinning e.g., alopecia arising from any one suitable diluent known in the art. or more factors responsible for the condition e.g., stress, 0084 Topical formulation(s) of the present invention chemotherapy, etc. may be presented in unit dose forms containing a predeter mined amount of the isolated Co-monoterpenoids or esters I0089 For example, a non-therapeutic or cosmetic use or enantiomers thereof per unit dose sufficient to reduce may comprise administering a formulation of the invention FGF5-dependent signalling in a hair follicle cell. It is to be as described herein to a non-alopecic Subject who wishes to understood that the concentration of monoterpenoid com maintain full, voluminous hair. A non-therapeutic formula pound may vary depending upon a range of parameters e.g., tion is also suitable for reducing or delaying hair loss in a including whether or not the formulation is for prevention or Subject who is not suffering from alopecia, but who is therapy, the site to which the topical formulation is to he suffering from loss of terminal hair natural hair loss. Alter applied, the half-life of the Co-monoterpenoid compound natively, or in addition, the non-therapeutic formulations are following administration of the topical formulation, the age, suitable for prevention of terminal hair loss in a subject sex and weight of the Subject, and the type of hair loss having no visible symptoms of allopecia, however Suffers condition, if any, to which the Subject is predispose or which from a genetic condition that predisposes him/her to future is to be treated. onset of allopecia, including androgenic alopecia. Alterna 0085. It is also to be understood that the topical formu tively, or in addition, the non-therapeutic formulations are lation(s) of the present invention may comprise a plurality of suitable for prevention of terminal hair loss in a non isolated Co-monoterpenoids or esters or enantiomers alopecic Subject about to undergo therapy with a cytotoxic thereofas described herein, e.g., Such as 2, 3, 4, 5, 6, 7, 8, or cytostatic agent or antiviral compound that will induce 9, 10 or more compounds. The skilled artisan will be aware loss of terminal hair. that it is possible to combine monoterpenoids that are active 0090 Accordingly, the present invention also provides a in performing the invention by combining one or more method of reducing and/or delaying and/or preventing loss perfume oils and/or one or more essential oils to achieve of terminal hair in a human or mammalian Subject who is not optimum concentrations of active monoterpenoids as deter Suffering from alopecia. Such a non-therapeutic method may mined by the activity profile(s) of the constituent monoter comprise administering a topical formulation of the inven penoid(s) described herein. tion as described in any example hereof to an area of the I0086. The topical formulations of the present invention dermis or skin of the human or mammalian Subject in which may also comprise one or more carriers, excipients or loss of terminal hair is to be reduced and/or delayed and/or emollients suitable for topical administration e.g., such as to prevented, or to an area of dermis adjacent or Surrounding an the dermis or skin of a Subject. For example, a carrier area of the dermis or skin of the human or mammalian suitable for topical administration may be selected from the Subject. The administration is generally for a time and under group consisting of a transdermal patch, lotion, ointment, conditions sufficient to reduce or delay or prevent the loss of paste, foam, emulsion, cream, serum, aerosol, spray, roll-on terminal hair in the Subject. In one example, the Subject to formulation, masque, cleanser, , conditioner, gel. whom the topical formulation is administered is a subject oil or moisturizer. A Suitable carrier can be a lubricating who wishes to maintain full, Voluminous hair by reducing formulation, water-based formulation, silicone-based for and/or delaying and/or preventing hair loss not caused by mulation, petroleum-based formulation, natural-oil based alopecia. Alternatively, the Subject is not suffering from formulation, an or massage formulation. alopecia, but Suffering from loss of terminal hair. Alterna 0087. The topical formulation of the present invention tively, the Subject may have no visible symptoms of alope may further comprise one or more adjunctive therapeutic cia, however Suffer from a genetic condition that predisposes agents. For example, the adjunctive agent may be selected the Subject to alopecia e.g., a genetic predisposition to hair from the group consisting of estradiol, Oxandrolone, minoxi loss or familial history of hair loss. Alternatively, the subject US 2016/0374979 A1 Dec. 29, 2016 may be about to undergo therapy with a cytotoxic or ment with a cytotoxic agent, treatment with a cytostatic cytostatic agent or antiviral compound that induces loss of agent, and treatment with an agent which induces necrosis or terminal hair. apoptosis of hair follicles as a side-effect of therapy. For 0091. It is to be understood that the frequency of dosage example, the Subject to whom the topical formulation is and the total amount of Co-monoterpenoid or ester or administered may be a human or mammalian Subject under enantiomer thereof in a unit dosage of the topical formula going treatment with a cytotoxic agent or cytostatic agent or tion for a non-therapeutic use may vary. Factors affecting to whom treatment with a cytotoxic agent or cytostatic agent frequency and amount of dosage include e.g., the site to has been prescribed. In one example, the topical formulation which the topical formulation is to be applied and/or the of the invention is co-administered with a cytotoxic cyto half-life of the specific Co-monoterpenoid compound in the static compound that causes hair loss e.g., in the case of a topical formulation following administration thereof, and/or Subject undergoing chemotherapy or radiation therapy or the age and/or sex and/or weight of the Subject. treatment for HIV-1 infection or AIDS. In such circum 0092. The topical formulations of the invention are useful stances, the efficacy of the Co-monoterpenoid or ester or for delaying or reducing or preventing loss of any terminal enantiomer thereof in the topical formulation counteracts the hair including, for example, Scalp hair and/or eyelash hair hair-loss effect of the cytotoxic or cytostatic compound. and/or eyebrow hair. The method may comprise adminis 0097. The frequency and dosage amount of Co-monoter tering the topical formulation of the invention to the scalp of penoid or ester or enantiomer thereof in a topical formula a human or mammalian Subject not suffering from alopecia tion administered to the Subject to treat alopecia may vary to reduce and/or delay and/or prevent loss of Scalp hair in depending upon a range of parameters e.g., the type of that subject. Alternatively, or in addition, the method may alopecia and/or the severity of the alopecia and/or the site to comprise administering the topical formulation of the inven which the topical formulation is to be applied and/or the tion to the eyelid or eyelash of a human or mammalian half-life of the specific Co-monoterpenoid compound in the Subject not suffering from alopecia to reduce and/or delay topical formulation following administration thereof and/or and/or prevent loss of eyelash hair in that subject. Alterna the age and/or sex and/or weight of the Subject. tively, or in addition, the method may comprise administer 0098. The topical formulations of the invention are useful ing the topical formulation of the invention to the face or for delaying or reducing or preventing loss of any terminal forehead or eyebrow of a human or mammalian Subject not hair in analopectic patient or Subject including, for example, Suffering from alopecia to reduce and/or delay and/or pre scalp hair and/or eyelash hair and/or eyebrow hair. For vent loss of eyebrow hair in that subject. example, the topical formulation may be for delaying or 0093. The non-therapeutic method of the invention may reducing or preventing loss of scalp hair in an alopectic also comprise promoting or enhancing growth of terminal patient or Subject. Alternatively, or in addition, the topical hair of the subject. In addition, topical formulation(s) of the formulation may be for delaying or reducing or preventing invention as described in any example hereof may promote loss of eyelash hair in an alopectic patient or Subject. or enhance growth of the terminal hair in a Subject. Alternatively, or in addition, the topical formulation may be 0094. In another example, the topical formulation(s) of for delaying or reducing or preventing loss of eyebrow hair the present invention as described in any example hereof are in an alopectic patient or Subject. useful for treating alopecia e.g., an acute form of allopecia or (0099. The topical formulation(s) of the invention for alopecia areata or androgenic alopecia, in a human or other therapeutic and/or non-therapeutic application may delay or mammalian Subject. An acute form of allopecia may be reduce or prevent loss of terminal hair by delaying hair induced by an acute event selected from pregnancy, stress, follicles comprising the terminal hair from entering catagen illness, treatment with a cytotoxic agent, treatment with a phase. Alternatively, or in addition, an anagen phase of hair cytostatic agent, and treatment with an agent that induces follicles composing the terminal hair may be extended to necrosis or apoptosis of hair follicles as a side-effect of thereby delay or reduce or prevent loss of terminal hair. In therapy. Accordingly, the topical formulation of the inven addition, topical formulation(s) of the invention as described tion is suitable for a human or mammalian Subject under in any example hereof may promote or enhance growth of going treatment with a cytotoxic agent or cytostatic agent, or the terminal hair in a Subject. to whom treatment with a cytotoxic agent or cytostatic agent 0100. The present invention also provides for use of at has been prescribed. Alternatively, or in addition, the topical least one isolated Co-monoterpenoid or isolated enantiomer formulation is suitable for be a human or mammalian Subject thereof or an isolated ester thereof with a carboxylic acid in Suffering from androgenic alopecia. the preparation of a topical medicament for the treatment of 0095 For example, the present invention also provides a hair loss in a Subject Suffering from alopecia, wherein the C method of treating alopecia e.g., an acute form of allopecia o-monoterpenoid is of formula (I): or alopecia areata or androgenic alopecia, in a human or mammalian Subject in need thereof, comprising administer formula (I) ing a topical formulation of the present invention as R3 described in any example hereof to an affected area of the dermis or skin of the human or mammalian Subject. Alter x1 N natively, or in addition, the formulation is administered to an area of dermis adjacent or Surrounding an affected area. The administration is generally for a time and under conditions sufficient to reduce or delay Of prevent loss of terminal hair R. in the subject. 17N, 0096. An acute form of alopecia may be induced by an acute event selected from pregnancy, stress, illness, treat US 2016/0374979 A1 Dec. 29, 2016 10 wherein: 0118. In yet another example, the topical medicament 01.01 R is hydrogen, hydroxy or oxygen; comprises a Co-monoterpenoid of formula (I) wherein Z is 0102 R, is absent or hydrogen or hydroxyl: CCHCHOCOCH. In a preferred embodiment, Z is (0103 R is a CH: CCHCHOCOCH, and the Co-monoterpenoid or 0104 X is CH or CH-OH, or enantiomer thereof is non-hydroxylated. 0105 X is CHCH, or CHOHCH, and X and Y 0119. In one example, the topical medicament comprises together form a single bond within a 6-membered ring; a Co-monoterpenoid or enantiomer thereof which is mono hydroxylated, wherein R is hydrogen, R is hydroxyl, X is 0106 Y is CH, when X is CH or CH-OH, or CH, Y is CH, and Z is an unsaturated C-C alkyl, such 01.07 Y is CH or COH when X is CHCH, or as CCHCH. CHOHCH; and I0120 In another example, the topical medicament com I0108 Z is a saturated or unsaturated C. C. alkyl or prises a Co-monoterpenoid or enantiomer thereof which is alkyl ester. monohydroxylated, wherein R is hydrogen or oxygen, R is 0109. By “topical medicament' is meant that the isolated absent or hydrogen or hydroxyl, X is CHCH or Co-monoterpenoid or isolated enantiomer thereof or an CHOHCH, Y is CH or COH, and Z is a saturated or isolated ester thereof with a carboxylic acid is formulated for unsaturated C alkyl. For example, the topical medicament application to the dermis of a mammal. may comprise a Co-monoterpenoid of formula (I) wherein 0110. The Co-monoterpenoid for use in the preparation R is oxygen, R is hydrogen or hydroxyl, X is CHCH, Y of the topical medicament may be monohydroxylated or is CH, and Z is a saturated C. alkyl, preferably, wherein R non-hydroxylated. is hydrogen. Alternatively, the topical medicament may 0111. In one example, the topical medicament comprises comprise a Co-monoterpenoid of formula (I) which is a Co-monoterpenoid of formula (I) wherein R is hydrogen. monohydroxylated, wherein R is hydrogen, R is hydrogen Alternatively, the topical medicament comprises a Co or hydroxyl, X is CHCH, Y is CH or COH, and Z is a monoterpenoid of formula (I) wherein R is Oxygen. saturated C. alkyl, preferably wherein Y is CH and/or R is 0112 In one example, the topical medicament comprises hydroxyl. Alternatively, the topical medicament may com a Co-monoterpenoid of formula (I) wherein X is CH and prise a Co-monoterpenoid of formula (I) which is mono Y is CH. Alternatively, the topical medicament comprises a hydroxylated, wherein R is hydrogen, R is hydrogen or Co-monoterpenoid of formula (I) wherein X is CH-OH and hydroxyl, X is CHCH, Y is CH or COH, and Z is a Y is CH. saturated C. alkyl, preferably wherein Y is COH and/or R 0113. In another example, the topical medicament com is hydrogen. Alternatively, the topical medicament may prises a Co-monoterpenoid of formula (I) wherein X is comprise a Co-monoterpenoid or enantiomer thereof which CH2CH2. For example, the topical medicament may com is monohydroxylated, wherein R is hydrogen or oxygen, R prise a Co-monoterpenoid of formula (I) wherein X is is absent, X is CHOHCH, Y is CH, and Z is an unsaturated CHCH and Y is CH. Alternatively, the topical medicament C alkyl. may comprise a Co-monoterpenoid of formula (I) wherein 0121. In another example, the topical medicament com X is CHCH and Y is COH. prises a Co-monoterpenoid enantiomer thereof which is 0114. In another example, the topical medicament com non-hydroxylated, and wherein R is hydrogen, R is absent, prises a Co-monoterpenoid of formula (I) wherein X is X is CH, Y is CH, and Z is CCHCHOCOCH. CHOHCH. For example, the topical medicament may 0.122 For example, the Co-monoterpenoid for use in the comprise a Co-monoterpenoid of formula (I) wherein X is manufacture of the topical medicament is selected from the CHOHCH and Y is CH. Alternatively, the topical medica group consisting of 3-Methyl-6-(propan-2-yl)cyclohex-2- ment may comprise a Co-monoterpenoid of formula (I) en-1-one (piperitone), 1-Isopropyl-4-methyl-3-cyclohexen wherein X is CHOHCH, and Y is COH. 1-ol (terpinen-4-ol), 2-(4-Methyl-3-cyclohexen-1-yl)-2-pro 0115. In one example, the topical medicament comprises panol (alpha-terpineol), 2-Methyl-5-methylethenyl)-2- a Co-monoterpenoid of formula (I) wherein R is hydrogen. cyclohexen-1-ol (carveol), 6-Isopropyl-3-methyl-2- Alternatively, the topical medicament comprises a Co cyclohexen-1-one (3-carvomenthenone); and 3,7-Dimethyl monoterpenoid of formula (I) wherein R is hydroxyl. Alter 1,6-octadien-3-ol (linalool). Preferably, the Co natively, the topical medicament comprises a Co-monoter monoterpenoid is 1-isopropyl-4-methyl-3-cyclohexen-1-ol penoid of formula (I) wherein R is absent. (terpinen-4-ol) or 3-Methyl-6-(propan-2-cyclohex-2-en-1- 0116. In one example, the topical medicament comprises one (piperitone). a Co-monoterpenoid of formula (I) wherein Z is a Saturated I0123. In another example, the topical medicament com C alkyl, such as, for example, CCH. Alternatively, the prises a carboxylic acid monoester of a Co-monoterpenoid topical medicament comprises a Co-monoterpenoid of for of formula (I) as hereinbefore described. For example, the mula (I) wherein Z is an unsaturated C-C alkyl e.g., Such carboxylic acid monoester may be a monoester with a as CCH or CCHCH. For example, in one embodiment, Z carboxylic acid selected from acetic acid, propionic acid and is CCH. In another embodiment, Z is CCHCH. formic acid. Preferably, the carboxylic acid is acetic acid 0117. In another example, the topical medicament com and/or the Co-monoterpenoid carboxylic acid ester for use prises a Co-monoterpenoid of formula (I) wherein Z is an in the manufacture of the topical medicament is selected unsaturated C-C alkyl and R is absent. Alternatively, the from the group consisting of (2E)-3,7-Dimethyl-2,6-octa topical medicament comprises a Co-monoterpenoid of for dien-1-yl acetate (geranyl acetate), 3,7-Dimethyl-1,6-octa mula (I) wherein Z is an unsaturated C-C alkyl and R is dien-3-yl acetate (linallyl acetate): 2-(4-Methyl-3-cyclo hydroxyl. Alternatively, the topical medicament comprises a hexen-1-yl)-2-propanyl acetate (terpinyl acetate); and Co-monoterpenoid of formula (I) wherein Z is an unsatu 5-isopropenyl-2-methyl-2-cyclohexen-1-yl acetate (carvyl rated C-C alkyl and R is hydrogen. acetate). More preferably, the Co-monoterpenoid carbox US 2016/0374979 A1 Dec. 29, 2016

ylic acid ester for use in the manufacture of the topical pinen-4-ol. Of these combinations, the combination of pip medicament is (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate eritone and (-)-terpinene-4-ol is particularly preferred. (geranyl acetate) or 3,7-Dimethyl-1,6-octadien-3-yl acetate I0127. As with the topical formulation of the invention, a (linallyl acetate). in a further example, the topical medica plurality of isolated Co-monoterpenoids or esters or ment of the present invention comprises an isolated enantiomers thereofas described herein, e.g., 2, 3, 4, 5, 6, 7, enantiomer of a Co-monoterpenoid of formula (I) as 8, 9, 10 or more compounds, may be used in the preparation described herein. For example, an isolated enantiomer of a of a topical medicament of the invention. Co-monoterpenoid of formula (I) for use in the manufacture I0128. The integers described herein for the composition of the topical medicament is selected from the group con and use of topical formulations for therapeutic applications, sisting of (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol. especially with respect to the concentrations of active (IS)-1-terpinen-4-ol), (IS)-1-Isopropyl-4-methyl-3-cyclo monoterpenoids and enantiomers and esters thereof, formu hexen-1-ol (+)-terpinen-4-ol. 2-(1R)-4-Methylcyclohex-3- lation and dosage, apply mutatis mutandis to the use of at en-1-yl)propan-2-ol (+)-alpha-terpineol, (6R)-3-methyl-6- least one isolated Co-monoterpenoid or isolated enantiomer (propan-2-yl)cyclohex-2-en-1-one or or (6R)-Isopropyl-3- thereof or an isolated ester thereof with a carboxylic acid in methyl-2-cyclohexen-1-one (-)-piperitone, (6S)-3- the preparation of a topical medicament for the treatment of Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)- hair loss in a Subject Suffering from alopecia. piperitone, (3S)-3,7-Dimethyl-1,6-octadien-3-ol (+)- I0129. A subject for which the topical medicament is Linalool. (3R)-3,7-Dimethyl-1,6-octadien-3-ol (-)- useful may be a human or mammalian Subject that has a Linalool, (1R, 5R)-2-Methyl-5-(1-methylethenyl)-2- genetic predisposition for alopecia or familial history of cyclohexen-1-ol (-)-cis-carveol. (1S,5S)-2-Methyl-5-(1- alopecia or is at risk of developing alopecia. Alternatively, or methylethenyl)-2-cyclohexen-1-ol (+)-cis-carveol, (1R, in addition, the subject for which the topical medicament is 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol (+)- useful may be a human or mammalian Subject that is trans-carveol, and (1S,5S)-2-Methyl-5-(1-methylethenyl)- Suffering from alopecia. The alopecia may be an acute form 2-cyclohexen-1-ol (-)-trans-carveol. Preferably, the iso of allopecia and/or alopecia areata and/or androgenic alope lated enantiomer of the Co-monoterpenoid is selected from cia. the group consisting of (R)-1-Isopropyl-4-methyl-3-cyclo 0.130 in particularly preferred embodiment, the topical hexen-1-ol (-)-terpinen-4-ol. (1S)-1-Isopropyl-4-methyl medicament is useful for treatment of androgenic alopecia in 3-cyclohexen-1-ol (+)-terpinen-4-ol, (6R)-3-methyl-6- a Subject Suffering from, or at risk of Suffering from, (propan-2-cyclohex-2-en-1-one or (6R)-Isopropyl-3- androgenic alopecia. methyl-2-cyclohexen-1-one (-)-piperitone, (6S)-3- I0131. In a further preferred embodiment, the topical Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)- medicament is useful for treatment of an acute form of piperitone, (1S, 5S)-2-Methyl-5-(1-methylethenyl)-2- alopecia. The acute form of allopecia may be induced by an cyclohexen-1-ol (+)-cis-carveol, and (1R, 5S)-2-Methyl acute event selected from pregnancy, stress, illness, treat 5-(1-methylethenyl)-2-cyclohexen-1-ol (+)-trans-carveol. ment with a cytotoxic agent, treatment with a cytostatic More preferably, the isolated enantiomer of the Co agent, and treatment with an agent which induces necrosis or monoterpenoid is (-)-terpinen-4-ol or (-)-piperitone or (+)- apoptosis of hair follicles as a side-effect of therapy. Accord piperitone. ingly, a Subject for which the topical medicament is useful 0.124 Aparticularly preferred embodiment of the present may be a human or mammalian Subject undergoing treat invention provides for use of isolated 1-Isopropyl-4-methyl ment with a cytotoxic agent or cytostatic agent or to whom 3-cyclohexen-1-ol (terpinen-4-ol) or an isolated enantiomer treatment with a cytotoxic agent or cytostatic agent has been or carboxylic acid ester thereof in the preparation of a topical prescribed. For example, the topical medicament may be medicament for the treatment and/or prevention of allopecia prepared for co-administration with a cytotoxic or cytostatic in a subject in need thereof. compound that causes hair loss e.g., in the case of a subject undergoing chemotherapy or radiation therapy or treatment 0.125. A further particularly preferred embodiment of the for HIV-1 infection or AIDS. In such circumstances, the present invention provides use of isolated 3-methyl-6-(pro efficacy of the Co-monoterpenoid or ester or enantiomer pan-2-yl)cyclohex-2-en-1-one (piperitone) or an isolated thereof in the topical medicament counteracts the hair-loss enantiomer or carboxylic acid ester thereof in the prepara effect of the cytotoxic or cytostatic compound. tion of a topical medicament for the treatment and/or pre (0132. As used herein the term “derived from Shall be vention of allopecia in a subject in need thereof. taken to indicate that a specified integer may be obtained 0126. A further particularly preferred embodiment of the from a particular source albeit not necessarily directly from present invention provides use of a combination of (i) that Source. isolated piperitone or an isolated enantiomer or carboxylic I0133. Throughout this specification, unless the context acid ester thereof and (ii) isolated terpinen-4-ol or an iso requires otherwise, the word “comprise', or variations such lated enantiomer or carboxylic acid ester thereof in the as "comprises' or “comprising, is understood to imply the preparation of a topical medicament for the treatment and/or inclusion of a stated Step or element or integer or group of prevention of alopecia in a subject in need thereof. This steps or elements or integers but not the exclusion of any combination includes a combination selected from the fol other step or element or integer or group of elements or lowing: (i) piperitone and terpinene-4-ol; (ii) piperitone and integers. (-)-terpinene-4-ol; (iii) piperitone and (+)-terpinen-4-ol: (iv) I0134. The term “hair' means any hair or fur on the body (-)-piperitone and terpinene-4-ol; (V) (-)-piperitone and of a mammal including a human, and includes, for example, (-)-terpinen-4-ol; (vi) (-)-piperitone and (+)-terpinen-4-ol; head hair, eyebrows, eyelashes, , , chest (vii) (+)-piperitone and terpinene-4-ol; (viii) (+)-piperitone hair, back hair, arm hair, , genital hair, nasal hair or and (-)-terpinen-4-ol; and (ix) (+)-piperitone and (+)-ter . US 2016/0374979 A1 Dec. 29, 2016

0135. As used herein, the term “treat” or “treating” or tion at which nonanal inhibits viability of FR-BaF3 cells by “treatment” shall be taken to include therapeutic treatment 50% (IC50) when those cells are cultured in the presence of of a pre-existing condition, wherein the aim is to prevent, FGF-5 or IL-3. ameliorate, reduce, slow down (lessen) or arrest progression 014.4 FIG. 1 (c) is a graphical representation showing the of hair thinning or hair loss e.g., associated with alopecia. It inhibitory activity of linalool at difference concentrations on follows that hair growth, or treatment of hair thinning, refers proliferation and viability of FR-BaF3 cells in the presence to normalization of thinned hair, Such as caused by alopecia. of FGF-5 or IL-3, This figure also illustrates the concentra Treatment preferably extends the anagen phase of a hair tion at which linalool inhibits viability of PR-BaF3 cells by follicle, or prevents or delays a follicle in anagen phase from 50% (IC50) when those cells are cultured in the presence of prematurely transitioning to catagen phase. FGF-5 or IL-3. 0136. As used herein, the term “delay' or “delaying 0145 FIG. 1(d) is a graphical representation showing the refers to a postponement or deferment of an event e.g., Such inhibitory activity of geranyl acetate at difference concen as loss of hair, until a time which is later that would trations on proliferation and viability of FR-BaF3 cells in the otherwise be expected, or the act by which something is presence of FGF-5 or IL-3. This figure also illustrates the postponed or deferred, including the slowing of an event or concentration at which geranyl acetate inhibits viability of process. FR-Bat 3 cells by 50% (IC50) when those cells are cultured 0137 As used herein, the tern “reduce” or “reducing in the presence of FGF-5 or IL-3 with respect to hair loss shall be taken to mean a decrease or 0146 FIG. 1(e) is a graphical representation showing the lessening in the loss of hair e.g., terminal hair, than would inhibitory activity of C-terpineol at difference concentra otherwise be expected in an individual following adminis tions on proliferation and viability of FR-BaF3 cells in the tration of a formulation or medicament of the invention. presence of FGF-5 or IL-3. This figure also illustrates the 0138 “Preventing”, “prevention”, “preventative” or concentration at which C-terpineol inhibits viability of FR “prophylactic' refers to keeping from occurring, or to hin BaF3 cells by 50% (IC50) when those cells are cultured in der, defend from, or protect from the occurrence of a the presence of FGF-5 or IL-3. condition, disease, disorder, or phenotype, including an 0147 FIG. 1(f) is a graphical representation showing the abnormality or symptom. A mammal in need of prevention inhibitory activity of 1-carveol at difference concentrations may be prone to develop the condition. on proliferation and viability of FR-BaF3 cells in the pres 0.139. The term “effective amount’ shall be taken to mean ence of FGF-5 or IL-3. This figure also illustrates the an amount of the Co-monoterpenoid compound of the concentration at which 1-carveol inhibits viability of FR invention which is capable of preventing and/or reducing BaF3 cells by 50% (IC50) when those cells are cultured in and/or delaying progression of hair thinning or hair loss in the presence of FGF-5 or IL-3. a mammal to a level which is beneficial to delay and/or 0148 FIG. 1(g) is a graphical representation showing the reduce and/or treat and/or prevent hair thinning or hair loss, inhibitory activity of (-)-terpinen-4-ol at difference concen particularly associated with alopecia. A therapeutically trations on proliferation and viability of FR-BaF3 cells in the effective amount may be determined empirically and in a presence of FGF-5 or IL-3. This figure also illustrates the routine manner in relation to treating hair thinning or hair concentration at which (-)-terpinen-4-ol inhibits viability of loss. FR-BaF3 cells by 50% (IC50) when those cells are cultured 0140. Throughout this specification, unless specifically in the presence of FGF-5 or IL-3. stated otherwise or the context requires otherwise, reference 014.9 FIG. 1(h) is a graphical representation showing the to a single step, composition of matter, group of steps or inhibitory activity of (+)-terpinen-4-ol at difference concen group of compositions of matter shall be taken to encompass trations on proliferation and viability of FR-BaF3 cells in the one and a plurality (i.e. one or more) of those steps, presence of FGF-5 or IL-3. This figure also illustrates the compositions of matter, groups of steps or group of com concentration at which (+)-terpinen-4-ol inhibits viability of positions of matter. FR-BaF3 cells by 50% (IC50) when those cells are cultured 01.41 Each definition or clarifying term described herein in the presence of FGF-5 or IL-3. shall be taken to apply mutatis mutandis to each and every 0150 FIG. 2(a) is a graphical representation showing the example of the invention unless the context requires other effect of linallyl acetate at difference concentrations on wise. Each example described herein is to be applied mutatis Alkaline Phosphatase (ALP) activity in dermal papilla (DP) mutandis to each and every other example unless specifi cells cultured in the presence of: (i) a GSK3 inhibitor and cally stated otherwise. FGF-5 or (ii) a GSK3 inhibitor only. ALP activity was determined by measuring absorbance at 490 nm. BRIEF DESCRIPTION OF THE DRAWINGS 0151 FIG. 2(b) is a graphical representation showing the relative difference in Alkaline Phosphatase (ALP) activity 0142 FIG. 1(a) is a graphical representation showing the (expressed as a percentage) in dermal papilla (DP) cells inhibitory activity of linallyl acetate at difference concentra cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 tions on proliferation and viability of FR-BaF3 cells in the or (ii) a GSK3 inhibitor only, following treatment with presence of FGF-5 or IL-3. This figure also illustrates the linallyl acetate at difference concentrations. ALP activity was concentration at which linallyl acetate inhibits viability of determined by measuring absorbance at 490 nm. FR-BaF3 cells by 50% (IC50) when those cells are cultured 0152 FIG.3(a) is a graphical representation showing the in the presence of FGF-5 or IL-3. effect of nonanal at difference concentrations on Alkaline 0143 FIG. 1(b) is a graphical representation showing the Phosphatase (ALP) activity in dermal papilla (DP) cells inhibitory activity of nonanal at difference concentrations on cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 proliferation and viability of FR-BaF3 cells in the presence or (ii) a GSK3 inhibitor only. ALP activity was determined of FGF-5 or IL-3, This figure also illustrates the concentra by measuring absorbance at 490 nm. US 2016/0374979 A1 Dec. 29, 2016

