Hair growth and rejuvenation: An overview

Journal of Dermatological Treatment. 2010; Early Online, 1–10

REVIEW ARTICLE

Hair growth and rejuvenation: An overview

MONA SEMALTY1, AJAY SEMALTY1, GEETA PANT JOSHI2 & MOHAN SINGH MANIYARI RAWAT2 J Dermatolog Treat Downloaded from informahealthcare.com by 117.254.208.54 on 06/11/10 For personal use only.

1

Department of Pharmaceutical Sciences, and 2Department of Chemistry, HNB Garhwal University Srinagar (Garhwal), Uttarakhand, India

Abstract Hair has psychological and sociological importance throughout the ages in framing the personality and general appearance of an individual. Significant progress is being made on discovering an effective and safe drug for hair growth. Angiogenesis, androgen antagonism, vasodilation, potassium channel opening and 5-alpha reductase inhibition are the major non-surgical therapeutic strategies of hair growth promotion. In spite of a flood of drugs claiming to be useful as hair growth promoters, more rational strategies, which can target the problem areas or stages of the hair growth cycle effectively, are still awaited. This article highlights the developments in hair rejuvenation strategies and reviews the potential of herbal drugs as safer and effective alternatives.

Key words: alopecia, baldness, hair growth, hair loss, herbal drugs, minoxidil

Introduction Hair has been a sign of beauty and a contribution to an individual’s personality since time immemorial. Alopecia (baldness), a dermatological disorder, is a common problem of cosmetology as well as primary health practice. It is common throughout the world and has been estimated to affect between 0.2% and 2% of the world’s population (1–3). The clinical severity of alopecia in a patient may not be a good indicator of a subsequent downturn in quality of life or psychological well-being of the patient. Drugs which claim to treat hair loss target a steadily growing, multi-billion dollar market worldwide. Great expectations are associated with pharmaceutical hair loss management, but still there is no radical improvement in the availability of more precise therapies (4). Much of that disappointment appears to result from unrealistic expectations, ill-targeted (and therefore inefficient) drug therapy and insufficient industrial interest in dissecting the basic mechanisms by which hair loss occurs and by which human hair growth promoters exert their effects.

Over the past several years about 300 000 products have claimed to help hair regrowth. With the exception of minoxidil and finasteride, none of them was found to be effective in hair growth promotion. Minoxidil, a synthetic (cardiovascular) drug, was scientifically proved to help the treatment of alopecia. The hair growth activity of minoxidil is actually the side effect of this cardiovascular drug (5). Currently, minoxidil (useful in both male and female pattern baldness) and finasteride (useful in male pattern baldness) are two US FDA-approved synthetic drugs finding concomitant use for treatment of androgenic alopecia, but their side effects have reduced their usage (6,7). Moreover, both the drugs are the result of serendipity, not of rational hair drug design. Therefore, to search for more precise therapies for alopecia, newer synthetic drugs or drugs of plant origin need to be explored. Herbal drugs have been widely used for hair growth promotion since ancient times in Ayurveda, Chinese and Unani systems of medicine. Natural products are very popular and well accepted in the cosmetic and hair care industries (8,9).

Correspondence: Mona Semalty, Department of Pharmaceutical Sciences, PB No.-32, HNB Garhwal University Srinagar (Garhwal)-246174, India. Fax: 91 1346 252174. E-mail: [email protected] (Received 26 September 2009; accepted 21 December 2009) ISSN 0954-6634 print/ISSN 1471-1753 online 2010 Informa UK Ltd. DOI: 10.3109/09546630903578574

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The goal of the present article is to provide an overview of available hair loss treatment alternatives. The article provides a brief review of the hair growth cycle and different causes of hair loss, followed by focuses on the various types of drugs available for alopecia. The article reviews various studies showing hair growth-promotion efficacy of modern and herbal drugs.

J Dermatolog Treat Downloaded from informahealthcare.com by 117.254.208.54 on 06/11/10 For personal use only.

