CA1292947C - Melatonin compositions and uses thereof - Google Patents
Melatonin compositions and uses thereofInfo
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- CA1292947C CA1292947C CA000503269A CA503269A CA1292947C CA 1292947 C CA1292947 C CA 1292947C CA 000503269 A CA000503269 A CA 000503269A CA 503269 A CA503269 A CA 503269A CA 1292947 C CA1292947 C CA 1292947C
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- melatonin
- composition
- skin
- methoxytryptamine
- hair
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Abstract
ABSTRACT
MELATONIN COMPOSITIONS
AND USES THEREOF
The invention relates a method for conditioning the skin of a human host to improve its cosmetic and physical appearance and for preventing balding. It comprises topically administering to a site on the skin of said host an effective amount of a composition comprising melatonin and a pharmaceutical carrier for causing improvement in the cosmetic and physical appearance of said skin.
MELATONIN COMPOSITIONS
AND USES THEREOF
The invention relates a method for conditioning the skin of a human host to improve its cosmetic and physical appearance and for preventing balding. It comprises topically administering to a site on the skin of said host an effective amount of a composition comprising melatonin and a pharmaceutical carrier for causing improvement in the cosmetic and physical appearance of said skin.
Description
MELATONIN COMPOS:tTIONS ~ z9Z9~7 Al`lD USES THEREO~
Field of The Invention The present invention primarily relates to a method and compositlon for topically treating the skin and/or scalp of a human host More particularly, the present invention rela~es to the topical treatment of specific conditions oE the skin and scalp of a human host so as to enhance the condition of the skin and to treat areas of hair growth either to selectively remove hair from areas which normally do not have hair growth or to assist in the rejuvenation of partially degenerated hair follicles by using melatonin compounds.
Even more particularly, the present invention relates to a method and composition for enhancing skin condition and ~one, the preventlon or ameliorat1on of the conditions or symptoms of acne, seborrhea, hirsuitism and for the rejuventation of partially degenerated hair follicles through the use o~ melatonin compounds, homologues or derivatives.
Background of The Invention ;
Melatonin is a hormone secreted by the pineal gland that controls seasonal and circadian hormonal rhythms, and alters the metabolism of testosterone and enhances the ; availability of estrogen receptors in target tissues.
, ;~
~ ` ' 129Z~47 ~ince the isolation of melatonin in 1959, reports o~
- its ability to inhibit luteinizing horlnone (I,~l) secretion with ~ - .. . . .
control of fertility led researchers (Flaugh et al., 1978) to investigate the action of melatonin analogs on plasma half life to produce compounds witll the same biological activity as melatonin but with a prolonyed serum hal~-life.
Schloot et al have determined that patients suffering from psoriasis have a .severe disorder of melatonin secretion.
Treatment with psoralen for rising the serum melatonin concentration of the patient is suggested. They suggested that the antimitotic effect of ~elatonin may be of importance or the regulation of increased epidermal mitotic rate and decreased cell turnover time.
Hous~ay et al (1966) (1) have shown that the pineal gland and the parenteral ac~ministration of melatonin acts on the skin ~ mice to slow hair growth waves in mice.
NouJ3say et al (1966) ~2) describe that the parenteral treatment of mice with melatonin effects the hair growth waves in mice.
Rc,se et al (1984) have shown that it i3 po.s3ible to induce the growth of winter pelage in mink by implanting melatonin.
Logan et al (1980) have found that melatonin can inhibit in vitro melanogenesis in hair follicles of the Siberian hamster.
Heath et al ~19~2) have shown that ollicular development was blocked in mice injected with mela tonin.
Rats were used in the a.ssay to ~easure effects on LH
release and ovulation. Melatonin analogs were given p.o. and intravenou~ly. Pronounced increa~e in activity and half~ e was noted with h~logenation on the G ~ositivn.
Field of The Invention The present invention primarily relates to a method and compositlon for topically treating the skin and/or scalp of a human host More particularly, the present invention rela~es to the topical treatment of specific conditions oE the skin and scalp of a human host so as to enhance the condition of the skin and to treat areas of hair growth either to selectively remove hair from areas which normally do not have hair growth or to assist in the rejuvenation of partially degenerated hair follicles by using melatonin compounds.
Even more particularly, the present invention relates to a method and composition for enhancing skin condition and ~one, the preventlon or ameliorat1on of the conditions or symptoms of acne, seborrhea, hirsuitism and for the rejuventation of partially degenerated hair follicles through the use o~ melatonin compounds, homologues or derivatives.
Background of The Invention ;
Melatonin is a hormone secreted by the pineal gland that controls seasonal and circadian hormonal rhythms, and alters the metabolism of testosterone and enhances the ; availability of estrogen receptors in target tissues.
, ;~
~ ` ' 129Z~47 ~ince the isolation of melatonin in 1959, reports o~
- its ability to inhibit luteinizing horlnone (I,~l) secretion with ~ - .. . . .
control of fertility led researchers (Flaugh et al., 1978) to investigate the action of melatonin analogs on plasma half life to produce compounds witll the same biological activity as melatonin but with a prolonyed serum hal~-life.
Schloot et al have determined that patients suffering from psoriasis have a .severe disorder of melatonin secretion.
Treatment with psoralen for rising the serum melatonin concentration of the patient is suggested. They suggested that the antimitotic effect of ~elatonin may be of importance or the regulation of increased epidermal mitotic rate and decreased cell turnover time.
Hous~ay et al (1966) (1) have shown that the pineal gland and the parenteral ac~ministration of melatonin acts on the skin ~ mice to slow hair growth waves in mice.
NouJ3say et al (1966) ~2) describe that the parenteral treatment of mice with melatonin effects the hair growth waves in mice.
Rc,se et al (1984) have shown that it i3 po.s3ible to induce the growth of winter pelage in mink by implanting melatonin.
Logan et al (1980) have found that melatonin can inhibit in vitro melanogenesis in hair follicles of the Siberian hamster.
Heath et al ~19~2) have shown that ollicular development was blocked in mice injected with mela tonin.
Rats were used in the a.ssay to ~easure effects on LH
release and ovulation. Melatonin analogs were given p.o. and intravenou~ly. Pronounced increa~e in activity and half~ e was noted with h~logenation on the G ~ositivn.
~,Y ~
Frohn et al (19an) reported a structural activity relationships between 23 indoleamines and melatonin utilizing . . .
an in vitro fish pigment bioassay. Indoles were dissolved in ethanol and given intraperitoneally. In this model, halogenation at 6- position and minor variations o the N-acyl group were without effect on comparable in vivo activity.
Indole was found to be more active than melatonin. The 6-chloro-2,3-dihydromelatonin was believed to be a possible long acting melatonin agonist.
In a study of antagonists to the brain receptors for diazepam, melatonin and metabolites were tested to determine the inhibition of diazepam binding to rat synaptosomal membranes. ~elatonin and its CNS metabolite N-acetyl 5-methoxy kynurenamine were foun~ to be the most potent antagonists and beta carboline metabolites of melatonin were also noted as high affinity antagonists to diazepam (~1arangos et al., 1981).
Rollag (1982) studied 18 different tryptophan derivatives, many o~ which are found in the pineal gland, to induce gonadal rec~ression and aspermia in syrian hamsters.
Only melatonin and 5-methoxy tryptamine were found to possess anti-gonadotrophin action. The action of 5-methoxytryptamine is supported in Pevet's review (1983) but melatonin is the most effective agent.
Similar studies were conducted by Richardson et al ~19~3), Vaughn et al (19~3) with 6-chloromelatonin being the only analogue to possess anti-gonadotrophic activity equal to melatonin. Their paper reviews the structural activity literature evaluating melatonin analoc~ues. This same group (Vaughan et al., 1982) explored the action of melatonin natural and synthetic analogues on the efEects oE cholesterol and - lZ9Z947 thyroid levels in male syrian hamsters as compared to melatonin. The native hormone melatonin was follnd to be the .. .. .
only structure lowering T4 (thyroxine) levels.
In a frog skin assay, Frohn, et al., ~19aO) concluded that the tl-acetyl group attached to 3- position determines binding ~ite affinity while the 5-methoxy group confers activity.
Melatonin and related metabolites were found to be the principal excretory products of the pineal gland (epiphysis cereberi), an endocrine organ present intracranially in all vertebrates (Reiter, 1983). In lower vertebrates there are true morphological photoreceptors present in the pineal gland but in mammals the pineal gland receives signals from neural sympathetic sources which effect the production of its principal secretory product melatonin (Reiter r 1983). The primary secretory route of melatonin in mammals is by way of the capillary bed of the gland itself (Rollag et al, 1977).
~ elatonin (N-acetyl-methoxytryptamine) is primarily derived from tryptophan and synthegized via the action of tryptophane hydroxylase (Lovenberg et al., 1967). The pineal gland i8 the primary place for a major portion of physiological indolamine metabolism including that of the neuroeffector serotonin which is a major source of melatonin synthesis.
~- Melatonin synthesis is governed by light exposure and in man and other mammals and primarily produced in conjunction with night or in darkness from its pineal endocrine source. In addition to the pineaI body, both the retina, the harderian gland (in rodents) and gastrointestinal tract are producers of melatonin (Ralph, 1981 Reiter et al, 1983: Raikhlin et al., 1~75).
. . .
lZ~Z947 Besides melatonin, 5-methoxytopllol (~ilson et al., 1978) and 5-methoxytryptamine (Pevet et al., 1983) are produced ~, by the pineal and have been found to have endocrine effects.
The primary role of the pineal gland relates to its contral of reproductive physiology (Tamarkin et al., 1985;
Aren~t et al., 1983: Stetson ~ Watson-Whitmyre, 1984). ~s mentioned previously, secretion of melatonin is governed by light to dark exposure of the animal and there are short day or long day seasonal breeding animals who are influenced differently by melatonin production governed by the seasonal light cycle.
An example of systemic melatonin effects on reproductive hormona-l cycling are seen in the depression of testosterone production in mice given melatonin (Petterborg &
Reiter, 1981). Alternatively, depending on species, testicular re~ression can be prevente~ and testo~terone activity maintained ~Turek, 1977; Stetson et al 1933) in hamsters.
Uelatonin, given by injection, can alter estrous cycling in female rats (Trentini, et al., 1980). Evidence sùpports the possibility that melatonin levels may be a factor in suppre~sion of puberty in man (Tamarkin et al., 1985).
Ilelatonin is entering the commercial animal husbandry market to control fertility (breeding time), fur coat development and appetite. For example in ewes 2mg~day, in pe~leted feed, which mimics nocturnal blood levels, controls the estrou.s cycle and sheep fertility (Lincoln, 1983);
(Kennaway et al., 198~). Similar effects on daily feeding have been observed in male white tailed deer (Bubenik, 19~3) with earlier seasonal antler and coat changes.
... .. . _5_ ._ ~ .. ..
lZ~Z947 t1elatonin injected subcutaneously in saline or oil pro~uces high transiel~t blood levels while oral adminstration _, . . . . ..
in saline or food pellets peoduces sustained blood levels ~Kennaway & Seamark, 1980). ~elatonin has been orally given in drinking water (Pevet and Tlaldar-s~isra, 1982) or by subcutaneous slow release implants, i.e., sialastic (Turek, 1977; Losee and Turek, 1980; Kennaway & Gilmore, 1984) or by injection (Sisk & Turek, 1982).
The duration of melatonin exposure is significant since constant levels can produce refractoriness, thus intermittant exposure and the relation of melatonin to the animals photoperi~d (light/dark cycle) is important (Stetson et al , 1983; Losee & Turek, 1980; Trentini et al., 1980; Stetson and Tay, 1933; Bittman, 1984; Tamarkin et al., 1985).
Melatonin injections can mimic syrian hamster short day photoperlod exposure with lncreases in body weight gain, feed efficiency, enhanced carcass lipid and brown adipose ti~sue ma~s and thermogenic capacity (Bartness & Uade, 1984).
The clinical use of melatonin in CI~S disease has been reviewed by Anton-Tay ~1974) an~ Romijn (1978) and there have been extensive studies of its intravenous, intrathecal and direct localized CNS implantation on behavior in a wide range o~ animal species that has led to clinical trial.
Waldhauser et al. (1984) have reviewed the clinical use of melatonin. They indicate that aproximately 150 subjects have received clinical melatonin intravenously or orally. In most cases, no significant toxicity was observed (Lerner &
~lorlund, 1978). As much as 3-6 gms of melatonin has been given orally daily for 1 month with reports of abdominal cramping and tranquilization (Papavasiliou, et al., 1972).