0153 FIG.3(b) is a graphical representation showing the or (ii) a GSK3 inhibitor only. ALP activity was determined relative difference in Alkaline Phosphatase (ALP) activity by measuring absorbance at 490 nm. (expressed as a percentage) in dermal papilla (DP) cells 0163 FIG. 8(b) is a graphical representation showing the cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 relative difference in Alkaline Phosphatase (ALP) activity or (ii) a GSK3 inhibitor only, following treatment with (expressed as a percentage) in dermal papilla (DP) cells nonanal at difference concentrations. ALP activity was cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 determined by measuring absorbance at 490 nm. or (ii) a GSK3 inhibitor only, following treatment with 0154 FIG. 4(a) is a graphical representation showing the piperitone at difference concentrations. ALP activity was effect of C-Terpineol at difference concentrations on Alka determined by measuring absorbance at 490 nm. line Phosphatase (ALP) activity in dermal papilla (DP) cells 0164 FIG. 9(a) is a graphical representation showing the cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 effect of minoxidil at difference concentrations on Alkaline or (ii) a GSK3 inhibitor only. ALP activity was determined Phosphatase (ALP) activity in dermal papilla (DP) cells by measuring absorbance at 490 nm. cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 0155 FIG. 4(b) is a graphical representation showing the or (ii) a GSK3 inhibitor only ALP activity was determined relative difference in Alkaline Phosphatase (ALP) activity by measuring absorbance at 490 nm. (expressed as a percentage) in dermal papilla (DP) cells 0.165 FIG. 9(b) is a graphical representation showing the cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 relative difference in Alkaline Phosphatase (ALP) activity or (ii) a GSK3 inhibitor only, following treatment with (expressed as a percentage) in dermal papilla (DP) cells C-Terpineol at difference concentrations. ALP activity was cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 determined by measuring absorbance at 490 nm. or (ii) a GSK3 inhibitor only following treatment with 0156 FIG. 5(a) is a graphical representation showing the minoxidil at difference concentrations. ALP activity was effect of (-)-Terpinen-4-ol at difference concentrations on determined by measuring absorbance at 490 nm. Alkaline Phosphatase (ALP) activity in dermal papilla (DP) 0166 FIG. 10(a) is a graphical representation showing cells cultured in the presence of: (i) a GSK3 inhibitor and the effect of an essential oil from Eucalyptus dives at FGF-5 or (ii) a GSK3 inhibitor only. ALP activity was difference concentrations on Alkaline Phosphatase (ALP) determined by measuring absorbance at 490 nm. activity in dermal papilla (DP) cells cultured in the presence 0157 FIG. 5(b) is a graphical representation showing the of: (i) a GSK3 inhibitor and FGF-5 or (ii) a GSK3 inhibitor relative difference in Alkaline Phosphatase (ALP) activity only. ALP activity was determined by measuring absorbance (expressed as a percentage) in dermal papilla (DP) cells at 490 nm. cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 0.167 FIG. 10(b) is a graphical representation showing or (ii) a GSK3 inhibitor only, following treatment with the relative difference in Alkaline Phosphatase (ALP) activ (-)-terpinen-4-ol at difference concentrations. ALP activity ity (expressed as a percentage) in dermal papilla (DP) cells was determined by measuring absorbance at 490 nm. cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 0158 FIG. 6(a) is a graphical representation showing the or (ii) a GSK3 inhibitor only, following treatment with an effect of (+)-terpinen-4-ol at difference concentrations on essential oil from Eucalyptus dives at difference concentra Alkaline Phosphatase (ALP) activity in dermal papilla (DP) tions. ALP activity was determined by measuring absor cells cultured in the presence of: (i) a GSK3 inhibitor and bance at 490 nm. FGF-5 or (ii) a GSK3 inhibitor only. ALP activity was 0168 FIG. 11 is a graphical representation of the Ham determined by measuring absorbance at 490 nm. ilton-Norwood Scale as used to assess male pattern bald 0159 FIG. 6(b) is a graphical representation showing the CSS. relative difference in Alkaline Phosphatase (ALP) activity 0169 FIG. 12 is a graphical representation of the Lugwig (expressed as a percentage) in dermal papilla (DP) cells Scale as used to assess female pattern baldness. cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 0170 FIG. 13 is a graphical representation showing the or (ii) a GSK3 inhibitor only, following treatment with percentage of subjects receiving the Placebo and Test for (+)-terpinen-4-ol at difference concentrations. ALP activity mulations who perceived a visual improvement in hair was determined by measuring absorbance at 490 nm. volume at days 7 and 14 of trial. 0160 FIG. 7(a) is a graphical representation showing the 0171 FIG. 14 is a graphical representation showing the effect of (+)-terpinen-4-ol at difference concentrations on percentage of subjects receiving the Placebo and Test for Alkaline Phosphatase (ALP) activity in dermal papilla (DP) mulations who perceived a visual reduction in hair loss at cells cultured in the presence of: (i) a GSK3 inhibitor and days 7 and 14 of trial. FGF-5 or (ii) a GSK3 inhibitor only. ALP activity was 0172 FIG. 15 is a graphical representation showing the determined by measuring absorbance at 490 nm. percentage of subjects receiving the Placebo and Test for 0161 FIG. 7(b) is a graphical representation showing the mulations who perceived that their hair was stronger at days relative difference in Alkaline Phosphatase (ALP) activity 7 and 14 of trial. (expressed as a percentage) in dermal papilla (DP) cells 0173 FIG. 16 is a graphical representation showing the cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 percentage of subjects receiving the Placebo and Test for or (ii) a GSK3 inhibitor only, following treatment with mulations who perceived that their hair was thicker at days (+)-terpinen-4-ol at difference concentrations. ALP activity 7 and 14 of trial. was determined by measuring absorbance at 490 nm. 0.174 FIG. 17 is a graphical representation showing the 0162 FIG. 8(a) is a graphical representation showing the percentage of subjects receiving the Placebo and Test for effect of piperitone at difference concentrations on Alkaline mulations who perceived that the respective treatment Phosphatase (ALP) activity in dermal papilla (DP) cells resulted in a reduction in hair fall at days 7 and 14 of the cultured in the presence of: (i) a GSK3 inhibitor and FGF-5 trial. US 2016/0374979 A1 Dec. 29, 2016

0175 FIG. 18 is a graphical representation showing the (0191 Y is CH or COH when X is CHCH, or percentage of subjects receiving the Placebo and Test for CHOHCH; and mulations who perceived that their hair had improved den 0.192 Z is a saturated or unsaturated C. Cs alkyl or sity at days 7 and 14 of the trial. alkyl ester. 0176 FIG. 19 is a graphical representation showing the (0193 For example, the Co-monoterpenoid may be percentage of subjects receiving the Placebo and Test for selected from the group consisting of 3-Methyl-6-(propan mulations who perceived that the respective treatment 2-yl)cyclohex-2-en-1-one (piperitone), 1-Isopropyl-4- resulted in a strengthening of fine hair at days 7 and 14 of methyl-3-cyclohexen-1-ol (terpinen-4-ol), 2-(4-Methyl-3- the trial. cyclohexen-1-yl)-2-propanal (alpha-terpineol), 2-Methyl-5- 0177 FIG. 20 is a graphical representation showing hair (1-methylethenyl)-2-cyclohexen-1-ol (carveol), shaft elongation (mm) over time for hair murine vibrissae 6-Isopropyl-3-methyl-2-cyclohexen-1-one (3-carvomenthe follicles cultured in the presence and absence of exogenous none); and 3,7-Dimethyl-1,6-octadien-3-ol (linalool). Pref FGF-5. erably, the Co-monoterpenoid is 1-Isopropyl-4-methyl-3- 0.178 FIG. 21 is a graphical representation showing rate cyclohexen-1-ol (terpinen-4-ol) or Methyl-6-(propan-2-yl) of hair shaft elongation over time (measured as percentage cyclohex-2-en-1-one (piperitone). More preferably, the Co growth relative to day 1) for hair murine vibrissae follicles monoterpenoid is Methyl-6-(propan-2-yl)cyclohex-2-en-1- cultured in the presence and absence of exogenous FGF-5. one (piperitone). 0179 FIG. 22 is a graphical representation showing hair 0194 In another example, the carboxylic acid monoester shaft elongation over time (measured as a percentage of of a Co-monoterpenoid of formula (I) may be a monoester growth relative to day 1) for hair murine vibrissae follicles with a carboxylic acid selected from acetic acid, propionic cultured in the presence and absence of piperitone. acid and formic acid. Preferably, the carboxylic acid is acetic acid. For example, a Co-monoterpenoid carboxylic acid DETAILED DESCRIPTION OF THE ester may be selected from the group consisting of (2E)-3, INVENTION 7-Dimethyl-2,6-octadien-1-yl acetate (geranyl acetate), 3.7- Dimethyl-1,6-octadien-3-yl acetate (linallyl acetate): 2-(4- 0180 Monoterpenoids Methyl-3-cyclohexen-1-yl)-2-propanyl acetate (terpinyl 0181. The present invention provides topical formula acetate); and 5-Isopropenyl-2-methyl-2-cyclohexen-1-yl tions comprising monoterpenoid compounds which are acetate (carvyl acetate). capable of reducing fibroblast growth factor 5 (FGF 5)-de (0195 In another example, the enantiomer of a Co pendant signalling in a hair follicle cell or part thereof. monoterpenoid of formula (I) may be selected from the 0182. The term “monoterpenoid' or “monoterpenoid group consisting of (R)-1-Isopropyl-4-methyl-3-cyclo compound' shall be taken to mean a hydrocarbon compound hexen-1-ol (-)-terpinen-4-ol. (IS)-1-Isopropyl-4-methyl having a monoterpene skeleton formed from two isoprene 3-cyclohexen-1-ol (+)-terpinen-4-ol. 2-(1R)-4-Methylcy units i.e., have the molecular formula CoH which has clohex-3-en-1-yl)propan-2-ol (+)-alpha-terpineol, (6R)-3- undergone biochemical modifications such as oxidation or methyl-6-(propan-2-yl)cyclohex-2-en-1-one or (6R)- rearrangement. Monoterpenoids may be acyclic, monocyclic Isopropyl-3-methyl-2-cyclohexen-1-one (-)-piperitone. or bicyclic. As used throughout this specification, the term (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)-pi “monoterpenoid compound shall be understood to include peritone, (3S)-3,7-Dimethyl-1,6-octadien-3-ol (+)-Lina monoterpenoids, enantiomers of monoterpenoids and lool, (3R)-3,7-Dimethyl-1,6-octadien-3-ol (-)-Linalool, monoterpenoid esters with a carboxylic acid. (1R, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol 0183 Preferably, the monoterpenoid compound of the (-)-cis-carveol. (1S,5S)-2-Methyl-5-(1-methylethenyl)-2- invention is Co-monoterpenoid, or an enantiomer thereof or cyclohexen-1-ol (+)-cis-carveol. (1R,5S)-2-Methyl-5-(1- an ester thereof with a carboxylic acid, of formula (I): methylethenyl)-2-cyclohexen-1-ol (+)-trans-carveol, and (1S, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol (-)-trans-carveol. formula (I) 0196. Certain monoterpenoids and carboxylic acid esters R3 thereof may contain chiral centres. It is to be understood that both racemic and diasteromeric mixtures, as well as the x1 N individual optical isomers, isolated or synthesized, which are substantially free of their enantiomeric or diastereomeric partners, are within the scope of the invention. Racemic R. mixtures may be separated into their individual, Substan Z tially optically pure isomers through well-known tech 1NR, niques, such as the separation of diastereomeric salts formed with optically active adjuncts e.g., acids or bases followed 0184 wherein: by conversion back to the optically active substances. The desired optical isomer may be synthesized by means of 0185. R is hydrogen, hydroxyl or oxygen; Stereospecific reactions, beginning with the appropriate Ste 0186 R is absent or hydrogen or hydroxyl: reoisomer of the desired starting material. 0187 R is CH3; 0.197 Monoterpenoid compounds which are capable of 0188 X is CH or CH-OH, or reducing fibroblast growth factor 5 (FGF59)-dependent sig (0189 X is CHCH, or CHOHCH, and X and Y nalling in a hair follicle cell or part thereof may be identified together form a single bond within a 6-membered ring; by any method known in the art for doing so. For example, (0190. Y is CH, when X is CH or CH-OH, or Such compounds may be identified by performing an Alka US 2016/0374979 A1 Dec. 29, 2016

line Phosphatase Dermal Papilla (ALP-DP) cell assay as invention will reduce or inhibit FGF-5 binding to FGFR1 by described in WO2013/105417. Alternatively, or in addition, at least 10% or at least 20% or at least 30% or at least 40% a monoterpenoid compound may be screened by one or or at least 50% or at least 60% or at least 70% or at least 80% more of the assays exemplified herein to determine whether or at least 90%. The ability of a Co-monoterpenoid or ester or not it is capable of reducing FGF5-dependent signalling. or enantiomer thereof to reduce binding of FGF-5 to FGFR1 0198 For example, a Co-monoterpenoid or ester or may be determined by a reduction in viability of a BaF3 cell enantiomer thereof useful in a topical formulation of the expressing FGFR1, wherein the BaF3 cell is dependent on invention will reduce or inhibit FGF-5 activity in the hair FGF-5 signalling for viability. follicle or pan thereof by about 10-90% or 20-90% or 0200 Sources of monoterpenoids and Enantiomers and 30-90% or 40-90% or 50-90% or 60-90% or 70-90% or Carboxylic Acid Eaters Thereof 80-90% or 10-80% or 20-80% or 30-80% or 40-80% or 0201 The monoterpenoid compounds and/or enantiom 50-80% or 60-80% or 70-80% or 10-70% or 20-70% or ers thereof and/or carboxylic acid esters thereof may be 30-70% or 40-70% or 50-70% or 60-70% or 10-60% or produced in microbial, yeast and/or plant cell culture sys 20-60% or 30-60% or 40-60% or 50-60% or 10-50% or tems known in the art, including microbial, yeast and/or 20-50% or 30-50% or 40-50% or 10-40% or 20-40% or plant cell culture systems which have been metabolically 30-40% or 10-30% or 20-30%. Alternatively, or in addition, engineered to increase synthesis/production of monoterpe a Co-monoterpenoid or ester or enantiomer thereofuseful in noids. See e.g., WO2011123576; Grover et al., Plant Cell, a topical formulation of the invention will reduce or inhibit Tissue & Organ Culture, 108(2):323-331, 2012: Reiling et FGF-5 activity in the hair follicle or pan by at least 10% or al., Biotechnology and Bioengineering, 87(2):200-212, at least 20% or at least 30% or at least 40% or at least 50% 2004; Albrecht et al., Biotechnology Letters, 21:791-795, or at least 60% or at leist 70% or at least SO% or at leist 1999. 90%, 0202 Alternatively, the monoterpenoid compounds and/ 0199 Alternatively, or in addition, a Co-monoterpenoid or enantiomers thereof and/or carboxylic acid esters thereof or ester or enantiomer thereofuseful in a topical formulation may be synthetic compounds. Synthetic monoterpenoid of the invention will reduce or inhibit FGF-5 binding to a compounds are well known in the art and are readily cognate fibroblast growth factor receptor (FGFR) in the hair available from a variety of commercial sources. For follicle or part thereof. For example, a Co-monoterpenoid example, a topical formulation of the invention may consist or ester or enantiomer thereofuseful in a topical formulation of or comprise a fragrance oil or perfume or a perfume of the invention will reduce or inhibit FGF-5 binding to derived from a fragrance oil or a perfume oil. fibroblast growth factor receptor 1 (FGFR1) by about 10-90% or 20-90% or 30-90% or 40-90% or 50-90% or 0203 Alternatively, the monoterpenoid compounds and/ 60-90% or 70-90% or 80-90% or 10-80% or 20-80% or or enantiomers thereof and/or carboxylic acid esters thereof 30-80% or 40-80% or 50-80% or 60-80% or 70-80% or may be natural compounds. 10-70% or 20-70% or 30-70% or 40-70% or 50-70% or 0204 Essential Oils 60-70% or 10-60% or 20-60% or 30-60% or 40-60% or 0205 The monoterpenoids and/or enantiomers thereof 50-60% or 10-50% or 20-50% or 30-50% or 40-50% or and/or carboxylic acid esters thereof may be in the form of 10-40% or 20-40% or 30-40% or 10-30% or 20-30%, a natural extract, or comprise a natural extract, Such as Alternatively, or in addition, a Co-monoterpenoid or ester essential oil or a perfume derived from an essential oil. See or enantiomer thereof useful in a topical formulation of the e.g., Table 1 below: TABLE 1. Compound Source of essential oil Geraniol Geraniol is found in essential oils of rose (~15% w/v), palmarosa (~80% w/v), Cymbopogon spp (~40-65% w/v), citronella java (-23% w/v), lemon balm (~20-40% w/v) and geranium (~10-30% w/v). Nerol Nerol is an isomeric alcohol found in essential oils from devana (~10% w/v), neroli and petitgrain of lemon(-5% w/v). B-Citronellol Found in citronella oils (10-50% w/v), as well as oils from geraniums (~10-40% w/v) and rose (18-55% w/v). Linalool Linalool can be found as (+)- and (-)-forms in oil of majoram (~60-80% w/v), basil (~40-60% w/v), lavender (40-50% w/v), bergamot (~15% w/v), Pelangonium geraniums (~10-15% w/v), neroli bigarde (~50% w/v) and Ylangylang (~10% w/v). C-Terpineol Found in essential oils of Anthemis altissina L. var. altissina (~25% w/v), clary sage oil. (~47% w/v), lavandin (~9% w/v), marjoram (~5-25% w/v), petitgrain (-5% w/v), cajuput (-5% w/v), tea tree (1.5-8% w/v). B-Terpineol Someric with C-terpineol, but is not isolated from natural sources in Sufficient amounts, Found in commercial terpineol. (+)-Terpinen-4-ol Synthetic racemate e.g., 50% (w.fw) (-)-Terpinen-4-ol and 50% (w.fw (+)-Terpinen-4-ol. (-)-Terpinen-4-ol Found in Eucalyptus dives (~3-5% w/v)'. Also found in tea tree oil and essential oil of sweet marjoram and lavender' (+)-Terpinen-4-ol Found in tea tree oil and essential oil of sweet marjoram and lavender' Nonanal Found in essential oils from mosses, such as in oil of Tortula muralis (~18% w/v), Homalothecium lutescens (-36% w/v), Hypnum cupressiforme (~12.5% w/v) and Pohlia nutans (~8% w/v). Menthol A constituent of oil from the Mentha genus (~30-75% w/v). I-Carveol Found in essential oil from caraway seed (>50% w/v), Spearmint (-65-70% w/v) and dill. US 2016/0374979 A1 Dec. 29, 2016

TABLE 1-continued Compound Source of essential oil Piperitone Found in oil from Eucalyptus dives (~35-60% w/v), Cymbopogon spp also known as lemon grass (~55-80% w/v), and Artemisia deserti krasch (~10-50% w/v), as well as in oil from plants of Mentha genus (~15-20% w/v). Linallyl acetate Found in essential oils of bergamot (~15-55% w/v), bergamot mint (~40-80% w/v), lavender (-20-40% w/v), lavandin (-20-40% w/v), marjoram (~20-25% w/v), thyme (~25% w/v), and clary sage (~15-70% w/v). It is the acetate ester of linalool and the two are often present together. Geranyl acetate Geranyl acetate is a constituent of numerous essential oils, including oils from carrot seed (-35-75% w/v), from citronella (-2-5% w/v palmarosa (~10% w/v), thyme (~25% w/v), clary sage (~5-10% w/v), lemongrass (~1-5% w/v and coriander seed (185% w/v). 'The Terpinen-4-ol in E. dives oil is predominantly the (-)-Terpinen-4-ol enantiomeric form E. dives oil is a good source of the enantiomer, which is more readily isolated from E. dives than from tea tree or sweet marjoram or lavender oil. 'Tea tree oil may comprise about 30-50% (wiv) Terpinen-4-ol, of which about 65% i.e. 19.5-32.5% (wivi) is (+)-Terpinen-4-ol and gnly 35% i.e., 10.5-17.5% (wivi) is (-)-Terpinen-4-ol. Sweet marjoram oil may comprise about 18-22% (wiv) Terpinen-4-ol, of which about 73% i.e. 13-16% (wivi) is (+)-Terpinen-4-ol and only 27% i.e., 5-6% (wivi) is (-)-Terpinen-4-ol. 'Lavender oil may comprise about 4.9-9.5% (wiv) Terpinen-4-ol, of which about 98.5% i.e. 4.8-9.4% (wiv) is (+)-Terpinen-4-ol and only about 1.5% i.e., 0.1% (wivi) is (-)-Terpinen-4-ol.

0206 Conveniently, an essential oil will be prepared extraction process that allows for the separation and collec from a plant source that provides an active monoterpenoid at tion of essential oils from the water soluble components and a concentration Sufficient to perform the invention, prefer starting materials e.g. leaves, twigs, Sticks, bark, roots, ete. ably without a need for any concentration of the oil and/or can be used according to the present invention. separation of enantiomeric forms. 0207 Techniques for extracting essential oils from natu 0210 Examples of other extraction processes include ral materials. Such as from plants, algae, fungi and yeast, are direct “hydrodistillation' in which the natural material is known and described in the art. A preferred method of boiled in an aqueous Solution and the vapors produced extracting essential oils from natural materials in accordance therefrom are collected and condensed to produce a distillate with the present invention is distillation, Such as by Steam from which the essential oil may be separated. Other extrac distillation or water distillation (also known as “hydrodis tion processes that involve partial refluxing, solvent extrac tillation'). tion and chromatography to remove essential oils are also 0208. In steam distillation, the natural material from contemplated for use in the present invention. For example, which the essential oil is to be extracted, such as plant physical processes for the isolation of monoterpenoid com foliage, bark or twigs etc., is introduced into a distilling pounds from naturally-occurring materials, including distil chamber through which steam is to be passed. Typically, the lation, Solvent extraction, and chromatography are described distilling chamber is configured to support the natural mate in Ziegler and Ziegler, Flavorings: production, composi rial in a manner which exposes the oil-rich areas of the tions, applications, regulations, 1 Ed. Wiley-VCH. Wein material to steam when passed through the chamber. In one heim, Germany. example, the natural material is suspended or held above 0211 A preferred essential oil will provide an effective water contained in the distilling chamber such that when the amount of an active monoterpenoid or enantiomer or car water is boiled, “wet steam' produced therefrom rises and boxylic acid derivative in downstream processing, such as to contacts the essential oil containing natural material. In produce a perfume or other formulation of the invention, or another example, steam is produced in a boiler and pumped to substantially purify the compound for other formulations into the distilling chamber containing the natural material disclosed herein. from which the oil is to be extracted. This is sometimes referred to as “dry steam'. In either case, steam is typically 0212 Preferred topical formulations of the invention generated with a temperature between 100-105° C. and comprise an essential oil or perfume comprising piperitone passed through the distilling chamber containing the essen or enantiomer thereof in an amount useful for performing tial oil-containing material. As the steam contacts the natural the invention. For example, the working examples hereof material, the cells and vesicles containing essential oils are demonstrate that piperitone elicits high alkaline phosphatase disrupted and the essential oils are released in the form of activity in dermal papillae. Accordingly, the essential oils of vapour. The vapour flow of essential oil and steam is Eucalyptus dives and/or Cymbopogon spp. and/or lemon typically directed to a condenser unit in which the vapour is grass and/or Artemisia deserti krasch and/or Mentha spp., condensed e.g., by a water cooled jacket Surrounding the and perfumes and other topical formulations of the invention condenser unit, to form a liquid distillate having an aqueous derived there from are useful in performing the invention. phase and an oil phase. The liquid distillate is directed into 0213. Other preferred topical formulations of the inven a collection vessel and the essential oil (oil phase) is tion comprise an essential oil comprising terpinen-4-ol separated from the hydrosol or aqueous portion (aqueous enantiomer thereof. Such as (-)-terpinen-4-ol, in amount(s) phase) according to the relative specific densities. The useful for performing the invention. For example, the work essential oil obtained from the distillate may be collected ing examples hereof demonstrate that (-)-terpinen-4-ol elic and used in accordance with the invention. its high alkaline phosphatase activity in dermal papillae and 0209 Although specific reference is made herein to a also has high FGF-5 inhibitory activity. Accordingly, the steam distillation process, it is to be understood that any essential oils of Eucalyptus dives and/or tea tree and/or US 2016/0374979 A1 Dec. 29, 2016

