USE OF MELATONIN OR RELATED COMPOUNDS FOR THE TREATMENT OF PSORIASIS

Abstract: The method relates to the making of compositions useful for curing psoriasis in living creatures, including humans. Said compositions contain an active indolamine derivative, most preferably melatonin. Certain preferred compositions for topical use consist of lotions, foams or sprays, while compositions for oral ingestion consist of tablets, caplets or capsules and similar items. Treatment is implemented by topical application with light massage only, or in combination with oral dosage which can be used alone or in combination with the topical treatment.

Description: Use of melatonin or related compounds for the treatment of psoriasis Field of the Invention The present invention relates to a method and composition for topically and/or orally treating the skin and/or scalp of a human host. More particularly, the present invention relates to the topical treatment of psoriasis vulgaris, a specific condition of the skin and scalp of a human host associated with epider-mal hyperplasia producing hyperkeratotic skin plaques of unsightly character. Psoriasis vulgaris, apart from its cosmetic and consequent emotional effects on its victims, is associated with extensive scaling and the shedding of large quantities of keratotic skin depending on the degree of skin involvement. Psoriasis involves 1-2X of the U.S. population, is exacerbating and remitting in quality and is frequently associated with characteristic patterns of inflammatory arthritis or spondylitis. The present invention concerns itself with a method for topical and systemic treatment of psoriasis to attenuate, remit, or prevent recurrence of psoriatic skin plaques. 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. Since the isolation of melatonin in 1959, reports of its ability to inhibit luteinizing hormone (LH) secretion with control of fertility led researchers (Flaugh et awl., 1978) to investigate the action of melatonin analogs on plasma half life to produce compounds with the same biological activity as melatonin but with a prolonged serum half-life. Houssay et al (1966 a,b) have shown that the pineal gland and the parenteral administration of melatonin acts on the skin of mice to slow hair growth waves in mice. Rose et al (1984) have shown that it is possible 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 (1982) have shown that follicular development was blocked, in mice injected with melatonin. Rats were used in the assay to measure effects on LH release and ovulation. Melatonin analogs were given p.o. and intravenously. Pronounced increase in activity and half-life was noted with halogenation on the 6 position. Frohn et al (1980) reported 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 of 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. Melatonin and its CNS metabolite N-acetyl 5-methoxys kynurenamine were found to be the most potent antagonists and beta carbolinemetabolites of melatonin were noted to be high affinity antagonists to diazepam (Marangos et al., 1981). Rollag (1982) studied 18 different tryptophan derivatives, many of which are found in the pineal gland, to induce gonadal regression 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 Pevetls review (1983) but melatonin is the most effective agent. Similar studies were conducted by Richardson et al (1983), Vaughn et al (1983) with 6-chloromelatonin being the only analogue to possess anti-gonadotrophic activity equal to melatonin. Their paper reviews the structural activity literature evaluating melatonin analogues. This same group (Vaughan et al., 1982) explored the action of melatonin natural and synthetic analogues on the effects of cholesterol and thyroid levels in male syrian hamsters as compared to melatonin. The native hormone melatonin was found to be the only structure lowering T4 (thyroxine) levels. In a frog skin assay, Frohn, et al., (1980) concluded that the N-acetyl group attached to 3-position determines binding site 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, 1983). The primary secretory route of melatonin in mammals is by way of the capillary bed of the gland itself (Rollag et awl., 1977). Melatonin (N-acetyl-methoxytryptamine) is primarily derived from tryptophan and synthesized via the action of tryptophane hydroxylase (Lovenberg et al., 1967). The pineal gland is 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 pineal 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., 1975). Besides melatonin, 5-methoxytophol (Wilson 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 control of reproductive physiology (Tamarkin et al., 1985; Arendt at al., 1983; Stetson & Watson-Whitmyre, 1984). As 