`~ -6-,, , . .. . _ . . .. . .. _---- ~
12~Z947 ~ qelatonin has been given clincally to volunteers by mouth in carbowax at 1-25 u~/kg (~nton-Tay, 1974) or clinically to voltlnteer~ by mout~ in-corn oil as a .04~ solution at a dose of 2mg/day for 4 weeks (~rendt et al., 1984). It has been given orally in dose.s of 250mg (Morlund and Lerner, 1977) and in doses up to 1.2g/day (Anton-Tay, 1974; Carmen et al., 1976 ~nton-Tay et al., 1971). These studies have demonstrated a systemic effect of melatonin with reports of melatonin induced fatigue and depression or sleep.
Melatonin has been given to human subjects in doses of 50mg intravenously (Pavel et al., 1981; Cramer et al., 1974) where it induced sleep with normal or enhanced REM
electroencephalographic patterns. Melatonin's sedative action has been confirmed by H. Lieverman, as cited by ~aldhauser et al (1984)~ and ar supported by the results of intranasal administration where melatonin, a~ a 0,85 per cent ethanol spray induced sleep in 70 per cent of patients within 40-60 minutes (~ollrath et al., 1981).
Melatonin has been studied p.o. and i.v. clinically in depression and in ~untington's chorea with no improvement or clinical worsening (Carman et al., 1976). In two patients with schizophrenia, I.V. melatonin (300mg) worsened hallucinatory symptoms (Altschule cited by Carman et al., 1976).
In epilepsy, melatonin has produced some benefit on i.v. administration at a 1 per cent solution in ethanol at dosages up to 1.25mg/kg i.v.. In Parkinsonism, given i.v. or p,o. for a daily total of 1.2 gms for 4 weeks ~Anton-Tay et al., 1971), amelioration o~ tremor and rigidi~y have been seen although results have not been consistent in studies of Parkinsonism with all investigators as Papavasilou et al., 1972 ~. . - . . . . .. . . . .
lZ9Z~47 has not seen benefit with doses as high as 6 gms daily. Carman et al. (197~) have review the CNS clinical stuclies up to that ~ time and the use of ~elatonin for the treatment of tre~or and rigidity looked promislng.
Melatonin has been given at dosages of lmg/kg i.m.
with advanced breast cancer for periods up to 2 months. These studies were conducted after trial at 5 and 20mg/kg i.m. daily for up to 10 days in monkeys with no report on clinical response other than a report of a decline in urinary estrogen ~Burns, 1973). Blask (1984) has reviewed the role of melatonin in the clinical treatment oE malignancy. ~e cites DiBella and Starr as achieving inhibitory clinical results in a variety of tumors.
In relation to endocrine action, Smythe and ~azarus (1974) have given 0.5gms of melatonin ~or 2 doses, 30 minutes apart with a reported melatonin related rise in growth hormone.
Melatonin has been used in veterinary medicine in the treatment of acanthosis nigricans in dogs. This disease is associated with thickening of the skin, pigmentation and pruritus. Rickards (1965) and ~i~k (1979) have successfully treated canine acanthosis nigricans by subcutaneous injection utilizing 2mg injections of melatonin for daily and extended weekly treatment periods.
In regard to local modulation and inhibition of steroid synthesis, melatonin on in vivo and in vitro treatment has shown in vivo an~ in vitro inhibition of te3ticular synth~sis from cholesterol and pregnenolone precursors of testosterone and androstenedione synthesis in the rat teste~
(Peat & Kinson, 1971).
. -8-q ~,.. , ., . ~ . . . . . - . ..
. ~ .
i. .. -, .
~Z9Z947 , The inhibiting effects of melatonin on testicular function have been associated with stimulation of - delta-4-reductase in ~ ive~ an(~ h~pot~al~us`tFrehn et al., 1974). Melatonin was found to specifically increase the 5-alpha reductase of semini~erous tubules for ~oth progesterone and te~3tosterone. Melatonin decreased androgen synthesis in both testicular interstitial cells and tubules ~El~is, 1972).
Similar increases in 5 alpha reductase activity in rats by melatonin have been observed on adrenal cortical function (Ogle & Kitay, 1977).
Melatonin reduced accessory sexual organ size in pinealectomized male rats kept in constant darkness without inhibiting testosterone metabolism leading the authors (Shirama et al., 198~) to suggest that melatonin is possibly acting at the tissue level to reduce the numbers of androgen receptors and/or the susceptability to androgen Orally administered, melatonin was foun~ to lower ventral prostate and seminal vesicle weight and the 3/beta-hydroxysteroid oxidoreductase was increased but not the S alpha reductase in the ventral prostate and seminal vesicles of pinealéctomized rats (Horst et al., 1982). The authors felt that this reflects on increased androgenic catabolism resulting in prostatic involution. The effects of melatonin on prostatic androgen receptors can depend on the age of the animal and light cycle exposure ~Moeller et al., 1983).
Melatonin in vitro when combined with chorinonic gonadotrophin or ovine luteiniæing hormone increased the secretion of esteogens and progesterone in isolated granulosa cells of the rat. Melatonin, in relation to ovarian function, showed a progonadal trophic effect (Fiske et al., 19841.
; ' ~' ' ' ' ' lZ9Z947 In recJard to local stimulation of estrogen receptor availability by melatonin in cutaneolls areas oE andro~ellic an~
estrog~;nic hormone sensitivity.~~``There is`evidence~that- -`~~ ~-~--~~7--~~:-melatonin increases cytoplasmic estrogen receptor activity in hamster uteri and similar effects have ~een observed in estrogen receptor binding activity in human breast cancer cells (~anforth et al., 1983).
Other reviews of the ph~siological role of melatonin are found in:
-G.M. VA~JG~N et al., titled "~vidence for a pineal-gonad relationship in the human~, published in Prog.
Reprod. ~iol Vol 4, p. 191-223, 1978.
-H.L. JUDD, titled "Biorhythms of gonadotrophins and testicular hormone secretion", published in Endocrine Rhythms, 1979.
-D.P. C~RDINALI et al., titled ~Melatonin action:
sites and possible mechanisms in brain~, published in ~The pineal gland and its endocrine role~, J. AX~LROD, F. FRASC~INI
and G P. VELO, eds. Proc. Wato Adv. Study, Erice, Italy, p.
551-575, Plenum Press, ~ew York, 1982.
-R.J. WURTMAN, et al., titled ~The secretion and effects of melatonin in humans~, published in ~The pineal gland and its endocrine role~, J. AXELROD, R. FRASCEIINI and G.P.
VELO, ed. Proc nato Avd., Erice, Italy, p. 551-575, Plenum Press, New York, 1982.
-The Third Colloquium of the European Pineal Study Group~ PECS 1984, published in EPSG Newsletter of August, 1984 -R.J. ~urtman et al, entitled ~Physiological Control of ~qelantonin Synthesis and Secretion: Mechanisms Generating Rhythms in 11elatonin, Methoxytryptophol~ and Arginine ,. . ~ . .. , .. , , . . ~ , , :l;Z9Z947 Vasotocin LeVels and Effects on the Pineal of Endogenous Catecholamines, tlle Estrous Cycl~, ànd Environmental Li~llti!~g~, J. of Neural Transmission, Sllppl. 13, 59-70 tl97~).
-Ivor Smith, entitled "Indoles of Pineal origin:
Biochemical and Physiological Status", Psychoneuroendocrinology, Vol. 8, No. l, pp 41-60 (1983).
Surprisin~ly, none of the prior art studies are concerned with the dermatological effects of the administration of melatonin to a human host. ~10reover, there have been no previous studies regarding the topical application of melatonin, its homologues or derivatives for humans. The prior art studies do indicate that the compounds of the invention can be safely administered to humans in the treatment oE various diseases.
Summary Of The Invention In accordance with the present invention, there is provided a method and composition for treating the skin and ~calp of a mammal by the administration of a composition ," ,~ ~
c~ontaining a melatonin compound in order to ~nprove the cosmetic, physical appearance or functional role.
More particularly, the present invention provides a composition for use in the treatment of the skin and/or scalp of a human host in order to enhance the ~kin's condition and tone, prevent or amellorate the conditions or symptoms of acne, seborrhea, hirsuitism an~ fot the rejuvention o live but degenerated hair follicles.
The preferred active o~ the compositions of the invention consists of melatonin itself. Among the chemical - ,. s .
lZ9Z947 -~
homologues useEul for the production of compositions according to the invention, there ean be mentioned the class of compounds which are represented by ~he general ~ormuI~a:
.
(C112)"~
il. which;
-n is 1 or 2 -Rl and ~2 are identical or dlfferent from each other and are H, N~2, COOH, ~H or acyl comprising from 1-4 carbon atoms or alkoxy comprising from 1 to 4 carbon atoms:
-X i8 0~ or alkoxy comprising from 1-4 carbon atoms:
-Y is ~ or NH2.
Preferred compounds ~or use in the compositions of the invention are tho~e in which Y is hydrogen and X is methoxy.
The most preferre~ compound i8 melatonin itself, the formula of which i8:
2 ~ ~i2 - NH - C - c~3 NH
~: ' ' " ' ' , .~ .
,~
~ -12-12~9~7 Other preferred compounds for use in the compositions of the inven~ion are 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-me~hoxyindole-3-aceti~ acid and 6-hydroxy-melatonin.
These compounds can be obtained by synthetic proce~se~, general methods of manllacture which can be derived rom those published by J. SZMUS~KOVICZ "Synthesis of ~-acetyl-5-methoxy-tryptamine~, J. Org. Chem. 25, 857 (1960),J.
SUPNIEWSKI et al., "Synthesis of melatonin (5-methoxy-N-acetyltryptamine", published in Bull. Acad. Polon.
Sci. Ser. Biol., 8, p. 479-481, 1960; or MASHKOVSK~ et al. in Farmakol. Toksikol., 26, n 1, 10, 1963, said methods being of course in each case adapted to the particular compound sought.
The term ~melatonin" is used hereafter to designate both the actual melatonin and the chemical homologues or derlvatives thereo~.
De~cription of The Preferred Embodiments In a first preferred embodiment of the invention, the composition is in a form suitable for topical application for humans. Advantageously, this composition is in the form of a cream, ointment-or lotion or another cosmetic liquid applicable externally. Such composition is then of a particular utility for preventing, attenuating or curing acne or for conditioning the skin to improve its appearance and texture Acne is a common inflammatory pilosebaceous disease characterized by comedones, papules, pustules, inflamed nodules, superficial pus-filled cystfi, and, in extreme cases, canalizing and deep inflammed, ~ometimes purulent sacs. Its -~3-' ' lZ9Z9~7 patho~enesis is complex; an interaction between hormones, keratinization, sebum and bacteria somehow determines the course and severity of the disease. The common form of acne is a feature of adolescence in both sexes, and androgen seems to be the essential factor, operating through stimulation of the sebaceous glands. Acne lesions predominate on the face but are also common on the neck, chest, upper back and shoulders.
The compositions in accordance with the present invention are particularly useful in the management of simple uncomplicated acne, such as, acne vulgaris. Acne vulgaris is a condition which involves the eru~tion of papules and pustules on an inflammatory base. The condition occurs primarily during puberty and adolescence due to overactive sebaceous apparatus which is believed to be affected by hormonal activity.
The other components of ~uch composition.~ can be the usual ones. It i~ advanta~eous to use compositions in which melatonin i8 associated with a lipophylic substance, both being dissolved in an appropriate solvant. For instance, the melatonin homologues may be used in the form of a solution in a water-ethanol mixture containing from 10% to 30~ vJv or more of ethanol. However, the amount of active ingredients may be more or less depending on the specific conditions to be treated and the degree of treatment needed.
The compositions for acne and seborrhea control or skin conditioning can also be use-3 in a therapeutic environment or application, in addition to the cosmetic uses which have been mentioned here above. Particularly, the compositlon o~
the invention, whether it be used locally or regionally in the form of a cream, oint~ent or lotion or Oe another form of composition, can also be used for the prevention or treatment .:
. .
lZ929~7 of androgen or drug-induced acne or seborrhea, for instance, in patients subjected to androgenous hormone therapy in cancer therapy.
In addition, melatonin can be used alone or in conjunction with topical estrogens to enhance topical or endogenous estrogen action on the skin for the prevention and treatment of acne or seborrhea or for cosmetic effects related to improving the texture and physical appearance of aging skin.