Sweet marjoram, and perfumes and other topical formula taken also permits determination of an amount of monoter tions of the invention derived there from are useful in penoid and/or enantiomer and/or carboxylic acid ester on a performing the invention. weight basis e.g., weight of the active compound per gram 0214 Particularly preferred topical formulations of the dried weight of plant material. invention, comprise an essential oil comprising piperitone or 0216. The weight of monoterpenoid and/or enantiomer enantiomer thereof and/or terpinen-4-ol or enantiomer and/or carboxylic acid ester in an oil or perfume may also be thereof. Such as, for example piperitone and/or (-)-terpinen known or readily derived, such as when the oil is prepared 4-ol, in amount(s) useful for performing the invention. For using purified compounds or starting material having a example, an essential oil from Eucalyptus dives is a Suitable known concentration of the active compound(s), to facilitate Source of both and both piperitone and (-)-terpinen-4-ol in determination of compound concentrations in the topical amounts for use in performing the invention. The essential formulation. oil of E. dives is particularly preferred for performing the invention because that oil has a high content of both pip 0217 Depending upon the concentration of active com eritone and (-)-terpinen-4-ol and because, as demonstrated pound(s) in a synthetic preparation, a fragrance oil having a herein, (i) piperitone and (-)-terpinen-4-ol each elicit higher Suitable concentration of one or more non-volatile active alkaline phosphatase activity in dermal papillae than a compounds is prepared readily by evaporation. A fragrance racemic mixture of terpinen-4-al or (+)-Terpinen-4-ol, and oil having a Suitable concentration of one or more active (ii) the (-)-terpinen-4-ol enantiomer has higher FGF-5 compounds is also prepared readily by dilution using ethanol inhibitory activity than (+)-terpinen-4-ol. Accordingly, the or other suitable diluent known in the art. E. dives essential oil provides an advantage in having both 0218 Combinations of oils are especially preferred when piperitone and (-)-terpinen-4-ol relative to essential oils that it desirable to combine active monoterpenoids or enantiom have predominantly (+)-terpinen-4-ol with little or no mea ers or carboxylic acid esters thereof, which are not each Surable piperitone such as tea tree or Sweet marjoram or represented in Sufficiently-high concentrations in a single oil lavender, or essential oils that have high levels of piperitone to have a cosmetic Or therapeutic effect, or that are not each with little or no measurable (-)-terpinen-4-ol such as the present in a single oil in amounts that are processed conve essential oils from Cymbopogon Spp or Artemisia deserti niently without combination. The skilled artisan will be krasch or Menthe spp. Thus, the essential oils of tea tree, aware that it is possible to combine monoterpenoids and/or Sweet marjoram, lavender, Cymbopogon spp., Artemisia enantiomers and/or carboxylic acid esters thereof that are deserti krasch or Menthe spp. are less desirable in some active in performing the invention by combining one or embodiments than the essential oil of E. dives. more perfume oils and/or one or more essential oils to 0215. The relative amounts of different monoterpenoids, achieve optimum concentrations of active compounds as enantiomers and carboxylic acid derivatives that are active determined by the activity profile(s) of the constituents as in performing this invention may be the same in an essential described herein. oil as in a plant extract from which the essential oil is 0219. Perfumes derived, or those relative amounts may be different. The skilled artisan will also be aware that the concentration of a 0220. In another preferred example, the topical formula given monoterpenoid compound may vary between different tion of the invention consists of or comprises a perfume plant extracts. Notwithstanding these variables, it is within derived from a fragrance oil or perfume oil or essential oil the skill of Such a person to produce an essential oil having or combination thereof. The perfume may comprise one oil, a suitable amount of an active monoterpenoid, enantiomer or Such as one essential oil or one fragrance oil, or it may carboxylic acid derivative, or suitable amounts of different comprise a combination of different oils, including a com active monoterpenoid, enantiomers or carboxylic acid bination of essential oils, a combination of fragrance oils, or derivatives. In this respect, the concentration of a given a combination of both essential oils and fragrance oils. synthetic monoterpenoid and/or enantiomer and/or carbox 0221) A perfume may be classified as “parfum' and ylic acid ester in an essential oil or fragrance oil or perfume comprise an amount of oil in a range from about 15% to may be determined without undue burden. For example, as about 25% by volume, including 15% or 16% or 17% or described herein above, headspace sampling permits analy 18% or 19% or 20% or 21% or 22% or 23% or 24% or 25% sis and quantitation of an amount of constituent monoter oil by Volume, in aqueous solution Such as ethanol and/or penoid compound(s) and/or enantiomer(s) thereof and/or water. Alternatively, a perfume may be classified as “soie de carboxylic acid ester(s) thereof by gas chromatography (GC) parfum' and comprise an amount of oil in a range from and/or mass spectrometry (MS) processes. Such analysis of about 15% to about 18% by volume, including 15% or 16% oil and/or perfume samples permits determination of an or 17% or 18% oil by volume, in aqueous solution such as amount of monoterpenoid and/or enantiomer and/or carbox ethanol and/or water. Alternatively, a perfume may be clas ylic acid ester in an oil or perfume or powder produced sified as “eau' and comprise an amount of oil in a range not therefrom on either a weight basis e.g., weight of the active exceeding about 15% by volume, including up to 1% or up compound relative to weight of powder or dried oil, or to 2% or up to 3% or up to 4% or up to 5% or up to 6% or alternatively on a Volume basis e.g., weight of active com up to 7% or up to 8% or up to 9% or up to 10% or up to 11% pound per unit volume of oil or perfume. Knowledge of a or up to 12% or up to 13% or up to 14% or up to 15% oil volume of oil from which a powder is obtained also permits by Volume, in aqueous solution Such as ethanol and/or water. calculation of an amount of active monoterpenoid and/or For example, within Such a range of concentration values, a enantiomer and/or carboxylic acid, ester on a Volume basis perfume classified as “eau fraiche' may comprise about 3% e.g., weight of active compound per unit volume of oil or or less oil by volume, a perfume classified as “eau de perfume. Knowledge of an amount of plant material that cologne' may comprise about 2% to about 5% oil by produced an essential oil from which analysed samples were Volume, a perfume classified, as 'eau de toilette may com US 2016/0374979 A1 Dec. 29, 2016

prise about 4% to about 10% oil by volume, and a perfume and not more than 5% includes 2.0% or 2.1% or 2.2% or classified as “eau de parfum’ may comprise about 8% to 2.3% or 2.4% or 2.5% or 2.6% or 2.7% or 2.8% or 2.9% or about 15% oil. 3.0% or 3.1% or 3.2% or 3.3% or 3.4% or 3.5% or 3.6% or 0222. In a preferred example, the topical formulation of 3.7% or 3.8% or 3.99% or 4.0% or 4.1% or 4.2% or 4.3% the present invention is a an eau comprising one or more or 4.4% or 4.5% or 4.6% or 4.7% or 4.8% or 4.9% or 4.91% monoterpenoids of the invention in aqueous ethanol solu or 4.92% or 4.93% or 4.94% or 4.95% or 4.96% or 4.97% tion, e.g., can fraiche or eau de cologne or eau de toilette or or 4.98% or 4.99% or 5%. eau de parfum, and more preferably, an eau fraiche or eau de 0225. An exemplary eau de toilette of the invention will cologne or can de toilette. comprise not less than 4% by Volume and not more than 0223) An exemplary eau fraiche of the invention will 10% by volume of an essential oil, such as an essential oil comprise not more than 3% by volume of an essential oil, from E. dives and/or an essential oil Cymbopogon spp and/or Such as an essential oil from E. dives and/or an essential oil an essential oil from Artemisia deserti krasch and/or an Cymbopogon spp and/or an essential oil from Artemisia essential oil from a plant of the Mentha genus and/or an deserti krasch and/or an essential oil from a plant of the essential oil of tea tree and/or an essential oil of sweet Mentha genus and/or an essential oil of tea tree and/or an marjoram. Such a perfume will comprise at least effective essential oil of Sweet marjoram. Such a perfume will com amounts of piperitone or enantiomer thereof Such as (-)- prise at least effective amounts of piperitone or enantiomer piperitone or (+)-piperitone and terpinen-4-ol or enantiomer thereof Such as (-)-piperitone or (+)-piperitone and terpinen thereof Such as (-)-terpinen-4-ol piperitone or enantiomer 4-ol or enantiomer thereof Such as (-)-terpinen-4-ol piperi thereof. Alternatively, an exemplary eau fraiche of the tone or enantiomer thereof. Alternatively, an exemplary eau invention will comprise not less than 4% by volume and not fraiche of the invention will comprise not more than 3% by more than 10% by Volume of fragrance oil comprising Volume of fragrance oil comprising piperitone or enantiomer piperitone or enantiomer thereof Such as (-)-piperitone or thereof such as (-)-piperitone or (+)-piperitone and not more (+)-piperitone in combination with not less than 4% by than 3% by volume of terpinen-4-ol or enantiomer thereof volume and not more than 10% by volume of terpinen-4-ol Such as (-)-terpinen-4-ol. Alternatively, an exemplary eau or enantiomer thereof Such as (-)-terpinen-4-ol. Alterna fraiche of the invention will comprise not more than 3% by tively, an exemplary eau fraiche of the invention will com Volume of fragrance oil comprising piperitone or enantiomer prise not less than 4% by volume and not more than 10% by thereof Such as (-)-piperitone or (+)-piperitone and/or a Volume of fragrance oil comprising piperitone or enantiomer fragrance oil comprising not more than 3% by volume of thereof such as (-)-piperitone or (+)-piperitone and/or a terpinen-4-ol or enantiomer thereof Such as (-)-terpinen-4- fragrance oil comprising not less than 4% by Volume and not ol. As used herein, the term “not more than 3%' includes more than 10% by volume of terpinen-4-ol or enantiomer O.O1% or 0.05% or 0.1% or 0.15% or 0.2% or 0.25% or 0.3% thereof Such as (-)-terpinen-4-ol. As used herein, the term or 0.35% or 0.4% or 0.45% or 0.5% or 0.55% or 0.6% or “not less than 4% and not more than 10% includes 4.0% or O.65% or 0.7% or 0.75% or 0.8% or 0.85% or 0.9% or 0.95% 4.1% or 4.2% or 4.3% or 4.4% or 4.5% or 4.6% or 4.7% or or 1.0% or 1.1% or 1.2% or 1.3% or 1.4% or 1.5% or 1.6% 4.8% or 4.9% or 5.0% or 5.1% or 5.2% or 5.3% or 5.4% or or 1.7% or 1.8% or 1.9% or 2.0% or 2.1% or 2.2% or 2.3% 5.5% or 5.6% or 5.7% or 5.8% or 5.9% or 6.0% or 6.1% or or 2.4% or 2.5% or 2.6% or 2.7% or 2.8% or 2.9% or 2.01% 6.2% or 6.3% or 6.4% or 6.5% or 6.6% or 6.7% or 6.8% or or 2.92% or 2.93% or 2.94% or 2.95% or 2.96% or 2.97% 6.9% or 7.0% or 7.1% or 7.2% or 7.3% or 7.4% or 7.5% or or 2.98% or 2.99%. 7.6% or 7.7% or 7.8% or 7.9% or 8.0% or 8.1% or 8.2% or 0224. An exemplary eau de cologne of the invention will 8.3% or 8.4% or 8.5% or 8.6% or 8.7% or 8.8% or 8.9% or comprise not less than 2% by volume and not more than 5% 9.0% or 9.1% or 9.2% or 9.3% or 9.4% or 9.5% or 9.6% or by Volume of an essential oil. Such as an essential oil from 9.7% or 9.8% or 9.9% or 10.0% E. dives and/or an essential oil Cymbopogon spp and/or an 0226 Formulations essential oil from Artemisia deserti krasch and/or an essen 0227. A monoterpenoid or enantiomer or carboxylic acid tial oil from a plant of the Mentha genus and/or an essential derivative thereof described according to any example oil of tea tree and/or an essential oil of sweet marjoram. Such hereof may be formulated in any form used in the pharma a perfume will comprise at least effective amounts of pip ceutical, quasi-drug, or cosmetic field, Suitable for topical eritone or enantiomer thereof Such as (-)-piperitone or administration to a human or mammal. (+)-piperitone and terpinen-4-ol or enantiomer thereof Such 0228 Conveniently, topical formulations of the inven as (-)-terpinen-4-ol piperitone or enantiomer thereof. Alter tion, including pharmaceutical and cosmetic forms, are natively, an exemplary can fraiche of the invention will prepared by dilution of an essential oil or substantially comprise not less than 2% by volume and not more than 5% purified compound. by Volume of fragrance oil comprising piped tone or 0229 Such pharmaceutical and cosmetic formulations enantiomer thereof Such as (-)-piperitone or (-)-piperitone include essential oils, perfume oils, perfumes, ointments, in combination with not less than 2% by volume and not liniments, creams, , lotions, pastes, jellies, sprays, more than 5% by volume of terpinen-4-ol or enantiomer aerosols, or in patches or impregnated dressings. For thereof Such as (-)-terpinen-4-ol. Alternatively, an exem example, the topical formulation may be a product for plary eau fraiche of the invention will comprise not less than preventing and/or treating hair loss, a product for growing 2% by volume and not more than 5% by volume of fragrance hair, a hair or scalp cosmetic (e.g. shampoo, , oil comprising piperitone or enantiomer thereof such as Scalp lotion scalp cream, hair tonic, etc.), a skincare product (-)-piperitone or (+)-piperitone and/or a fragrance oil com (e.g. lotion, cream, face cream, face lotion, milk, pack, prising not less than 2% by volume and not more than 5% liquid facial wash, Soap, etc.), a body care product (e.g. body by volume of terpinen-4-ol or enantiomer thereof such as cream, body lotion, Soap, liquid wash, bath additive, etc.). a (-)-terpinen-4-ol. As used herein, the term “not less than 2% UV protective agent (e.g. Sun block, Sunscreen lotion, tan US 2016/0374979 A1 Dec. 29, 2016

ning oil, etc.), or a cosmetic (e.g. eyeliner, eyebrow pencil, about 70% (v/v), including 10% (v/v) or 20% (v/v) or 30% cream, lotion, etc.), The term “ointment embraces formu (v/v) or 40% (v/v) or 50% (v/v) or 0% (v/v) or 70%(v/v). In lations (including creams) having oleaginous, water-soluble another example, the or each Co-monoterpenoid or ester or and emulsion-type bases, e.g., petrolatum, lanolin, polyeth enantiomer thereof, or a perfume oil comprising same, as ylene glycols, as well as mixtures thereof. These may be described according to any example hereof may be diluted applied directly to the skin or an area of dermis comprising in aqueous ethanol up to about 70% (w/v), including 10% hair follicles. (w/v) or 20% (w/v) or 30% (w/v) or 40 (w/v) or 50% (w/v) 0230. In producing a formulation of the invention, an or 60% (w/v) or 70%(w/v). In yet another example, the or essential oil or perfume oil or perfume, or one or more each Co-monoterpenoid or ester or enantiomer thereof, or a isolated active monoterpenoids and/or enantiomers thereof perfume oil comprising same, as described according to any and/or carboxylic acid esters thereof is/are presented in an example hereof may be diluted in aqueous ethanol up to amount Suitable for performing the invention i.e., producing about 70% (w/w), including 10% (w/w) or 20% (w/w) or an efficacious result in a cosmetic or therapeutic context 30% (w/w) or 40% (w/w) or 50% (w/w) or 60% (w/w) or described herein. The amount may vary depending on the 70%(v/w). nature of the formulation, the purpose, and the duration of 0233. In the case of a perfume oil or perfume derived treatment or cosmetic application. therefrom, or other topical formulation comprising Substan 0231. In one example, a concentration of each active tially purified Co-monoterpenoids or esters or enantiomers Co-monoterpenoid or ester or enantiomer thereof is an thereof, the concentration of each isolated active Co amount that is present in an essential oil having the desired monoterpenoid or ester or enantiomer thereof is formulated cosmetic or therapeutic activity, prepared by conventional in an amount consistent with the activity profile of that procedures for a plant material that produces the active compound, with or without additional carriers, excipients, compound as a secondary metabolite. Preferred formula emollients, diluents, fillers, dispersants, stabilisers, prServa tions comprise essential oils described herein, including tives, emulsifying agents, Solubilizing agents, anti-crystal essential oil from E. dives and/or an essential oil Cym lization agents, surfactants, cosmetic components, or bopogon Spp and/or an essential oil from Artemisia deserti adjunctive agents. For example, each Co-monoterpenoid or Krasch and/or an essential oil from a plant of the Mentha ester or enantiomer thereof, or a perfume oil comprising genus and/or an essential oil of tea tree and/or an essential same, as described according to any example hereof is oil of sweet marjoram. Particularly preferred formulations diluted in aqueous ethanol (up to about 50% (v/v) including comprise essential oil from E. dives. Alternatively, a con 10% (v/v) or 20% (v/v) or 30% (v/v) or 40% (v/v) or 50% centration of each active Co-monoterpenoid or ester or (v/v) ethanol solution) to provide a final concentration of enantiomer thereof is an amount that is present in a combi compound having the desired activity. This ensures the nation of Such essential oils e.g., essential oil from E. dives desired cosmetic or therapeutic activity. in combination with an essential oil from tea tree and/or an 0234. In another example, the or each Co-monoterpe essential oil of Sweet marjoram. Conveniently, the essential noid or ester or enantiomer thereof, or a perfume oil com oil is not processed to concentrate the active agent(s), but prising same, as described according to any example hereof comprises the active agent(s) in Sufficient concentration(s) to may be diluted in aqueous ethanol up to about 70% (v/v), provide for use of the essential oil in an undiluted form, or including 10% (v/v) or 20% (v/v) or 30% (v/v) or 10% (v/v) diluted during downstream processing using an aqueous or 50% (v/v) or 60% (v/v) or 70%(v/v). In another example, Solvent Suitable for topical use, e.g., ethanol in water, to an the or each Co-monoterpenoid or ester or enantiomer effective concentration of the active agent(s). One or more thereof, or a perfume oil comprising same, as described carriers, excipients, emollients, diluents, fillers, dispersants, according to any example hereof may be diluted in aqueous stabilisers, preservatives, emulsifying agents, Solubilizing ethanol up to about 70% (w/v), including 10% (w/v) or 20% agents, anti-crystallization agents, Surfactants, cosmetic (w/v) or 30% (w/v) or 40% (w/v) or 50% (w/v) or 60% (w/v) components, or adjunctive agents, may be added to an or 70%(w/v). In yet another example, the or each Co essential oil provided that the final concentration of each monoterpenoid or ester or enantiomer thereof, or a perfume active Co-monoterpenoid or ester or enantiomer thereof is oil comprising same, as described according to any example an amount having the desired cosmetic or therapeutic activ hereof may be diluted in aqueous ethanol up to about 70% ity. (w/w), including 10% (w/w) or 20% (w/w) or 30% (w/w) or 0232. In the case of a perfume derived from an essential 40% (w/w) or 50% (w/w) or 60% (w/w) or 70%(w/w). oil, the concentration of the active Co-monoterpenoid or 0235. The concentration of monoterpenoid compound in ester or enantiomer thereof is in an amount that ensures a formulation may vary depending upon a range of param classification of the formulation as a perfume as described, eters e.g., including whether or not the formulation is for with or without additional carriers, excipients, emollients, prevention or therapy, the site to which the topical formu diluents, fillers, dispersants, stabilisers, preservatives, emul lation is to be applied, the half-life of the monoterpenoid Sifying agents, Solubilizing agents, anti-crystallization compound following administration of the formulation, the agents, Surfactants, cosmetic components, or adjunctive age, sex and weight of the Subject to which the formulation agents. For example, the essential oil(s) described according is to be applied, and type of hair loss condition, if any, to to any example hereofis(are) diluted in aqueous ethanol (up which the subject is predispose or which is to be treated. to about 50% (v/v) including 10% (v/v) or 20% (v/v) or 30% 0236 Standard procedures are employed to prepare the (v/v) or 40% (v/v) or 50% (v/v) ethanol solution) to provide topical formulations, especially once an oil or paste or a final concentration of compound having the desired activ powder comprising the active compound(s) has been pre ity and desired concentration of essential oil. In another pared. See, e.g., Hardman, et al. (2001) Goodman and example, the essential oil as described according to any Gilman's The Pharmacological Basis of Therapeutics, example hereof may he diluted in aqueous ethanol up to McGraw-Hill, New York, N.Y.: Gennaro (2000) Remington: US 2016/0374979 A1 Dec. 29, 2016 20

The Science and Practice of Pharmacy, Lippincott, Wil 0243 Topical formulations may or may not contain sta liams, and Wilkins, New York, N.Y.; Avis, et al. (eds.) (1993) bilisers and/or preservatives to inhibit or retard drug decom Pharmaceutical Dosage Forms: Parenteral Medications, position reactions e.g., by oxidation or bacterial action, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Phar depending on the dispenser and nature of use. Such preser maceutical Dosage Forms: Tablets, Marcel Dekker, NY: vatives include E216, E218, chlorobutanol hemihydrate, Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage methyl-, propyl-, or butyl-parahydroxybenzoic acid, betain, Forms: Disperse Systems, Marcel Dekker, NY: Weiner and chlorhexidine, benzalkonium chloride, and the like. Kotkoskie (2000) Excipient Toxicity and Safety, Marcel 0244 Topical formulations of the invention may also Dekker, Inc., New York, N.Y.). comprise an emulsifying/solubilizing component compris 0237 For example, the topical formulations may include ing one or more of metallic alkyl Sulfate, quaternary ammo one or more carriers, excipients or emollients, suitable for nium compounds, salts of fatty acids, SulfoSuccinates, tau topical administration e.g., such as to the dermis or skin of rates, amino acids, lauroyl macrogol glycerides, a Subject. caprylocaproyl macrogolglycerides, Stearoyl macrogol glyc 0238 Excipients will typically be included to improve erides, linoleoyl macrogol glycerides, oleoyl macrogol glyc solubility and/or bioadhesion. Suitable excipients include erides, polyalkylene glycol, polyethylene glycol, polypro Solvents, co-solvents, emulsifiers, plasticizers, Surfactants, pylene glycol, polyoxethylene-polyoxypropylene thickeners, pH modifiers, emollients, antioxidants, and copolymer, polyoxyethylene fatty alcohol ether, fatty acid, chelating agents, wetting agents, and water absorbing polyethoxylated fatty acid ester, propylene glycol fatty acid agents. Formulations may also include one or more addi ester, polyoxyethylene-glycerol fatty ester, polyglycolized tives, for example, dyes, colored pigments, pearlescent glycerides polyglycerol fatty acid ester, Sorbitan ester, poly agents, deodorizers, and odor maskers. ethoxylated sorbitan ester, polyethoxylated cholesterol, 0239 Diluents or fillers increase the bulk of a solid polyethoxylated castor oil, polyethoxylated Sterol, lecithin, dosage form so that a practical size is provided for com or polyethoxylated vegetable oil. pression of tablets or formation of beads and granules. 0245 Topical formulations of the invention may also Suitable diluents include, but are not limited to dicalcium comprise an anti-crystallizationt/solubilizing component phosphate dihydrate, calcium sulfate, lactose, Sucrose, man which, when present, generally comprises one or more of nitol, Sorbitol, cellulose, microcrystalline cellulose, kaolin, metallic alkyl Sulfate, polyvinylpyrrolidone, lauroyl mac Sodium chloride, dry starch, hydrolyzed starches, pregelati rogol glycerides, caprylocaproyl macrogolglycerides, nized Starch, silicone dioxide, titanium oxide, magnesium Stearoyl macrogol glycerides, linoleoyl macrogol glycerides, aluminum silicate and powdered Sugar. oleoyl macrogol glycerides, polyalkylene glycol, polyethyl 0240 For topical use on the skin and the scalp, the ene glycol, polypropylene glycol, polyoxyethylene-poly formulation may comprise ointments, creams, liniments or oxypropylene copolymer, fatty alcohol, polyoxyethylene patches as a carrier. These topical formulations may or may fatty alcohol ether, fatty acid, polyethoxylated fatty acid not contain preservatives, depending on the dispenser and ester, propylene glycol fatty acid ester, fatty ester, glycerides nature of use. Suitable preservatives are described above. of fatty acid, polyoxyethylene-glycerol fatty ester, polygly Various matrices for slow release delivery may also be used. colized glycerides, polyglycerol fatty acid ester, Sorbitan 0241 For topical use on the eyelids or eyebrows, the ester, polyethoxylated Sorbitan ester, polyethoxylated cho monoterpenoid or enantiomer or carboxylic acid derivative lesterol, polyethoxylated castor oil, polyethoxylated sterol, compound(s) may be formulated in aqueous alcohol solu lecithin, or polyethoxylated vegetable oil. tions, creams, ointments or oils exhibiting physiologically 0246 Topical formulations of the invention may also acceptable osmolarity by addition of pharmacologically comprise one or more surfactants. Surfactants may be acceptable buffers and salts. Such topical formulations may anionic, cationic, amphoteric or nonionic Surface active or may not, depending on the dispenser, contain preserva agents. Suitable anionic Surfactants include, but are not tives such as benzalkonium chloride, chlorhexidine, chlo limited to, those containing carboxylate, Sulfonate and Sul robutanol; parahydroxybenzoic acids and phenylmercuric fate ions. Examples of anionic Surfactants include Sodium, salts such as nitrate, chloride, acetate, and borate, or anti potassium, ammonium of long chain alkyl Sulfonates, and oxidants, as well as additives like EDTA, sorbitol, boric acid alkyl aryl Sulfonates such as sodium dodecylbenzene Sul etc. as additives. Furthermore, particularly aqueous solu fonate; dialkyl Sodium sulfo Succinates, such as sodium tions may contain viscosity increasing agents such as poly dodecylbenzene Sulfonate; dialkyl Sodium sulfoSuccinates, saccharides e.g., methylcellulose, mucopolysaccharides, Such as Sodium bis-(2-ethylthioxyl)-SulfoSuccinate; and e.g., hyaluronic acid and chondroitin Sulfate, or polyalcohol alkyl Sulfates Such as sodium lauryl Sulfate. Cationic Sur e.g., polyvinylalcohol. Various slow releasing gels and factants include, but are not limited to, quaternary ammo matrices may also be employed as well as Soluble and nium compounds such as benzalkonium chloride, benzetho insoluble ocular inserts, for instance, based on Substances nium chloride, cetrimonium bromide, Stearyl forming in-situ gels. Depending on the actual formulation dimethylbenzyl ammonium chloride, polyoxyethylene and and specific monoterpenoid compound to be used, various coconut amine. Examples of nonionic Surfactants include amounts of the monoterpenoid compound and different dose ethylene glycol monostearate, propylene glycol myristate, regimens may be employed. Particularly preferred topical glyceryl monostearate, glyceryl Stearate, polyglyceryl-4- formulations are essential oils, perfume oils, or perfumes. oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, 0242 Topical formulations may also comprise one or PEG-00 monolaurate polyoxyethylene monolaurate, poly more dispersants e.g., phosphate-buffered saline (PBS), sorbates, polyoxyethylene octylphenylether, PEG-1000 saline, glucose, sodium lauryl Sulfate (SLS), polyvinylpyr cetyl ether, polyoxyethylene tridecyl ether, polypropylene rolidone (PVT), polyethylene glycol (PEG), and hydroxy glycol butyl ether, Stearoyl monoisopropanolamide, and propylmethylcellulose (HPMC). polyoxyethylene hydrogenated tallow amide. Examples of US 2016/0374979 A1 Dec. 29, 2016 amphoteric Surfactants include Sodium N-dodecyl-3-ala placenta extract, photosensitizers, ginseng extract, biotin, nine, Sodium N-lauryl-3-iminodipropionate, myristoam mononitro guaiacol, carpronium chloride or hydrates phoacetate, lauryl betaine and lauryl Sulfobetaine. thereof. Vitamin E or variants thereof, Swertia japonica (also 0247. If desired, various matrices for slow release deliv known as Swertia chirata) extract, capsicum tincture, ery of the monoterpenoid compound may also be used. cepharanthine, nicotinic acid or variants thereof, estradiol. 0248. The topical formulations compositions described ethynylestradiol, randic acid, 5C.-reductase inhibitor, 12-tet herein may further comprise components which are gener radecanoylphorbol-13-acetate, herbal medicine Such as ally used in cosmetics, for example, oils, detergents, UV Polygonatum rhizome, Uncaria, Silybum marianum, henna, absorbers, alcohols, chelating agents, pH modifiers, preser Glycyrrhiza, estradiol benzoate, diphenhydramine, resorcin, Vatives, thickeners, pigments, fragrances, and skin nutri hinokitiol. 1-menthol, salicylic acid, Polygonum root tional Supplements. Specifically, the composition may com extract, Panax japonicus rhizome extract, panthenol, sele prise active ingredients used for skin cosmetics, such as Zinc nium disulfide, pyridoxine hydrochloride, dipyrithione Zinc, oxide microparticles, titanium oxide, UV absorbers such as pyrithione Zinc, Sulfur, piroctonc olamine, pyrithione Zinc, Parsol MCX and Parsol 1789, vitamins such as ascorbic Sulfur, glycyrrhetinic acid Stearyl, glycyrrhizinate dipotas acid, moisturising agents such as hyaluronate Sodium, pet sium, allantoin, dialkylmonoamine variants, Perilla frute rolatum, glycerin, and urea, hormonal agents, skin-lighten scens extract, Poria Sclerotium extract, B-glycyrrhetinic ing agents such as kojic acid, arbutin, placenta extract, and acid, miconazole nitrate, benzoic acid, Sodium salicylate, rucinol, Steroid drugs, inhibitors of production or release of phytosterol, wine yeast extract, takanal, ethinyl estradiol. a chemical mediator Such as arachidonate metabolite and isopropylmethylphenol, cepharanthine biotin, D-pantoth histamine (e.g. indometacin and ibuprofen), anti-inflamma enyl alcohol, Paconia extract, Tilia extract, Sophora extract, tory drugs such as receptor antagonist, anti-androgenic Sophora flavescens extract, Zingiber Officinale (Ginger) root agents, sebum Secretion Suppressing agents such as vitamin extract, 6-benzylaminoprine, pentadecanoic glyceride, t-fla A acid, royal jelly extract, and royal jelly acid, peripheral Vanone, Sweet Hydrangea leaf extract, adenosine, and pan blood-vessel dilators such as tocopherol nicotinate, alpros tothenylethylether. tadil, isoxSuprine hydrochloride, and tolazoline hydrochlo 0251. It will be understood that the topical formulations ride, carbon dioxide with peripheral blood-vessel dilating of the present disclosure may comprise any one or more of activity, blood circulation promoting agents such as minoxi the Co-monoterpenoids or ester or enantiomer thereof, or dil, carpronium chloride, capsicum tincture, vitamin E vari perfume oils or essential oils comprising same as described ants, ginkgo extract, and Swertia japonica extract, cellular according to any example hereof, in combination with one stimulants such as pentadecanoic acid glyceride and nico or more other components described herein e.g., carriers, tinic-aid amide, antimicrobials such as hinokitiol, L-men excipients, emollients, diluents, fillers, dispersants, stabilis thol, and isopropylmethylphenol, glycyrrhizinic acid and ers, preservatives, emulsifying agents, solubilizing agents, variants or salts thereof, ceramide and ceramide analogs. anti-crystallization agents, Surfactants, cosmetic compo 0249 Topical formulations of the present invention may nents, and/or adjunctive agents. be compatible with various types of adjunctive agents with 0252 For example, a preferred topical formulation in which they are combinable or capable of being administered accordance with the present disclosure may comprise pip sequentially or simultaneously or concomitantly. For eritone, Rosa multiflora extract, Poterium officinale extract, example a topical formulation comprising one or more Swertia chirata extract, ethanol. 1,3-butylene glycol, pan monoterpenoid compounds capable of reducing fibroblast thenyl ethyl ether, glycyrrhetinic acid, citric acid anhydrous, growth factor 5 (FGF5)-dependent signalling in a hair Sodium citrate and purified water. follicle cell or part thereof may further comprise an adjunc 0253 Particularly preferred topical formulations are as tive agent which is effective for treatment or prevention of follows: 0.095% (v/v) Piperitone formulation hair loss. Alternatively, or in addition, a topical formulation comprising a monoterpenoid compound as hereinbefore described may be formulated for co-administration with one Ingredient % (w/v) Amount (mg/ml) or more adjunctive agents effective for treatment or preven (-)-piperitone O.O88 Rosa multiflora fruit extract (dry) 1.0 (in solution) 1.67 tion of hair loss. In such circumstances, the efficacy of the Poterium officinale root extraxt 1.0 (in solution) 2.50 monoterpenoid compound is preferably Supplemented by (dry) the action of the adjunctive agent. For example, the topical Swertia chirata whole plant 0.03 (in solution) 3.60 formulation may comprise an adjunctive agent selected from extract (dry) Ethanol 6O.O 600.00 the group consisting of estradiot, OXandrolone, minoxidil, 1,3-Butylene Glycol 3.0 30.00 Sanguisorba officinalis (also known as Poterium officinale) Panthenyl ethyl ether O.3 3.00 extract, Rosa multiflora extract, Brown algae extract, loquat Glycyrrhetinic acid O.1 1.00 leaf extract, Pecan shell extract, Squill extract, sodium Citric acid anhydrous O.O2S O.25 phytate, Fucus vesiculosus extract, phytic acid, nonanal, and Sodium citrate O.O24 O.24 Lipidure-C. Purified water C.S. 0250 Alternatively, or in addition, a topical formulation of the invention may further comprise one or more cellular 0.5% (v/v) Piperitone formulation stimulants, blood circulation promoting agents, anti-andro gen drugs, sebum secretion Suppressing agents, immuno Suppressants, antihistamine agents, antimicrobials, focal Ingredient % (w/v) Amount (mg/ml) stimulants, emollients, antiphlogistics, low-molecular anti (-)-piperitone O465 apoptotic agents, estradiol, Oxandrolone, minoxidil or ana Rosa multiflora fruit extract 1.0 (in solution) 1.67 log/variant thereof, pantothenic acid or variants thereof, US 2016/0374979 A1 Dec. 29, 2016 22