Hair growth cycle Hair is the cumulative, physical result of a coordinated process of cellular proliferation and differentiation within a hair follicle. Hair follicles are epidermally derived appendages which arise as a result of inductive events between specialized dermal fibroblasts acting on bipotential epithelial stem cells. The stem cells which commit to a hair follicle fate enter a period of massive proliferation that culminates in the formation of a mature hair follicle (10). The hair follicle cycle is a complex process and entails involvement of cell differentiation, epithelial– mesenchymal interactions, stem cell augmentation, pattern formation, apoptosis (programmed cell death), cell and organ growth cycles, and pigmentation. The most important reason for studying the cycling of

the hair follicle is that the follicle is a regenerating system (Figure 1). By traversing the phases of the cycle (growth, regression, resting, shedding, then growth again), the follicle demonstrates the unusual ability to completely regenerate itself (11). Normal hair follicles cycle between a growth stage (anagen), a degenerative stage (catagen), a resting stage (telogen) and a shedding stage (exogen). The scalp hairs have a relatively long life cycle: the anagen stage ranges from 2 to 5 years, the catagen stage ranges from a few days to a few weeks, and the telogen stage is approximately 3 months (12,13). Hair cycle disturbances have dramatic effects on visible hair growth. If anagen gets prematurely terminated and catagen occurs too early, this must result in effluvium and alopecia; the affected skin region will subsequently sport largely catagen and/or telogen follicles, whose loosely anchored club hairs are eventually shed (i.e. the normal anagen/telogen rate on the scalp [roughly 4:1] changes in favor of telogen). This is exactly what happens, for example, as a consequence of drug-induced damage to the proliferating cells of the anagen hair bulb, such as in drug-induced telogen effluvium or when inflammatory cells attack the anagen hair bulb in alopecia areata (12). Therefore, the therapeutic manipulation of hair follicle cycling is a key challenge

Folliculogenesis Epithelium/ messenchyme

Anagen Placode

Germ

Peg

Catagen

Bulbose peg

Telogen

B

B

E

P

IRS

H ORS

CTS

S B

P

H

B B

P

M

P

Figure 1. The formation of hair follicles in the fetus and cycling transformations in the adult. In the fetus, a thickening forms at one focus of the primitive epithelium to form a placode. Below the placode dermal cells aggregate and thereafter the epithelium grows down as a finger to produce the multilayer, shaft-producing hair follicle. In the adult, three phases of the growth cycle are recognized: a growth phase (anagen), a regressing phase (catagen): and a resting phase (telogen). It is the lower follicle that regenerates at the beginning of each cycle by utilizing intimate and powerful epithelial–mesenchymal interactions of the stem cells in the bulge (B) and the inductive mesenchymal cells of the papilla (P). CTS, connective tissue sheath; E, epidermis; H, hair shaft; IRS, inner root sheath; M, hair matrix; ORS, outer root sheath; S, sebaceous gland.

Hair growth and rejuvenation in hair loss management. Effective therapeutic strategies for hair loss in declining order of importance are: . . .

inhibition of catagen development in order to prolong anagen induction of anagen in telogen follicles inhibition of exogen.


Hair loss and alopecia Hair loss is a natural daily phenomenon, but this shedding of hair cannot be the main cause of hair loss. Every strand of hair on a human head is genetically programmed to a cycle that includes growth, stabilization, aging and shedding. On average, every day a human head sheds about 50–125 hairs (depending on sex), but most of them will come back after the resting stage as the follicle itself is not destroyed (14). Trouble begins when the loss exceeds re-growth, or the re-growth is weak and unhealthy. A loss of 100 hairs per day can be considered ‘normal’ not pathologic. But a loss of more than 100 hairs per day constitutes a pathological effluvium. Androgenetic alopecia (AGA) is one of the dermatological conditions most commonly faced by the dermatologist or general physician. The condition affects up to 30% of men under the age of 30 and more than 50% of men over the age of 50. Despite a widespread belief that AGA is only experienced by men, it also affects women, although the clinical signs are usually milder and the phenotype is different (15). As the condition progresses, scalp hairs and their follicles become progressively miniaturized, and the terminal hair

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normally found on the adult scalp is replaced by vellus hairs which are shorter, finer and non-pigmented. Concomitantly, the average length of time spent by hairs in anagen (growth phase) decreases, and the proportion of hairs in telogen (resting phase) increases (16). Baldness or alopecia can be classified as follows: male pattern baldness, female pattern baldness, alopecia areata (an autoimmune disorder causing small, patchy circular bald patches in several parts of the scalp), alopecia totalis (total loss of scalp hair), and alopecia universalis (total loss of hair from the entire body) (17). Another way in which hair loss (alopecia) can be classified is according to factors leading to it. There are two different types of hair loss, known medically as: Anagen effluvium: caused by medications taken internally, such as chemotherapy representatives, excessive doses of vitamin A or some hypertension medications. Telogen effluvium: caused by an increased number of hair follicles entering the latent or rather dead stage. The most common causes of telogen effluvium leading to alopecia could be physical and emotional stress, and thyroid or another hormonal irregularity. The growth of hairs is affected by various factors, which are listed in Table I (18). Current strategies for hair growth and rejuvenation There are a number of ways in which a drug may stimulate hair growth: it may increase the linear