The prime use of melatonin, alone or in conjunction with estrogens will be during adolescence when the oiliness of skin and the plugging of sebaceous glands results in acne vulgaris and seborrhea. ~lternatively, alone or in conjunction with estrogen in pre or post menopausal women where dryness and 108g of skin texture has been agcribed to the decline in estrogen. The estrogen~ may be applied separately or in combination with the melatonin.
An additional use for melatonin is by direct applica tion to the vaginal mucosa, alone or in conjunction with estrogen to restore the quality and secreting capacity of atrophic sexual skin in the vagina.
The topical application of melatonin, alone or in conjunction with estrogen (oral or parenteral administration) will improve the texture (elasticity and vascularity) of skin subject to atrophy seen in association with the 105s o estrogen with aging.
Whatever the use of the topical composition or lotion, the concentration of the active compound therein should be su~ficient for providing a good local absorption o the active ingeedients.
~29Z~47 The mechanism of melatonins local action }s based on the observations that it ~auses a local increase of the binding activity of estrogen receptors and can ameliorate the action of testosterone on the skin through enhancement of the local efEect o~ estrogen.
In re~ard to the above, the cause of acne vulgaris and seborrhea (increased sebum production, oily skin) can be due to an excess of testosterone or related androgenic hormones.
Current treatment of acne vulgaris includes the topical or systemic use of agents that provide estrogen or suppress the production of testosterone.
A suitable acne preparation may comprise the following:
t1elatonin lO~ in a colorless, greaseless lotion which contains water, aluminum hydroxifle, isopropyl stearate, PEG-lOO
stearate, glyceryl stearate, cetyl alcohol, glycereth-26, isocetyl stearate, glycerin, dimethicone copolyol, sodium citrate, citric acid, methylparaben, propylparaben, fragrance.
The preparation amongst the beneficial effects which the preparation provides are:
l.~ helps heal and prevent acne pimples.
11elatonin dries up and kills acne causing bacteria to help prevent new ones.
2.) helps absorb excess skin oil oEten associated with acne blemishes. The preparation preferably contains aluminum hydroxide, or other like materials, such as bentonite, which is a special oil absorbing ingredient that allows the lotion to absorb more excess skin oil than melatonin alone.
3.) helps the skin look fresh. Extra oil absorption helps the skin look less oily, more natural. If desired, the preparation can also contain ~ulfur and/or .
~,. , .~ ,. . .:
~ ~......
lZ9Z947 r~ ~inol or other known active ingredients to help heal the acne pimples. However, the additional ingredients may be applied ~eparately.
The following publications describe the various methods of treating the acne condition:
- C. R. DARLEY et al., titled: ~Circulating testosterone, sex hor~one binding globulin and prolactin in wo~en with late onset or persistent acne vulgaris~. Br. J.
Dermatology, 106: 517-S22 - G. S. GINSBERG et al. (1981) titled: ~Androgen abnormalities in acne vulgaris~. Acta De~matovener 61: 431-434. ~
- R. P~L~T~I, et al., (1978) titled: ~Treatment of ' acne w~th cyproterone acetate and ethenyl estradiol~, Acth ~erlnatovener 58: 449-454.
- J. H. CHeRK (19~0) titled: ~Improvement of lntractable acne in man following testosterone suppression using dana~ol~. Cutis: 2~: 393-394.
- J. B. SCHMIDT, J. SPONA (1983) titled: 'Hormone receptors in nor~al skin and acne~. Endocrinologica Fxperimentalis 17: 137-144, 1983.
- J. ZABEL: titled: ~Uptake of H-testosterone in the skin of healthy women and in the skin of patients with acne vulqaris~. Acth ~istochem: 64: 243-248.
As previously mentioned, melatonin has been shown to have a direct effect on the metabolism of steroids in peripheral organs such as ovary, testes, adrenals and ptostate. Thus, its action on the ~kin may be by cutaneous ~3~ ' l~Z~47 ~alteration in the metabolism oE androgens, i.e., blocking the targeting effects of testosterone on sebaceous glands and hair follicles. Alternatively, rnelatonin may produce its therapeutic effect via an increase in estrogenic receptors in the skin and seborrheic glands. Melatonin can felninize the skin by increasing its capacity to respond to estrogen through an increase in cutaneous estrogen receptors or through an attenuation of androgen response.
The action of estrogen as a skin conditioner is enhanced by melatonin's local action in modulating the increase in estrogen;c receptors. Thus melatonin's action on aging skin of postmenapausal women or aging males is mediated by enhancing local estrogenic effects. This is of value in restoring cosmetic quality to the skin (moisturn, vascularity, elasticity) as well as re~toring the local respQnse of vaginal epithelium to estrogen More generally, the compositions of the invention (either in the form of lotions, creams, or ointments) of the invention are useful for the up-keeping of skin in good condition or for skin-regeneration, particularly in an aging population. The administration or use of melatonin will allow in particular the restoration of the skin functions including elasticity and moisture content. Even more generally melatonin is capable of controlling body odors by altering sebaceous secretions, the up-keeping of skin moisture and of all key factors associated with hormones involved with sebaceous or secretion which govern in part sexual attraction. The invention particularly includes perfume compositions deodorants or toiletries supplemented with melatonin.
. . .
lZ~Z947 second preEerred emb~diment oE the invention relates ~ to compositions containing melatonin, their chemical homologues .. . .
an~ derivatives, for preventing hair growth in androgenic skin sensitive areas that are cosmetically of concern for aesthetic and sexual differentiation reasons, i.e., face, upper lip, chin, cheeks, neck or on the body: chest, breast, nipples, abdomen, pelvic triangle, shoulders, back, buttock and extremities.
This particular invention provides selective regionalized or local hair loss, hair prevention, slowing or attenuation of hair growth in areas of androgenic (masculine) growth patterns where hirsuitism is considered superfluous.
This embodiment of the invention involves the application of melatonin, its homologues or derivatives for the control of:
(1) Facial Hair: To 3ecrease the frequency or eliminate the need for shaving or to make the beard more amenable to shaving.
(2) Hirsuitism: Hirsutism is defined as excessive hair growth in areas usually not hairy. In most instances, excessive growth of body hair in women cannot be traced to an endocrine cause, but occasionally a mild androgenic influence of ovarian or adrenal origin is suspect. Hirsutism is seen frequently at menopause and with systemic androgenic steroid or corticosteroid therapy, and may occur in porphyia cutanea tarda. To reverse or prevent excess terminal hair growth in areas of excess (androgenic) masculine growth patterns. This is particularly applicable to -19~
.~.. A . . ..
1292~47 women to control facial or body hair to meet cultural or individual views of what is cosmetically acceptable regarding facial or body hair. Hirsuitism is a problem in as many as 5%
of women or even moee depending on esthetic or cultural values.
This invention strictly considered ~hould not be considered to be a depilatory but in effect a modulator and attenuating influence on the stimulating action oE androgenic hormones on hair growth. In this regard, androgenic hor~ones are responsible for facial hair arowth in men and women as well as the male pattern of body hair and the thickness and quantitative measurement of hair growth as part of a spectrum of virilization of which hir~uitism can be a significant part.
The following publication discloses additional methods of treating hirsuitism which may be used in conjunction with the present invention.
- HATCH et al. titled ~Hirsuitism: ~mplications, etiology and management~ Am. J. Obstetrics and yynecology 140:
815-830, 1981.
In regard to the applicati~n of melatonin for the control of facial and body hair, it is advantageous to use compositions in which ~elatonin i.s associated with a lipophilic ~ubstance, both being dissolved in an appropriate ~olvent~ For instance, the melatonin homologues are used in the form o~ a ~ol~ n in a water-ethanol mixture containing ~ro~ 10% to 30~
v/v or more of et~lanol. ~lternatively, it can be administered as a cream or ointment. However, the amount of active ingreAients in the composition may ~e more or less depending on -21)-:12~Z9'~7 the speci~ic conditions to be treated alld the degree of treatment needed.
, ... . .. .
~ The compositions ~or hair control can also be used in a therapeutic environment or application, in addition to the cosmetic uses which have been mentioned here above.
Particularly, tl-le composition Oe the invention, whether it be in the form of a lotion or of another form of composition, can al80 be used for the preventlon or treatment o~ hormone-lnduced virilization, for instance in patients subjected to androgen hormone therapy in cancer therapy or with corticosteroid administration for anti-tumor or anti-inflammatory action which, as it is well known, can cause temporary or prolonged hirsuitism. The topical application of melatonin can avoid or attenuate hormone induced hirsuitism.
Alternative medical uses for melatonin are seen in its application to prevent or attenuate hair growth wherein frequent shaving results in signi~icant irritation.
To avoid urunculitis or ingrown hairs and to ease the discomfort of adhesive bandage removal and depilation for co~metic purpose~.
Whatever the use of the topical composition or lotion for attenuating or prevènting hair growth, the concentration of the active compound therein should be sufficient for providing a good local absorption of the active principle. It is believed that melatonin, when so applied, causes a local increase of the binding activity of estrogen receptors and also neutralizes the action of local testosterone The composition5 can also be in a forJn suitable for oral administration in combination wi~h topical treatrnent.
These oral compositions then contalning an effective amount of . . j .
~.. . . ...
. .
.~ , . . . . . . _ . _ . . _ _ .. _ .. _ ~ ., - , .
129Z94~ .
the active compoun(~ to produce the same e~fects. The complete innocuity and absence of toxic side effects of melatonin are .. ..
By way o~ example, relative concentration~ of 10 per cent to above 1 per cent in weight of the melatonin or melatonin derivatives in lotions or other liquid solutions of 10 4 per cent to 1 per cent in ointment or cream compositions. When oral use is considered, effective daily dosages range from about 0.1 to about 100 mg/kg/day, the solid orally administrable compositions being dosed accordingly.
The ~ifferent fields of application which have been mentioned above should not be considered as limitative. It goes without saying that the invention is applicable to any field involving limitation of hair growth in androgenically respon-3ing cutaneou~ sites.
A third embodiment of the invention relates to compositions containing an effective amount of melatonin associated with a vehicle which makes said composition suitable for topical application Eor preventin~ hair fall or regeneration of hai~ to the extent where the hair root.s or follicles are not yet fully degenerated or dead. That is, hair follicles which are sitll capable of sustaining hair growth and can be rejuvenated. ~s a matter of fact, it has been found that the definitive death of hair often takes place about 3 or 4 years after the actual fall. Therefore, under such circumstances, renewed growth oE hair whic~ is not yet dead can even be observed. The other components of such compositions can be the usual ones It i5 advantageous to use compositions in which melatonin is associated with a lipophyl;ic sub.stance, both being dissolved in an appropriate solvent. For instance, . . = ., ~ . . , 1~92 947 the melatonin homol(!glles are use(l in ~he orln o~ a solution ln a water-ethanol mixture containing froln 10 % to 30 ~ v/v or more o~ ethanol. IloWever, the amount o~ active ingredients in the composition can be more or less depending upon the patient, the conditions oE the scalp and the efect desired.
In accordance with the present invention, the compos1tiQn~ for h~ir control or rey~neration can also be used in a therapeutical environment or applicatiorl, in addition to the cosmetic uses which have been mentioned here above.
Particularly, the composition of the invention, whether it be in the form of a lotion or of another form of composition, can also be used for the prevention or treatment of drug-induced or toxic alopecia, Eor instance in patients subjected to androgenous hormone therapy or cancer chemotherapy which, as it i8 well known, o~ten cause.s temporary complete hair fall. The topical a~plication oE melatonin then both slows down the drug-induced alopecia, and/or favors the hair recovery when the therapy concerned is over.
Toxic alopecia is distinguishable fro~ male-pattern baldness. Toxic alopecia is usually temporary and may follow a severe, often febrile illness. It may also be seen in myxedema, hypopituitarism, following pregnancy, and with some drugs. In such cases there is degeneration of the hair follicles which unless stimulated or rejuvenated would re~ult in a permanent loss of the hair follicles.
Whatever the use of the topical composition or lotion, th~ concentr~tion oE the active co~poun-.l th~rein shoul~ be sufficient for providing a good local absorption of the active principle. It is believed that melatonin, when 50 applied, causes a local increa5e of the binding activity of estrogen r~ceptors and al;Q nelJtral~e; the local t~sto.sterone.
~.. -. .. .