-continued istered, and the hair loss condition suffered by the subject or to which the subject is susceptible. Ingredient % (w/v) Amount (mg/ml) 0259 For example, a topical formulation in unit dose Poterium officinale root extract 1.0 (in solution) 2.50 form may comprise an amount of each active Co-monoter Swertia chirata whole plant extract 0.03 (in solution) 3.60 Ethanol 6O.O 600.00 penoid or ester or enantiomer thereof per unit dose sufficient 1,3-Butylene Glycol 3.0 30.00 to reduce FGF5-dependent signalling in a hair follicle cell Panthenyl ethyl ether O.3 3.00 e.g., by reducing FGF-5 activity in the hair follicle or part Glycyrrhetinic acid O.1 1.00 Citric acid anhydrous O.O2S O.25 thereof and/or by reducing binding of FGF-5 to its cognate Sodium citrate O.O24 O.24 receptor in the hair follicle or part thereof. Purified water C.S. 0260 An amount of Co-monoterpenoid or ester or enantiomer thereof in a unit dose of topical formulation is 0254. Other exemplary formulations in accordance with generally sufficient to reduce or inhibit FGF-5 activity in the the resent disclosure are described in the working examples hair follicle or part thereof. For example, the amount of hereof. Co-monoterpenoid or ester or enantiomer thereof in a unit dose of the topical formulation may be sufficient to reduce Dosage Units and Frequency of Administration or inhibit FGF-5 activity in the hair follicle or part thereof over the course of a treatment by about 10-90% or 20-90% 0255. The dose of monoterpenoid compound in the topi or 30-90% or 40-90% or 50-90% or 60-90% or 70-90% or cal formulation, and frequency of administration thereof, 80-90% or 10-80% or 20-80% or 30-80% or 40-80% or may be appropriately modified depending on the circum 50-80% or 60-80% or 70-80% or 10-70% or 20-70% or Stances. 30-70% or 40-70% or 50-70% or 60-70% or 10-60% or 0256 Typically, topical formulations of the invention are 20-60% or 30-60% or 40-60% or 50-60% or 10-50% or applied repeatedly for a Sustained period of time topically on 20-50% or 30-50% or 40-50% or 10-40% or 20-40% or the part of the body to he treated or which is susceptible to 30-40% or 10-30% or 20-30%. Preferably, an amount of hair loss, for example, the eyelids, eyebrows, skin or scalp. Co-monoterpenoid or ester or enantiomer thereof in a unit The preferred dosage regimen will generally involve regular, dose of the topical formulation is sufficient to reduce or Such as daily, weekly, twice-weekly, or thrice-weekly, inhibit FGF-5 activity in the hair follicle or part over the administration for a period of treatment of at least one about course of a treatment by at least 10% or at least 20% or at one month, more preferably at least three months, and most least 30% or at least 40% or at least 50% or at least 60% or preferably at least six months as required to reduce and/or at least 70% or at least 80% or at least 90%. delay and/or prevent loss of terminal hair in the subject. For 0261 Alternatively, or in addition an amount of Co example, the monoterpenoid compound or topical formula monoterpenoid or ester or enantiomer thereof in a unit dose tion comprising same may be administered 1, 2, 3, 4, 5, 6 or of topical formulation is generally sufficient to reduce or 7 times per week, corresponding with one use per day that inhibit FGF-5 binding to a cognate fibroblast growth factor the monoterpenoid compound or topical formulation com receptor (FGFR) in a hair follicle or part thereof. For prising same is applied. Alternatively, the topical formula example, the amount of Comonoterpenoid or ester or tion of the invention may be administered to a subject daily enantiomer thereof in a unit dose of the topical composition or twice daily or every two days or every three days or every may be sufficient to reduce or inhibit FGF-5 binding to four days or every five days or every six days or weekly as fibroblast growth factor receptor 1 (FGFR1) in a hair follicle required. On any day, the topical formulation may be admin or part thereof over the course of a treatment by about istered 1, 2, 3, 4 or 5 times per day. 10-90% or 20-90% or 30-90% or 40-90% or 50-90% or 0257 it is to be understood that terminal hair includes 60-90% or 70-90% or 80-90% or 10-80% or 20-80% or Scalp hair, eyelash hair and/or eyebrow hair. Accordingly, 30-80% or 40-80% or 50-80% or 60-80% or 70-80% or the topical formulation may be administered to the scalp. 10-70% or 20-70% or 30-70% or 40-70% or 50-70% or eyelid, eyelash, face, forehead and/or eyebrow of a human 60-70% or 10-60% or 20-60% or 30-60% or 40-60% or or mammalian Subject on which terminal hair would nor 50-60% or 10-50% or 20-50% or 30-50% or 40-50% or mally grow to reduce and/or delay and/or prevent loss of 10-40% or 20-40% or 30-40% or 10-30% or 20-30%. terminal hair. Alternatively, or in addition, the topical for Preferably, an amount of Co-monoterpenoid or ester or mulation may be administered to an area adjacent to the enantiomer thereof in a unit dose of the topical formulation Scalp, eyelid, eyelash, face, forehead and/or eyebrow of a is sufficient to reduce or inhibit FGF-5 binding to FGFR1 in human or mammalian Subject in which terminal hair nor a hair follicle or part thereof over the course of a treatment mally grows to reduce and/or delay and/or prevent loss of by at least 10% or at least 20% or at least 30% or at least terminal hair. 40% or at least 50% or at least 60% or at least 70% or at least 0258. The total amount of monoterpenoid compound in a 80% or at least 90%. topical formulation to be administered to the subject to 0262 An ability of a Co-monoterpenoid or ester or reduce and/or delay and/or prevent loss of terminal hair will enantiomer thereof to reduce binding of FGF-5 tea FGFR1 vary depending upon a range of parameters e.g., the duration may be determined by a reduction in viability of a BaF3 cell of cosmetic or therapeutic administration, the site to which expressing FGFR1, wherein the BaF3 cell is dependent on the topical formulation is to be applied, the half-life of the FGF-5 signalling for viability. For example, an amount of a specific monoterpenoid compound in the topical formulation compound required to reduce and/or inhibit and/or prevent following administration thereof, the age, sex and weight of binding of FGF-5 to FGFR1 may be determined using the subject to which the topical formulation is to be admin FR-BaF3 cell cultured in the presence of FGF-5 e.g., such as US 2016/0374979 A1 Dec. 29, 2016

described in Ito et al., Journal of Cellular Physiology, 0269. A unit dosage of the composition will typically 197:273-283, 2003 or in the accompanying worldng have a volume dependent on the formulation. For example, examples. an essential oil or perfume is conveniently administered e.g., 0263. Alternatively, or in addition, an amount of Co as a spray, in an amount not exceeding about 1 or 2 or 3 or monoterpenoid or ester or enantiomer thereof in a unit dose 4 or 5 ml per dose. A liquid formulation is conveniently of topical formulation is generally sufficient to sufficient to administered in an amount not exceeding about 5 or 6 or 7 delay a hair follicle comprising terminal hair from entering or 8 or 9 or 10 ml per dose, whereas a lotion or cream may catagen phase. be administered in a smaller Volume e.g., not exceeding 0264. Alternatively, or in addition, an amount of about 1 or 2 or 3 or 4 or 5 ml per dose. For application to Comonoterpenoid or ester or enantiomer thereof in a unit Small areas such as the eyelash or eyebrow or eyelid, a much dose of topical formulation is generally sufficient to suffi smaller volume e.g., a 50 uL, or 100 uL or 250 uL or 500 uL cient to extend an anagen phase of hair follicles comprising droplet, may be employed. terminal hair. 0270 Exemplary unit dosages of up to about 10 ml 0265 A topical formulation of the invention, including a Volume may comprise each active Co-monoterpenoid or unit dose thereof, may comprise at least about 0.01% (w/v), ester or enantiomer thereof in a range from about 1 g to or at least about 0.05% (w/v), or at least about 0.1% (w/v). about 10000 mg. or in a range from about 2 ug to about or at least about 0.25% (w/v), or at least about 0.5% (w/v), 10000 mg. or in a range from about 3 ug to about 10000 mg. or at least about 0.75% (w/v), or at least about 1.0% (w/v), or in a range from about 4 Lig to 10000 mg, or in a range from or at least about 1.25% (w/v), or at least about 1.5% (w/v), about 5 g to about 10000 mg. or in a range from about 6 or at least about 1.75% (w/v), or at least about 2.0% (w/v), ug to about 10000 mg, or in a range from about 7ug to about or at least about 2.25% (w/v), or at least about 2.5% (w/v), 10000 mg. or in a range from about 8 ug to about 10000 mg. or at least about 2.75% (w/v), or at least about 3.0% (w/v), or in a range from about 9 ug to about 60000 mg. or in a or at least about 3.25% (w/v) or at least about 3.5% (w/v), range from about 10 ug to about 10000 mg. or at least about 3.75% (w/v), or at least about 4.0% (w/v) 0271 For example, a unit dose up to about 10 ml volume or at least about 4.25% (w/v), or at least about 4.5% (w/v), consisting essentially of a perfume classified as an eau, or a or at least about 4.75% (w/v) or at least about 5.0% (w/v), shampoo, conditioner, lotion or cream, may comprise each or at least about 5.25% (w/v), or at least about 5.5% (w/v), active Co-monoterpenoid or ester or enantiomer thereof in or at least about 5.75% (w/v), or at least about 6.0% (w/v) a range from about 50 ug to about 6000 mg. or in a range or at least about 6.25% (w/v), or at least about 6.5% (w/v), from about 40 ug to about 6000 mg. or in a range from about or at least about 6.75% (w/v), or at least about 7.0% (w/v) 30 g to about 6000 mg. or in a range from about 20 ug to of each Co-monoterpenoid or ester or enantiomer thereof. about 6000 mg. or in a range from about 10 ug to about 6000 0266. In a preferred example, a topical formulation of the mg, or in a range from about 50 g to about 5000 mg, or in invention, including a unit dose thereof, comprises between a range from about 50 ug to about 4000 mg. or in a range 0.01-2.5% (w/v), or between 0.05-1.0% (w/v), or between from about 50 ug to about 3000 mg. or in a range from about 0.075-0.5% (w/v) of each Co-monoterpenoid or ester or 50 ug to about 2000 mg. or in a range from about 50 ug to enantiomer thereof. about 1000 mg, or in a range from about 50 ug to about 1 0267 A topical formulation of the invention, including a mg, or in a range from about 50 ug to about 2 mg, or in a unit dose thereof, may comprise at least about 0.01% (v/v), range from about 50 g to about 3 mg, or in a range from or at least about 0.05% (v/v), or at least about 0.1% (v/v), or about 50 g to about 4 mg. or in a range from about 50 ug at least about 0.25% (v/v), or at least about 0.5% (v/v), or at to about 5 mg, or in a range from about 50 g to about 6 mg, least about 0.75% (v/v), or at least about 1.0% (v/v), or at or in a range from about 50 g to about 7 mg, or in a range least about 1.25% (v/v), or at least about 1.5% (v/v), or at from about 50 ug to about 8 mg. or in a range from about 50 least about 1.75% (v/v), or at least about 2.0% (v/v), or at ug to about 9 mg, or in a range from about 50 ug to about least about 2.25% (v/v), or at least about 2.5% (v/v), or at 10 mg. or in a range from about 500 ug to about 10 mg. or least about 2.75% (v/v), or at least about 3.0% (v/v), or at in a range from about 500 ug to about 20 mg, or in a range least about 3.25% (v/v) or at least about 3.5% (v/v), or at from about 500 ug to about 30 mg. or in a range from about least about 3.75% (v/v), or at least about 4.0% (v/v) or at 500 ug to about 40 mg. or in a range from about 500 ug to least about 4.25% (v/v), or at least about 4.5% (v/v), or at about 50 mg. or in a range from about 500 ug to about 60 least about 4.75% (v/v) or at least about 5.0% (v/v), or at mg, or in a range from about 500 ug to about 70 mg or in least about 5.25% (v/v), or at least about 5.5% (v/v), or at a range from about 500 ug to about 80 rug, or in a range from least about 5.75% (v/v), or at least about 6.0% (v/v) or at about 500 ug to about 90 mg. or in a range from about 500 least about 6.25% (v/v), or at least about 6.5% (v/v), or at ug to about 100 mg, or in a range from about 1 mg to about least about 6.75% (v/v), or at least about 7.0% (v/v) of each 100 mg. or in a range from about 1 mg to about 200 mg, or Co-monoterpenoid or ester or enantiomer thereof. in a range from about 1 mg to about 300 mg, or in a range 0268. In a preferred example, a topical formulation of the from about 1 mg to about 400 mg, or in a range from about invention, including a unit dose thereof, comprises between 1 mg to about 500 mg, or in a range from about 1 mg to 0.01-2.5% (v/v), or between 0.05-1.5% (v/v), or between about 600 mg. or in a range from about 1 mg to about 700 0.075-1.0% (n/v) or between 0.1-0.5% (v/v) of each Co mg, or in a range from about 1 mg to about 800 mg, or in monoterpenoid or ester or enantiomer thereof. For example, a range from about 1 mg to about 900 mg, or in a range from a topical formulation of the invention comprises about 0.1% about 1 mg to about 1000 mg. or in a range from about 10 (v/v) e.g., such as 0.095% (v/v), of each Co-monoterpenoid mg to about 1000 mg. or in a range from about 10 mg to or ester or enantiomer thereof. In another example, a topical about 1000 mg. or in a range from about 10 mg to about formulation of the invention comprises about 0.5% (v/v) of 2000 mg. or in a range from about 10 mg to about 3000 mg. each Co-monoterpenoid or ester or enantiomer thereof. or in a range from about 10 mg to about 4000 mg. or in a US 2016/0374979 A1 Dec. 29, 2016 24 range from about 10 mg to about 5000 mg. or in a range extract, photosensitizers, ginseng extract, biotin, mononitro from about 10 mg to about 6000 mg, or in a range from guaiacol, carpronium chloride or hydrates thereof, vitamin E about 10 mg to about 7000 mg. or in a range from about 10 or variants, thereof, Swertia japonica extract, capsicum mg to about 8000 mg. or in a range from about 10 mg to tincture, cepharanthine, nicotinic acid or variants thereof, about 9000 mg. or in a range from about 10 mg to about estradiol, ethynylestradiol, randic acid, 50C-reductase 10000 mg. inhibitor. 12-tetradecanoylphorbol-13-acetate, herbal medi 0272. In general a concentration of active compound in cine Such as Polygonatum rhizome, Uncaria, Silybum mari an essential oil will be about 10-fold to about 100-fold the anum, henna, Glycyrrhiza, estradiol benzoate, diphenhy concentration in an eau, and a concentration of active dramine. resorcin hinokitiol, 1-menthol, Salicylic acid, compound in a parfum will be about 4-fold to about 6,6-fold Polygonum root extract, Panax japonicus rhizome extract, the concentration in present an eau. For example, a unit panthenol, selenium disulfide, pyridoxine hydrochloride, dosage of up to about 10 ml Volume consisting essentially of dipyrithione Zinc, pyrithione Zinc, Sulfur, piroctone olamine, essential oil or parfum may comprise each active Co pyrithione Zinc, Sulfur, glycyrrhetinic acid Stearyl, glycyr monoterpenoid or ester or enantiomer thereof in a range rhizinate dipotassium, allantoin, dialkylmonoamine vari from about 1 mg to about 6000 mg. or in a range from about ants, Perilla frutescens extract, Poria Sclerotium extract, 1 mg to about 5000 mg, or in a range from about 1 mg, to B-glycyrrhetinic acid, miconazole nitrate, benzoic acid, about 4000 mg. or in a range from about 1 mg to about 3000 Sodium salicylate, phytosterol, wine yeast extract, takanal, mg, or in a range from about 1 mg to about 2000 mg, or in ethinyl estradiol, isopropylmethylphenol, cepharanthine as range from about 1 mg to about 1000 mg, or in a range biotin, D-pantothenyl alcohol, Paconia extract, Tilia extract, from about 1 mg to about 500 mg, or in a range from about Sophora extract, Sophora flavescens extract, Zingiber Offi 1 mg to about 100 mg. or in a range from about 1 mg to cinale (Ginger) root extract, 6-benzylaminoprine, pentade about 50 mg, or in a range from about 1 mg to about 30 mg. canoic glyceride, t-flavanone, Sweet Hydrangea leaf extract, or in a range from about 1 mg to about 20 mg. or in a range adenosine, and pantothenylethylether. from about 1 mg to about 10 mg. or in a range from about 0277. In one example, a topical formulation comprising a 100 mg to about 6000 mg, or in a range from about 100 mg monoterpenoid compound is administered sequentially or to about 5000 mg, or in a range from about 100 mg to about simultaneously with an adjunctive therapeutic agent for 4000 mg. or in a range from about 100 mg. to about 3000 treatment of the same condition e.g., estradiol and/or oxan mg, or in a range from about 100 mg to about 2000 mg. or drolone and/or minoxidil and/or finasteride or an agent that in a range from about 100 mg to about 1000 mg. blocks the conversion of testosterone to dihydrotesterone. 0273 A total amount of monoterpenoid compound The adjunctive therapeutic agent is co-administered under administered to a subject may be in a range from about 0.1 conditions and in accordance to a standard treatment regime ng per day to about 100 mg per day or from about 1 ng per for that agent. The skilled artisan will appreciate that such day to about 10 mg per day or from about 10 ng per day to treatment regimens provide enhanced therapeutic benefit to about 1 mg per day. the patient, and may be more than additive in their effect. 0274. An amount of active compound administered to the 0278 Alternatively, or in addition, a topical formulation subject may be in a range from 0.001 ug/cm/day to 1,000 comprising a monoterpenoid compound is administered ug/cm/day or from 0.005ug/cm/day to 500 ug/cm/day or sequentially or simultaneously with a cytotoxic or cytostatic from 0.01 ug/cm/day to 100 ug/cm/day or from 0.05 compound that causes hair loss e.g., in the case of a subject ug/cm/day to 50 ug/cm/day or from 0.1 g/cm/day to 10 undergoing chemotherapy or radiation therapy or treatment ug/cm/day. for HIV-1 infection or AIDS. In such circumstances, the 0275 An amount of active compound to be applied efficacy of the monoterpenoid compound counteracts the topically on the scalp is in the range of about 0.1 ng to about hair-loss effect of the cytotoxic or cytostatic compound. The 100 mg per day, more preferably about 1 ng to about 10 mg cytotoxic or cytostatic compound will generally be admin per day, and most preferably about 10 ng to about 1 mg per istered in accordance to a standard treatment regime for that day depending on the specific monoterpenoid compound agent. and formulation comprising same. Subjects and medical indications 0276 A topical formulation of the invention may be 0279 Topical formulations of the present invention are administered alone or in combination with other active Suitable for administration to human and other mammalian ingredients e.g., sequentially or simultaneously or concomi Subjects, including companion animals such as dogs and tantly with other drug compositions for therapy of the same cats, and domestic animals such as horses, Zoo animals such or a different condition. For example, the other drug may be as felids, canids, bovids, ungulates and primates, or labora combined with a topical formulation of the invention. Such tory animals such as rodents, lagomorphs and primates. other active ingredients may include e.g., one or more 0280. The subject to which a topical formulation of the cellular stimulants, blood circulation promoting agents, anti invention is administered may be a subject who wishes to androgen drugs, sebum secretion Suppressing agents, immu maintain full, Voluminous hair for cosmetic purposes by nosuppressants, antihistamine agents, antimicrobials, focal reducing and/or delaying and/or preventing loss and/or stimulants, emollients, antiphlogistics or low-molecular thinning of terminal hair. In Such circumstances, the Subject anti-apoptotic agents. Specifically, the other active ingredi may be a subject who does not suffer from alopecia, but may ents may include at least one of estradiol, Oxandrolone suffer from loss and/or thinning of terminal hair. Alterna minoxidil or analogs/variants thereof, Sanguisorba officina tively, or in addition, the subject may have no visible lis root extract, Rosa multiflora extract, Brown algae extract, symptoms of allopecia, but is genetically predisposed to loquat leaf extract, Pecan shell extract, squill extract, sodium develop hair thinning, hair loss or alopecia in the future. The phytate, Fucus Vesiculosus extract, phytic acid, nonanal, topical formulations are also particularly useful for treating Lipidure-C, pantothenic acid or variants thereof, placenta alopecia e.g., an acute form of allopecia, alopecia areata or US 2016/0374979 A1 Dec. 29, 2016

androgenic alopecia. Accordingly, the Subject to which the isolated ester thereof with a carboxylic acid, wherein said topical formulation is to be administered may be human or Co-monoterpenoid or enantiomer or ester is in an amount other mammalian Subject who is Suffering from hair loss or sufficient to reduce fibroblast growth factor 5 (FGF5)- hair thinning, or predisposed to alopecia e.g., an acute form dependent signalling in a hair follicle cell, and wherein the of allopecia, alopecia areata or androgenic alopecia, or hair Co-monoterpenoid is of formula (I): loss. 0281. The topical formulation of the present invention is particularly Suited for administration to a human or mam formula (I) malian Subject Suffering from androgenic alopecia or who R3 has a predisposition or familial history of androgenic alo pecia. Administration of a topical formulation of the inven x1N tion to the human or mammalian Subject suffering from, or at risk of Suffering from, alopecia may delay and/or reduce and/or prevent loss of terminal hair in the subject by R. delaying hair follicles comprising the terminal hair from Z entering catagen phase. Alternatively, or in addition, admin 1NR, istration of a topical formulation of the invention to the human or mammalian Subject suffering from, or at risk of 0286 wherein. Suffering from, alopecia may delay and/or reduce and/or (0287 R is hydrogen, hydroxyl or oxygen; prevent loss of terminal hair in the Subject by extending an 0288 R is absent or hydrogen or hydroxyl; anagen phase of hair follicles comprising the terminal hair. 0289 R is CH: 0282. The present invention is also particularly suited for 0290 X is CH or CH-OH, or administration to a Subject Suffering from or at risk of 0291 X is CHCH or CHOHCH and X and Y Suffering from an acute form of allopecia induced by an acute together form a single bond within a 6-membered ring; event selected from pregnancy, stress, illness, a cytotoxic 0292 Y is CH when X is CH or CH-OH, or agent, a cytostatic agent, and treatment with an agent which 0293 Y is CH or COH when X is CHCH, or induces necrosis or apoptosis of hair follicles as a side-effect CHOHCH; and of therapy. The cytotoxic or cytostatic agents may be endog 0294 Z is a saturated or unsaturated C. Cs alkyl or enous e.g., as generated in response to stress, or may be alkyl ester. exogenous e.g., as administered during chemotherapy for 0295 B. The topical formulation according to example treatment of cancer, Subject undergoing chemotherapy or embodiment A, wherein the Co-monoterpenoid is a mono radiation therapy or treatment for HIV-1 infection or AIDS. hydroxylated compound. 0283. The present invention is particularly suited to treat 0296 C. The topical formulation according to example ment and/or prevention of allopecia in Subjects that are either embodiment A, wherein R is hydrogen. undergoing cancer treatment with a cytotoxic or cytostatic 0297 D. The topical formulation according to example compound or with radiation therapy, Subjects who are under embodiment A, wherein R1 is oxygen. going treatment for HIV-1 infection or AIDS with antiviral 0298 E. The topical formulation according to example compound, or to whom such therapies has been prescribed. embodiment A, wherein X is CH and Y is CH. The subject may be treated before therapy with a cytotoxic 0299 F. The topical formulation according to example or cytostatic antiviral compound commences, or before: and embodiment A, wherein X is CH2OH and Y is CH after Such therapy has commenced. The present invention 0300 G. The topical formulation according to example also provides for therapy with a topical formulation as embodiment A, wherein X is CHCH. described herein after treatment with a cytotoxic or cyto 0301 H. The topical formulation according to example static or antiviral compound has commenced. Cytotoxic, embodiment A, wherein X is CHOHCH. cytostatic and/or antiviral compounds which cause hair loss 0302 I. The topical formulation according to example are known in the art. embodiment G, wherein Y is CH. 0284. For example, a subject may apply a topical formu 0303 J. The topical formulation according to example lation described herein as a fine line at the skin-eyelash embodiment G, wherein Y is COH. border of each eyelid, and as a cream to the scalp, once a day 0304 K. The topical formulation according to example several weeks e.g., two weeks or three weeks, prior to the embodiment H, wherein Y is CH. initiation of a chemotherapy regimen (e.g., doxorubicin, 0305 L. The topical formulation according to example cyclophosphamide, and paclitaxel, or 5-fluoruracil, leuco embodiment H, wherein Y is COH. Vorin and Oxaliplatin). The patient may continue applying 0306 M. The topical formulation according to example the topical formulation throughout and after cessation of the embodiment A, wherein R is hydrogen. chemotherapy regimen. The patient would not generally 0307 N. The topical formulation according to example experience the total hair loss normally associated with embodiment A, wherein R is hydroxyl. chemotherapy, and may recover more rapidly when chemo 0308 O. The topical formulation according to example therapy ceases. A few weeks after completion of the che embodiment A, wherein R is absent. motherapy, the patient may stop applying the topical for 0309 P. The topical formulation according to example mulation. If hair is lost at this stage, treatment is resumed. embodiment A, wherein Z is a saturated C alkyl. 0310 Q. The topical formulation according to example Example Embodiments of the Invention: embodiment P, wherein Z is CCH. 0285 A. A topical formulation comprising an isolated 0311. R. The topical formulation according to example Co-monoterpenoid or isolated enantiomer thereof or an embodiment A, wherein Z is an unsaturated C-C alkyl. US 2016/0374979 A1 Dec. 29, 2016 26