Table I. Factors leading to hair loss. Factors

Description

Major physical–emotional stress

Surgery, severe illness, diet or nutrition changes and emotional stress can cause hair loss

Chemotherapy

Cholesterol-lowering drugs, Parkinson medications, anti-ulcer drugs, anticoagulants, agents for gout, anti-arthritic drugs derived from vitamin A, anticonvulsants for epilepsy, antidepressants, beta-blocker drugs, antithyroid agents, antineoplastics, blood thinners, male hormones (anabolic steroids)

Genetic predisposition

Genetic component to androgenetic hair loss exists (polygenic inheritance)

Dihydrotestosterone (DHT)

Increased level of DHT (the testosterone metabolite) shortens the hair cycle and progressively miniaturizes scalp follicles and this may be due to the atherosclerotic process blocking the microvasculature that nourishes the hair follicles

Excessive sebum

Excessive sebum causes a high level of 5-alpha reductase and pore clogging, thus malnutrition of the hair root

Cardiovascular diseases

High levels of LDL in cardiac patients are converted to 5-alpha reductase enzyme, which produces DHT from testosterone, causing hair loss

Smoking

Tobacco smoke damages the lining of blood vessels, leading to less production of nitric oxide and thus inducing hair loss

Endogenous substances

bax, bcl-2 and insulin-like growth factor binding protein-3 (e.g. VEGF) promote hair growth

LDL = low-density lipoprotein; VEGF = vascular endothelial growth factor.


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growth rate of hair; increase the diameter of the hair fibre; alter the hair cycle, either shortening telogen or prolonging anagen; or act through a combination of these effects. Among the surgical treatment methods, the introduction of micrografts (one to two hair follicular unit grafts) and minigrafts (three to four hair follicular unit grafts) has made a most significant advancement in the care of male pattern baldness and female androgenic alopecia; natural and aesthetically pleasing results are possible. Additionally, many other applications in the reconstruction of facial and scalp hair have been found; some of these include restoration of hair loss due to (iatrogenic) post-surgical causes (i.e. after facial rejuvenation procedures or procedures involving incisions on hairbearing facial skin or scalp) and burns or traumatic injuries (19). Various non-surgical pharmacotherapeutic alternatives available for hair growth and rejuvenation are discussed in the following sections. Vitamins, nutrients and minerals Vitamin deficiencies are also thought to be the cause of alopecia and for which the treatment would be dietary vitamin supplementation. The use of biotin as a treatment for alopecia was suggested by evidence that biotin (vitamin H) deficiency causes hair loss. Biotin is a water-soluble vitamin that acts as an essential cofactor for four different carboxylases, each of which catalyzes an essential step in intermediary metabolism. An analysis of hair shows that it is composed of iron, oxygen, hydrogen, nitrogen and sulphur. The blood must be supplied with these minerals so that nourishment will be carried to the scalp. Angiogenesis, the formation of new blood vessels from the pre-existing vascular network, is a driving force of hair growth. It is indispensable for embryonic development as interruption of angiogenic events blocks the growth of the embryo and results in early mortality. After birth, angiogenesis plays both adaptive role enabling the regeneration of damaged body parts and is also involved in numerous pathological changes. Understanding of the basic mechanisms of blood vessel formation is necessary for the establishment of effective therapeutic strategies for amelioration of diseases. The major angiogenic regulator is vascular endothelial growth factor (VEGF), named also VEGF-A, which is one of several members of the VEGF family. In adult organisms, physiological angiogenesis is limited and occurs during regeneration of uterine epithelium in the menstrual cycle, development of the ovum and formation of corpus luteum and hair growth (20). VEGF has a central role