~Z~Z947 The topical application in a signi~icant nllmber of _perso"s WllO used a melatonin lotion ~y topical hea~
a2pi-~a ~~~ resulte~-In--the--c~mpIë~-~~in~rrUp~ioli of ~~~~h ir~ ~
fall which they were experiencing previously. Melatonin was also foun~ to act in them as a regulator of sebaceous glands.
Prior to the present invention, there have been no clin;cal or laboratory studies with regard to the topical application of melatonin to cutaneous areas.
The following tests were conducted utilizing ten male subjects suffering from hair loss and baldness, a preparation containinq melatonin in a concentration of lmg/ml in 30 % ethyl alcohol.
Th~ solution of melatonin (Fluka AG, Buchs, Switzerland) was prepared containing lmg/ml in 3~ ethyl alcohol. The solution was kept in a dark bottle at 4 (3egrees C. The stability o melatonin ln the solution was periodically checked by HPLC and no degradation oc changes were observed in the course of three months.
A group of ten balding men with variable degree of hair loss, dander and sebaceous, fatty secretion of the scalp, aging 30 to 50 year~, were treated daily in the evening t6 to lO p.m.) with topic applications of melatonin by imbibition of the balding areas with melatonin solution combined with a light massage of the scalp for five minutes. The solution was left to dry and to act overnight. The treatment was continued for two weeks and then continued at three days intervals, twice a week for a further three months.
The effect of melatonin on scalp hair was evident after a few days o~ initiation of it~ topical application.
Loss of hair ~irst decreased and then completely stopped and --2~ ~
~ Z9Z947 permanently abrogated. Thinning, brittle fr~gile hair in balding areas grew vigorously and became identical to healthy normal hair in those areas maintaining hair gro~th. E~owever, completely bald areas where hair had been lost for a long time (years), c~id not show any regeneration oE hair geowth. Also, in the areas treated wlth melatonin, dander, epitherlial Aesquamation and excessive sebaceous secretion disappeared completely and the scalp skin showed a clean, healthy, elastic appearance. Apparently, hair pigmentation was not affected.
White, greying hair or black hair maintained their original color. When the treatment was interrupted for two weeks, a modest hair loss was observed which was immediately reversed by fuether continuation of melatonin application. No significant or alarming local or general toxic ~ide effects o topic adminlstration o~ melatonin have been ob5erved at five month~
a~ter beginning of the te~ts.
Even when administered ~ os at very high doses and for a long time, melatonin has been found to be singularly free of toxicity. Thus, topic use o~ melatonin floes not constitute a danger if one considers that, in humans, pineal secretion of melatonin is a normal physiologic event with typical night-day periodicity.
This activity of rnelatonin on restoration and maintenance of scalp hair growth doe~ thus constitute a valid ~physiological" prophylaxis and therapy of the balding syndrome in humans suffering from toxic alopecia Although the invention relates primarily to the topical application of melantonin, it is understood that topical treatment rnay be in combination with oral or parenteral administration of melantonin depending upon the patient and the severity of the contlition to be trt~atcd.
~~
.... . .. . ..
lZ9Z~47 ay way oE example, theee may be ment~oned merely by way o~ exam~les, relative concentrations of 10-4 per cent to about 1 per cent in weight, of the melatonin or ~elatonin derivatives in lotions or other liquid solutions of, 10 4 per cent to 1 per cent in ointment compositions. Other suitable pharmaceutical carriers which may.be utilized in the invention are described in F. W. Martin et al. ~Remington's Pharmaceutical Sciences~ 14th Ed. Mack Publishing Co~pany, Easton, PA. 1965.
Generally, it i8 advantageous to apply or use the compositions of the invention in the evening and prior to going to sleep when melatonin endogenous production is reduces at a lower level. However, this is not a limiting condition for the use o~ melatonin compositions.
The followlna references together with other references which are mentioned hereinbefore relate to studies on various animal in the treatment of various conditions.
REFERENCES
(1) Flaugl~, ~l.E., Crowell, T.~., Clemens, J.A., Sawyer, B.D.: Synthesis and evaluation of the a~ti-ovulatory activity of a variety of Inelatonin analogues. J. Med.
Chem. 22: 63-69, lg79.
(2) ~rohn, ~1.A., Seaborn, C.l., Johnson, D.W., Phillipou, G., Sea~ark, R.F., t~atthew~, G.D.: Structu~e-activity relation~hip of melatonin analogues. ~ife Science~
27: 2043-2046, 1980.
-2~-~ ~,~
(3) Relly, R.~ mato, F., Seamark, R.F.:
N-Acetyl-5-merthoxy kynurenamine, a brain metabolite _. , ~, ., of melatonin, is a potent inhibitor of prostaglandin biosynthesis. Biochem. Biophy. Res. Commun. 121:
372-379, 1984.
(4) Marangos, P.J., Patel, J., Hirata, F., Sonheim, D., Paul, S.M., Skolnick, P., Goodwin, F.K.; Inhibition of diazepam binding by tryptophan derivatives including melatonin and its brain metabolite N-acetyl-5-methoxy kynurenamine. Lie Sciences 29: 259-267, 1981.
Frohn et al (19an) reported a structural activity relationships between 23 indoleamines and melatonin utilizing . . .
an in vitro fish pigment bioassay. Indoles were dissolved in ethanol and given intraperitoneally. In this model, halogenation at 6- position and minor variations o the N-acyl group were without effect on comparable in vivo activity.
Indole was found to be more active than melatonin. The 6-chloro-2,3-dihydromelatonin was believed to be a possible long acting melatonin agonist.
In a study of antagonists to the brain receptors for diazepam, melatonin and metabolites were tested to determine the inhibition of diazepam binding to rat synaptosomal membranes. ~elatonin and its CNS metabolite N-acetyl 5-methoxy kynurenamine were foun~ to be the most potent antagonists and beta carboline metabolites of melatonin were also noted as high affinity antagonists to diazepam (~1arangos et al., 1981).
Rollag (1982) studied 18 different tryptophan derivatives, many o~ which are found in the pineal gland, to induce gonadal rec~ression and aspermia in syrian hamsters.
Only melatonin and 5-methoxy tryptamine were found to possess anti-gonadotrophin action. The action of 5-methoxytryptamine is supported in Pevet's review (1983) but melatonin is the most effective agent.
Similar studies were conducted by Richardson et al ~19~3), Vaughn et al (19~3) with 6-chloromelatonin being the only analogue to possess anti-gonadotrophic activity equal to melatonin. Their paper reviews the structural activity literature evaluating melatonin analoc~ues. This same group (Vaughan et al., 1982) explored the action of melatonin natural and synthetic analogues on the efEects oE cholesterol and - lZ9Z947 thyroid levels in male syrian hamsters as compared to melatonin. The native hormone melatonin was follnd to be the .. .. .
only structure lowering T4 (thyroxine) levels.
In a frog skin assay, Frohn, et al., ~19aO) concluded that the tl-acetyl group attached to 3- position determines binding ~ite affinity while the 5-methoxy group confers activity.
Melatonin and related metabolites were found to be the principal excretory products of the pineal gland (epiphysis cereberi), an endocrine organ present intracranially in all vertebrates (Reiter, 1983). In lower vertebrates there are true morphological photoreceptors present in the pineal gland but in mammals the pineal gland receives signals from neural sympathetic sources which effect the production of its principal secretory product melatonin (Reiter r 1983). The primary secretory route of melatonin in mammals is by way of the capillary bed of the gland itself (Rollag et al, 1977).
~ elatonin (N-acetyl-methoxytryptamine) is primarily derived from tryptophan and synthegized via the action of tryptophane hydroxylase (Lovenberg et al., 1967). The pineal gland i8 the primary place for a major portion of physiological indolamine metabolism including that of the neuroeffector serotonin which is a major source of melatonin synthesis.
~- Melatonin synthesis is governed by light exposure and in man and other mammals and primarily produced in conjunction with night or in darkness from its pineal endocrine source. In addition to the pineaI body, both the retina, the harderian gland (in rodents) and gastrointestinal tract are producers of melatonin (Ralph, 1981 Reiter et al, 1983: Raikhlin et al., 1~75).
. . .
lZ~Z947 Besides melatonin, 5-methoxytopllol (~ilson et al., 1978) and 5-methoxytryptamine (Pevet et al., 1983) are produced ~, by the pineal and have been found to have endocrine effects.
The primary role of the pineal gland relates to its contral of reproductive physiology (Tamarkin et al., 1985;
Aren~t et al., 1983: Stetson ~ Watson-Whitmyre, 1984). ~s mentioned previously, secretion of melatonin is governed by light to dark exposure of the animal and there are short day or long day seasonal breeding animals who are influenced differently by melatonin production governed by the seasonal light cycle.
An example of systemic melatonin effects on reproductive hormona-l cycling are seen in the depression of testosterone production in mice given melatonin (Petterborg &
Reiter, 1981). Alternatively, depending on species, testicular re~ression can be prevente~ and testo~terone activity maintained ~Turek, 1977; Stetson et al 1933) in hamsters.
Uelatonin, given by injection, can alter estrous cycling in female rats (Trentini, et al., 1980). Evidence sùpports the possibility that melatonin levels may be a factor in suppre~sion of puberty in man (Tamarkin et al., 1985).
Ilelatonin is entering the commercial animal husbandry market to control fertility (breeding time), fur coat development and appetite. For example in ewes 2mg~day, in pe~leted feed, which mimics nocturnal blood levels, controls the estrou.s cycle and sheep fertility (Lincoln, 1983);
(Kennaway et al., 198~). Similar effects on daily feeding have been observed in male white tailed deer (Bubenik, 19~3) with earlier seasonal antler and coat changes.
... .. . _5_ ._ ~ .. ..
lZ~Z947 t1elatonin injected subcutaneously in saline or oil pro~uces high transiel~t blood levels while oral adminstration _, . . . . ..
in saline or food pellets peoduces sustained blood levels ~Kennaway & Seamark, 1980). ~elatonin has been orally given in drinking water (Pevet and Tlaldar-s~isra, 1982) or by subcutaneous slow release implants, i.e., sialastic (Turek, 1977; Losee and Turek, 1980; Kennaway & Gilmore, 1984) or by injection (Sisk & Turek, 1982).
The duration of melatonin exposure is significant since constant levels can produce refractoriness, thus intermittant exposure and the relation of melatonin to the animals photoperi~d (light/dark cycle) is important (Stetson et al , 1983; Losee & Turek, 1980; Trentini et al., 1980; Stetson and Tay, 1933; Bittman, 1984; Tamarkin et al., 1985).
Melatonin injections can mimic syrian hamster short day photoperlod exposure with lncreases in body weight gain, feed efficiency, enhanced carcass lipid and brown adipose ti~sue ma~s and thermogenic capacity (Bartness & Uade, 1984).
The clinical use of melatonin in CI~S disease has been reviewed by Anton-Tay ~1974) an~ Romijn (1978) and there have been extensive studies of its intravenous, intrathecal and direct localized CNS implantation on behavior in a wide range o~ animal species that has led to clinical trial.
Waldhauser et al. (1984) have reviewed the clinical use of melatonin. They indicate that aproximately 150 subjects have received clinical melatonin intravenously or orally. In most cases, no significant toxicity was observed (Lerner &
~lorlund, 1978). As much as 3-6 gms of melatonin has been given orally daily for 1 month with reports of abdominal cramping and tranquilization (Papavasiliou, et al., 1972).
`~ -6-,, , . .. . _ . . .. . .. _---- ~
12~Z947 ~ qelatonin has been given clincally to volunteers by mouth in carbowax at 1-25 u~/kg (~nton-Tay, 1974) or clinically to voltlnteer~ by mout~ in-corn oil as a .04~ solution at a dose of 2mg/day for 4 weeks (~rendt et al., 1984). It has been given orally in dose.s of 250mg (Morlund and Lerner, 1977) and in doses up to 1.2g/day (Anton-Tay, 1974; Carmen et al., 1976 ~nton-Tay et al., 1971). These studies have demonstrated a systemic effect of melatonin with reports of melatonin induced fatigue and depression or sleep.
Melatonin has been given to human subjects in doses of 50mg intravenously (Pavel et al., 1981; Cramer et al., 1974) where it induced sleep with normal or enhanced REM
electroencephalographic patterns. Melatonin's sedative action has been confirmed by H. Lieverman, as cited by ~aldhauser et al (1984)~ and ar supported by the results of intranasal administration where melatonin, a~ a 0,85 per cent ethanol spray induced sleep in 70 per cent of patients within 40-60 minutes (~ollrath et al., 1981).