0312 S. The topical formulation according to example 0336 6-Isopropyl-3-methyl-2-cyclohexen-1-one embodiment R, wherein R is absent. (3-carvomenthenone); and 0313 T. The topical formulation according to example 0337 3,7-Dimethyl-1,6-octadien-3-ol (linalool). embodiment R, wherein R is hydroxyl. 0338 AM. The topical formulation according to example 0314 U. The topical formulation according to example embodiment AL, wherein the Co-monoterpenoid is embodiment R, wherein R is hydrogen. 3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (piperitone). 0315 V. The topical formulation according to example 0339 AN. The topical formulation according to example embodiment R, wherein Z is CCH. embodiment AL, wherein the Co-monoterpenoid is 1-Iso 0316 W. The topical formulation according to example propyl-4-methyl-3-cyclohexen-1-ol (terpinen-4-ol). embodiment R, wherein Z is CCHCH. 0340 AO. The topical formulation according to example 0317 X. The topical formulation according to example embodiment A comprising a carboxylic acid monoester of embodiment A, wherein Z is CCHCHOCOCH. the Co-monoterpenoid. 0318 Y. The topical formulation according to example embodiment X, wherein Co-monoterpenoid or enantiomer 0341 AP. The topical formulation according to example thereof is a non-hydroxylated compound. embodiment AN, wherein the carboxylic acid monoester is 0319 Z. The topical formulation according to example a monoester with a carboxylic acid selected from acetic acid, embodiment A, wherein the Co-monoterpenoid or propionic acid and formic acid. enantiomer thereof is a monohydroxylated compound, R is 0342 AQ. The topical formulation according to example hydrogen, R is hydroxyl, X is CH, Y is CH, and Z is an embodiment AP, wherein the carboxylic acid is acetic acid. unsaturated C-C alkyl, 0343) AR. The topical formulation according to example 0320 AA. The topical formulation according to example embodiment AQ, wherein the Co-monoterpenoid carbox embodiment Z, wherein Z is CCHCH. ylic acid ester is selected from the group consisting of 0321 AB. The topical formulation according to example 0344 (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate embodiment A, wherein the Co-monoterpenoid is a non (geranyl acetate); hydroxylated compound wherein R is hydrogen, R is 0345 3,7-Dimethyl-1,6-octadien-3-yl acetate (linallyl absent, X is CH, Y is CH, and Z is CCHCHOCOCH. acetate); 0322 AC. The topical formulation according to example 0346 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanyl embodiment A, wherein the Co-monoterpenoid or acetate (terpinyl acetate); and enantiomer thereof is a monohydroxylated compound, R is 0347 5-Isopropenyl-2-methyl-2-cyclohexen-1 hydrogen or oxygen, R is absent or hydrogen or hydroxyl, acetate (carvyl acetate). X is CHCH or CHOHCH, Y is CH or COH, and Z is a 0348 AS. The topical formulation according to example saturated or unsaturated C alkyl. embodiment AR, wherein the C-to-monoterpenoid carbox 0323 AD. The topical formulation according to example ylic acid ester is selected from the group consisting of embodiment AC, wherein R is oxygen, R is hydrogen or (0349 (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate hydroxyl, X is CHCH, Y is CH, and Z is a saturated C. (geranyl acetate); and 3,7-Dimethyl-1,6-octadien-3-yl alkyl. acetate (linallyl acetate). 0324 AE. The topical formulation according to example 0350 AT. The tropical formulation according to example embodiment AD, wherein R is hydrogen. embodiment A comprising an isolated enantiomer of the 0325 AF. The topical formulation according to example Co-monoterpenoid. embodiment AC, wherein R is hydrogen, R is hydrogen or 0351 AU. The topical formulation according to example hydroxyl, X is CHCH, Y is CH or COH, and Z is a embodiment AT, wherein the isolated enantiomer is selected saturated C alkyl. from the group consisting of: 0326 AG. The topical formulation according to example 0352 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol embodiment AF, wherein Y is CH. (-)-terpinen-4-ol; 0327 AH. The topical formulation according to example 0353 (1S)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol embodiment AG, wherein R is hydroxyl. (+)-terpinen-4-ol; 0328 AI. The topical formulation according to example embodiment AF, wherein Y is COH. 0354 2-(1R)-4-Methylcyclohex-3-en-1-yl)propan-2- 0329 AJ. The topical formulation according to example ol (+)-alpha-terpineol; embodiment Al, wherein R is hydrogen. 0355 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1- 0330 AK. The topical formulation according to example one (-)-piperitone; embodiment AC, wherein R is absent, X is CHOHCH, Y 0356 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1- is CH, and Z is an unsaturated C alkyl. one (+)-piperitone; 0331 AL. The topical formulation according to example 0357 (3S)-3,7-Dimethyl-1,6-octadien-3-ol (+)-Lina embodiment A, wherein the Co-monoterpenoid is selected lool: from the group consisting of 0358 (3R)-3,7-Dimethyl-1,6-octadien-3-ol: 0332 3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one 0359 (1R, 5R)-2-Methyl-5-(1-methylethenyl)-2-cy (piperitone); clohexen-1-ol (-)-cis-carveol: 0333 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (ter 0360 (1S,5S)-2-Methyl-5-(1-methylethenyl)-2-cyclo pinen-4-ol); hexen-1-ol (+)-cis-carveol; 0334 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanol (al 0361 (2R, 5S)-2-Methyl-5-(1-methylethenyl)-2-cy pha-terpineol); clohexen-1-ol (+)-trans-carveol; and 0335 2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- 0362 (1S, 5R)-2-Methyl-5-(1-methylethenyl)-2-cy ol (carveol): clohexen-1-ol (-)-trans-carveol. US 2016/0374979 A1 Dec. 29, 2016 27

0363 AV. The topical formulation according to example 0387 BF. The topical formulation according to example embodiment AU, wherein the isolated enantiomer is selected embodiment BE, wherein the natural product is selected from the group consisting of from a plant or part thereof, a plant extract, an essential oil, 0364 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol and a perfume comprising said essential oil. (-)-terpinen-4-ol; 0388 B.G. The topical formulation according to any one 0365 (1S)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol of example embodiments BA to BD, wherein the piperitone (+)-terpinen-4-ol; or isolated enantiomer thereof is in the form of an essential 0366 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1- oil from Eucalyptus dives or perfume comprising said essen one (-)-piperitone; tial oil. 0367 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1- 0389 BH. The topical formulation according to any one one (+)-piperitone; of example embodiments AZ or BB to BD, wherein the 0368 (1S,5S)-2-Methyl-5-(1-methylethenyl)-2-cyclo terpinen-4-ol or isolated enantiomer thereof is provided in hexen-1-ol (+)-cis-carveol; and the form of an essential oil from Eucalyptus dives or 0369 (1R, 5S)-2-Methyl-5-(1-methylethenyl)-2-cy perfume comprising said essential oil. clohexen-1-ol (+)-trans-carveol. 0390 BI. The topical formulation according to any one of 0370 AW. The topical formulation according to example example embodiments A to BE, wherein the Co-monoter embodiment 4 AV, wherein the isolated enantiomer is: penoid or enantiomer thereof is a synthetic compound. 0371 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol 0391 B.J. The topical formulation according to any one of (-)-terpinen-4-ol. example embodiments A to BI, comprising at least two 0372 AX. The topical formulation according to example compounds selected from the Co-monoterpenoid and/or embodiment AV, wherein the isolated enantiomer is: ester and/or enantiomer thereof. 0373 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1- 0392 BK. The topical formulation according to any one one (-)-piperitone. of example embodiments A to BJ, wherein the total amount 0374. AY. The topical formulation according to example of Co-monoterpenoid or ester or enantiomer thereof is an embodiment AV, wherein the isolated enantiomer is: amount sufficient to reduce or inhibit FGF-5 activity in the 0375 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1- hair follicle or part thereof. one (+)-piperitone. 0393 BL. The topical formulation according to any one 0376 AZ. A topical formulation comprising isolated of example embodiments A to BK, wherein the total amount 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (terpinen-4-ol) or of Co-monoterpenoid or ester or enantiomer thereof is an an isolated enantiomer or carboxylic acid ester thereof, amount sufficient to reduce or inhibit FGF-5 binding to a wherein said terpinene-4-ol or enantiomer or ester thereof is cognate fibroblast growth factor receptor (FGFR) in the hair in an amount sufficient to reduce fibroblast growth factor 5 follicle or part thereof. (FGF5)-dependent signalling in a hair follicle cell. 0394 BM. The topical formulation according to example 0377 BA. A topical formulation comprising isolated embodiment BL, wherein the cognate FGFR is FGFR1. 3-methyl-6-(propan-2-yl)cyclohex-2-en-1-one (piperitone) 0395 BN. The topical formulation according to any one or an isolated enantiomer or carboxylic acid ester thereof, of example embodiments BL or BM, wherein a reduction in wherein said piperitone or enantiomer or ester thereof is in FGF-5 binding is determined by a reduction in viability of an amount sufficient to reduce fibroblast growth factor 5 a BaF3 cell expressing fibroblast growth factor receptor 1 (FGF5)-dependent signalling in a hair follicle cell. (FGFR1) wherein said BaF3 cell is dependent on FGF-5 0378 BB. The topical formulation according to example signalling for viability. embodiment AZ or BA, wherein the formulation comprises 0396 BO. The topical formulation according to any one (i) isolated 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (ter of example embodiments A to BN comprising a topical pinen-4-ol) or an isolated enantiomer and (ii) isolated carrier, excipient or emollient. 3-methyl-6-(propan-2-yl)cyclohex-2-en-1-one (piperitone) 0397 BR The topical formulation according to any one or an isolated enantiomer thereof. of example embodiments A to BO, further comprising one or 0379 BC. The topical formulation according to example more adjunctive agents effective for treatment or prevention embodiment BB, therein: of hair loss. 0380 (1) the isolated enantiomer of terpinene-4-ol is: 0398 BO. The topical formulation according to example 0381 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol embodiment BR wherein the one or more adjunctive agents (-)-terpinen-4-ol; and/or is/are selected from the group consisting of estradiol, oxan 0382 (ii) the isolated enantiomer of piperitone is: drolone, minoxidil, Sanguisorba officinalis root extract, 0383 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2- Rosa multiflora extract, Brown algae extract, loquat leaf en-1-one (-)-piperitone or extract, Pecan shell extract, Squill extract, Sodium phytate, 0384 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2- Fucus vesiculosus extract, phytic acid, nominal, and Lipi en-1-one (+)-piperitone. dure-C. 0385 BD. The topical formulation according to example 0399 BR. The topical formulation according to any one embodiment 54 or 55, wherein the terpinen-4-ol or of example embodiments A to BQ for delaying loss of enantiomer thereof is in an amount Sufficient to reduce terminal hair in a subject. fibroblast growth factor 5 (FGF5)-dependent signalling in a 0400 BS. The topical formulation according, to any one hair follicle cell. of example embodiments A to BQ when used to delay loss 0386 BE. The topical formulation according to any one of terminal hair in a subject. of example embodiments A to BD, wherein the Co 0401 BT. The topical formulation according to example monoterpenoid or ester or enantiomer thereof is a natural embodiment BR or BS, wherein the terminal hair is scalp product or isolated from a natural product. hair, eyelash hair, or eyebrow hair. US 2016/0374979 A1 Dec. 29, 2016 28

0402 BU. The topical formulation according to any one 0416) CI. The method according to any one of example of example embodiments BR to BT, wherein delaying loss embodiments BX to CH, wherein terminal hair growth is of terminal hair comprises delaying hair follicles comprising promoted or enhanced. the terminal hair from entering catagen phase. 0417 CJ. The topical formulation according to any one of 0403 BV. The topical formulation according to any one example embodiments A to BQ for treatment or prevention of example embodiments BR to BT, wherein delaying loss of allopecia in a subject. of terminal hair comprises extending an anagen phase of hair 0418 CK. The topical formulation according to example follicles comprising the terminal hair. embodiment CJ, wherein the alopecia is androgenic alope 0404 BW. The topical composition according to any one cia of example embodiments BR to BV for promoting and/or 0419 CL. The topical formulation according to example enhancing growth of the terminal hair. embodiment CK, wherein the alopecia is alopecia areata. 0405 BX. A method of reducing or delaying or prevent 0420 CM. The topical formulation according to example ing loss of terminal hair in a Subject who is not suffering embodiment CK, wherein the alopecia is an acute form of from alopecia, said method comprising administering the alopecia. topical formulation according to any one of example 0421 CN. The topical formulation according to example embodiments A to BQ to an area of the dermis or skin of a embodiment CM, wherein the acute form of allopecia is subject in which loss of terminal hair is to be reduced or induced by an acute event selected from pregnancy, stress, delayed or prevented or an area of dermis adjacent or illness, treatment with a cytotoxic agent, treatment with a Surrounding thereto for a time and under conditions Sufi cytostatic agent, and treatment with an agent which induces cient to reduce or delay or prevent the loss of terminal hair. necrosis or apoptosis of hair follicles as a side-effect of 0406 BY. The method according to example embodi therapy. ment BX wherein the time and conditions reduce loss of 0422 CO. The topical formulation according to example terminal hair in a Subject Suffering from hair loss. embodiment CK, wherein the alopecia is alopecia induced 0407 BZ. The method according to example embodi by chemotherapy. ment BX wherein the time and conditions delay loss of 0423 CP. A method of treatment or prevention of alope terminal hair in a Subject having a genetic predisposition to cia in a subject, said method comprising administering the hair loss or familial history of hair loss. topical formulation according to any one of example 0408 CA. The method according to example embodi embodiments A to BQ to an area of the dermis or skin of a ment BX wherein the time and conditions prevent loss of subject in which the alopecia is to be treated or prevented or terminal hair in a Subject having a genetic predisposition to an area of dermis adjacent or Surrounding thereto for a time hair loss or familial history of hair loss. and under conditions sufficient to reduce or delay or prevent 04.09 CB. The method according to any one of example the loss of terminal hair in the subject. embodiments BX to CA, wherein said method comprises 0424 CQ. The method according to example embodi administering the topical formulation to the Subject daily or ment CP, wherein the subject has a genetic predisposition for twice daily or every two days or every three days or every alopecia or familial history of alopecia. four days or every five days or every six days or weekly. 0425 CR. The method according to example embodi 0410 CC. The method according to example embodi ment CP, herein the subject suffers from an existing alopecia ment CB, wherein said method comprises administering the 0426 CS. The method according to any one of example topical formulation to the subject for one month or two embodiments CP to CR, wherein the alopecia is androgenic months or three months or four months or five months or six alopecia. months. 0427 CT. The method according to any one of example 0411 CD. The method according to any one of example embodiments CR to CT, wherein the alopecia is alopecia embodiments BX to CC, wherein the terminal hair is scalp areata. hair, and wherein said method comprises administering the 0428 CU. The method according to any one of example topical formulation to the scalp of the subject. embodiments CR to CT, wherein the alopecia is, an acute 0412 CE. The method according to any one of example form of allopecia. embodiments BX to CC, wherein the terminal hair is eyelash 0429 CV. The method according to example embodi hair, and wherein said method comprises administering the ment CU, wherein the acute form of allopecia is induced by topical formulation to the eyelid or eyelash of the subject. an acute event selected from pregnancy, stress, illness, 0413 CF. The method according to any one of example treatment with a cytotoxic agent, treatment with a cytostatic embodiments BX to CC, wherein the terminal hair is eye agent, and treatment with an agent which induces necrosis or brow hair, and wherein said method comprises administer apoptosis of hair follicles as a side-effect of therapy. ing the topical formulation to the face or forehead or 0430 CW. The method according to any one of example eyebrow of the subject. embodiments CP to CR, wherein the alopecia is alopecia 0414 CG. The method according to any one of example induced by chemotherapy. embodiments BX to CF, wherein delaying loss of terminal 0431 CX. The method according to any one of example hair comprises delaying hair follicles comprising the termi embodiments CP to CW, wherein said method comprises nal hair from entering catagen phase. administering the topical formulation to the Subject daily or 0415 CH. The method according to any one of example twice daily or every two days or every three days or every embodiments BX to CF, wherein delaying loss of terminal four days or every five days or every six days or weekly. hair comprises extending an anagen phase of hair follicles 0432 CY. The method according to example embodi comprising the terminal hair. ment CX, wherein said method comprises administering the US 2016/0374979 A1 Dec. 29, 2016 29 topical formulation to the subject for one month or two 0454 DL. The use according to example embodiment DI, months or three months or four months or five months or six wherein Y is COH. months. 0455 DM. The use according to example embodiment 0433. CZ. The method according to any one of example DJ, wherein Y is CH. embodiments CP to CY, wherein the alopecia involves scalp 0456 DN. The use according to example embodiment hair, and wherein said method comprises administering the DJ, wherein Y is COH. topical formulation to the scalp of the subject. 0457 DO. The use according to example embodiment 0434 DA. The method according to any one of example DI, wherein R is hydrogen. embodiments CP to CY, wherein the alopecia involves 0458 DP. The use according to example embodiment eyelash hair, and wherein said method comprises adminis DC, wherein R is hydroxyl. tering the topical formulation to the eyelid or eyelash of the 0459 DQ. The use according to example embodiment Subject. DC, wherein R is absent. 0435 DB. The method according to any one of example 0460 DR. The use according to example embodiment embodiments CP to CY, wherein the alopecia involves DC, herein Z is a saturated C. alkyl. eyebrow hair, and wherein said method comprises admin 0461 DS. The use according to example embodiment istering the topical formulation to the face or forehead or DR, wherein Z is CCH. eyebrow of the subject. 0462 DT. The use according to example embodiment 0436 DC. Use of at least one isolated Co-monoterpe DC, wherein Z is an unsaturated C-C alkyl. noid or isolated enantiomer thereof or an isolated ester 0463 DU. The use according to example embodiment thereof with a carboxylic acid in the preparation of a topical DT, wherein R is absent. medicament for the treatment or prevention of allopecia in a 0464 DV. The use according to example embodiment Subject, wherein the Co-monoterpenoid is of formula (I): DT, wherein R is hydroxyl. 0465 DW. The use according to example embodiment DT, wherein R is hydrogen. formula (I) 0466 DX. The use according to example embodiment R3 DT, wherein Z is CCH. 0467 DY. The use according to example embodiment x1N DT, wherein Z is CCHCH. 0468 DZ. The use according to example embodiment DT, wherein Z is CCHCHOCOCH. R. 0469 EA. The use according to example embodiment Z DZ, wherein the Co-monoterpenoid or enantiomer thereof 1 NR, is a non-hydroxylated compound. 0470 EB. The use according to example embodiment 0437 wherein: DC, wherein the Co-monoterpenoid or enantiomer thereof 0438 R is hydrogen, hydroxyl or oxygen; is a monohydroxylated compound, R is hydrogen, R is hydroxyl, X is CH, Y is CH, and Z is an unsaturated 0439 R is absent or hydrogen or hydroxyl; C-C alkyl. 0440 R is a CH: 0471 EC. The use according to example embodiment 0441 X is CH or CH-OH, or EB, wherein Z is CCHCH. 0442 X is CHCH, or CHOHCH, and X and Y 0472. ED. The use according to example embodiment together form a single bond within a 6-membered ring; DC, wherein the Co-monoterpenoid is a non-hydroxylated 0443 Y is CH, when X is CH or CH-OH, or compound wherein R is hydrogen, R is absent, X is CH, 0444 Y is CH or COH when X is CHCH or Y is CH, and Z is CCHCHOCOCH. CHOHCH, and 0473) EE. The use according to example embodiment 0445 Z is a saturated or unsaturated C. C. alkyl or DC, wherein the Co-monoterpenoid or enantiomer thereof alkyl ester. is a monohydroxylated compound, R is hydrogen or oxy 0446 DD. The use according to example embodiment gen, R is absent or hydrogen or hydroxyl. X is CHCH or DC, wherein the Co-monoterpenoid is a monohydroxylated CHOHCH, Y is CH or COH, and Z is a saturated or compound. unsaturated C. alkyl. 0447 DE. The use according to example embodiment 0474 EF. The use according to example embodiment EE, DC, wherein R is hydrogen. wherein R is oxygen, R is hydrogen or hydroxyl. X is 0448 DF. The use according to example embodiment CHCH. Y is CH, and Z is a saturated C. alkyl. DC, wherein R is oxygen. 0475 EG. The use according to example embodiment EF, 0449 DG. The use according to example embodiment wherein R is hydrogen. DC, wherein X is CH and Y is CH. 0476 EH. The use according to example embodiment 0450 DH. The use according to example embodiment EE, wherein R is hydrogen, R is hydrogen or hydroxyl. X DC, wherein X is CH-OH and Y is CH. is CHCH. Y is CH or COH, and Z is a saturated C. alkyl. 0451 DI. The use according to example embodiment DC, 0477 EI. The use according to example embodiment EH, wherein X is CHCH. wherein Y is CH. 0452 DJ. The use according to example embodiment 0478 E.J. The use according to example embodiment EI, DC, wherein X is CHOHCH. wherein R is hydroxyl. 0453 DK. The use according to example embodiment 0479 EK. The use according to example embodiment DI, wherein Y is CH. EH, wherein Y is COH. US 2016/0374979 A1 Dec. 29, 2016 30

0480 EL. The use according to example embodiment 0507 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1- EK, wherein R is hydrogen. one (-)-piperitone; 0481 EM. The use according to example embodiment 0508 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1- ED, wherein R, is absent, X is CHOHCH, Y is CH, and Z one (+)-piperitone; is an unsaturated C alkyl. 0509 (3S)-3,7-Dimethyl-1,6-octadien-3-ol (+)-Lina 0482 EN. The use according to example embodiment lool: DC, wherein the use comprises use of a Co-monoterpenoid 0510 (3R)-3,7-Dimethyl-1,6-octadien-3-ol (-)-Lina selected from the group consisting of: lool: 0483 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (ter 0511 (1R, 5R)-2-Methyl-5-(1-Methylethenyl)-2-cy pinen-4-ol); clohexen-1-ol (-)-cis-carveol: 0484 3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one 0512 (1S,5S)-2-Methyl-5-(1-methylethenyl)-2-cyclo (piperitone); hexen-1-ol (+)-cis-carveol; 0485 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanol (al 0513 (1R, 5S)-2-Methyl-5-(1-methylethenyl)-2-cy pha-terpineol); clohexen-1-ol (+)-trans-carveol; and 0486 2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- 0514 (1S, 5R)-2-Methyl-5-(1-methylethenyl)-2-cy ol (carveol): clohexen-1-ol (-)-trans-carveol. 0487 6-Isopropyl-3-methyl-2-cyclohexen-1-one 0515 EX. The use according to example embodiment (3-carvomenthenone); and EW, wherein the isolated enantiomer is selected from the 0488 3,7-Dimethyl-1,6-octadien-3-ol (linalool). group consisting of 0489 EO. The use according to example embodiment 0516 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol EN, wherein the Co-monoterpenoid is 1-Isopropyl-4- (-)-terpinen-4-ol; methyl-3-cyclohexen-1-ol (terpinen-4-ol). 0517 (1S)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol 0490 EP. The use according to example embodiment EN, (+)-terpinen-4-ol; wherein the Co-monoterpenoid is 3-Methyl-6-(propan-2- 0518 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1- yl)cyclohex-2-en-1-one (piperitone). one (-)-piperitone; 0491 EQ. The use according to example embodiment 0519 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1- DC, wherein the use comprises use of a carboxylic acid one (+)-piperitone; monoester of the Co-monoterpenoid. 0520 (1S, 5S)-2-Methyl-5(1-methylethenyl)-2-cyclo 0492 ER. The use according to example embodiment hexen-1-ol (+)-cis-carveol; and EQ, wherein the carboxylic acid monoester is a monoester 0521 (1R,5S)-2-Methyl-5-(1-methylethenyl)-2-cyclo with a carboxylic acid selected from acetic acid, propionic hexen-1-ol (+)-trans-carveol. acid and formic acid. 0522 EY. The use according to example embodiment 0493 ES. The use according to example embodiment ER, EX, wherein the isolated enantiomer is: wherein the carboxylic acid is acetic acid. 0523 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol 0494 ET. The use according to example embodiment (-)-terpinen-4-ol. EQ, wherein the Co-monoterpenoid carboxylic acid 0524 EV. The use according to example embodiment monoester is selected from the group consisting of EX, wherein the isolated enantiomer is: 0495 (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate 0525 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1- (geranyl acetate); one (-)-piperitone. 0496 3,7-Dimethyl-1,6-octadien-3-yl acetate (linallyl 0526 FA. The use according to example embodiment acetate); EX, wherein the isolated enantiomer is: 0497 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanyl 0527 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1- acetate (terpinyl acetate); and one (+)-piperitone. 0498 5-Isopropenyl-2-methyl-2-cyclohexen-1-yl 0528 FB. Use of an isolated Co-monoterpenoid or acetate (carvyl acetate). enantiomer thereof in the preparation of a topical medica 0499 EU. The use according to example embodiment ment for the treatment or prevention of allopecia in a Subject, ET, wherein the Co-monoterpenoid carboxylic acid wherein the isolated Co-monoterpenoid is 1-Isopropyl-4- monoester is selected from the group consisting of methyl-3-cyclohexen-1-ol (terpinen-4-ol). (0500 (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate 0529 F.C. Use of an isolated Co-monoterpenoid or (geranyl acetate); and enantiomer thereof in the preparation of a topical medica 0501 3,7-Dimethyl-1,6-octadien-3-yl acetate (linallyl ment for the treatment or prevention of allopecia in a Subject, acetate). wherein the isolated Co-monoterpenoid is 3-methyl-6-(pro 0502 EV. The use according to example embodiment pan-2-yl)cyclohex-2-en-1-one (piperitone). DC, wherein the use comprises use of an isolated enantiomer 0530 FD. The use according to example embodiment FB of the Co-monoterpenoid. or FC, wherein the topical medicament comprises (i) iso 0503 EW. The use according to example embodiment lated 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (terpinen-4- EV, wherein the isolated enantiomer is selected from the ol) or an isolated enantiomer and (ii) isolated 3-methyl-6- group consisting of (propan-2-yl)cyclohex-2-en-1-one (piperitone) or an 0504 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol isolated enantiomer thereof. (-)-terpinen-4-ol; 0531 FE. The use according to example embodiment FD, 0505 (1S)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol wherein: (+)-terpinen-4-ol; 0532 (i) the isolated enantiomer of terpinene-4-ol is: 0506. 2-(1R)-4-Methylcyclohex-3-en-1-yl)propan-2- 0533 (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol ol (+)-alpha-terpineol; (-)-terpinen-4-ol; and/or US 2016/0374979 A1 Dec. 29, 2016