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 hormonal cycling are seen in the depression of testosterone production in mice given melatonin (Petterborg & Reiter, 1981). Alternatively, depending on species, testicular regression can be prevented and testosterone activity maintained (Turet, 1977; Stetson et al., 1983) in hamsters. Melatonin, given by injection, can alter estrous cycling in female rats (Trentini, et al., 1980). Evidence supports the possibility that melatonin levels may be a factor in suppression of puberty in man (Tamarkin et al., 1985). Melatonin is entering the commercial animal husbandry market to control fertility (breeding time), fur coat development and appetite. For example, in ewes 2mg/day, in pelleted feed, which mimics nocturnal blood levels, controls the estrous cycle and sheep fertility (Lincoln, 1983; Kennaway et al., 1982). Similar effects on daily feeding have been observed in male white tailed deer (Bubenik, 1983) with earlier seasonal antler and coat changes. Melatonin injected subcutaneously in saline or oil produces high transient blood levels while oral administration in saline or food pellets produces sustained blood levels (Kennaway & Seamark, 1980). Melatonin has been orally given in drinking water (Pevet and Haldar.-Misra, 1982) or by subcutaneous slow release implants, i.e., sialastic (Turek, 1977; Losee & 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 intermittent exposure and the relation of melatonin to the animals photoperiod (light/dark cycle) is important (Stetson et al., 1983; Losee & Turek, 1980; Trentini et al., 1980; Stetson & Tay, 1983; Bittman, 1984; Tamarkin et al., 1985). Melatonin injections can mimic syrian hamster short day photoperiod exposure with increases in body weight gain, feed efficiency, enhanced carcass lipid and brown adipose'tissue mass and thermogenic capacity (Bartness & Wade, 1984). The clinical use of melatonin in CNS disease has. been reviewed by Anton-Tay (1974) and Romijn (1978) and there have been extensive studies of its intravenous, intrathecal and direct localized CNS implantation on behavior in a wide range of animal species that has led to clinical trial. Waldhauser et al. (1984) have reviewed the clinical use of melatonin. They indicate that approximately 150 subjects have received clinical melatonin intravenously or orally. In most cases, no significant toxicity was observed (Lerner & Norlund, 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). Melatonin has been given clinically to volunteers by mouth in carbowax at 1-25 ug/kg (Anton-Tay, 1974) or clinically to volunteers by mouth in corn oil as a .04% solution at a dose of 2mg/day for 4 weeks (Arendt et al., 1984). It has been given orally in doses of 250mg (Norlund and Lerner, 1977) and in doses up to 1.2g/day (Anton-Tay, 1974; Carmen et al., 1976; Anton-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 Waldhauser et al (1984), and are supported by the results of intranasal administration where melatonin, as a 0.85 per cent ethanol spray induced sleep in 70% of patients within 40-60 minutes (Vollrath et al., 1981). Melatonin has been studied p.o. and i.v. clinically in depression and in Huntington'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% 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 of tremor and rigidity have been seen although results have not been consistent in studies of parkinsonism with all investigators as Papavasiliou et al., (1972) has not seen benefit with doses as high as 6gms daily. Carman, et al. (1976) have reviewed the CNSD clinical studies up to that time and the use of melatonin for the treatment of tremor and rigidity looked promising. 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 of malignancy. He cites DiBella and Starr as achieving inhibitory clinical results in a variety of tumors. In relation to endocrine action, Smythe and Lazarus (1974) have given 0.5 gms of melatonin for 2 doses, 30 minutes apart with a reported melatonin related rise in growth hormone in contrast to depression in growth hormone reported elsewhere (Starr, 1969; 1970; Kuzmanovic et al., 1985; Attanasi at al., 1985). 