Melatonin has been studied p.o. and i.v. clinically in depression and in ~untington's chorea with no improvement or clinical worsening (Carman et al., 1976). In two patients with schizophrenia, I.V. melatonin (300mg) worsened hallucinatory symptoms (Altschule cited by Carman et al., 1976).
In epilepsy, melatonin has produced some benefit on i.v. administration at a 1 per cent solution in ethanol at dosages up to 1.25mg/kg i.v.. In Parkinsonism, given i.v. or p,o. for a daily total of 1.2 gms for 4 weeks ~Anton-Tay et al., 1971), amelioration o~ tremor and rigidi~y have been seen although results have not been consistent in studies of Parkinsonism with all investigators as Papavasilou et al., 1972 ~. . - . . . . .. . . . .
lZ9Z~47 has not seen benefit with doses as high as 6 gms daily. Carman et al. (197~) have review the CNS clinical stuclies up to that ~ time and the use of ~elatonin for the treatment of tre~or and rigidity looked promislng.
Melatonin has been given at dosages of lmg/kg i.m.
with advanced breast cancer for periods up to 2 months. These studies were conducted after trial at 5 and 20mg/kg i.m. daily for up to 10 days in monkeys with no report on clinical response other than a report of a decline in urinary estrogen ~Burns, 1973). Blask (1984) has reviewed the role of melatonin in the clinical treatment oE malignancy. ~e cites DiBella and Starr as achieving inhibitory clinical results in a variety of tumors.
In relation to endocrine action, Smythe and ~azarus (1974) have given 0.5gms of melatonin ~or 2 doses, 30 minutes apart with a reported melatonin related rise in growth hormone.
Melatonin has been used in veterinary medicine in the treatment of acanthosis nigricans in dogs. This disease is associated with thickening of the skin, pigmentation and pruritus. Rickards (1965) and ~i~k (1979) have successfully treated canine acanthosis nigricans by subcutaneous injection utilizing 2mg injections of melatonin for daily and extended weekly treatment periods.
In regard to local modulation and inhibition of steroid synthesis, melatonin on in vivo and in vitro treatment has shown in vivo an~ in vitro inhibition of te3ticular synth~sis from cholesterol and pregnenolone precursors of testosterone and androstenedione synthesis in the rat teste~
(Peat & Kinson, 1971).
. -8-q ~,.. , ., . ~ . . . . . - . ..
. ~ .
i. .. -, .
~Z9Z947 , The inhibiting effects of melatonin on testicular function have been associated with stimulation of - delta-4-reductase in ~ ive~ an(~ h~pot~al~us`tFrehn et al., 1974). Melatonin was found to specifically increase the 5-alpha reductase of semini~erous tubules for ~oth progesterone and te~3tosterone. Melatonin decreased androgen synthesis in both testicular interstitial cells and tubules ~El~is, 1972).
Similar increases in 5 alpha reductase activity in rats by melatonin have been observed on adrenal cortical function (Ogle & Kitay, 1977).
Melatonin reduced accessory sexual organ size in pinealectomized male rats kept in constant darkness without inhibiting testosterone metabolism leading the authors (Shirama et al., 198~) to suggest that melatonin is possibly acting at the tissue level to reduce the numbers of androgen receptors and/or the susceptability to androgen Orally administered, melatonin was foun~ to lower ventral prostate and seminal vesicle weight and the 3/beta-hydroxysteroid oxidoreductase was increased but not the S alpha reductase in the ventral prostate and seminal vesicles of pinealéctomized rats (Horst et al., 1982). The authors felt that this reflects on increased androgenic catabolism resulting in prostatic involution. The effects of melatonin on prostatic androgen receptors can depend on the age of the animal and light cycle exposure ~Moeller et al., 1983).
Melatonin in vitro when combined with chorinonic gonadotrophin or ovine luteiniæing hormone increased the secretion of esteogens and progesterone in isolated granulosa cells of the rat. Melatonin, in relation to ovarian function, showed a progonadal trophic effect (Fiske et al., 19841.
; ' ~' ' ' ' ' lZ9Z947 In recJard to local stimulation of estrogen receptor availability by melatonin in cutaneolls areas oE andro~ellic an~
estrog~;nic hormone sensitivity.~~``There is`evidence~that- -`~~ ~-~--~~7--~~:-melatonin increases cytoplasmic estrogen receptor activity in hamster uteri and similar effects have ~een observed in estrogen receptor binding activity in human breast cancer cells (~anforth et al., 1983).
Other reviews of the ph~siological role of melatonin are found in:
-G.M. VA~JG~N et al., titled "~vidence for a pineal-gonad relationship in the human~, published in Prog.
Reprod. ~iol Vol 4, p. 191-223, 1978.
-H.L. JUDD, titled "Biorhythms of gonadotrophins and testicular hormone secretion", published in Endocrine Rhythms, 1979.
-D.P. C~RDINALI et al., titled ~Melatonin action:
sites and possible mechanisms in brain~, published in ~The pineal gland and its endocrine role~, J. AX~LROD, F. FRASC~INI
and G P. VELO, eds. Proc. Wato Adv. Study, Erice, Italy, p.
551-575, Plenum Press, ~ew York, 1982.
-R.J. WURTMAN, et al., titled ~The secretion and effects of melatonin in humans~, published in ~The pineal gland and its endocrine role~, J. AXELROD, R. FRASCEIINI and G.P.
VELO, ed. Proc nato Avd., Erice, Italy, p. 551-575, Plenum Press, New York, 1982.
-The Third Colloquium of the European Pineal Study Group~ PECS 1984, published in EPSG Newsletter of August, 1984 -R.J. ~urtman et al, entitled ~Physiological Control of ~qelantonin Synthesis and Secretion: Mechanisms Generating Rhythms in 11elatonin, Methoxytryptophol~ and Arginine ,. . ~ . .. , .. , , . . ~ , , :l;Z9Z947 Vasotocin LeVels and Effects on the Pineal of Endogenous Catecholamines, tlle Estrous Cycl~, ànd Environmental Li~llti!~g~, J. of Neural Transmission, Sllppl. 13, 59-70 tl97~).
-Ivor Smith, entitled "Indoles of Pineal origin:
Biochemical and Physiological Status", Psychoneuroendocrinology, Vol. 8, No. l, pp 41-60 (1983).
Surprisin~ly, none of the prior art studies are concerned with the dermatological effects of the administration of melatonin to a human host. ~10reover, there have been no previous studies regarding the topical application of melatonin, its homologues or derivatives for humans. The prior art studies do indicate that the compounds of the invention can be safely administered to humans in the treatment oE various diseases.
Summary Of The Invention In accordance with the present invention, there is provided a method and composition for treating the skin and ~calp of a mammal by the administration of a composition ," ,~ ~
c~ontaining a melatonin compound in order to ~nprove the cosmetic, physical appearance or functional role.
More particularly, the present invention provides a composition for use in the treatment of the skin and/or scalp of a human host in order to enhance the ~kin's condition and tone, prevent or amellorate the conditions or symptoms of acne, seborrhea, hirsuitism an~ fot the rejuvention o live but degenerated hair follicles.
The preferred active o~ the compositions of the invention consists of melatonin itself. Among the chemical - ,. s .
lZ9Z947 -~
homologues useEul for the production of compositions according to the invention, there ean be mentioned the class of compounds which are represented by ~he general ~ormuI~a:
.
(C112)"~
il. which;
-n is 1 or 2 -Rl and ~2 are identical or dlfferent from each other and are H, N~2, COOH, ~H or acyl comprising from 1-4 carbon atoms or alkoxy comprising from 1 to 4 carbon atoms:
-X i8 0~ or alkoxy comprising from 1-4 carbon atoms:
-Y is ~ or NH2.
Preferred compounds ~or use in the compositions of the invention are tho~e in which Y is hydrogen and X is methoxy.
The most preferre~ compound i8 melatonin itself, the formula of which i8:
2 ~ ~i2 - NH - C - c~3 NH
~: ' ' " ' ' , .~ .
,~
~ -12-12~9~7 Other preferred compounds for use in the compositions of the inven~ion are 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-me~hoxyindole-3-aceti~ acid and 6-hydroxy-melatonin.
These compounds can be obtained by synthetic proce~se~, general methods of manllacture which can be derived rom those published by J. SZMUS~KOVICZ "Synthesis of ~-acetyl-5-methoxy-tryptamine~, J. Org. Chem. 25, 857 (1960),J.
SUPNIEWSKI et al., "Synthesis of melatonin (5-methoxy-N-acetyltryptamine", published in Bull. Acad. Polon.
Sci. Ser. Biol., 8, p. 479-481, 1960; or MASHKOVSK~ et al. in Farmakol. Toksikol., 26, n 1, 10, 1963, said methods being of course in each case adapted to the particular compound sought.
The term ~melatonin" is used hereafter to designate both the actual melatonin and the chemical homologues or derlvatives thereo~.
De~cription of The Preferred Embodiments In a first preferred embodiment of the invention, the composition is in a form suitable for topical application for humans. Advantageously, this composition is in the form of a cream, ointment-or lotion or another cosmetic liquid applicable externally. Such composition is then of a particular utility for preventing, attenuating or curing acne or for conditioning the skin to improve its appearance and texture Acne is a common inflammatory pilosebaceous disease characterized by comedones, papules, pustules, inflamed nodules, superficial pus-filled cystfi, and, in extreme cases, canalizing and deep inflammed, ~ometimes purulent sacs. Its -~3-' ' lZ9Z9~7 patho~enesis is complex; an interaction between hormones, keratinization, sebum and bacteria somehow determines the course and severity of the disease. The common form of acne is a feature of adolescence in both sexes, and androgen seems to be the essential factor, operating through stimulation of the sebaceous glands. Acne lesions predominate on the face but are also common on the neck, chest, upper back and shoulders.
The compositions in accordance with the present invention are particularly useful in the management of simple uncomplicated acne, such as, acne vulgaris. Acne vulgaris is a condition which involves the eru~tion of papules and pustules on an inflammatory base. The condition occurs primarily during puberty and adolescence due to overactive sebaceous apparatus which is believed to be affected by hormonal activity.
The other components of ~uch composition.~ can be the usual ones. It i~ advanta~eous to use compositions in which melatonin i8 associated with a lipophylic substance, both being dissolved in an appropriate solvant. For instance, the melatonin homologues may be used in the form of a solution in a water-ethanol mixture containing from 10% to 30~ vJv or more of ethanol. However, the amount of active ingredients may be more or less depending on the specific conditions to be treated and the degree of treatment needed.
The compositions for acne and seborrhea control or skin conditioning can also be use-3 in a therapeutic environment or application, in addition to the cosmetic uses which have been mentioned here above. Particularly, the compositlon o~
the invention, whether it be used locally or regionally in the form of a cream, oint~ent or lotion or Oe another form of composition, can also be used for the prevention or treatment .:
. .
lZ929~7 of androgen or drug-induced acne or seborrhea, for instance, in patients subjected to androgenous hormone therapy in cancer therapy.
In addition, melatonin can be used alone or in conjunction with topical estrogens to enhance topical or endogenous estrogen action on the skin for the prevention and treatment of acne or seborrhea or for cosmetic effects related to improving the texture and physical appearance of aging skin.
The prime use of melatonin, alone or in conjunction with estrogens will be during adolescence when the oiliness of skin and the plugging of sebaceous glands results in acne vulgaris and seborrhea. ~lternatively, alone or in conjunction with estrogen in pre or post menopausal women where dryness and 108g of skin texture has been agcribed to the decline in estrogen. The estrogen~ may be applied separately or in combination with the melatonin.
An additional use for melatonin is by direct applica tion to the vaginal mucosa, alone or in conjunction with estrogen to restore the quality and secreting capacity of atrophic sexual skin in the vagina.
The topical application of melatonin, alone or in conjunction with estrogen (oral or parenteral administration) will improve the texture (elasticity and vascularity) of skin subject to atrophy seen in association with the 105s o estrogen with aging.
Whatever the use of the topical composition or lotion, the concentration of the active compound therein should be su~ficient for providing a good local absorption o the active ingeedients.
~29Z~47 The mechanism of melatonins local action }s based on the observations that it ~auses a local increase of the binding activity of estrogen receptors and can ameliorate the action of testosterone on the skin through enhancement of the local efEect o~ estrogen.
In re~ard to the above, the cause of acne vulgaris and seborrhea (increased sebum production, oily skin) can be due to an excess of testosterone or related androgenic hormones.