0534 (ii) the isolated enantiomer of piperitone is: 0550 FS. The use according to any one of example 0535 (6R)-3-methyl-6-(propan-2-yl)cyclohex-2- embodiments DC to FR, wherein the subject has a genetic en-1-one (-)-piperitone or predisposition for alopecia or familial history of allopecia. 0536 (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2- 0551 FT. The use according to any one of example en-1-one (+)-piperitone. embodiments DC to FS, wherein the subject suffers from an 0537 FR The use according to any one of example existing alopecia. embodiments FB to FE, wherein the isolated 3-methyl-6- 0552 FU. The use according to any one of example (propan-2-yl)cyclohex-2-en-1-one (piperitone) or isolated embodiments DC to FS, wherein the alopecia is androgenic enantiomer thereof is in the form of an essential oil of alopecia. Eucalyptus dives or a perfume comprising said essential oil. 0553 FV. The use according to any one of example 0538 FG. The use according to any one of example embodiments DC to FS, wherein the alopecia is alopecia embodiment FC to FE, wherein the isolated 1-Isopropyl-4- areata. methyl-3-cyclohexen-1-ol (terpinen-4-ol) or isolated 0554 FW. The use according to any one of example enantiomer thereof is in the form of an essential oil from embodiments DC to FS, wherein the alopecia is an acute Eucalyptus dives or a perfume comprising said essential oil. form of allopecia. 0539 FH. The use according to any one of example 0555 FX. The use according to example embodiment embodiments DC to FE, wherein the Co-monoterpenoid or FW, wherein the acute form of allopecia is induced by an ester or enantiomer thereof is a natural product or derived acute event selected from pregnancy, stress, illness, treat from a natural product. ment with a cytotoxic agent, treatment with a cytostatic 0540 FI. The use according to example embodiment FH, agent, and treatment with an agent which induces necrosis or wherein the natural product is selected from a plant or part apoptosis of hair follicles as a side-effect of therapy. thereof, a plant extract, an essential oil and a perfume 0556 FY. The use according to any one of example comprising said essential oil. embodiments DC to FS, wherein the alopecia is alopecia 0541. F.J. The use according to any one of example induced by chemotherapy. embodiments DC to FE, wherein the Co-monoterpenoid or ester or enantiomer thereof is a synthetic compound. EXAMPLES 0542 FK. The use according to any one of example EXAMPLE 1. embodiments DC to FJ, wherein the use comprises use of at least two compounds selected from the Co-monoterpenoid Extraction of Essential Oil from Eucalyptus dives and/or ester and/or enantiomer thereof. by Steam Distillation 0543 FL. The use according to any one of example embodiments DC to FK, wherein the medicament comprises 0557. This example describes extraction of essential oils a total amount of Co-monoterpenoid or ester or enantiomer from Eucalyptus dives by Steam distillation and an exem thereof sufficient to reduce or inhibit FGF-5 activity in the plary chemical composition for an essential, oil of Eucalyp hair follicle or part thereof. tus dives as determined by gas chromatography. 054.4 FM. The use according to any one of example 0558 Fresh Eucalyptus dives foliage is separated from a embodiments DC to FK, wherein the medicament comprises Eucalyptus dives plant and introduced into a distilling cham a total amount of Co-monoterpenoid or ester or enantiomer ber through which steam is to be passed. The distilling thereof sufficient to reduce or inhibit FGF-5 binding to a chamber is configured to Support the Eucalyptus dives cognate fibroblast growth factor receptor (FGFR) in the hair foliage in a manner which exposes the leaves to steam when follicle or part thereof. passed through the chamber. Steam is then generated with a 0545 FN. The use according to example embodiment temperature between 100-105° C. e.g., in a boiler, and FM, wherein the cognate FGFR is FGFR1. passed through the distilling chamber containing the Euca lyptus dives leaves. As the steam contacts the leaves, the 0546 FO. The use according to example embodiment cells and vesicles containing essential oils are disrupted and FM or FN, wherein a reduction in FGF-5 binding is deter the essential oils are released in the form of vapour. The mined by a reduction in viability of a BaF3 cell expressing vapour flow of essential oil and steam is directed to a fibroblast growth factor receptor 1 (FGFR1) wherein said condenser unit in which the vapour is condensed e.g., by a BaF3 cell is dependent on FGF-5 signalling for viability. water cooled jacket Surrounding the condenser unit, to form 0547 FP. The use according to any one of example a liquid distillate having an aqueous phase and an oil phase. embodiments DC to FO, wherein the medicament comprises The liquid distillate is directed into a collection vessel and a topical carrier, excipient or emollient. the essential oil (oil phase) is separated from the hydrosol or 0548 FQ. The use according to any one of example aqueous portion (aqueous phase) according to the relative embodiments DC to FP, wherein the medicament comprises specific densities. The essential oil obtained from the steam one or more adjunctive agents effective for treatment or distillation of Eucalyptus dives is collected and used in prevention of hair loss. accordance with the invention. 0549 FR. The use according to example embodiment 0559 An essential oil extracted from Eucalyptus dives by FQ, wherein the one or more adjunctive agents is/are steam distillation as described supra may be tested for selected from the group consisting of estradiol, Oxandrolone, chemical composition by gas chromatography e.g., to deter minoxidil, Sanguisorba officinalis root extract, Rosa multi mine its suitability for use in the present invention. An flora extract, Brown algae extract, loquat leaf extract, Pecan exemplary chromatographic analysis for an essential oil of shell extract, squill extract, Sodium phytate, Fucus vesicu Eucalyptus dives showing a typical chemical composition losus extract, phytic acid, nonanal, and Lipidure-C. thereof is presented below. US 2016/0374979 A1 Dec. 29, 2016 32

Typical Profile of Major Chemical Constituents of were maintained in RPMI RPMI-1640 with 10% FBS and Essential of from Eucalyptus dives 1.3x10'7 M of murine IL-3 (Sigma, St Louis, Mich.) containing antibiotic G418 sulfate (Promega, Medison, 0560 Wis.). The inventors compared proliferation of FR/BaF3 cells in culture medium containing IL3 or FGF-5 and a different concentration in the range from 0.005% (w/v) to Chemical constituent Amount (w/v) 1.0% (w/v) of each test compound listed in Example 1. The Piperitone 39-55% FR-BaF3 cells were seeded at 5x10"/mL cells per well in 1.8 cineole trace C-phellandrane 15-25% 96-well, micro-culture plates (Falcon) in RPMI-1640 culture 3-phellandrane 1-4% medium containing 10% fetal bovine serum, 5 g/mL hepa Globulol 2-6% rin. Recombinant human FGF-5 (rhFGF-5; 1 ug/mL) was Terpinene-4-ol 3-5% added to one group, and IL-3 (0.2 ng/mL) (Sigma) was para-cymene O.1-10% C-pinene O. 1-2% added to another group. The test compounds were then 8-terpinene O.S.-3.5% introduced to the micro-culture plate wells. Total volume of limonene trace media per well was 100 ul. Control groups lacking test compound were also prepared for each of the IL-3-supple mented and FGF-5-supplemented samples. The plates were EXAMPLE2 then incubated at 37° C. in 5% CO, for 3 days. 0566. After 3 days, colorimetric assays were performed Test Compounds using a Cell Counting Kit-8 (CCK-8) (Wako) according to 0561. This example demonstrates availability of exem the manufacturers instructions to measure cell proliferation plary isolated monoterpenoid compounds tested for Suitabil or Suppression thereof by the test compound at varying ity in performing the invention. concentrations. Briefly, 10 ul (1:2 dilution) of the CCK-8 0562 Test compounds were all commercially available. reagent was added to each micro-culture plate well after which time the plates were incubated at 7° C. for 3 hours. However, compounds derived from natural sources that are Absorbance at 450 nm was then measured using a m a Substantially-purified form are also contemplated. microplate reader. Cell viability and proliferation for the IL-3-supplemented and FGF-5-Supplemented groups was Test Compound Source calculated as a measure of the optical density (OD) of cells treated with a test compound relative to the OD of the Linallyl acetate Tokyo Chemical Industry respective untreated controls, excluding the OD of blank Nonanal Tokyo Chemical Industry Linalool Tokyo Chemical Industry controls (media only). Dose response curves were plotted Geranyl acetate Tokyo Chemical Industry and the respective inhibitory concentrations (IC50) for the C-Terpineol Tokyo Chemical Industry test compounds were determined. 1-Carveol Tokyo Chemical industry (-)-Terpinen-4-ol Tokyo Chemical Industry 0567 Suppression of FGF-5-dependent cell proliferation (+)-Terpinen-4-ol Tokyo Chemical Industry and viability was observed in FR-BaF3 cells to which (+)-Terpinen-4-ol (+) 50%, (-) 50% Tokyo Chemical Industry (-)-terpinen-4-ol, (+)-terpinen-4-ol, C-terpineol, linallyl Nerol Tokyo Chemical Industry (-)-Menthol Tokyo Chemical Industry acetate, geranyl acetate, linalool and 1-carveol were added beta-Citronellol Tokyo Chemical Industry (data presented m FIGS. 1(a)-1(h)). ICs values for each Geraniol Tokyo Chemical Industry compound are presented in Table 2. Piperitone ((-)-Piperitone) Tokyo Chemical Industry TABLE 2 Inhibitory activity of test compounds on FGF-5-dependent EXAMPLE3 cell proliferation Effect of Test Compounds on FGF-5 Signalling ICso (% FGF-5 Specificity 0563 This example demonstrates the preparation and use Test Compound FGF-5 IL-3 IL-1 FGF-5 of a transgenic FR-Ba/F3 cell line for identifying com Linallyl acetate 0.4 O.9 2.25 pounds of the invention having FGF-5 modulatory activity. Nonanal O.1 O.9 9 0564 Ba/F3 is a murine interleukin-3 (IL-3)-dependent Linalool <0.03 O.9 30> (BR) pro-B cell line. IL3-independent Ba/F3 clones expressing Geranyl acetate O.1 O.8 8 (BR) C-Terpineol -0.01 O.OS 5> FGFR-1 or FGFR-1c on their cell surface and exhibiting I-Carveol O.OS O.1 2 FGF-5-dependent proliferation (e.g., Smedley at al., Neo (-)-4-Terpinen-4-ol O.S >1.0 2> plasia, 1: 349-355, 1999: Demiroglu et al., Blood, 98: (+)-4-Terpinen-4-ol O.11 >1.0 9.1 - 3778-3783, 2001; Ito et al., Journal of Cellular Physiology, Piperitone O.O24 O.S9 25 (+)-4-Terpinen-4-ol NT NT NT 197: 273-283, 2003), were employed to assay compounds Nerol 1.O- 1.O- ND for their ability to inhibit FGF-5 activity. That is, compounds (-)-Menthol 1.O- 1.O- ND were tested for their ability to modulate proliferation of beta-Citronellol 1.O- 1.O- ND FR-Ba/F3 cells in the presence of recombinant human Geraniol 1.O- 1.O- ND FGF-5 (rhFGF-5) prepared according to Maeda et al., Nishi BR: less reproducible Nihon Hifuka, 69(1): 81-86, 2007. ND; not determined, 0565 Briefly, a suitable plasmid expressing FGFR-1c NT: not tested. was introduced into human ER-Ba? E3 cells, and the cells US 2016/0374979 A1 Dec. 29, 2016 33

0568. From this result, the following test compounds cells from the cell culture dish. Approximately 5x10 of the were considered as potent FGF-5-inhibitory active sub dissociated cells were resuspended in 500 ml of assay Stances: medium containing 445 ml of DMEM medium, 50 ml of 0569. Linallyl acetate 10% fetal calf serum and 5 ml of antibiotic. 0570. Nonanal 0580 Aliquots of the cell suspension were transferred to (0571 C-Terpineol the wells of cell culture dishes, and a single monoterpenoid 0572 (-)-4-Terpinen-4-ol listed in Example 1 e.g., (-)-4-terpinen-4-ol, (+)-4-terpinen 0573 (+)-4-Terpinen-4-ol 4-ol. (+)-4-terpinen-4-ol, C-terpineol, nonanal, linallyl acetate or piperitone, is added to each well at a concentration (0574 Piperitone, of 0.005 (mg/ml) or 0.01 (mg/ml) or 0.05 (mg/ml) or 0.1 (0575 (+)-4-Terpinen-4-ol. (mg/ml) or 0.5 (mg/ml). Cell Suspensions were transferred to wells of a further cell culture dish to which minoxidil was EXAMPLE4 then added at a concentration of 0.005 (mg/ml) or 0.01 (mg/ml) or 0.05 (mg/ml) or 0.1 (mg/ml) or 0.5 (mg/ml). A Effect of Test Compounds on Proliferation of DP Wnt/B-catenin pathway activation agent e.g., Wnt3a or Cells as Determined by Alkaline Phosphatase GSK-3. Inhibitor IX, as added to each of the cell cultures to (ALP) Activity produce an “activated cell culture'. Control cell cultures 0576. This example demonstrates the use of an alkaline containing the same monoterpenoid compound or minox phosphatase (ALP) activity assay for identifying compounds odil, but lacking the Wnt/B-cinenin pathway activation of the invention having the ability to modulate proliferation agent, were processed in parallel. These activated and con of dermal papillae (DP) cells, and preferably modulate trol cell cultures were divided further into duplicate cell anagen phase of the cell cycle thereof. culture samples either lacking FGF-5 or to which recombi 0577. Dermal papilla cells were prepared according to the nant human FGF-5 (rhFGF-5; 1 g/mL)) was added. Table methods described in WO2013/105417, Briefly, hairs were 3 illustrates the cell culture and sample design matrix as pulled from the scalp of a healthy subject (32 year old male) herein described. showing normal non-alopecia hair growth using tweezers. 0581. The cell culture samples were each cultured at 37° Hair follicles with dermal papilla were thus obtained at a rate C. for 3 days under atmosphere containing less than 5% of approximately one for every 100 hairs pulled. The hair CO. Colorimetric assays were performed using a Cell follicles with dermal papilla were separated from the hair Counting Kit-8 (CCK-8) according to the manufacturers using tweezers and transferred into a saline for inspection instructions to measure cell proliferation of the DP cells. An under a microscope. Under a microscope, each dermal assay control contained cell culture media in the absence of papilla was isolated from a respective hair follicle using DP cells (“medium background'). Absorbances (450 nm) for tweezers and a scalpel. Approximately 2000 isolated dermal each activated cell culture sample and the corresponding papilla cells were then transferred to a 35 mm cell culture control cell culture sample were determined using a dish together 1-2 ml of cell culture medium, after which time microplate reader, and the relative absorbance of each acti the cells were cultured at 37° C. to produce a primary cell vated cell culture sample was determined by the following culture of dermal papilla. The cell culture medium consisted ratio: of approximately 90% DMEM medium, 10% fetal bovine serum (final concentration: 10%), FGF2 (final, concentra tion: 10 ng/ml), and penicillin-streptornycin Solution (final (A450 nmactivated cell culture - A450 nm nedium backround) concentration: 1 g/ml) for every 2 mL of medium. Cell (A450 nmcontrol cell culture - A450 nmmedium backround) culture conditions were maintained for more than 14 days until dermal papilla cells covered approximately 40% of the 0582 Each activated cell culture sample and each control area of the 35 mm culture dish, at which time subcultures cell culture sample was then washed twice in Saline at room were performed. To prepare the subcultures, the cell culture temperature. The cells were lysed by freeze-thawing medium was removed from the 35 mm culture dish and the employing three freeze-thaw cycles. In each freeze-thaw adherent cells were washed once with 2 ml of saline (at room cycle, the cell suspension was frozen for 5 minutes at -80° temperature). 1 ml Trypsin-EDTA solution (0.1% trypsin C. and thawed by incubating cells for 5 minutes at room and 0.02% EDTA) was then added to the 35 mm culture dish temperature. To the lysed cells, p-nitrophenyl phosphate 1 and left to stand for 4 minutes at 37° C. Dissociated dermal mg/ml) in 1M diethanolamine buffer solution was added, papilla cells were then recovered from the 35 mm dish, and and each lysate was incubated at 37°C. for 30 minutes. The seeded to a new 100 mm dish, and cultured in media under relative absorbance (490 nm) of each activated cell culture the same conditions as for the primary cell culture described sample to each corresponding control cell sample was above. determined as a relative measure of alkaline phosphatase 0578. When the dermal papilla cells covered approxi (ALP) activity. Similar readings were obtained for p-nitro mately 70-80% of the area of each 100 mm culture dish, the phenyl phosphate (1 mg/ml) in 1M diethanolamine buffer sub-confluent cells were subcultured as before. The process solution lacking DP cells (“buffer background'). was repeated until sufficient cells were obtained to screen 0583 ALP activity was determined by the following compounds of interest. ratio: 0579. Once sufficient DP cells were obtained, the cells were harvested to provide a cell suspension. To harvest the DP cells, the cell culture medium was removed from the (A490 nmactivated cell culture - A490 nmbuffer backround) culture dish, and the adherent cells were washed with saline (A490 nmcontrol cell culture - A490 nmbuffer backround) at room temperature. Trypsin-EDTA solution was then added under conditions described Supra to dissociate the US 2016/0374979 A1 Dec. 29, 2016 34

0584) Table 3 demonstrates sample design for the DP as by preventing and/or delaying and/or reducing premature ALP assay described in the preceding paragraphs: onset of catagen in the hair follicle, and even extending the TABLE 3 Sample matrix for DP-ALP assays “FGF-5 group DP cell “FGF-5-free group DP cell culture + GSK3 inhibitor DX+. FGFS culture + GSK3 inhibitor IX Test compound Approx. concentration (mg/ml) Approx. concentration (mg/ml) Linallyl acetate control 0.005 0.01 0.05 0.1 0.5 control 0.005 Nonanal control 0.005 0.01 0.05 0.1 0.5 control 0.005 C-Terpeneol control 0.005 0.01 0.05 0.1 0.5 control 0.005 (-)-Terpinen-4-ol control 0.005 0.01 0.05 0.1 0.5 control 0.005 (+)-Terpinen-4-ol control 0.005 0.01 0.05 0.1 0.5 control 0.005 (+)-Terpinen-4-ol control 0.005 0.01 0.05 0.1 0.5 control 0.005 Piperitone control 0.005 0.01 0.05 0.1 0.5 control 0.005 Minoxidi control 0.005 0.01 0.05 0.1 0.5 control 0.005

0585 ALP activity was plotted as a function of the anagen phase of the hair follicle thereby prolonging hair concentration of each test compound in the presence and growth. Such compounds are also effective for treatment of absence of rhFGF-5 (FIGS. 2a, 3a, 4a, 5a, 6a, 7a, 8a and alopecia. 9a). Normalised dose response curves were also obtained showing relative change in ALP activity following addition, EXAMPLE 5 of the respective test compounds at different doses in the presence and absence of FGF-5 (FIGS. 2b, 3b, 4b, 5b, 6b, Compound Formulations 7b, 8b and 9b). Data indicate that the test compounds Piperitone, (-)-terpinen-4-ol, (t)-terpinen-4-ol, C-terpineol. 0591. This example describes formulation of monoterpe and (+)-terpinen-4-ol each increased relative ALP activity of noids for use in performing the invention. DP cells treated FGF-5. Taken together with data from 0592 One or more test compound(s) identified in Example 2 hereof, this induced increase in ALP activity Example 2 and/or Example 3 is/are formulated with a topical suggests that the respective test compounds inhibit FGF-5- carrier e.g., as described in Remington's Pharmaceutical dependent signalling and extend the anagen phase of the DP Sciences, 21th Ed. Philadelphia, Pa...: Lippincott Williams & cell cycle and/or prevent DP cells from entering catagen. In Wilkins, 2005, to produce a non-therapeutic topical formu contrast, minoxidil showed a poor ability to increase relative lation for treatment or prevention of hair loss or a non ALP activity in DP cells treated FGF-5 suggesting that therapeutic topical formulation for treatment of allopecia. minoxidil is a poor inhibitor of FGF-5-dependent signalling 0593. The topical formulation may contain the test com in DP cells. pounds) in any dose Suitable for reducing and/or delaying 0586. The FGF-5-inhibitory activity of the test com and/or treating and/or preventing hair loss or hair thinning pounds, from most active to least active, as determined by e.g., as determined by testing in an animal model described DP-ALP assay, may be ranked as follows: herein. 0587 Most Active Least Active 0594. In one example, the topical formulation contains Piperitone-(-)-terpinen-4-old-(+)-Terpinen-4?-Terpineold the test compound in a dose of about 0.01% by weight of (+)-Terpinen-4-ol D Linallyl Acetate active compound per unit volume of topical formulation 0588. The inventors then repeated the DP-ALP assay (w/v) or by volume of oil or perfume per unit volume of the described Supra employing Eucalyptus dives essential oil topical formulation (v/v). In one example, the topical for eXtract. mulation contains the test compound in a dose of about 0.1% 0589 ALP activity of DP cells treated with Eucalyptus by weight of active compound per unit volume of topical dives extract was plotted as a function of the concentration formulation (w/v) or by volume of oil or perfume per unit in the presence and absence of rhFGF-5 (FIG. 10a). A volume of the topical formulation (v/v). In another example, normalised dose response curve was also obtained showing, the topical formulation contains the test compound in a dose relative change in ALP activity following addition of Euca of about 0.5% by weight of active compound per unit lyptus dives extract at different doses in the presence and volume of topical formulation (w/v) or by volume of oil or absence of FGF-5 (FIG. 10b). The data indicate that Euca perfume per unit volume of the topical formulation (v/v). In lyptus dives extract increased relative ALP activity of DP another example, the topical formulation contains the test cells treated FGF-5, Suggesting that Eucalyptus dives extract compound in a dose of about 1.0% by weight of active is able to inhibit FGF-5-dependent signalling and extend the compound per unit volume of topical formulation (w/v) or anagen phase of the DP cell cycle and/or prevent DP cells by volume of oil or perfume per unit volume of the topical from entering catagen. formulation (V/v). In another example, the topical formula 0590 Test compounds, and extracts comprising same, tion contains the test compound in a dose of about 2.0% by which have been shown herein to increase and/or restore weight of active compound per unit volume of topical ALP activity in DP cells treated with FGF-5 and inhibit formulation (w/v) or by volume of oil or perfume per unit FGF-5-signalling in DP cells are considered by the inventors volume of the topical, formulation (v/v). In another to be effective for reducing hair loss and/or hair thinning example, the topical formulation contains the test compound associated with FGF-5 signalling in the dermal papilla, Such in a dose of about 3.0% by weight of active compound per US 2016/0374979 A1 Dec. 29, 2016 35 unit volume of topical formulation (w/v) or by volume of oil ate, polysorbate 80, PEG-5 stearate dimethicone, laureth-2, or perfume per unit volume of the topical formulation (v/v). citric acid, sodium citrate, butylene glycol, laureth-20, meth 0595. The topical formulation may additionally contain ylparaben, propylparaben, sodium salicylate, alcohol (etha one or more other agents effective for reducing and/or nol), and fragrances. delaying and/or treating and/or preventing hair loss or hair thinning i.e., one or more “adjunctive agents'. For example, EXAMPLE 7 a topical formulation may contain a primary agent identified in Example 2 and/or Example 3 as being capable of inhib Shampoo Formulation Comprising iting FGF-5-signalling and/or binding FGF-5 and optionally (+)-Terpinen-4-ol any one or more of the adjunctive agents as illustrated in 0598. This example describes a shampoo formulation Table 4. comprising (t)-terpinen-4-ol. TABLE 4 Combinations of active agents for inclusion in topical formulations Primary Agent Linallyl Geranyl 1- (+)- acetate Linalool acetate C-Terpineol Carveol (-)-Terpineol (+)-Terpineol Terpineol Piperitone

Adjunctive Linallyl acetate ------agent Linalool ------added Geranyl acetate ------individually C-Terpineol ------O 1-Carveol ------collectively (-)-Terpinen-4-ol ------to (+)-Terpinen-4-ol ------primary (+)-Terpinen-4-ol ------agent Piperitone ------Nerol ------(-)-Menthol ------beta-Citronellol ------Geraniol Estradiol ------Oxandrolone ------Minoxidi ------Sanguisorba officinalis ------root extract Rosa multiflora extract ------Brown algae extract ------Loquat leaf extract ------Pecan shell extract ------Squill extract ------Sodium phytate ------Fictis vesiculosis extract ------Phytic acid ------Nonanal ------Lipidure-C ------Swertia japonica extract ------

EXAMPLE 6 0599 An exemplary shampoo for use in accordance with the invention comprises (t)-terpinen-4-ol, in a Substantially Shampoo Formulation Comprising (-)-terpinen-4-ol pure form or as a constituent of an essential oil Such as from 0596. This example describes a shampoo formulation tea tree or Sweet marjoram, as an active ingredient to inhibit comprising (-)-terpinen-4-ol. FGF-5-dependent signalling in a hair follicle or part thereof. An exemplary shampoo comprising (t)-terpinen-4-ol may 0597 An exemplary shampoo for use in accordance with the invention comprises (-)-terpinen-4-ol, in a Substantially also comprise one or more of the following additional pure form or as a constituent of an essential oil Such as E. ingredients: purified water, Sodium laureth Sulfate, lauryl dives, as an active ingredient to inhibit FGF-5-dependent betaine, dipropylene glycol, lauramide DEA, glycol distear signalling in a hair follicle or part thereof. An exemplary ate, Sanguisorba officinalis root extract, Rosa multiflora fruit shampoo comprising (-)-terpinen-4-ol may also comprise extract, Swertia japonica extract, chlorella Vulgaris extract, one or more of the following additional ingredients: purified Moringa pterygosperma seed extract, Eucalyptus globulus water, Sodium laureth Sulfate, lauryl betaine, dipropylene leaf extract, polyduaternium-64, polyduaternium-51, glycol, lauramide DEA, glycol distearate, Sanguisorba offi Sodium lauroyl methylalanine, glycerol, polyduaternium-10 cinalis root extract, Rosa multiflora fruit extract, Swertia japonica extract, chlorella Vulgaris extract, Moringa ptery sorbitan stearate, polysorbate 80, PEG -5 stearate, dimethi gosperma seed extract, Eucalyptus globulus leaf extract, cone, laureth-2, citric acid, Sodium citrate, butylene glycol, polyduaternium-64, polyduaternium-51 Sodium lauroyl laureth-20, methylparaben, propylparaben, Sodium salicy methylalanine glycerol, polyduaternium-10, Sorbitan Stear late, alcohol (ethanol), and fragrances. US 2016/0374979 A1 Dec. 29, 2016 36