in promoting angiogenesis as well as influencing diverse cell functions, including cell survival, proliferation and the generation of nitric oxide and prostacyclin (21). The perifollicular capillary network is coupled to the hair cycle, increasing during anagen and then regressing during catagen and telogen. It has been investigated that metabolically ‘resting’ telogen follicles have considerably lower perfusion requirements than larger, rapidly growing, anagen hair follicles. With the use of standardized quantitative histomorphometry, electron microscopy, and CD31 (platelet endothelial cell adhesion molecule-1 [PECAM-1]) immunohistochemistry as an endothelial cell marker, it was shown that the cutaneous microvasculature is substantially rearranged during anagen development, that there is endothelial cell proliferation, and that there is an increase in endothelial cell numbers in anagen (22). Taken together, these studies suggest that anagen development, at least in species with a synchronized hair cycle, is associated not only with a rearrangement of the skin vasculature and a concomitant increase in skin perfusion, but also with genuine and substantial angiogenesis. Therefore, modulation of angiogenesis is considered as therapeutic strategies of great importance for hair growth (23). The role of various nutrients and minerals in preventing hair loss is summarized in Table II.

Table II. Role of nutrients and minerals in the prevention of hair loss. Nutrients and minerals

Mechanism of preventing hair loss

Niacin (vitamin B3)

.

.

Vitamin B complex

. . .

Ascorbic acid (vitamin C)

.

Tocoferol (vitamin E)

.

Zinc

.

Essential fatty acids (primrose and salmon oil)

.

Amino acids (L-cysteine and L-methionine)

.

.

Enhances blood flow to scalp through vasodilatory effects Reduces the level of cholesterol and hence the level of 5-alpha reductase on scalp Improves blood flow to scalp Decreases cholesterol accumulation to scalp Protects hair and scalp from free radical damage Improves blood flow to scalp and maintains capillaries carrying blood to follicles Enhances oxygen uptake and thus improves blood flow to scalp Enhances immune function and thus stimulates hair growth Improves hair texture Prevents loss of dry brittle hairs Improves quality of hair texture

Hair growth and rejuvenation Anti-androgen therapy


Flutamide and cyproterone acetate in combination with ethinyl-estradiol have been reported to show some effectiveness in female pattern baldness. Spironolactone is a steroid used mainly as a diuretic and antihypertensive agent. Side effects cause androgenreceptor blockade and direct inhibition of testosterone production by the adrenal gland. Therefore, this aldosterone antagonist (spironolactone) is used in dosages from 75 mg to 150 mg per day with some benefit in hair loss.

Heterocyclics

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solution must be applied to the balding area twice a day, every day. Decreasing the dosage to once a day results in some hair loss, and discontinuing application causes regression to pretreatment baldness within 3–6 weeks. The disadvantages of minoxidil are: (i) lifetime commitment; (ii) high cost: it is not covered by health insurance schemes as it is considered a cosmetic; (iii) its side effects – including itching and prickling, headaches, dizzy spells and, in some, heartbeat irregularities (34). Although apparently safe when rubbed into the scalp – since little is absorbed into the bloodstream – it is a vasodilator and not recommended for anyone with heart trouble. Its safety in pregnant women, men over the age of 49 years and long-term use is unknown.

Minoxidil Minoxidil was first used in tablet form as a medicine to treat high blood pressure, but it was noticed that some patients being treated with minoxidil experienced excessive hair growth (hypertrichosis) as a side effect. Further research showed that by applying topical minoxidil solution directly to the scalp, it could prove to be beneficial to those people experiencing hair loss. Topical minoxidil (2,4-diamino6-piperidino pyrimidine-3-oxide) is the only drug approved by the Food and Drug Administration to treat male and female pattern baldness. Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarcolemmal KATP channels (24). There is some evidence that the stimulatory effect of minoxidil on hair growth is also due to the opening of potassium channels by minoxidil sulphate, but this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle (25,26). Minoxidil stimulates mitosis in epithelial cells, inhibits collagen synthesis, prolongs the survival of epithelial cells in tissue culture and stimulates vascular endothelial growth factor and prostaglandin synthesis (27–30). It has therefore been suggested that the drug slows the aging of hair matrix cells. It is postulated that it delays or prevents the entry of some follicles into the next anagen phase for long periods of time and stimulates these follicles back into active production. Various studies have verified the hair growth-promotion activity of minoxidil (31,32). Also, both 5% and 2% topical minoxidil helped improve psychosocial perceptions of hair loss in women with female pattern hair loss (33). Topical minoxidil is effective at a concentration of 2%. Successful treatment, however, does require a lifetime commitment. The topical