Current treatment of acne vulgaris includes the topical or systemic use of agents that provide estrogen or suppress the production of testosterone.
A suitable acne preparation may comprise the following:
t1elatonin lO~ in a colorless, greaseless lotion which contains water, aluminum hydroxifle, isopropyl stearate, PEG-lOO
stearate, glyceryl stearate, cetyl alcohol, glycereth-26, isocetyl stearate, glycerin, dimethicone copolyol, sodium citrate, citric acid, methylparaben, propylparaben, fragrance.
The preparation amongst the beneficial effects which the preparation provides are:
l.~ helps heal and prevent acne pimples.
11elatonin dries up and kills acne causing bacteria to help prevent new ones.
2.) helps absorb excess skin oil oEten associated with acne blemishes. The preparation preferably contains aluminum hydroxide, or other like materials, such as bentonite, which is a special oil absorbing ingredient that allows the lotion to absorb more excess skin oil than melatonin alone.
3.) helps the skin look fresh. Extra oil absorption helps the skin look less oily, more natural. If desired, the preparation can also contain ~ulfur and/or .
~,. , .~ ,. . .:
~ ~......
lZ9Z947 r~ ~inol or other known active ingredients to help heal the acne pimples. However, the additional ingredients may be applied ~eparately.
The following publications describe the various methods of treating the acne condition:
- C. R. DARLEY et al., titled: ~Circulating testosterone, sex hor~one binding globulin and prolactin in wo~en with late onset or persistent acne vulgaris~. Br. J.
Dermatology, 106: 517-S22 - G. S. GINSBERG et al. (1981) titled: ~Androgen abnormalities in acne vulgaris~. Acta De~matovener 61: 431-434. ~
- R. P~L~T~I, et al., (1978) titled: ~Treatment of ' acne w~th cyproterone acetate and ethenyl estradiol~, Acth ~erlnatovener 58: 449-454.
- J. H. CHeRK (19~0) titled: ~Improvement of lntractable acne in man following testosterone suppression using dana~ol~. Cutis: 2~: 393-394.
- J. B. SCHMIDT, J. SPONA (1983) titled: 'Hormone receptors in nor~al skin and acne~. Endocrinologica Fxperimentalis 17: 137-144, 1983.
- J. ZABEL: titled: ~Uptake of H-testosterone in the skin of healthy women and in the skin of patients with acne vulqaris~. Acth ~istochem: 64: 243-248.
As previously mentioned, melatonin has been shown to have a direct effect on the metabolism of steroids in peripheral organs such as ovary, testes, adrenals and ptostate. Thus, its action on the ~kin may be by cutaneous ~3~ ' l~Z~47 ~alteration in the metabolism oE androgens, i.e., blocking the targeting effects of testosterone on sebaceous glands and hair follicles. Alternatively, rnelatonin may produce its therapeutic effect via an increase in estrogenic receptors in the skin and seborrheic glands. Melatonin can felninize the skin by increasing its capacity to respond to estrogen through an increase in cutaneous estrogen receptors or through an attenuation of androgen response.
The action of estrogen as a skin conditioner is enhanced by melatonin's local action in modulating the increase in estrogen;c receptors. Thus melatonin's action on aging skin of postmenapausal women or aging males is mediated by enhancing local estrogenic effects. This is of value in restoring cosmetic quality to the skin (moisturn, vascularity, elasticity) as well as re~toring the local respQnse of vaginal epithelium to estrogen More generally, the compositions of the invention (either in the form of lotions, creams, or ointments) of the invention are useful for the up-keeping of skin in good condition or for skin-regeneration, particularly in an aging population. The administration or use of melatonin will allow in particular the restoration of the skin functions including elasticity and moisture content. Even more generally melatonin is capable of controlling body odors by altering sebaceous secretions, the up-keeping of skin moisture and of all key factors associated with hormones involved with sebaceous or secretion which govern in part sexual attraction. The invention particularly includes perfume compositions deodorants or toiletries supplemented with melatonin.
. . .
lZ~Z947 second preEerred emb~diment oE the invention relates ~ to compositions containing melatonin, their chemical homologues .. . .
an~ derivatives, for preventing hair growth in androgenic skin sensitive areas that are cosmetically of concern for aesthetic and sexual differentiation reasons, i.e., face, upper lip, chin, cheeks, neck or on the body: chest, breast, nipples, abdomen, pelvic triangle, shoulders, back, buttock and extremities.
This particular invention provides selective regionalized or local hair loss, hair prevention, slowing or attenuation of hair growth in areas of androgenic (masculine) growth patterns where hirsuitism is considered superfluous.
This embodiment of the invention involves the application of melatonin, its homologues or derivatives for the control of:
(1) Facial Hair: To 3ecrease the frequency or eliminate the need for shaving or to make the beard more amenable to shaving.
(2) Hirsuitism: Hirsutism is defined as excessive hair growth in areas usually not hairy. In most instances, excessive growth of body hair in women cannot be traced to an endocrine cause, but occasionally a mild androgenic influence of ovarian or adrenal origin is suspect. Hirsutism is seen frequently at menopause and with systemic androgenic steroid or corticosteroid therapy, and may occur in porphyia cutanea tarda. To reverse or prevent excess terminal hair growth in areas of excess (androgenic) masculine growth patterns. This is particularly applicable to -19~
.~.. A . . ..
1292~47 women to control facial or body hair to meet cultural or individual views of what is cosmetically acceptable regarding facial or body hair. Hirsuitism is a problem in as many as 5%
of women or even moee depending on esthetic or cultural values.
This invention strictly considered ~hould not be considered to be a depilatory but in effect a modulator and attenuating influence on the stimulating action oE androgenic hormones on hair growth. In this regard, androgenic hor~ones are responsible for facial hair arowth in men and women as well as the male pattern of body hair and the thickness and quantitative measurement of hair growth as part of a spectrum of virilization of which hir~uitism can be a significant part.
The following publication discloses additional methods of treating hirsuitism which may be used in conjunction with the present invention.
- HATCH et al. titled ~Hirsuitism: ~mplications, etiology and management~ Am. J. Obstetrics and yynecology 140:
815-830, 1981.
In regard to the applicati~n of melatonin for the control of facial and body hair, it is advantageous to use compositions in which ~elatonin i.s associated with a lipophilic ~ubstance, both being dissolved in an appropriate ~olvent~ For instance, the melatonin homologues are used in the form o~ a ~ol~ n in a water-ethanol mixture containing ~ro~ 10% to 30~
v/v or more of et~lanol. ~lternatively, it can be administered as a cream or ointment. However, the amount of active ingreAients in the composition may ~e more or less depending on -21)-:12~Z9'~7 the speci~ic conditions to be treated alld the degree of treatment needed.
, ... . .. .
~ The compositions ~or hair control can also be used in a therapeutic environment or application, in addition to the cosmetic uses which have been mentioned here above.
Particularly, tl-le composition Oe the invention, whether it be in the form of a lotion or of another form of composition, can al80 be used for the preventlon or treatment o~ hormone-lnduced virilization, for instance in patients subjected to androgen hormone therapy in cancer therapy or with corticosteroid administration for anti-tumor or anti-inflammatory action which, as it is well known, can cause temporary or prolonged hirsuitism. The topical application of melatonin can avoid or attenuate hormone induced hirsuitism.
Alternative medical uses for melatonin are seen in its application to prevent or attenuate hair growth wherein frequent shaving results in signi~icant irritation.
To avoid urunculitis or ingrown hairs and to ease the discomfort of adhesive bandage removal and depilation for co~metic purpose~.
Whatever the use of the topical composition or lotion for attenuating or prevènting hair growth, the concentration of the active compound therein should be sufficient for providing a good local absorption of the active principle. It is believed that melatonin, when so applied, causes a local increase of the binding activity of estrogen receptors and also neutralizes the action of local testosterone The composition5 can also be in a forJn suitable for oral administration in combination wi~h topical treatrnent.
These oral compositions then contalning an effective amount of . . j .
~.. . . ...
. .
.~ , . . . . . . _ . _ . . _ _ .. _ .. _ ~ ., - , .
129Z94~ .
the active compoun(~ to produce the same e~fects. The complete innocuity and absence of toxic side effects of melatonin are .. ..
By way o~ example, relative concentration~ of 10 per cent to above 1 per cent in weight of the melatonin or melatonin derivatives in lotions or other liquid solutions of 10 4 per cent to 1 per cent in ointment or cream compositions. When oral use is considered, effective daily dosages range from about 0.1 to about 100 mg/kg/day, the solid orally administrable compositions being dosed accordingly.
The ~ifferent fields of application which have been mentioned above should not be considered as limitative. It goes without saying that the invention is applicable to any field involving limitation of hair growth in androgenically respon-3ing cutaneou~ sites.
A third embodiment of the invention relates to compositions containing an effective amount of melatonin associated with a vehicle which makes said composition suitable for topical application Eor preventin~ hair fall or regeneration of hai~ to the extent where the hair root.s or follicles are not yet fully degenerated or dead. That is, hair follicles which are sitll capable of sustaining hair growth and can be rejuvenated. ~s a matter of fact, it has been found that the definitive death of hair often takes place about 3 or 4 years after the actual fall. Therefore, under such circumstances, renewed growth oE hair whic~ is not yet dead can even be observed. The other components of such compositions can be the usual ones It i5 advantageous to use compositions in which melatonin is associated with a lipophyl;ic sub.stance, both being dissolved in an appropriate solvent. For instance, . . = ., ~ . . , 1~92 947 the melatonin homol(!glles are use(l in ~he orln o~ a solution ln a water-ethanol mixture containing froln 10 % to 30 ~ v/v or more o~ ethanol. IloWever, the amount o~ active ingredients in the composition can be more or less depending upon the patient, the conditions oE the scalp and the efect desired.
In accordance with the present invention, the compos1tiQn~ for h~ir control or rey~neration can also be used in a therapeutical environment or applicatiorl, in addition to the cosmetic uses which have been mentioned here above.
Particularly, the composition of the invention, whether it be in the form of a lotion or of another form of composition, can also be used for the prevention or treatment of drug-induced or toxic alopecia, Eor instance in patients subjected to androgenous hormone therapy or cancer chemotherapy which, as it i8 well known, o~ten cause.s temporary complete hair fall. The topical a~plication oE melatonin then both slows down the drug-induced alopecia, and/or favors the hair recovery when the therapy concerned is over.
Toxic alopecia is distinguishable fro~ male-pattern baldness. Toxic alopecia is usually temporary and may follow a severe, often febrile illness. It may also be seen in myxedema, hypopituitarism, following pregnancy, and with some drugs. In such cases there is degeneration of the hair follicles which unless stimulated or rejuvenated would re~ult in a permanent loss of the hair follicles.
Whatever the use of the topical composition or lotion, th~ concentr~tion oE the active co~poun-.l th~rein shoul~ be sufficient for providing a good local absorption of the active principle. It is believed that melatonin, when 50 applied, causes a local increa5e of the binding activity of estrogen r~ceptors and al;Q nelJtral~e; the local t~sto.sterone.
~.. -. .. .
~Z~Z947 The topical application in a signi~icant nllmber of _perso"s WllO used a melatonin lotion ~y topical hea~
a2pi-~a ~~~ resulte~-In--the--c~mpIë~-~~in~rrUp~ioli of ~~~~h ir~ ~
fall which they were experiencing previously. Melatonin was also foun~ to act in them as a regulator of sebaceous glands.
Prior to the present invention, there have been no clin;cal or laboratory studies with regard to the topical application of melatonin to cutaneous areas.
The following tests were conducted utilizing ten male subjects suffering from hair loss and baldness, a preparation containinq melatonin in a concentration of lmg/ml in 30 % ethyl alcohol.
Th~ solution of melatonin (Fluka AG, Buchs, Switzerland) was prepared containing lmg/ml in 3~ ethyl alcohol. The solution was kept in a dark bottle at 4 (3egrees C. The stability o melatonin ln the solution was periodically checked by HPLC and no degradation oc changes were observed in the course of three months.
A group of ten balding men with variable degree of hair loss, dander and sebaceous, fatty secretion of the scalp, aging 30 to 50 year~, were treated daily in the evening t6 to lO p.m.) with topic applications of melatonin by imbibition of the balding areas with melatonin solution combined with a light massage of the scalp for five minutes. The solution was left to dry and to act overnight. The treatment was continued for two weeks and then continued at three days intervals, twice a week for a further three months.
The effect of melatonin on scalp hair was evident after a few days o~ initiation of it~ topical application.