EXAMPLE 8 chary sage, as an active ingredient to inhibit FGF-5-depen dent signalling in a hair follicle or part thereof. An exem Shampoo Formulation Comprising C-Terpineol plary shampoo comprising linallyl acetate may also comprise one or more of the following additional ingredients: purified 0600 This example describes a shampoo formulation water, Sodium laureth Sulfate, lauryl betaine, dipropylene comprising C-Terpineol. glycol, lauramide DEA, glycol distearate, Sanguisorba offi 0601. An exemplary shampoo for use in accordance with cinalis root extract, Rosa multiflora fruit extract, Swertia the invention comprises C-Terpineol, in a Substantially pure japonica extract, chlorella Vulgaris extract, Moringa ptery form or as a constituent of an essential oil such as from gosperma seed extract, Eucalyptus globulus leaf extract, Anthemis altissima or clary Sage or lavandin, as an active polyduaternium-64, polyduaternium-51, sodium lauroyl ingredient to inhibit FGF-5-dependent signalling in a hair methylalanine, glycerol, polyduaternium-10, Sorbitan Stear follicle or part thereof. An exemplary shampoo comprising ate, polysorbate 80, PEG-5 stearate, dimethicone, laureth-2, (C)-Terpineol may also comprise one or more of the fol citric acid, sodium citrate, butylene glycol, laureth-20, meth lowing additional ingredients: purified water, Sodium laureth ylparaben, propylparaben, sodium salicylate, alcohol (etha Sulfate, lauryl betaine, dipropylene glycol, lauramide DEA, nol), and fragrances. glycol distearate, Sanguisorba officinalis root extract, Rosa multiflora fruit extract, Swertia japonica extract, chlorella EXAMPLE 11 Vulgaris extract, Moringa pterygosperma seed extract, Eucalyptus globulus leaf extract, polyduaternium-64, poly Shampoo Formulation Comprising Linalool quaternium-51, Sodium lauroyl methylalanine, glycerol, polyduaternium-10, Sorbitan Stearate, polysorbate 80, 0606. This example describes a shampoo formulation PEG-5 stearate, dimethicone, laureth-2, citric acid, sodium comprising linalool. citrate, butylene glycol, laureth-20, methylparaben, propyl 0607 An exemplary shampoo for use in accordance with paraben, Sodium salicylate, alcohol (ethanol), and fra the invention comprises linalool, in a Substantially pure form grances. or as a constituent of an essential oil such as from marjoram or lavender or bergamotor Pelargonium geranium, or neroli, EXAMPLE 9 as an active ingredient to inhibit FGF-5-dependent signal ling in a hair follicle or part thereof. An exemplary shampoo Shampoo Formulation Comprising comprising linallyl acetate may also comprise one or more of (+)-Terpinen-4-ol the following additional ingredients: purified water, sodium laureth Sulfate, lauryl betaine, dipropylene glycol lauramide 0602. This example describes a shampoo formulation DEA, glycol distearate, Sanguisorba officinalis root extract, comprising (+)-terpinen-4-ol. Rosa multiflora fruit extract, Swertia japonica extract, chlo rella Vulgaris extract, Moringa pterygosperma seed extract, 0603 An exemplary shampoo for use in accordance with Eucalyptus globulus leaf extract, polyduaternium-64, poly the invention comprises (+)-terpinen-4-ol, in a Substantially quaternium-51, Sodium lauroyl methylalanine, glycerol, pure form or as a constituent of an essential oil Such as from polyduaternium-10, Sorbitan Stearate, polysorbate 80, tea tree or marjoram or lavender, as an active ingredient to inhibit FGF-5-dependent signalling in a hair follicle or part PEG-5 stearate, dimethicone, laureth-2, citric acid, sodium thereof. An exemplary shampoo comprising (+)-terpinen-4- citrate, butylene glycol, laureth-20 methylparaben, propyl ol may also comprise one or more of the following addi paraben, Sodium salicylate, alcohol (ethanol), and fra tional ingredients: purified water, Sodium laureth Sulfate, grances. lauryl betaine, dipropylene glycol, lauramide DEA, glycol distearate, Sanguisorba officinalis root extract, Rosa multi EXAMPLE 12 flora fruit extract, Swertia japonica extract, chlorella Vul garis extract, Moringa pterygosperma seed extract, Euca Shampoo Formulation Comprising Geranyl Acetate lyptus globulus leaf extract, polyduaternium-64. polyduaternium-51, Sodium lauroyl methylalanine, glycerol, 0608. This example describes a shampoo formulation polyduaternium-10, Sorbitan Stearate, polysorbate 80. comprising geranyl acetate. PEG-5 stearate, dimethicone, laureth-2, citric acid, sodium 0609. An exemplary shampoo for use in accordance with citrate, butylene glycol, laureth-20, methylparaben, propyl the invention comprises geranyl acetate, in a Substantially paraben, Sodium salicylate, alcohol (ethanol), and fra pure form or as a constituent of an essential oil Such as from grances. carrot seed or citronella or palmarosa, as an active ingredient to inhibit FGF-5-dependent signalling in a hair follicle or part thereof. An exemplary shampoo comprising geranyl EXAMPLE 10 acetate may also comprise one or more of the following additional ingredients: purified water, Sodium laureth Sul Shampoo Formulation Comprising Linallyl Acetate fate, lauryl betaine, dipropylene glycol, lauramide DEA, glycol distearate, Sanguisorba officinalis root extract, Rosa 0604. This example describes a shampoo formulation multiflora fruit extract, Swertia japonica extract, chlorella comprising linallyl acetate. Vulgaris extract, Moringa pterygosperma seed extract, 0605 An exemplary shampoo for use in accordance with Eucalyptus globulus leaf extract, polyduaternium-64, poly the invention comprises linallyl acetate, in a Substantially quaternium-51, Sodium lauroyl methylalanine, glycerol pure form or as a constituent of an essential oil Such as from polyduaternium-10, Sorbitan Stearate, polysorbate 80, bergamot or lavender or marjoram or lavandin or thyme or PEG-5 stearate, dimethicone, laureth-2, citric Kid, sodium US 2016/0374979 A1 Dec. 29, 2016 37 citrate, butylene glycol, laureth-20, methylparaben, propyl exemplary tonic may also comprise one or more of the paraben, Sodium salicylate, alcohol (ethanol), and fra following additional ingredients: purified water, ethanol, grances. butylene glycol, panthenyl ethyl ether, Swertia japonica (or Swertia chirata) extract, glycyrrhetinic acid, citric acid, EXAMPLE 13 Sodium citrate, maltodextrin, Ginkgo biloba extract, Erio botrya japonica leaf extract, Poterium officinale root extract Shampoo Formulation Comprising 1-carveol and Rosa multiflora fruit extract. 0610 This example describes a shampoo formulation 0.617 For example, an exemplary tonic formulation of comprising 1-carveol. the invention comprises (-)-terpinen-4-ol, purified water, 0611. An exemplary shampoo for use in accordance with ethanol, butylene glycol, Poterium officinale root extract, the invention comprises 1-carveol, Rosa multiflora fruit extract, panthenol ethyl ether, Swertia 0612 M a substantially pure form or as a constituent of japonica (or Swertia chirata) extract, glycyrrhetinic acid, an essential oil such as from spearmint or caraway seed, as citric acid, Sodium citrate, and maltodextrin, wherein the an active ingredient to inhibit FGF-5-dependent signalling in (-)-terpinen-4-ol is present in an amount between 0.01-3.0% a hair follicle or part thereof. An exemplary shampoo or 0.01-0.3% by weight of active compound per unit volume comprising 1-carveol may also comprise one or more of the of topical formulation (w/v) or by volume of essential oil per following additional ingredients: purified water, sodium unit volume of the topical formulation (v/v). laureth Sulfate, laurel betaine, dipropylene glycol, lauramide 0618. For example, a formulation comprising both (-)- DEA, glycol distearate, Sanguisorba officinalis root extract, terpinen-4-ol and piperitone in Suitable concentration ranges Rosa multiflora fruit extract, Swertia japonica extract, chlo is prepared as a dilution of the essential oil from E. dives in rella Vulgaris extract, Moringa pterygosperma seed extract, a dilution range from about 1:10,000 (v/v) to about 1:33 Eucalyptus globulus leaf extract, polyduaternium-64, poly (v/v), including 1:1,000 (v/v) or 1:500 (v/v) or 1:100 (v/v) quaternium-51, Sodium lauroyl methylalanine, glycerol, or 1:50 (v/v). polyduaternium-10, Sorbitan Stearate, polysorbate 80, EXAMPLE 16 PEG-5 stearate, dimethicone, laureth-2, citric acid, sodium citrate, butylene glycol, laureth-20, methylparaben, propyl Tonic Formulation Comprising (E)-Terpinen-4-ol paraben, sodium salicylate alcohol (ethanol), and fragrances. 0619. This example describes a tonic formulation com EXAMPLE 1.4 prising (t)-terpinen-4-ol. 0620. An exemplary tonic for use in accordance with the Shampoo Formulation Comprising Piperitone invention comprises (E)-terpinen-4-ol, in a Substantially pure form or as a constituent of an essential oil Such as from 0613. This example describes a shampoo formulation lavender or other suitable source shown in Table 1, as an comprising piperitone. active ingredient to inhibit FGF-5-dependent signalling in a 0614. An exemplary shampoo for use in accordance with hair follicle or part thereof. An exemplary tonic formulation the invention comprises piperitone, in a Substantially pure may also comprise one or more of the following additional form or as a constituent of an essential oil such as from ingredients purified water, ethanol, butylene glycol, panthe Eucalyptus dives or lemon grass or mint, as an active nyl ethyl ether, Swertia japonica (or Swertia chirata)extract, ingredient to inhibit FGF-5'-dependent signalling in a hair glycyrrhetinic acid, citric acid, sodium, citrate, maltodextrin, follicle or part thereof. An exemplary shampoo comprising Ginkgo biloba extract, Eriobotrya japonica leaf extract, piperitone may also comprise one or more of the following Poterium officinale root extract and Rosa multiflora fruit additional ingredients: purified water, Sodium laureth Sul eXtract. fate, lauryl betaine, dipropylene glycol, lauramide DEA, 0621 For example, an exemplary tonic formulation of glycol distearate, Sanguisorba officinalis root extract, Rosa the invention comprises (E)-terpinen-4-ol, purified water, multiflora fruit extract, Swertia japonica extract, chlorella ethanol, butylene glycol, Poterium officinale root extract, Vulgaris extract, Moringa pterygosperma seed extract, Rosa multiflora fruit extract, panthenyl ethyl ether, Swertia Eucalyptus globulus leaf extract, polyduaternium-64, poly japonica (or Swertia chirata) extract, glycyrrhetinic acid, quaternium-51, Sodium lauroyl methylalanine, glycerol, citric acid, Sodium citrate, and maltodextrin, wherein the polyduaternium-10, Sorbitan Stearate, polysorbate 80, (+)-terpinen-4-ol is present in an amount between 0.01-3.0% PEG-5 stearate, dimethicone, laureth-2, citric acid, sodium or 0.01-0.3% by weight of active compound per unit volume citrate, butylene glycol, laureth-20, methylparaben, propyl of topical formulation (w/v) or by volume of essential oil per paraben, Sodium salicylate, alcohol (ethanol), and fra unit volume of the topical formulation (v/v). grances. EXAMPLE 17 EXAMPLE 1.5 Tonic Formulation Comprising C-Terpineol Took Formulation Comprising (-)-Terpinen-4-ol 0622. This example describes a tonic formulation com 0615. This example describes a tonic formulation com prising C-Terpineol. prising (-)-terpinen-4-ol. 0623. An exemplary tonic for use in accordance with the 0616. An exemplary tonic for use in accordance with the invention comprises C-Terpineol, in a Substantially pure invention comprises (-)-terpinen-4-ol, in a Substantially form or as a constituent of an essential oil Such as from clary pure form or as a constituent of an essential oil Such as from sage or other Suitable source shown in Table 1, as an active Eucalyptus dives, as an active ingredient to inhibit FGF-5- ingredient to inhibit FGF-5-dependent signalling in a hair dependent signalling in a hair follicle or part thereof. An follicle or part thereof. An exemplary tonic formulation may US 2016/0374979 A1 Dec. 29, 2016 also comprise one or more of the following additional Ginkgo biloba extract, Eriobotrya japonica leaf extract, ingredients: purified water, ethanol, butylene glycol, pan Poterium officinale root extract and Rosa multiflora fruit thenyl ethyl ether, Swertia japonica (or Swertia chirata) eXtract. extract, glycyrrhetinic acid, citric acid, sodium citrate, 0630. For example, an exemplary tonic formulation of maltodextrin, Ginkgo biloba extract, Eriobotrya japonica the invention comprises linallyl acetate, purified water, etha leaf extract, Poterium officinale root extract and Rosa mul nol, butylene glycol, Poterium officinale root extract, Rosa tiflora fruit extract. multiflora fruit extract, panthenyl ethyl ether, Swertia 0624 For example, an exemplary tonic formulation of japonica (or Swertia chirata) extract, glycyrrhetinic acid, the invention comprises (C)-Terpineol, purified water, etha citric acid, Sodium citrate, and maltodextrin, wherein the nol, butylene glycol, Poterium officinale root extract, Rosa linallyl acetate is present in an amount between 0.01-3.0% or multiflora fruit extract, panthenyl ethyl ether, Swertia 0.01-0.3% by weight of active compound per unit volume of japonica (or Swertia chirata ) extract, glycyrrhetinic acid, topical formulation (w/v) or by volume of essential oil per citric acid, Sodium citrate, and maltodextrin, wherein the unit volume of the topical formulation (v/v). (C)-Terpineol is present in an amount between 0.01-3.0% or 0.01-0.3% by weight of active compound per unit volume of EXAMPLE 20 topical formulation (w/v) or by volume of essential oil per unit volume of the topical formulation (v/v). Tonic Formulation Comprising Linalool 06.31 This example describes a tonic formulation com EXAMPLE 1.8 prising linalool. 0632 An exemplary tonic for use in accordance with the Tonic Formulation Comprising (+)-terpinen-4-ol invention comprises linalool, in a substantially pure form or as a constituent of an essential oil such as from lavender or 0625. This example describes a tonic formulation com other Suitable source shown in Table 1, as an active ingre prising (+)-terpinen-4-ol. dient to inhibit FGF-5-dependent signalling in a hair follicle 0626. An exemplary tonic for use in accordance with the or part thereof. An exemplary tonic formulation may also invention comprises (+)-terpinen-4-ol, in a Substantially comprise one or more of the following additional ingredi pure form or as a constituent of an essential oil Such as from ents: purified water, ethanol, butylene glycol, panthenyl tea tree or other suitable source shown in Table 1, as an ethyl ether, Swertia japonica (or Swertia chirata) extract, active ingredient to inhibit FGF-5-dependent signalling in a glycyrrhetinic acid, citric acid, Sodium citrate, maltodextrin, hair follicle or part thereof. An exemplary tonic formulation Ginkgo biloba extract, Eriobotrya japonica leaf extract, may also comprise one or more of the following additional Poterium officinale root extract and Rosa multiflora fruit ingredients: purified water, ethanol, butylene glycol, pan eXtract. thenyl ethyl ether, Swertia japonica (or Swertia chirata) 0633 For example, an exemplary tonic formulation of extract, glycyrrhetinic acid, citric acid, sodium citrate, the invention comprises linalool, purified water, ethanol, maltodextrin, Ginkgo biloba extract, Eriobotrya japonica butylene glycol, Poterium officinale root extract, Rosa mul leaf extract, Poterium officinale root extract and Rosa mul tiflora fruit extract, panthenyl ethyl ether, Swertia japonica tiflora fruit extract. (or Swertia chirata) extract, glycyrrhetinic acid, citric acid, 0627. For example, an exemplary tonic formulation of Sodium citrate, and maltodextrin, wherein the linalool is the invention comprises (+)-terpinen-4-ol, purified water, present in an amount between 0.01-3.0% or 0.01-0.3% by ethanol, butylene glycol, Poterium officinale root extract, weight of active compound per unit volume of topical Rosa multiflora fruit extract, panthenyl ethyl ether, Swertia formulation (w/v) or by volume of essential oil per unit japonica (or Swertia chirata) extract, glycyrrhetinic acid, volume of the topical formulation (v/v). citric acid, Sodium citrate, and maltodextrin, wherein the (+)-terpinen-4-ol is present in an amount between 0.01-3.0% EXAMPLE 21 or 0.01-0.3% by weight of active compound per unit volume of topical formulation (w/v) or by volume of essential oil per Tonic Formulation Comprising Geranyl Acetate unit volume of the topical formulation (v/v). 0634. This example describes a tonic formulation com prising geranyl acetate. EXAMPLE 19 0635 An exemplary tonic for use in accordance with the invention comprises geranyl acetate, in a substantially pure Tonic Formulation Comprising Linallyl Acetate form or as a constituent of an essential oil Such as from carrot seed or other suitable source shown in Table 1, as an 0628. This example describes a tonic formulation com active ingredient to inhibit FGF-5-dependent signalling in a prising linallyl acetate. hair follicle or part thereof. An exemplary tonic formulation 0629. An exemplary tonic for use in accordance with the may also comprise one or more of the following additional invention comprises linallyl acetate, in a Substantially pure ingredients: purified water, ethanol, butylene glycol, pan form or as a constituent of an essential oil such as from thenyl ethyl ether, Swertia japonica (or Swertia chirata) lavender or other suitable source shown in Table 1, as an extract, glycyrrhetinic acid, citric acid, sodium citrate, active ingredient to inhibit FGF-5-dependent signalling in a maltodextrin, Ginkgo biloba extract, Eriobotrya japonica hair follicle or part thereof. An exemplary tonic may also leaf extract, Poterium officinale root extract and Rosa mul comprise one or more of the following additional ingredi tiflora fruit extract. ents: purified water, ethanol, butylene glycol, panthenyl 0636 For example, an exemplary tonic formulation of ethyl ether, Swertia japonica (or Swertia chirata) extract, the invention comprises geranyl acetate, purified water, glycyrrhetinic acid, citric acid, Sodium citrate, maltodextrin, ethanol, butylene glycol, Poterium officinale root extract, US 2016/0374979 A1 Dec. 29, 2016 39

Rosa Multiflora fruit extract, panthenyl ethyl ether, Swertia 0643 For example, a formulation comprising both (-)- japonica (or Swertia chirata) extract, glycyrrhetinic acid, terpinen-4-ol and piperitone in Suitable concentration ranges citric acid, Sodium citrate, and maltodextrin, wherein the is prepared as a dilution of the essential oil from E. dives in geranyl acetate is present in an amount between 0.01-3.0% a dilution range from about 1:10,000 (v/v) to about 1:33 or 0.01-0.3% by weight clif active compound per unit (v/v), including 1:1,000 (v/v) or 1:500 (v/v) or 1:100 (v/v) volume of topical formulation w/v) or by volume of essen or 1:50 (v/v). tial oil per unit volume of the topical formulation (v/v). EXAMPLE 24 EXAMPLE 22 Perfume Formulation Comprising (-)-Terpinen-4-ol Tonic formulation Comprising 1-Carveol 0644. This example describes a perfume formulation 0637. This example describes a tonic formulation com comprising (-)-terpinen-4-ol. prising 1-carveol. 0638. An exemplary tonic for use in accordance with the 0645 An exemplary perfume for use in accordance with invention comprises 1-carveol, in a Substantially pure form the invention may comprise (-)-terpinen-4-ol, in a Substan or as a constituent of an essential oil such as from spearmint tially pure form or as a constituent of an essential oil Such or other suitable source shown in Table 1, as an active as from Eucalyptus dives, formulated in an ethanol base ingredient to inhibit FGF-5-dependent signalling in a hair comprising between 10% and 60% ethanol and purified follicle or part thereof. An exemplary tonic formulation may water. The essential oil will be present in an amount in a also comprise one or more of the following additional range of 0.01% -10% (v/v) of the perfume formulation. ingredients: purified water, ethanol, butylene glycol, pan 0646 For example, a perfume comprising both (-)-ter thenyl ethyl ether, Swertia japonica (or Swertia chirata) pinen-4-ol and piperitone in Suitable concentration ranges is extract, glycyrrhetinic acid, citric acid, sodium citrate, prepared as a dilution of the essential oil from E. dives in a maltodextrin, Ginkgo biloba extract, Eriobotrya japonica dilution range from about 1:10,000 (v/v) to about 1:10 (v/v), leaf extract, Poterium officinale root extract and Rosa mul including 1:1,000 (v/v) or 1:500 (v/v) or 1:100 (v/v) or 1:50 tiflora fruit extract. (v/v) or 1:20 (v/v). 0639 For example, an exemplary tonic formulation of 0647. A preferred perfume formulation will comprise the invention comprises 1-carveol, purified water, ethanol, (-)-terpinen-4-ol in an amount of at least about 0.01% by butylene glycol, Poterium officinale root extract, Rosa mul weight of active compound per unit voiunie of topical tiflora fruit extract, panthenyl ethyl ether, Swertia japonica formulation (w/v) or by volume of oil per unit volume of the (or Swertia chirata) extract, glycyrrhetinic acid, citric acid, topical formulation (v/v), such as about 0.095% by weight of Sodium citrate, and maltodextrin, wherein the 1-carveol is active compound per unit volume of topical formulation present in an amount between 0.01-3.0% or 0.01-0.3% by (w/v) or by volume of oil per unit volume of the topical weight of active compound per unit volume of topical formulation (v/v). formulation (w/v) or by volume of essential oil per unit 0648. A perfume in accordance with the invention may volume of the topical formulation (v/v). also comprise one or more additional ingredients, such as one or more aromatic compounds and/or Swertia japonica EXAMPLE 23 (or Swertia chirata) extract. Tonic Formulation Comprising Piperitone EXAMPLE 25 0640 This example describes a tonic formulation com prising piperitone. Perfume Formulation Comprising (+)-Terpinen-4-ol 0641 An exemplary tonic for use in accordance with the invention comprises piperitone, in a substantially pure form 0649. This example describes a perfume formulation or as a constituent of an essential oil such as from Euca comprising (t)-terpinen-4-ol. lyptus dives, as an active ingredient to inhibit FGF-5- 0650. An exemplary perfume for use in accordance with dependent signalling in a hair follicle or part thereof. An the invention may comprise (E)-terpinen-4-ol, in a Substan exemplary tonic formulation may also comprise one or more tially pure form or as a constituent of an essential oil Such of the following additional ingredients: purified water, etha as tea tree oil, formulated in an ethanol base comprising nol, butylene glycol, panthenyl ethyl ether, Swertia japonica between 10% and 60% ethanol and purified water. The (or Swertia chirata) extract glycyrrhetinic acid, citric acid, essential oil will he present in an amount in a range of about Sodium citrate, maltodextrin, Ginkgo biloba extract, Erio 0.01% to about 10% (v/v) of the perfume formulation. botrya japonica leaf extract, Poterium officinale root extract 0651 A preferred perfume formulation will comprise and Rosa multiflora fruit extract. (+)-terpinen-4-ol in an amount of at least 0.01% by weight 0642 For example, an exemplary tonic formulation of of active compound pet unit volume of topical formulation the invention comprises piperitone, purified water, ethanol, (w/v) or by volume of oil per unit volume of the topical butylene glycol, Poterium officinale root extract, Rosa mul formulation (v/v), such as about 0.095% by weight of active tiflora fruit extract, panthenyl ethyl ether, Swertia japonica compound per unit volume of topical formulation (w/v) by (or Swertia chirata) extract, glycyrrhetinic acid, citric acid, volume of oil per unit volume, of the topical formulation Sodium citrate, and maltodextrin, wherein the piperitone is (v/v). present in an amount between 0.01-3.0% or 0.01-0.3% by 0652. A perfume in accordance with the invention may weight of active compound per unit volume of topical also comprise one or more additional ingredients, such as formulation (w/v) or by volume of essential oil per unit one or more aromatic compounds and/or Swertia japonica volume of the topical formulation (v/v). (or Swertia chirata) extract. US 2016/0374979 A1 Dec. 29, 2016 40

EXAMPLE 26 weight of active compound per unit volume of topical formulation (w/v) or by volume of oil per unit volume of the Perfume Formulation Comprising C-Terpineol topical formulation (v/v), such as about 0.095% by weight of 0653. This example describes a perfume formulation active compound per unit volume of topical formulation comprising C-Terpineol. (w/v) or by volume of oil per unit volume of the topical 0654 An exemplary perfume for use in accordance with formulation (v/v). the invention may comprise C-Terpineol, in a Substantially 0663 A perfume in accordance with the invention may pure form or as a constituent of an essential oil such as clary also comprise one or more additional ingredients, such as sage oil, formulated in an ethanol base comprising between one or more aromatic compounds and/or Swertia japonica 10% and 60% ethanol and purified water. The essential oil (or Swertia chirata) extract. will he present in an amount in a range of 0.01%-10% V/v of the perfume formulation. EXAMPLE 29 0655. A preferred perfume formulation will comprise (C)-Terpineol in an amount of at least about 0.01% by Perfume Formulation Comprising Linalool weight of active compound per unit volume of topical formulation (w/v) or by volume of oil per unit volume of the 0664. This example describes a perfume formulation topical formulation (v/v), such as about 0.095% by weight of comprising linalool. active compound per unit volume of topical formulation 0665 An exemplary perfume for use 01 accordance with (w/v) or by volume of oil per unit volume of the topical the invention may comprise linalool, in a substantially pure formulation (v/v). A perfume in accordance with the inven form or as a constituent of an essential oil such as lavender tion may also comprise one or more additional ingredients, oil, formulated in an ethanol base comprising between 10% Such as one or more aromatic compounds and/or Swertia and 60% ethanol and purified water. The essential oil will be japonica (or Swertia chirata) extract. present in an amount in a range: of 0.01%-10% (v/v) of the perfume formulation. EXAMPLE 27 0666. A preferred perfume formulation will comprise linalool in an, amount of at least about 0.01% by weight of Perfume Formulation Comprising (+)-terpinen-4-ol active compound per unit volume of topical formulation 0656. This example describes a perfume formulation (w/v) or by volume of oil per unit volume of the topical comprising (+)-terpinen-4-ol. formulation (v/v), such as about 0.095% by weight of active 0657. An exemplary perfume fur use in accordance with compound per unit volume of topical formulation (w/v) or the invention may comprise (+)-terpinen-4-ol, in a Substan by volume of oil per unit volume of the topical formulation tially pure form or as a constituent of an essential oil Such (v/v). as tea tree oil, formulated in an ethanol base comprising 0667 A perfume in accordance with the invention may between 10% and 60% ethanol and purified water. The also comprise one or more additional ingredients, such as essential oil will be present in an amount in a range of one or more aromatic compounds and/or Swertia japonica 0.01%-10% (v/v) of the perfume formulation. (or Swertia chirata) extract. 0658) A preferred perfume formulation will comprise (+)-terpinen-4-ol in an amount of at least about 0.01% by EXAMPLE 30 weight of active compound per unit volume of topical formulation (w/v) or by volume of oil per unit volume of the Perfume Formulation Comprising Geranyl Acetate topical formulation (v/v), such as about 0.095% by weight of active compound per unit volume of topical formulation 0668. This example describes a perfume formulation (w/v) or by volume of oil per unit volume of the topical comprising geranyl acetate. formulation (v/v). 0669. An exemplary perfume for use in accordance with 0659 A perfume in accordance with the invention may the invention may comprise geranyl acetate, in a Substan also comprise one or more additional ingredients, such as tially pure form or as a constituent of an essential oil Such one or more aromatic compounds and/or Swertia japonica as carrot seed oil, formulated in an ethanol base comprising (or Swertia chirata) extract. between 10% and 60% ethanol and purified water. The geranyl acetate or essential oil comprising same will be EXAMPLE 28 present in an amount in a range of 0.01%-10% (v/v) of the perfume formulation. Perfume Formulation Comprising Linallyl Acetate 0670 A preferred perfume formulation will comprise 0660. This example describes a perfume formulation geranyl acetate in an amount of at least about 0.01% by comprising linallyl acetate. weight of active compound per unit volume of topical 0661. An exemplary perfume for use in accordance with formulation (w/v) or by volume of oil per unit volume of the the invention may comprise linallyl acetate, in a Substantially topical formulation (v/v), such as about 0.095% by weight of pure form or as a constituent of an essential oil such as active compound per unit volume of topical formulation lavender oil, formulated in an ethanol base comprising (w/v) or by volume of oil per unit volume of the topical between 10% and 60% ethanol and purified water. The formulation (v/v). essential oil will be present in an amount in a range of 0671 A perfume in accordance with the invention may 0.01%-10% (v/v) of the perfume formulation. also comprise one or more additional ingredients, such as 0662 A preferred perfume formulation will comprise one or more aromatic compounds and/or Swertia japonica linallyl acetate in an amount of at least about 0.01% by (or Swertia chirata) extract. US 2016/0374979 A1 Dec. 29, 2016

