Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-18
2001-08-28
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S561000
Reexamination Certificate
active
06281241
ABSTRACT:
The invention relates to the use of melatonin and melatonin-containing preparations for the treatment of androgenetic alopecia of the female type.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone with a broad spectrum of action [1,2], produced and secreted from the pineal gland under the influence of &bgr;-adrenergic receptors having a circadian rhythm. Although the mechanisms of the action of melatonin are still not comprehensively clarified in detail, melatonin appears to control the adaptation of the organism to environmental stimuli, in particular light and temperature. The toxicity of melatonin is not detectable, even on oral administration of several grams per day [3]. In the case of topical application in a nanocolloid preparation, and of alcoholic solutions, no local or systemic side effects were seen in over 60 subjects. Animal experimental studies indicate that the systemic administration of melatonin improves the thickness and structure of coat hair [4,5 ].
The influence of the duration of daylight exposure to the seasonal change of coat has been described for the sheep [6], the Kashmir goat and some other species of goat [7], red deer [8] and mink [9]. The mitotic activity of the secondary follicles and the hair growth resulting therefrom increases from the beginning of summer until the winter, to stop in the spring. After a resting stage, in which the hairs of the primary and secondary follicles fall out, a new growth cycle begins with induction of a new anagenic phase.
This cycle of hair growth and of molting is disturbed if the pineal gland is removed [5]. Welch [10] was able to show that by administration of melatonin in cashmere goats the initialization of the growth activity of the secondary follicles in the spring can be accelerated. In New Zealand, goats were treated with melatonin over a period of 14 days in order to initiate the spring growth, and compared with untreated goats. The histological examination of biopsies of the skin which were taken during the 14 days showed, in the goats which had been treated with melatonin, an induction of hair growth by changeover of the hair follicle from the telogenic phase to the proanagenic phase, while the hair follicles of the untreated goats remained in the telogenic phase [11].
In in-vitro investigations of hair follicles of the cashmere goat in the hair organ culture model, it was likewise possible to detect the influence of melatonin on the hair growth of the follicle. In the 24 hour interval, the administration of melatonin in concentrations from 150 mg/ml led to a greater growth of the hair shafts than the lower dose and the control. Over the total period of 120 hours, the differences in the longitudinal growth were significant (p =0.05). The best growth rates and maximal total growth after 120 hours were recorded with the administration of the melatonin concentration of 300 ng/l [12].
U.S. Pat. No. 4,476,674 discloses the use of melatonin for the treatment of various disorders in humans which are accompanied by hair loss, namely the treatment of toxic alopecia, e.g. alopecia induced by treatment with medicaments, and the treatment of alopecia of the male type. A reference to the use of melatonin for treatment in the case of androgenetic alopecia of the female type is not found.
Androgenetic alopecia of the female type differs significantly from toxic alopecia. Significant differences also exist with respect to androgenetic alopecia of the male type, namely with respect to the clinical intensity, the mechanism of action and the treatability.
1. Differences in the Clinical Intensity
Although androgenetic alopecia occurs in both sexes, the clinical intensity is typically different.
The hair loss pattern of the male type (male pattern alopecia) has already been described by Hamilton in 1942 and modified by Eblin and Rook in 1972. In this, marked receding of the hairline is seen in stage 1, which is accompanied from stage 2 with increasing thinning of the occipital hair and then with increasing confluence of both areas in stage 4 results in the appearance of a largely bald scalp with a residual fringe of hair in the occipital region [13, 14].
The hair loss pattern of the female type (female pattern alopecia) differs markedly from the male type, as in this form no receding of the hairline occurs and complete baldness of the scalp never results. This form was divided into three stages by Ludwig, with especially the centroparietal (crown of the head) region diffusely thinning out as the stages progress. Even in the case of advanced alopecia in women, there is usually still a thin fringe of hair of 1 to 2 cm between the forehead and thinned crown region [15].
2. Differences in the Mechanism of Action
The term “androgenetic alopecia” is understood as meaning forms of hair loss which occur under the influence of androgens in the presence of a genetic disposition. They are associated with an acceleration of the hair cycle, which leads to the proliferation of telogenic hairs and increasing occurrence of thin miniature hairs.
In men, the high androgen levels, together with the given constitutional sensitivity of the hair roots to androgens, regularly lead to male alopecia.
In women, who have 10 times lower androgen levels than men, the absolute amount of androgen is less responsible for the development of hair loss than the increased end organ sensitivity to androgens. In over 90% of women, this mechanism leads to female pattern alopecia, while in the other cases male pattern alopecia can also occur. In this case, increased androgen levels are often found [16]. Likewise, a rare female pattern alopecia can occur in men, which in this case too has no similarity to male pattern alopecia and also does not change into this.
3. Differences in Treatability
Differences are also seen in the therapeutic mechanisms of action.
The studies extensively carried out in recent years on alopecia in men showed a very good response of a 5-alpha-reductase inhibitor (finasteride), which inhibits the conversion of testosterone to dihydrotestosterone. It was possible to achieve stopping of the hair loss in 80% of the cases and a slight to marked improvement in the hair density in 66% of the cases [17]. Thus the pathological mechanism of the male hair loss type still seems to be limited rather by the amount of androgens reacted than by the sensitivity of the roots.
Up to now, unpublished data on experiments with finasteride in postmenopausal women did not show any superior efficacy compared with placebo. This gives the decisive reference to the increased sensitivity of the hair roots to the small amounts of androgens present in women.
Moreover, the use of finasteride in women of childbearing age is contraindicated, as reduced levels of dihydrotestosterone, the active metabolite of testosterone, in a male fetus can lead to malformations of the external genitals.
In a scientific investigation leading to the present patent application, it has now been found that melatonin is a suitable active compound for the treatment of androgenetic alopecia of the female type. Significantly better results from the use of melatonin in androgenetic alopecia in women compared with those of diffuse alopecia in women were found with respect to the telogenic rates. The use of melatonin in androgenetic alopecia in women is thus to be delimited as a specific medicinal indication from androgenetic alopecia in men and diffuse alopecia in women and implies a novel principle of action. It can be presumed that melatonin, in the androgen-mediated mechanism in women, develops modulating properties which are not effective in men on account of the high androgen concentration.
For the treatment of androgenetic alopecia of the female type, a melatonin preparation is preferably applied topically. Application can take place here in the form of sprays, solutions, lotions, creams, ointments, shampoos, conditioners or other su
Arent Fox Plotkin Kintner Kahn PLLC.
ASAT AG Applied Science and Technology
Fay Zohreh
Kwon Brian-Yong
LandOfFree
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