Loss of hair ~irst decreased and then completely stopped and --2~ ~
~ Z9Z947 permanently abrogated. Thinning, brittle fr~gile hair in balding areas grew vigorously and became identical to healthy normal hair in those areas maintaining hair gro~th. E~owever, completely bald areas where hair had been lost for a long time (years), c~id not show any regeneration oE hair geowth. Also, in the areas treated wlth melatonin, dander, epitherlial Aesquamation and excessive sebaceous secretion disappeared completely and the scalp skin showed a clean, healthy, elastic appearance. Apparently, hair pigmentation was not affected.
White, greying hair or black hair maintained their original color. When the treatment was interrupted for two weeks, a modest hair loss was observed which was immediately reversed by fuether continuation of melatonin application. No significant or alarming local or general toxic ~ide effects o topic adminlstration o~ melatonin have been ob5erved at five month~
a~ter beginning of the te~ts.
Even when administered ~ os at very high doses and for a long time, melatonin has been found to be singularly free of toxicity. Thus, topic use o~ melatonin floes not constitute a danger if one considers that, in humans, pineal secretion of melatonin is a normal physiologic event with typical night-day periodicity.
This activity of rnelatonin on restoration and maintenance of scalp hair growth doe~ thus constitute a valid ~physiological" prophylaxis and therapy of the balding syndrome in humans suffering from toxic alopecia Although the invention relates primarily to the topical application of melantonin, it is understood that topical treatment rnay be in combination with oral or parenteral administration of melantonin depending upon the patient and the severity of the contlition to be trt~atcd.
~~
.... . .. . ..
lZ9Z~47 ay way oE example, theee may be ment~oned merely by way o~ exam~les, relative concentrations of 10-4 per cent to about 1 per cent in weight, of the melatonin or ~elatonin derivatives in lotions or other liquid solutions of, 10 4 per cent to 1 per cent in ointment compositions. Other suitable pharmaceutical carriers which may.be utilized in the invention are described in F. W. Martin et al. ~Remington's Pharmaceutical Sciences~ 14th Ed. Mack Publishing Co~pany, Easton, PA. 1965.
Generally, it i8 advantageous to apply or use the compositions of the invention in the evening and prior to going to sleep when melatonin endogenous production is reduces at a lower level. However, this is not a limiting condition for the use o~ melatonin compositions.
The followlna references together with other references which are mentioned hereinbefore relate to studies on various animal in the treatment of various conditions.
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-2~-~ ~,~
(3) Relly, R.~ mato, F., Seamark, R.F.:
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, . . ... . . . .
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12~Z9~7 (21) Danfortll, J.~., Tamarkin, L., Do, R., ~ippman, E.:
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';~,.' ~
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the rat. J. ~ndocrinol. 60: 507-515, 1974 .. . . . ... . . . . . .
~,...
lZ9Z9~7 - `
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.. . . ~ ...
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l~Z9~7 (4~) Ogle, T.F., Kitay, J.l.: Ef~ect of melatonin and an aqueous pineal extract on adrenal secretion of reduced ~_ .. - .
..... , ......... . . ~ .. ; . ;, steroid metabolites in female rats.
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Neural Transmis. 51: 303-311, 1981.
12~Z947 (46) Pevet, P., ~al-3ar-Misra, C.: Ef~ect of orally ,. . .. . . . , ,, . ., ~ ............. . . . . . . . .. . . . . .
-~ - ac~ministered melatonin on reproductive funct~on~of the golden hamster. Experientia 38: 1493-1494, 1982.
~7) Raikhlin, M.T., Kvetnoy, I.r~.~ Tolkachev, V.N.:
Melatonin may be synthesized in enterochromaffin cells. Nature 225: 344-345, 1975.
(48) Ralph, C.L.: Melatonin production by extra-pineal tissues. Adv. in the biosciences. ed.
149) Rollag, t5.D., tlorgan, R~J., Niswender, G.D.: Route of melatonin secretion in sheep. Biomed. Sci. Instrum.
13: 111-117, 1977.
(50) ~omijn, ~I.J : The pineal, a tran~uillizing organ?
Life Sciences 23: 2257-2274, 1978.
(51) Rose, J., .Stormshak, F., Oldfield, J., Adair, J.:
Introduction of winter fur growth in mink (mustela vison) with melatonin. J. ~nimal Sci. 58: 57-61, 1984.
~52) Russel, J.., Reiter: ~he pineal gland: An intermediary between the environment and the endocrine system in Psychoneuroendocrinoloy 8: 31-40, 1983.
(53) Shirama, K., Furuya, T., Takeo, Y., Shimuzu, K., Maekawa, K.: Direct effect of melatoni.n on the accessory sexual organs in pinealectomized male rats kept in constant darkness. J. ~ndoc~ olog-~ '35:
87-94, 1982.
, ;. ., .. - " . . . ... .. . . ., .. , . ., . , .~, . .
- lz9z9~7 `` `
(54) Sisk, C.L., Turek, F.W.: Daily melatonin injections mimic the short day-induced increase in negativ~
` .
feedback e~fects of testosterone on gonadotropin~
secretion in hamsters. Biol. of ReprodUction 27:
602-608, 1982.
(55) Smythe, G.A., Lazarus, L.: Growth hormone response ~o melatonin in man. Science, lB4: 1373-1374, 1974.
(56) Stetson, ~.H., Rollag, t~.D., Watson-Whitmyre, M, Tate-Ostroff, B.: The effect of daily injections and constant release implants of melatonin on the endogenous pineal rhythm in golden hamsters. Proc.
Soc. Exp. Biol. Med. 174: 119-122, 1983.
(57) Stet~on, M.f~ , Tay, D.E.: Time course of sensitivity of golden hamsters to melatonin injections throughout the day. Biol. of Réproduction 29: 432-438, 1983.
t58) Stetson~ r1~ Watson-Whitmyre, M.: P~ysiology of the pineal and its hormone melatonin in animal reproduction in rodents. In: The Pineal Gland, ed. R.
J. Reiter, Raven Press, ~lew York, 1984, pp. 109-153.
(591 Tamarkin, L., Baird, C.J., ~lmeida, O.F~X.:
Melatonin: A coordinating signal ~or mammalian reproduction. Science 227: 714-720, 1985.
~60) Trentini, G.P., t~ess, B., DeGaetani, Poggioli, R., Ferrari, P., DiGregorio, C.: The role o~ melatonin .. _.~
~2~Z947 and brain serotoninergic system in the maintenance of rat ovariall cyclicity. Pineal Function, ed. C. D.
~ Matthews, R. F. seamark. Elsevier/North-Holland, pp.
77-86, 1981.
~61) Turek, F.W.: ~ntigonadal effect oE melatonin in pinealectomized and intact male hamsters. Proc. Soc.
Bxp. Biol. !led. 15S: 31-34, 1977.
(62) Vaughan, M.K., ~erbert, D.C., Brainard, G.C , Johnson, L.Y., Zeagler, J.W., Reiter, R.J.: A comparison of blinding and afternoon melatonin injections on the histology of the reproductive crgans, pineal ultrastructure and gonadotrophin hormone levels in female syrian hamsters. Adv. in the Biosciences. Rd.
N, Birau, W. Schoot, V. 29: Melatonin-current status and pre~pectives. Pergamon Press~ ~lew York, 1981, pp.
65-75.
(63) Vollrath, ~., Semm, P., Gammel, G.: Sleep induction by intranasal application of melatonin. Advanc.
Biosciences 29: 327-329 11elatonin-Current Status and Perspectives, ed. N. Birau, W. Schloot, Pergamon Press, NY, 1981.
(64) ~1aldhauser, F., Lynch, H.J., Wurtman, R.J.: Melatonin in human body ~luids: Clinical significance. The Pineal Gland. ed. R. J. Reiter. Raven Press, N~, p.
345-370, l9B4.
.. .. .
... , . ,. __ lZ9Z947 (65) Wilson, l3~W., Lynch, Tl.~J., Ozak.i, Y.: 5 methoxytryptophol in rat seruin and pineal: detection, quant;tation and evidence for daily rhymicity. Life Sci. 23: 1019-1024, 197B.
~leuroendocrinology B: 61-73, 1983.
t6) Richardson~ B.A.~ Vaughn, t1 K., Petterborg, L.J., Johnson, ~.Y., King, T-S., Smith, I., Reiter, R.J.:
Natural and synthetic analogues of melatonin and related compounds. Effects on the reproductive system of the male syrian hamster. J. I~eurol. Transmission 56: 187-197, 19~3.
~7) Rollag, M.D.: Ability of tryptophan derivatives to rnimic melatonin's action upon the syrian hamster reproductive system. ~ife Sciences 31: 2699-2707, 198~.
(8) Vaugh~n, r1.~ ichardson, B.~., ,Johnson, L.Y., Petterborg, L.J., Powand~, M-C., Reiter, R.J., Smith, I.: Natural and synthetic Analogue3 of Inelatonin and related compounds. II Effects on plasma thyroid hormones and cholesterol levels in rnale syrian hamsters. J. Neural Trans. 56: 279-291, 1983.
, . ~. .
(9) Anton-Tay, F., Diaz, J.~., Fernandez-Guardiola: On t~e effect of melatonin upon human brain: Its possible therapeutic implications. Life Sciences 10:
841-85~, 1971.
(10) Anton-Tay, F.: Melatonin: Effects on brain function.
~dvance Biochem Psychopharmacol. 11: 31S-324, Raven Press, N.Y., 1974 . .
(11) Arendt, J., Symons, ~ aud, C.A., Pryde, S.J.:
Melatonin can induce early onset of the breeding season in ewes. J. En-30crinol 97: 395-400, 1983.
~12) Arendt, J., 80rbely, A.~., Franey, C., Wright, J.:
The effects o chronic, small doses of melatonin given in the late afternoon on fatigue in man: ~
preliminary study. ~leuroscience Letters 45: 317-321, 1984.
(13) Bartness, T.J., llade, G.N.: Photoperiod control of body weight and energy metabolism in Syrian hamsters (mesocricetus auratus) role o pineal gland, melatonin, gonads and diet. Endacrinology 114:
492-4q~, 198~.
~14) Bittman, E.L.: Melatonin and photoperiodic time measurement measurement: Evidence rom rodents and -2~~
~....:., - .
' '"' , ~29Z9~7 ruminantAs. The Pineal ~land, e(~. R. J. Reite, Raven Press, N.Y., pp. I55-192, 1984.
(lS) Blask, n.E.: The pineal, and oncostatic gland? In:
The Pineal Gland. ed. R. J. Reiter, Raven Press, New -York, 1984, pp. 276-277.
(16) ~ubenik, G.J.: Shift of seasonal cycle in white-tail deer by oral administration of melatonin. J. Exp.
zool. 225: 155-156, 1983.
(17) Burns, J.K.: Administration of Inelatonin to non-human primates and to women with breast carcinoma. J.
Physiol. 229: 38-39, 1973.
(18) Carman, J S., Post, R.M., Buswell, R., Goodwin, F.K.:
Negative e~ects o~ ~nelatonin on depression ~mer. J, Psychiatr. 133: 1181-1186, 1976.
(19) Cotzias, G.C., Papavasiliou, P.S., Ginos, J., Steck, A., Dubyl S.: Metabolic modification of Parkinson's disease and of chronic manganese poisoning. In: ~nn.
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::
(20) Cramer, H., Rudolph, J., Consbruch, U., Kendel, K.:
on the effects of melatonin on sleep and behavior in man. ~dv ~iochem Psychopharmacol. 11: 187-191, Raven Press, New York, 1974.
, . . ... . . . .
. .
12~Z9~7 (21) Danfortll, J.~., Tamarkin, L., Do, R., ~ippman, E.:
Melatonin in~uced increase in cytoplasmic estrogen -~~receptor activity-in-hamster-ut~ri. End~crl-nol~o~y 113: 81-85, 1983.
(22) Danforth, ~.N., Jr., Tamarkin, L., Lippman, M.E.:
Melatonin increases estrogen receptor binding activity of human breast cancer cells. Nature 305: 323-325, 1983.
(23) Ellis, L.C.: Inhibition of rat testicular androgen synthesis in vitro by melatonin and serotonin.
Endocrinology 90: 17-28, 1972.
(24) Ellis, L.C., Urry, R.L.: Direct in vitro effects of melatonin on steroid biotransformation. Physiologist 15: 1~5, 1972.