Pyridine derivatives These include pinacidil, nicorandil, RP-49356 and P-1075. They are K+-channel openers. They play a role in regulation of the hair growth cycle. Potassium channel biology is a widely diverse field that has an impact on many aspects of physiology. More than 15 different types of potassium channels have been identified in various tissues. These channels are classified into four subtypes: voltage dependent, calcium dependent, receptor coupled, and miscellaneous. Specific classes are defined by the magnitude of the electrical conductance of the channel, the types of pharmacological agents that block the channel, and the physiologic properties of the channel. Potassium channel openers stimulate proliferation of cells in cultured vibrissae and skin keratinocytes. They elicit hypertrichosis in humans (35–37). Buhl et al. tested the effect of topical application of minoxidil and three other potassium channel openers on scalp hair growth in balding macaques. Minoxidil, cromakalim and P-1075 (a pinacidil analogue) all stimulated hair growth over a 20-week treatment period. A fourth potassium channel opener, RP-49,356, was not effective. Systemic pinacidil induces hypertrichosis in 2–13% of patients (38).

Benzothiazide derivative Diazoxide is also a K+-channel opener. Diazoxide was reported to increase the uptake of thymidine in a dose-dependent fashion in 4-day cultures of mouse vibrissae follicles (31,39). Oral diazoxide causes hypertrichosis in most hypoglycemic children and about 1% of adults, and induces some scalp hairs in 25% of the balding patients (40).

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Steroids


4-Aza steroids Finasteride is a 4-aza steroidal drug which acts by inhibiting the 5-alpha reductase (enzyme) that transforms testosterone into the dihydrotestosterone (DHT) form, responsible for hair loss (41,42). It was originally used to treat benign prostate hyperplasia or prostate enlargement. Blocking the action of DHT seems to stimulate growth of stronger, thicker and more pigmented hair. In a study, finasteride was administered orally at 0.5 mg/day, alone or in combination with topical 2% minoxidil, for 20 weeks to determine the effects on scalp hair growth in balding adult male stump tail macaque monkeys. A l-day dose-finding study showed that both 0.5- and 2.0-mg doses of the drug produced a similar diminution in serum DHT in male stumptails (42). In another study, finasteride was found to regrow a noticeable amount of hair in about 40% of balding men (43). Finasteride may not be very effective in men over 60 years (44). As DHT is required for normal sexual functions in men, the side effects of finasteride include sexual performance problems (in about 3% of the sample), such as impotence, loss of libido, reduced sperm counts or erectile dysfunction. Finasteride is also not approved for women (even in small concentrations it causes a specific birth defect – hypospadias, which involves abnormalities of the external genitalia of a male fetus) and has not been shown to work for a receding hairline at the

temple. These side effects may last for as long as the medicine is taken. Besides finasteride, other 4-aza steroidal drugs are dutasteride, episteride and turosteride.

6-Aza steroids These are 6-aza androstane derivatives and show hair growth activity. They are type I 5-alpha reductase (located in the sebaceous glands) inhibitors but are not time-dependent like finasteride, which is a time-dependent inhibitor of type II 5-alpha reductase (45,46).

Natural products Many ancient Ayurvedic (ancient Indian system of medicine) and Chinese herbal drugs have been reported and documented as potent hair growth promoters. The natural products are reported to be more effective alternatives for hair growth therapy than the synthetic drugs. Numerous bioactive plant compounds have been tested for potential clinical applications. Various natural products associated with hair growth activity are listed in Table III. In the search for a safe and effective alternative therapy for hair loss, many studies on herbal drugs have been performed in the last few decades. Recently, it was reported that epigallocatechin-3-gallate, a major polyphenolic constituent of green tea,

Table III. Herbal drugs for hair growth promotion. Herbal drug

Mechanism of preventing hair loss

Grape seed

.

Rosemary oil

. .

Sage (Salvia officinalis)

. .

Emu oil

.

Aloe vera

.

Contains proanthocyanidins, which are potent antioxidants and act as a smooth muscle relaxant in blood vessels and capillaries, preventing or offsetting damage to the hair follicle blood supply Improves blood flow to scalp Cleansing the scalp and stimulating the hair root Thickens hair shafts and helps dissolve sebum deposits Improves blood flow to scalp Inhibits 5-alpha reductase and thus lowers the DHT level in the scalp

Bee pollen

.