EXAMPLE 31 0682 One or more topical formulations described in the preceding examples is administered to a rodent model of Perfume Formulation Comprising 1-Carveol androgenic alopecia described by Crabtree et al., Endocri 0672. This example describes a perfume formulation nology, 151(5): 2373-2380, 2010 (test groups). The topical comprising 1-carveol. formulations are applied twice daily to the dermis of mice in 0673. An exemplary perfume for use in accordance with the respective test group for a period of 30 days or 60 days the invention may comprise 1-carveol, in a Substantially or 90 days or 120 days. Hair/fur loss and hair/fur growth is pure form or as a constituent of an essential oil such as monitored throughout the application period to determine spearmint oil, formulated in an ethanol base comprising the effect of the topical formulations comprising test com between 10% and 60% ethanol and purified water. The pound(s) of the invention on hair loss and/or hair thinning in essential oil will he present in an amount in a range of mice to which the formulation has been administered rela 0.01%-10% (v/v) of the perfume formulation. tive to a control group to which a placebo or control has been 0674) A preferred perfume formulation will comprise administered. 1-carveol in an amount of at least about 0.01% by weight of active compound per unit volume of topical formulation EXAMPLE 34 (w/v) or by volume of oil per unit volume of the topical Testing of Formulations in a Primate Model of formulation (v/v), such as about 0.095% by weight of active Androgenic Alopecia compound per unit volume of topical formulation (w/v) or by volume of oil per unit volume of the topical formulation 0683. This example shows exemplary means for testing (v/v). efficacy of topical formulations of the invention on therapy 0675. A perfume in accordance with the invention may of androgenic alopecia. also comprise one or more additional ingredients, such as 0684. One or more topical formulations described in the one or more aromatic compounds and/or Swertia japonica preceding examples is administered to a primate model of (or Swertia chirata) extract. androgenic alopecia described by Brigham et al., Clinical Dermatology 6:177-187, 1998 and/or Sundberg et al., EXAMPLE 32 Experimental and Molecular Pathology 67:118-130, 1999. A topical formulation is applied to the dermis of the animal Perfume Formulation Comprising Piperitone in the respective test group for a period of 30 days or 60 days or 90 days or 120 days. For example, a shampoo formulation 0676. This example describes a perfume formulation as described may he administered to wet fur, massaged into comprising piperitone. the animal's skin and left for a period of 2-3 minutes, and 0677 An exemplary perfume for use in accordance with washed off. Alternatively, a tonic formulation as described the invention may comprise piperitone, in a Substantially may be administered to fur 1-2 tunes per day, e.g., morning pure form or as a constituent of an essential oil from and evening, and massaged into the skin. Hair/fur loss and Eucalyptus dives, formulated in an ethanol base comprising hair/fur growth is monitored throughout the test period to between 10% and 60% ethanol and purified water. The determine the effect of the topical formulation(s) on hair loss essential oil will be present in an amount in a range of and/or hair thinning in those animals to which a topical 0.01%-10% (v/v) of the perfume formulation. formulation has been administered relative to a control 0678 For example, a perfume comprising both (-)-ter group to which a placebo or control has been administered. pinen-4-ol and piperitone in Suitable concentration ranges is prepared as a dilution of the essential oil from E. dives in a EXAMPLE 35 dilution range from about 1:10,000 (v/v) to about 1:10 (v/v), including 1:1,000 (v/v) or 1:500 (v/v) or 1:100 (v/v) or 1:50 Testing of Topical Formulations in a Rodent Model (v/v) or 1:20 (v/v). of Alopecia Areata 0679. A preferred perfume formulation will comprise 0685. This example shows exemplary means for testing piperitone in an amount of at least about 0.01% by weight efficacy of topical formulations of the invention on therapy of active compound per unit volume of topical formulation of androgenic areata. (w/v) or by volume of oil per unit volume of the topical 0686. One or more topical formulations described in the formulation (v/v), such as about 0.095% by weight of active preceding examples is administered to a C3H/He mouse compound per unit volume of topical formulation (w/v) or model of alopecia areata described by Sundberg et al., by volume of oil per unit volume of the topical formulation Journal of Investigative Dermatology, 102:847-56, 1994. A (v/v). topical formulation is applied to the dermis of the animal in 0680 A perfume in accordance with the invention may the respective test group for a period of 30 days or 60 days also comprise one or more additional ingredients. Such as or 90 days or 120 days. For example, a shampoo formulation one or more aromatic compounds and/or Swertia japonica as described may be administered to wet fur, massaged into (or Swertia chirata) extract. the animal's skin and left for a period of 2-3 minutes, and washed off. Alternatively, a tonic formulation as described is EXAMPLE 33 administered to fur 1-2 times per day, e.g., morning and Testing of Topical Formulations in a Rodent Model evening, and massaged into the skin. Hair/fur loss and of Androgenic Alopecia hair/fur growth is monitored throughout the test period to determine the effect of the topical formulation(s) on hair loss 0681. This example shows exemplary means for testing and/or hair thinning in those animals to which a topical efficacy of topical formulations of the invention on therapy formulation has been administered relative to a control of androgenic alopecia. group to which a placebo or control has been administered. US 2016/0374979 A1 Dec. 29, 2016 42

EXAMPLE 36 istered to a male or female Subject (as appropriate) who is not suffering from alopecia. To administer, the shampoo Testing of Topical Formulations in a Rodent Model formulation is applied to wet hair, massaged into the scalp of Acute Alopecia with fingertips and left on the scalp for a period of 2-3 minutes, after which time the shampoo is rinsed thoroughly 0687.f Thisf topical example fi showslati exemplaryf the i means for htesting from hair. This process is performed once daily throughout efficacy of topical formulations of the 1nvention on therapy the test period. Alternatively, a tonic formulation is applied of acute alopecia. to the scalp twice daily e.g., morning and evening, through 10688). One or more topical formulations described in the out the test period, and after each application the tonic is preceding examples is administered to a C57BL/6 mouse massaged gently into the scalp. Hair loss, hair growth and model of acute alopecia described by Paus et al., American hair volume is monitored throughout the four month period Journal of Pathology 144:719-734, 1994. Adolescent, 6- to to determine the effect of the shampoo formulation on hair 8-week-old, female, syngeneic C57BL/6 mice (15 g to 20 loss and/or hair thinning and/or hair volume in the Subject to g Weight) with normal, black fur are housed in community which the shampoo formulation is administered. cages with 12-hour light cycles and fed mouse chow and 0691 Hair growth rate, anagen/catagen ratio, hair shaft water ad libitum. Mice in telogen, as determined homoge- diameter are determined by Phototrichogram. neously pink color of their back skin, are depilated to induce a synchronized anagen, by applying a melted wax/rosin EXAMPLE 38 mixture to the back skin and by peeling off this mixture after hardening. About 9 days following depilation, the mice are Efficacy of Topical Formulations for Treating Hair then injected once intraperitoneally with 150 mg/kg body Loss in Humans weight aqueous Solution of cyclophosphamide, optionally with cyclosporine A administered intraperitoneally in 0.5 ml 0692. This example demonstrates the efficacy of an corn oil, at each of 7, 9 and 11 days post-depilation (250 exemplary topical formulation to: (1) reduce hair fall/loss; mg/kg per dose) to prolong the testing period by delaying (2) increase hair growth; and/or (3) increase anagen:catagen recovery from cyclophosphamide-induced alopecia. If ratio, in males and females Suffering from male and female required, animals are given a further injection of cyclophos pattern baldness respectively. phamide to extend the testing period. A topical formulation (0693 Trial Design of the invention as described according to any example 0694. The trial was designed as a randomised, single hereof is applied to the dermis of the animal in the respective blinded, placebo controlled clinical trial of a topically test group for a period of up to 30 days or up to 60 days or applied FGF-5 inhibiting lotion for treating hair loss. up to 90 days or up to 120 days. For example, a shampoo 0695 Trial Cohort formulation as described may be administered to wet fur, 0696. A total of 20 adult subjects between the age of massaged into the animal’s skin and left for a period of 2-3 25-55 having mild to moderate male and female pattern minutes, and washed off. Alternatively, a tonic formulation baldness were included in the trial. as described is administered to fur 1-2 times per day, e.g., 0697 The inclusion criteria for subjects were as follows: morning and evening, and massaged into the skin. Skin color 0698. Subjects exhibited pattern baldness on Hamil changes indicating the effect of test drugs on hair cycling ton-Norwood scale 2 to 4 for men (FIG. 11) or Ludwig and follicle melanogenesis, and hair regrowth, are monitored scale I-2 to II-2 for women (FIG. 12) which was not throughout the test period to determine the effect of the complicated with other crucial hair disorders, such as topical formulation(s) on hair loss and/or hair thinning in alopecia areata (cyclic alopecia), loose anagen Syn those animals to which a topical formulation has been drome, acute anagen or telogen effluvium and trichot administered relative to a control group to which a placebo illomania etc. Based on confirmatory visual assessment or control has been administered. Mice are also sacrificed to by suitably trained medical practitioners e.g., Staff permit histological analysis of follicle responses and recov MD's from AMA Laboratory Inc.: ery (morphometry) in the presence and absence of the 0699 Subjects were healthy, non-obese and not under topical formulations. Together, these data define a pattern of going or recently completing any medical interventions hair follicle response to the topical formulation(s), and or using any medications, and not utilising any other monoterpenoid-mediated recovery from acute alopecia. hair loss treatment; and 0700 Subjects were within a healthy weight range for EXAMPLE 37 height i.e., body mass index (BMI) between 19-26. (0701 Subjects were excluded from the trial if they: Testing of Topical Formulations for 0702 were suffering from scalp inflammation or a skin Non-Therapeutic or Cosmetic Purposes condition, had known allergies to any lotion ingredi ents, were receiving any hair loss treatments currently 0689. This example shows exemplary means for testing or in the last 6 weeks prior to enrollment, were preg efficacy of topical formulations of the invention on hair loss nant, breastfeeding or planning a pregnancy in next 6 and/or hair thinning and/or hair volume when applied to the months; and/or dermis of a human Subject not suffering from alopecia. 0703 had undergone hypothyroidism or thyroid hor 0690. One or more topical formulations described in the mone treatment in the 6 weeks prior to enrollment. preceding examples is administered to a male or female (0704 Trial Methodology Subject (as appropriate) who is not suffering from alopecia. 0705 Patients were randomised into two (2) sex- and The topical formulation is applied to the scalp twice daily age-matched groups (n=10/group; sex ratio was set to 1:1, e.g., morning and evening, for a period of up to four months. i.e., 5 males and 5 females, but skewed as far as 7:3 based For example, a shampoo formulation as described is admin- on ability to recruit suitable subjects). Group 1 received a US 2016/0374979 A1 Dec. 29, 2016

Placebo Formulation and Group 2 received a Test Formu seconds, (iii) fresh PBS for 10 seconds, and (iv) another lation. In each case, the formulation was self-applied twice fresh PBS for 10 seconds. This washing process was daily for two weeks. repeated twice. After washing, the skin cut was placed 0706 The formulations were as follows: inverted to expose the vibrissae follicles in Dulbecco's 0707 Placebo Formulation: Modified Eagle's Medium (DMEM; Wako Pure Chemical, Osaka, Japan) at 37°C. Under a dissecting microscope, the Surrounding tissue was removed from the follicles using Ingredient % (w/v) Amount (mg/ml) tweezers, carefully so as not to destroy the structure of the Ethanol 60.0 600.00 follicles. The isolated follicles were then placed immedi Purified water C.S ately into Williams' E medium (Life Technologies, Carls bad, USA). Those follicles that exhibited fine growing fibers were then transected leaving 0.5 mm of the hair shaft from (0708 Test Formulation: 0.095% (v/v) Piperitone the frontier with the hair bulb. 0716. From the isolated mouse vibrissae follicles, only early anagen follicles were selected and randomized into Ingredient % (w/v) Amount (mg/ml) groups with 30 follicles per group. The anagen phase (-)-piperitone O.O88 follicles were laid individually on 0.7 mmx03 mm Gelfoam Rosa multiflora fruit extract 1.0 (in solution) 1.67 (Pfizer, New York, USA) submerged in 0.5 ml Williams’ E Poterium officinale root extract 1.0 (in solution) 2.50 Swertia chirata whole plant extract 0.03 (in solution) 3.60 medium supplemented with 30 ug/mL Insulin (Wako Pure Ethanol 6O.O 600.00 Chemical), 10 ng/mL Hydrocortisone (Sigma-Aldrich, St. 1,3-Butylene Glycol 3.0 30.00 Louis. USA) and 2 mM GlutaMAX (Life Technologies) Panthenyl ethyl ether O.3 3.00 without any preservatives in a 24-well plate. Glycyrrhetinic acid O.1 1.00 Citric acid anhydrous O.O2S O.25 0717 FGF-5 Cultures Sodium citrate O.O24 O.24 0718. A stock of FGF-5 solution (100 ug/mL) was pre Purified water C.S. pared by dissolving 100 g of FGF-5 protein (R&D Sys tems, Minneapolis, USA) in 1 ml of PBS (Takara Bio, Otsu, 0709 Subjects agreed to use the same shampoo and to Japan). The stock solution was diluted further in culture maintain the same hair style, hair length and hair colour medium to yield a culture medium with a final FGF-5 throughout the duration of the study, and to refrain from concentration of 300 ng/mL. This culture medium was used cutting the scalp hair shorter than 1 inch in length during that for culturing follicles in the FGF-5 treatment group. In time. Subjects were evaluated for compliance by phone/ contrast, the follicles cultured in medium without the addi email contact after the first week. tion of FGF-5 served as controls. 0719. Follicles in each of the treatment and control 0710 Self-assessment was performed by questionnaire groups were incubated at 37°C. at 5% CO for 8 days, while prior to treatment and at days 7 and 14 of the study. exchanging the respective culture mediums every 2 days. 0711 Results From Day 1, elongation of hair shafts was observed and the 0712. At day 7 of the study, subjects in Group 2 applying elongation length was measured for each hair shaft every 24 the Test Formulation perceived improved hair volume, hours from Day 1 to Day 8 using a micrometer under reduced hair loss, stronger hair, thicker hair, improved hair microscope. The follicles which showed apparently abnor density and strengthening of fine hair to a greater extent than mal growth (extremely low or no) growth were excluded those subjects in Group 1 applying the Placebo Formulation from the data set. Among the early anagen phase follicles (FIGS. 13-16, 18 and 19 respectively). This trend continued at day 14, with the additional observation that subjects in in selected for culture, almost 30% of them were qualified up the Group 2 applying the Test Formulation perceived that to Day 8. hair fall was prevented to a greater extent relative to those 0720 Piperitone Cultures subjects in Group 1 applying the Placebo Formulation (FIG. 0721. A stock of Piperitone solution with a concentration 17). Based on the foregoing data, it was found that the of 100 mg/ml was prepared by dissolving 100 mg of topical application of Test Formulation 1 was effective for Piperitone (Tokyo Chemical Industry. Tokyo, Japan) in 1 ml treating hair loss in Subjects Suffering from male pattern of Ethanol. The stock solution was diluted further in culture medium to yield a culture medium with a final Piperitone baldness and female pattern baldness. concentration of 0.1 mg/mL. This culture medium was used EXAMPLE 39 for culturing follicles in the Piperitone treatment group. In contrast, the follicles cultured in medium without the addi Efficacy of Piperitone to Increase Hair Growth in tion of Piperitone served as controls. Hair Follicles from Marine Vibrissae ex vivo 0722. Follicles in each of the treatment and control groups were incubated at 37° C. at 5% CO, for 5 days, while 0713 Methodology exchanging the culture medium every 3 days. From Day 1, 0714 Preparation of Follicles elongation of hair shafts was observed and the elongation 0715. Five week old male C3H mice (supplied by Japan length was measured for each hair shaft every 24 hours from SLC. Inc., Hamamatsu, Japan) were used for isolation of Day 1 to Day 5. using a micrometer under microscope. The vibrissae follicles. The mice were sacrificed and the vibris follicles which showed apparently abnormal growth (ex sae follicles were carefully dissected from the mystacial pad. tremely low or no) growth were excluded from data set. Briefly, the mystacial pad was cut into two sides (left and Among the early anagen phase follicles selected for the right). The skin cut, picked at the edge by tweezers, was culture, almost 30% of them were qualified up to Day 5. washed in (i) 70% Ethanol for 30 seconds, (ii) PBS for 10 0723 Results US 2016/0374979 A1 Dec. 29, 2016 44

0724 FGF-5 Cultures 2. The topical formulation according to claim 1, wherein 0725. The addition of exogenous FGF-5 to follicle cul the Co-monoterpenoid is selected from the group consisting tures was shown to slow the rate of hair shaft elongation of: over time (FIGS. 20 and 21). This is particularly apparent 3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (piperi from the growth curves presented in FIGS. 20 and 21, which tone); show that the rate of hair growth diminishes over time for 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (terpinen-4-ol); those follicles cultured in the presence of FGF-5 relative to 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanol (alpha-terpi those follicles in the control group, particularly from days neol); 5-8. This observation supports the inventor's theory that 2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol (car FGF-5-dependent signalling is important in the processes veol): that lead to hair loss and/or thinning. 6-Isopropyl-3-methyl-2-cyclohexen-1-one (3-carvomen 0726 Piperitone Cultures thenone); and 0727. As is apparent from FIG. 22, hair shaft elongation 3,7-Dimethyl-1,6-octadien-3-ol (linalool). continued steadily and consistently throughout the culture 3. The topical formulation according to claim 2, wherein period for those follicles cultured in medium containing the Co-monoterpenoid is 3-Methyl-6-(propan-2-yl)cyclo piperitone. In contrast, the rate of hair shaft elongation for hex-2-en-1-one (piperitone) or 1-Isopropyl-4-methyl-3-cy follicles in the control group declined from days 3-5 due to clohexen-1-ol (terpinen-4-ol). the uninhibited activity of endogenous FGF-5 secreted by 4. The topical formulation according to claim 1 compris the follicles. Based on results, the inventors observed that ing a carboxylic acid monoester of the Co-monoterpenoid. the addition of piperitone to the culture medium increased 5. The topical formulation according to claim 4, wherein hair growth by inhibiting the activity of endogenous FGF-5 the carboxylic acid monoester is a monoester with a car secreted by the follicles. boxylic acid selected from acetic acid, propionic acid and 0728. It will be appreciated by persons skilled in the art formic acid. that numerous variations and/or modifications may be made 6. The topical formulation according to claim 2, wherein to the invention as shown in the specific embodiments the Co-monoterpenoid carboxylic acid ester is selected without departing from the scope of the invention as broadly from the group consisting of: described. The present embodiments are, therefore, to be (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate (geranyl acetate); considered in all respects as illustrative; and not restrictive. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linallyl acetate); 1. A topical formulation comprising an isolated Co 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanyl acetate (ter monoterpenoid or isolated enantiomer thereof or an isolated pinyl acetate); and ester thereof with a carboxylic acid, wherein said topical 5-Isopropenyl-2-methyl-2-cyclohexen-1-yl acetate formulation is formulated to extend an anagen phase of a (carvyl acetate). hair follicle cell comprising a hair and/or to delay a hair 7. The topical formulation according to claim 1 compris follicle cell comprising a hair from entering a catagen phase ing an isolated enantiomer of the Co-monoterpenoid. in a Subject to which the formulation is applied by reducing 8. The topical formulation according to claim 7, wherein or inhibiting fibroblast growth factor 5 (FGF5)-dependent the isolated enantiomer is selected from the group consisting signalling in the hair follicle cell, and wherein the Co of: monoterpenoid is of formula (I): (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol (-)-ter pinen-4-ol; (1S)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol (+)-ter formula (I) pinen-4-ol; R3 2- (1R)-4-Methylcyclohex-3-en-1-yl)propan-2-ol (+)- alpha-terpineol; x1 N (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1-one (-)- piperitone; (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)- R. piperitone; (3S)-3,7-Dimethyl-1,6-octadien-3-ol (+)-Linalool: 17N, (3R)-3,7-Dimethyl-1,6-octadien-3-ol (-)-Linalool: (1R, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- wherein: ol (-)-cis-carveol; R is hydrogen, hydroxyl or oxygen; (1S, 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- R is absent or hydrogen or hydroxyl, ol (+)-cis-carveol; (1R, 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- R is CH: ol (+)-trans-carveol; and X is CH or CH-OH, or (S.5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- X is CHCH or CHOHCH and X and Y together form ol (-)-trans-carveol. a single bond within a 6-membered ring; 9. The topical formulation according to claim 1, wherein Y is CH, when X is CH or CH-OH, or the Co-monoterpenoid is isolated 1-Isopropyl-4-methyl-3- Y is CH or COH when X is CHCH, or CHOHCH: cyclohexen-1-ol (terpinen-4-ol) or an isolated enantiomer or and carboxylic acid ester thereof. Z is a saturated or unsaturated C. Cs alkyl or alkyl 10. The topical formulation according to claim 1, wherein ester. the Co-monoterpenoid is isolated 3-methyl-6-(propan-2-yl) US 2016/0374979 A1 Dec. 29, 2016 cyclohex-2-en-1-one (piperitone) or an isolated enantiomer 31. The method according to claim 20, wherein the topical or carboxylic acid ester thereof. formulation comprises 3-Methyl-6-(propan-2-yl)cyclohex 2-en-1-one (piperitone) or 1-Isopropyl-4-methyl-3-cyclo 11-13. (canceled) hexen-1-ol (terpinen-4-01). 14. The topical formulation according to claim 1 com 32. The method according to claim 20, wherein the topical prising a topical carrier, excipient or emollient. formulation comprises a carboxylic acid monoester of the 15. The topical formulation according to claim 1, further Co-monoterpenoid. comprising one or more adjunctive agents effective for 33. The method according to claim 32, wherein the treatment or prevention of hair loss. Co-monoterpenoid carboxylic acid monoester is a 16. A method of extending an anagen phase of a hair monoester with a carboxylic acid selected from acetic acid, follicle cell comprising a hair and/or delaying a hair follicle propionic acid and formic acid. cell comprising a hair from entering a catagen phase, said 34. The method according to claim 32, wherein the method comprising administering the topical formulation Co-monoterpenoid carboxylic acid ester is selected from according claim 1 to an area of the dermis or skin of a the group consisting of: Subject comprising one or more hair follicle cells comprising (2E)-3,7-Dimethyl-2,6-octadien-1-yl acetate (geranyl acetate); hair(s) or an area of dermis adjacent or Surrounding thereto. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linallyl acetate); 17. The method according to any one of claims 16, 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanyl acetate (ter wherein: pinyl acetate); and (i) the hair is scalp hair and the method comprises 5-Isopropenyl-2-methyl-2-cyclohexen-1-yl acetate administering the topical formulation to the scalp of the (carvyl acetate). Subject; 35. The method according to claim 16, wherein the topical (ii) the hair is eyelash hair and the method comprises formulation comprises an isolated enantiomer of a Co administering the topical formulation to the eyelid or monoterpenoid selected from the group consisting of: eyelash of the subject; and/or (R)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol (-)-ter (iii) the hair is eyebrow hair and the method comprises pinen-4-ol; administering the topical formulation to the face or (1S)-1-Isopropyl-4-methyl-3-cyclohexen-1-ol (+)-ter forehead or eyebrow of the subject. pinen-4-ol; 18. (canceled) 2-(1R)-4-Methylcyclohex-3-en-1-yl)propan-2-ol (+)-al 19. The method according to claim 16, wherein hair pha-terpineol: growth is promoted or enhanced. (6R)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1-one (-)- 20. A method of treatment or prevention of allopecia in a piperitone; Subject, said method comprising extending an anagen phase (6S)-3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (+)- of a hair follicle cell comprising a hair and/or delaying a hair piperitone; follicle cell comprising a hair from entering a catagen phase (3S)-3,7-Dimethyl-1,6-octadien-3-ol (+)-Linalool: by administering the topical formulation according to claim (3R)-3,7-Dimethyl-1,6-octadien-3-ol (-)-Linalool: 1 to an area of the dermis or skin of a subject in which the (1R, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- alopecia is to be treated or prevented or an area of dermis ol (-)-cis-carveol; adjacent or Surrounding thereto. (1S, 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- ol (+)-cis-carveol; 21. The method according to claim 20, wherein: (1R, 5S)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- (i) the alopecia involves scalp hair and the method com ol (+)-trans-carveol; and prises administering the topical formulation to the scalp (1S, 5R)-2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1- of the subject; ol (-)-trans-carveol. (ii) the alopecia involves eyelash hair and the method 36. The method according to claim 16, wherein the topical comprises administering the topical formulation to the formulation comprises isolated 1-Isopropyl-4-methyl-3-cy eyelid or eyelash of the subject; and/or clohexen-1-ol (terpinen-4-ol) or an isolated enantiomer or (iii) the alopecia involves eyebrow hair and the method carboxylic acid ester thereof. comprises administering the topical formulation to the 37. The method according to claim 16, wherein the topical face or forehead or eyebrow of the subject. formulation comprises isolated 3-methyl-6-(propan-2-yl)cy 22-29. (canceled) clohex-2-en-1-one (piperitone) or an isolated enantiomer or 30. The method according to claim 16, wherein the topical carboxylic acid ester thereof. formulation comprises a Co-monoterpenoid selected from 38. The method according to claim 16, wherein the topical the group consisting of: formulation further comprises one or more adjunctive agents 3-Methyl-6-(propan-2-yl)cyclohex-2-en-1-one (piperi effective for treatment or prevention of hair loss. 39. The topical formulation according to claim 1, wherein tone); the topical formulation is effective for treatment or preven 1-Isopropyl-4-methyl-3-cyclohexen-1-ol (terpinen-4-ol); tion of allopecia. 2-(4-Methyl-3-cyclohexen-1-yl)-2-propanol (alpha-terpi 40. The topical formulation according to claim 1, wherein neol); the hair is terminal hair. 2-Methyl-5-(1-methylethenyl)-2-cyclohexen-1-ol (car 41. The method according to claim 16, wherein the hair is veol): terminal hair. 6-Isopropyl-3-methyl-2-cyclohexen-1-one (3-carvomen 42. The method according to claim 20, wherein the hair is thenone); and terminal hair. 3,7-Dimethyl-1,6-octadien-3-ol (linalool).