(25) Piske, V.M., Parker, K.L., Ulmer, R.~., Hoonow, H., Aziz, N.: Effect of melatonin alone or in combination with human chorionic gonadotropin or ovine luteinizing hormone on the in vitro secretion of estrogens on prosterone by granulosa cells of rats. Endocrinology 114,: 407-410, 1984.
';~,.' ~
~26) Frehn, J.L., I~rry, R.L., Ellls, L.C.: Effect of melatonin and short photoperiod on delta-4-reductase ~: activity in liver an~ hypothalamus o~ the ham~ter an~
the rat. J. ~ndocrinol. 60: 507-515, 1974 .. . . . ... . . . . . .
~,...
lZ9Z9~7 - `
~27) Heath, Il.W., Iynch, G.R.: Intraspecific differences for melatonin-induced reproductive regression and the seasonal mo~t ~n peromyscus Ieucopus. Gen and Comp.
en~ocrinol. 48: 289-295, 1982.
(28) Horst, 11-J, Buck, A., ~dam, K-U: Orally administered melatonin stimulates the 3 alpha/beta hydroxy steroid oxidoreductase but not the 5 alpha reductase in the ventral prostate and seminal vesicles of pinealectomized rats. Experientia 38: 968-970, 1982.
(29) Houssay, A.B., Pazo, J.H., Epper, C.E.: Effects of the pineal gland upon the hair cycles in mice. ACTA
Physiol. Lat. Am. 202-205, 1966.
(30) HoU~say~ ~.B.~ P~Zo, J.~ , ~pper, ~.E.: Effects of the pineal gland upon the hair cycles in mice. J.
Invest. ~ermatol. 47: 230-234, 1966.
(31) Kennaway, D.J., Seamark, R.F.: Circulating levels of melatonin following its oral administration or subcutaneou~s inje tion in sheep and goats. Aust. J.
~iol. Sci. 33: 349-53, 1980.
(32) Kennaway, D.J., Gilmore, T.~., Beamark, R.F.: Effect of melatonin feeding on serum prolactin and gona~otropin level~ and the 0n8et o~ seasonal estroUs cyclicity in sheep. Endocrinology 110: 1766-1772, 1~82.
.. . . ~ ...
. _ _ ~29Z947 (33) KennaWay, D.J., Gilmore, ~r.~ ect of melatonin implants in ewe lambs. J. Reprod. Fert. 70: 39-45, ".. j, ,"" .. . . . . . . ..... . . . . . . ............... ... . ... . .. . .. ..
19~4.
~34) Lerner, ~.B., Morlund, J.~J.: Melatonin: Clinical Pharmacology J. Neural Transm. (Suppl.) 13: 339~347, 1978.
(35) Lincoln, G.: Melatonin as a seasonal time cue: The commercial story. Nature 302: 755, 1983.
(36) Losee, S.H., Turek, F.U.: Melatonin treatment prevents the termination of the gonadal re~ractory condition normally observed in hamsters exposed to long days. In Pineal Function. ed. C. D. Matthews, R.
F. Seamark. Elservier/North ~olland, pp~ 67-75, 1981.
(37) Lovenberg, W~., Jequier, ~., Sjoerdsma, A.:
Tryptophan hydroxylation: l~easurement in pineal gland brainstem and carcinoid tumor. Science, lSS:
217-219, 1967.
(38) Moeller, H., Koz, A., Rodl, W., Frick, H-J., Gupta, D.: Role of pineal gland in the regulation of prostatic androgen receptors in pubertal ~nd mature rats. Res. Exp. Med. 183: 157-16S, 1~83.
~39) ~ordlund, J.J., ~erner, A.~.: The effects of oral - melatonin on skin color and the release oE pituitary hormones. J. Clin. ~ndocrinol. Metabl 45: 768-774, 1977.
l~Z9~7 (4~) Ogle, T.F., Kitay, J.l.: Ef~ect of melatonin and an aqueous pineal extract on adrenal secretion of reduced ~_ .. - .
..... , ......... . . ~ .. ; . ;, steroid metabolites in female rats.
Neuroendocrinology 23: 113-120, 1977.
~11 PapaVasilioU, P.S., Cotzias, G.C., Duby, S.E., Steck, A.J., Bell, M., Lawrence, W.H.: Melatonin and parkinsonism. JAM~ 221: 88, 1972.
(42) Pavel, S., Goldstein, R., Petrescu, M., Popa, M.:
Melatonin, vasotocin and RE~ sleep in prepuberal boys. ~dvanc. Biosciences 29: 343-347, 1981 in Melatonin-Current status and Perspectives t ed. N.
Birau, ~. Schloot, Pergamon Press, NY, 1981.
(43) Peat, F., Kinson, ~ Te.~ticular steroidogenesis in vitro in the rat in response to blinding, pinealectomy and to the aAdition of melatonin. steroids 17:
251-264, 1971.
~44) Petterborg, L.J., Reiter, R.J.: Effect o~ photoperiod and subcutaneous melatonin implants on the reproductive status of adult white footed mice - (percomycus leucopus) U. ~ndrol. 2: 222-224, 1981.
(45) Pevet, P., Raldar-Misra, C., Ocal, T.: Effect of 5 methoxytryptaminme and 5 methoxytryptophol on the reproductive system of the male golden hamster. J.
Neural Transmis. 51: 303-311, 1981.
12~Z947 (46) Pevet, P., ~al-3ar-Misra, C.: Ef~ect of orally ,. . .. . . . , ,, . ., ~ ............. . . . . . . . .. . . . . .
-~ - ac~ministered melatonin on reproductive funct~on~of the golden hamster. Experientia 38: 1493-1494, 1982.
~7) Raikhlin, M.T., Kvetnoy, I.r~.~ Tolkachev, V.N.:
Melatonin may be synthesized in enterochromaffin cells. Nature 225: 344-345, 1975.
(48) Ralph, C.L.: Melatonin production by extra-pineal tissues. Adv. in the biosciences. ed.
149) Rollag, t5.D., tlorgan, R~J., Niswender, G.D.: Route of melatonin secretion in sheep. Biomed. Sci. Instrum.
13: 111-117, 1977.
(50) ~omijn, ~I.J : The pineal, a tran~uillizing organ?
Life Sciences 23: 2257-2274, 1978.
(51) Rose, J., .Stormshak, F., Oldfield, J., Adair, J.:
Introduction of winter fur growth in mink (mustela vison) with melatonin. J. ~nimal Sci. 58: 57-61, 1984.
~52) Russel, J.., Reiter: ~he pineal gland: An intermediary between the environment and the endocrine system in Psychoneuroendocrinoloy 8: 31-40, 1983.
(53) Shirama, K., Furuya, T., Takeo, Y., Shimuzu, K., Maekawa, K.: Direct effect of melatoni.n on the accessory sexual organs in pinealectomized male rats kept in constant darkness. J. ~ndoc~ olog-~ '35:
87-94, 1982.
, ;. ., .. - " . . . ... .. . . ., .. , . ., . , .~, . .
- lz9z9~7 `` `
(54) Sisk, C.L., Turek, F.W.: Daily melatonin injections mimic the short day-induced increase in negativ~
` .
feedback e~fects of testosterone on gonadotropin~
secretion in hamsters. Biol. of ReprodUction 27:
602-608, 1982.
(55) Smythe, G.A., Lazarus, L.: Growth hormone response ~o melatonin in man. Science, lB4: 1373-1374, 1974.
(56) Stetson, ~.H., Rollag, t~.D., Watson-Whitmyre, M, Tate-Ostroff, B.: The effect of daily injections and constant release implants of melatonin on the endogenous pineal rhythm in golden hamsters. Proc.
Soc. Exp. Biol. Med. 174: 119-122, 1983.
(57) Stet~on, M.f~ , Tay, D.E.: Time course of sensitivity of golden hamsters to melatonin injections throughout the day. Biol. of Réproduction 29: 432-438, 1983.
t58) Stetson~ r1~ Watson-Whitmyre, M.: P~ysiology of the pineal and its hormone melatonin in animal reproduction in rodents. In: The Pineal Gland, ed. R.
J. Reiter, Raven Press, ~lew York, 1984, pp. 109-153.
(591 Tamarkin, L., Baird, C.J., ~lmeida, O.F~X.:
Melatonin: A coordinating signal ~or mammalian reproduction. Science 227: 714-720, 1985.
~60) Trentini, G.P., t~ess, B., DeGaetani, Poggioli, R., Ferrari, P., DiGregorio, C.: The role o~ melatonin .. _.~
~2~Z947 and brain serotoninergic system in the maintenance of rat ovariall cyclicity. Pineal Function, ed. C. D.
~ Matthews, R. F. seamark. Elsevier/North-Holland, pp.
77-86, 1981.
~61) Turek, F.W.: ~ntigonadal effect oE melatonin in pinealectomized and intact male hamsters. Proc. Soc.
Bxp. Biol. !led. 15S: 31-34, 1977.
(62) Vaughan, M.K., ~erbert, D.C., Brainard, G.C , Johnson, L.Y., Zeagler, J.W., Reiter, R.J.: A comparison of blinding and afternoon melatonin injections on the histology of the reproductive crgans, pineal ultrastructure and gonadotrophin hormone levels in female syrian hamsters. Adv. in the Biosciences. Rd.
N, Birau, W. Schoot, V. 29: Melatonin-current status and pre~pectives. Pergamon Press~ ~lew York, 1981, pp.
65-75.
(63) Vollrath, ~., Semm, P., Gammel, G.: Sleep induction by intranasal application of melatonin. Advanc.
Biosciences 29: 327-329 11elatonin-Current Status and Perspectives, ed. N. Birau, W. Schloot, Pergamon Press, NY, 1981.
(64) ~1aldhauser, F., Lynch, H.J., Wurtman, R.J.: Melatonin in human body ~luids: Clinical significance. The Pineal Gland. ed. R. J. Reiter. Raven Press, N~, p.
345-370, l9B4.
.. .. .
... , . ,. __ lZ9Z947 (65) Wilson, l3~W., Lynch, Tl.~J., Ozak.i, Y.: 5 methoxytryptophol in rat seruin and pineal: detection, quant;tation and evidence for daily rhymicity. Life Sci. 23: 1019-1024, 197B.
Claims (12)
1. A composition adapted for treating acne and seborrhea, selectively decreasing body and facial hair growth, conditioning skin, and reducing excessive hair fall, said composition comprising: a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a suitable pharmaceutical carrier.
2. The composition of claim 1, wherein the pharmaceutical carrier is a topical pharmaceutical carrier.
3. The composition of claim 1, wherein the pharmaceutical carrier is suitable for oral administration.
4. A composition adapted for treating acne and seborrhea which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine,
5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a suitable oral pharmaceutical carrier.
5. A composition adapted for treating acne and seborrhea which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a suitable topical pharmaceutical carrier.
5. A composition adapted for treating acne and seborrhea which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a suitable topical pharmaceutical carrier.
6. A composition adapted for decreasing body and facial hair growth which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a pharmaceutically acceptable topical carrier.
7. A composition adapted for reducing excessive hair fall which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a pharmaceutically acceptable oral carrier.
8. A composition adapted for reducinq excessive hair fall which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a pharmaceutically acceptable topical carrier.
9. A composition adapted for conditioning skin which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin; in admixture with a pharmaceutically acceptable oral carrier.
10. A composition adapted for conditioning skin which comprises a compound selected from the group consisting of melatonin, 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin: in admixture with a pharmaceutically acceptable topical carrier.
11. The composition of claim 2, wherein the concentration of said compound ranges from 10-4 to 1 per cent by weight.
12. The composition of claim 1, wherein said compound is melatonin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000503269A CA1292947C (en) | 1986-03-04 | 1986-03-04 | Melatonin compositions and uses thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000503269A CA1292947C (en) | 1986-03-04 | 1986-03-04 | Melatonin compositions and uses thereof |
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| Publication Number | Publication Date |
|---|---|
| CA1292947C true CA1292947C (en) | 1991-12-10 |
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ID=4132602
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112426408A (en) * | 2020-12-08 | 2021-03-02 | 广州帝奇医药技术有限公司 | Melatonin composition and preparation process thereof |
-
1986
- 1986-03-04 CA CA000503269A patent/CA1292947C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112426408A (en) * | 2020-12-08 | 2021-03-02 | 广州帝奇医药技术有限公司 | Melatonin composition and preparation process thereof |
| CN112426408B (en) * | 2020-12-08 | 2023-12-19 | 广州帝奇医药技术有限公司 | Melatonin composition and preparation process thereof |
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