Its proteolytic enzymes slough off dead skin cells and open pores Increases membrane fluidity and permeability and the outward flow of toxins and inward flow of nutrients Inhibits 5-alpha reductase activity Protects small blood vessels and micro-capillaries against loss of tone and fragility Being rich in L-cysteine, it stimulates hair growth (since hair is 8% L-Cysteine)

Green tea

.

A potent inhibitor of 5-alpha reductase and thus lowers the DHT level in the scalp

Saw palmetto (Serenoa repens)

.

Blocks DHT production

Nettles (Urtica dioica)

.

Provides silica for hair growth Improves blood flow to scalp Improves blood flow to scalp which leads to dense hair growth

.

Ginkgo biloba

. .

.

Hibiscus rosasinensis DHT = dihydrotestosterone.

.


Hair growth and rejuvenation might be useful in the prevention or treatment of androgenetic alopecia by selectively inhibiting 5-alpha reductase activity (47–49). Polyphenolic compounds (such as epigallocatechin-3-gallate) and catechins of green tea are the major phytoconstituents that are responsible for its hair growth activity. Adhirajan et al. (2003) evaluated the petroleum ether extract of the leaves and flowers of Hibiscus rosasinensis for its potential on hair growth by in vivo and in vitro methods. From the study it is concluded that the leaf extract, when compared to the flower extract, exhibits more potency on hair growth (50). In another study, Adhirajan et al. (2001) studied a mixture of petroleum ether extract of Eclipta alba Hassk. (compositiae), Citrullus colocynthis Schrad. (cucerbitaceae) and Tridax procumbens Linn. (compositeae) in various concentrations in the form of herbal cream and herbal oil (51). The ratio of E. alba, C. colocynthis and T. procumbens in 3:1:2 showed excellent hair growth activity with 35% more anagen hair follicles as compared to 20% with a standard drug (2% ethanolic solution of minoxidil). Roy et al. studied the effect of successive petroleum ether and ethanol extracts of C. colocynthis and Cuscuta reflexa on hair growth in albino rats (52,53). The extracts were incorporated into an oleaginous ointment base and were applied topically on the shaved denuded skin of albino rats. The time required for initiation of hair growth as well as completion of the hair growth cycle was recorded. The hair growth initiation time was significantly reduced to half on treatment with the petroleum ether extracts compared with untreated control animals. The time required for complete hair growth was also considerably reduced. The treatment was successful in bringing a greater number of hair follicles (> 70%) to the anagen phase than standard minoxidil. In another study, the polyherbal formulation of C. reflexa (Roxb.), C. colocynthis (Schrad.) and E. alba (Hassk.) were developed and evaluated the same for hair growth-promoting activity. The hair growth initiation time was markedly reduced to one-third on treatment with the prepared formulation compared with control animals (54). The time required for complete hair growth was also reduced by 32%. Quantitative analysis (by the method described by Uno) (55) of the hair growth cycle after treatment with prepared herbal formulations and minoxidil (2%) exhibited a greater number of hair follicles in the anagen phase compared with controls. Rho et al. examined the effects of 45 plant extracts that have been traditionally used for treating hair loss in oriental medicine in order to identify potential stimulants of hair growth. Asiasari radix extract showed hair growth-promoting potential (56). In another study, Rho et al. studied the hair growth-promoting effect of Sophora flavescens and

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showed that it can be used as a potential hair growth promoter (57). An independent study was designed to test the effectiveness of topical crude onion juice (Allium cepa L.) in the treatment of patchy alopecia areata. The patients were divided into two groups. The first group (active: onion juice) consisted of 23 patients (16 males and seven females). The second group (control: tap-water) consisted of 15 patients (eight males and seven females). The two groups were advised to apply the treatment twice daily for 2 months. Re-growth of terminal coarse hairs started after 2 weeks of treatment in the active group. At 4 weeks, hair re-growth was seen in 17 patients (73.9%), and at 6 weeks hair re-growth was observed in 20 patients (86.9%); it was significantly higher among males (93.7%) compared with females (71.4%). In the control group, hair re-growth was apparent in only two patients (13%) at 8 weeks of treatment with no sex difference (58). The extract of Illicium anisatum increases subcutaneous blood flow in mice. In a study, an organ culture system was used to examine the hair follicle elongation effect of this extract (59). In this study, B6C3HF1 mouse vibrissae follicles were cultured in serum-free medium for 7 days at 31 C. Follicles treated with water-soluble extracts of the leaves, fruits and roots of I. anisatum or shikimic acid grew significantly longer than controls. Bisbenzylisoquinoline alkaloids were isolated from Stephania cepharantha and their proliferative activities on cultured hair cells from the murine skin were evaluated (60). Cepharanthine, cepharanoline, isotetrandrine, and berbamine showed significant activities in the range of 0.01–0.1 mg/ml, but had no activity on cultured keratinocytes or fibroblasts from the murine skin. Recently, stem cells inducing the anagen phase in the hair follicle cycle have been discovered in the bulge region of the outer root sheath (ORS). To find growth-promoting agents for the ORS cells, the effect of various botanical extracts on the growth of cultured human hair follicles was evaluated. It was found that Laminaria angustata extract increased ORS cell growth. Further, hair growth in the shaved skin of C3H mice was also promoted by the topical application of the extract (61). The other herbal drugs studied for hair growth activity include nagarmotha (Cyperus rotundus), neem (Azadirachta indica), amla (Emblica officinalis), Brahmi (Bacopa monnieri), bahera (Terminalia bellirica), methi (Trigonella foenumgraecum), laljari (Geranium wallichianum), bhallataka (Semecarpus anacardium) and capsicum. Various patents have also been granted for hair growth potential of herbal

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drugs such as Ginkgo biloba, Berberis vulgaris, Zingiberis recens, Pinellia ternata, Flos carthami, Angelicae sinesis, Paenoiae rubra, Cacumen biotae, Sesami nigrum, Polygoni multiflori, Fructus mori, Capsicum annum and Oleum ricin (62–65).


Miscellaneous Various topical sensitizers such as dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE), and diphenylcyclopropenone (DPCP) have determined the re-growth of hair in patients with alopecia. Anthralin, the only non-specific irritant widely used for hair growth in alopecia areata, is applied topically as a 0.5% or 1% cream to affected areas once per day for 20–45 minutes; overnight application can also be used in certain patients who can tolerate the side effects (66). LY 191704 (a benzoquinoline derivative), All-transretinoic acid [(tretinoin) (3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-non-2,4,6,8 tetraenoic acid)], 6-benzyl-aminopurine (6-BA) and pentadecanoic acid (PDA), cromakalim, etanercept, infliximab, RU58841 and latanoprost are some newer hair growth-promoting agents (67,68).

vasodilation through potassium channel opening and 5-alpha reductase inhibition are the major non-surgical therapeutic strategies for hair growth promotion. Modern synthetic drugs have been found to show potential in promoting hair growth. Various clinical trials and studies have validated the use of hair growth-promoting modern synthetic drugs. But, in spite of proven hair growth-promotion effects, therapy with the synthetic drugs has become questionable due to their occasional lack of efficacy, safety or their side effects. Herbal drugs may provide a new revolution for hair growth. A majority of hair growth-promotion studies performed with herbal drugs are preliminary and more scientific data are necessary to prove those activities. This can be attained by careful and accurate characterization of the active chemical compounds, elucidation of the molecular mechanisms of their actions, development of more reliable hair follicle organ culture for ex vivo studies, in vivo studies on proper animal models of hair loss and, finally, analysis of their safety and effectiveness in clinical trials. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Patient consideration Alopecia is a disease of enormous psychosocial significance. Moreover, drug-induced hair regrowth in alopecia areata may be very slow; a cosmetic response may take 1–2 years to achieve. Fiedler reported three key elements to effectively treat the patient: (i) help the patient understand the disease; (ii) encourage the patient to share his or her feelings with the physician, family, friends, and other sufferers of the disease; and (iii) help the patient to maintain a sense of hope for future scientific knowledge and treatment of the disease (66). With a thorough knowledge of the potential benefits and risks of each treatment or combination treatment, the physician, with the patient’s understanding and cooperation, may then embark on what may be in severe cases a lengthy and sometimes unproductive therapeutic process.

Conclusion Hair growth-promoting agents are lifestyle drugs. The current status of treatment of alopecia is the result of recent advances in our understanding of its aetiology and progression. Angiogenesis (through endogenous substances), androgen antagonism,

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