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 Kirk (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 and in vitro inhibition of testicular synthesis from cholesterol and pregnenolone precursors of testosterone and androstenedione synthesis in the rat testes (Peat & Kinson, 1971). The inhibiting effects o-f melatonin on testicular function have been associated with stimulation of delta-4-reductase in rat liver and hypothalamus (Frehn et al., 1974). Melatonin was found to specifically increase the 5-alpha reductase of seminiferous tubules for both progesterone and testosterone. Melatonin decreased androgen synthesis in both testicular interstitial cells and tubules (Ellis, 1972). Similar increases in 5 alpha reductase activity in rats by melatonin have been observed on adrenal cortical function (Ogle and Kitay, 1977). Melatonin reduced accessory sexual organ size in pinealec tomized-.male rats kept in constant darkness without inhibiting testosterone metabolism leading the authors (Shirama et al., 1982) to suggest that melatonin is possibly acting at the tissue level to reduce the numbers of androgen receptors and/or the susceptibility to androgen. Orally administered, melatonin was found to lower ventral prostate and seminal vesicle weight and the 3/beta-hydroxysteroid oxidoreductase was increased but not the 5 alpha reductase in the ventral prostate and seminal vesicles of pinealectomized 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 luteinizing hormone increased the secretion of estrogens and progesterone in isolated granulosa cells of the rat. Melatonin, in relation to ovarian function, showed a progonadal trophic effect (Fiske et al., 1984). In regard to local stimulation of estrogen receptor availability by melatonin in cutaneous areas of androgenic and estrogenic hormone sensitivity. There is evidence that melatonin increases cytoplasmic estrogen receptor activity in hamster uteri and similar effects have been observed 'in estrogen receptor binding activity in human breast cancer cells (Danforth et al., 1983). Other reviews of the physiological role of melatonin are found in: -G.M. VAUGHN et al., titled "Evidence for a pineal-gonad relationship in the human," published in Prog. Reprod. Biol Vol. 4, p. 191-223, 1978. -H.L. JUDD, titled "Biorhythms of gonadotrophins and testicular hormone secretion," published in Endocrine Rhythms, 1979. -D.P. CARDINALI et al., titled "Melatonin action: sites and possible mechanisms in brain," published in "The Pineal gland and its endocrine role," J. AXELROD, F. FRASCHINI and G.P. VELO, ed. Proc. Nato Adv. Study, Erice, Italy, p. 551-575, Plenum Press, New 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. FRASCHINI 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. WURTMAN et al., entitled "Physiological Control of Melatonin Synthesis and Secretion: Mechanisms Generating Rhythms in Melatonin, Methoxytryptophol, and Arginine. Vasotocin Levels and effects on the pineal of endogenous catecholamines, the estrous cycle and environmental lightening", J. of Neural Transmission, Suppl. 13, 59-70, 1978. -Ivor Smith, entitled "Indoles of Pineal Origin: Biochemical and Physiological Status", Psychoneuroendocrinology, Vol. 8, No. 1, pp. 41-60, 1983. -Tamarkin L., et al.: entitled "Melatonin: A coordinating signal for mammalian reproduction" Science 227: 714-720, 1985. -Wurtman RJ, Waldhauser F: Mel-atonin in Humans. Proc. First Int. Cong. on Melatonin in Humans. Center for Brain Sciences and metabolism. Charitable Trust. Kendall Square, Cambridge, Mass., 1985. Surprisingly, none of the prior art studies are concerned with the dermatological effects of the administration of melatonin to a human host. Moreover, 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 of various diseases. Summary of the Invention In accordance with the present invention, there is provided a method and composition for clinically treating the skin and scalp of man by the administration of a composition containing a melatonin compound in order to produce clinical improvement or remission in psoriasis vulgaris (hereafter called psoriasis). More particularly, the present invention provides a composition for use in the treatment of the skin and/or scalp of a human host with psoriasis in order to prevent or ameliorate the conditions or symptoms of psoriasis. The preferred active ingredient of the compositions of the invention consists of melatonin itself. Among the chemical homologues useful for the production of compositions according to the invention, there can be mentioned the class of compounds which are represented by the general formula: EMI9.1 - n is 1 or 2 - R1 and R2 identical or different from each other are H, NH2, COOH, OH, acyl comprising from 1-4 carbon atoms or alkoxy comprising from 1 to 4 carbon atoms: -X is OH or alkoxy comprising from 1-4 carbon atoms: -Y is H, OH or NH2. Preferred compounds for use in the compositions of the invention are those in which Y is hydrogen and X is methoxy. The most preferred compound is melatonin itself, the formula of which is: EMI9.2 Other preferred compounds for use in the compositions of the invention are 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxy melatonin. These compounds can be obtained by synthetic processes, general methods of manufacture which can be derived from those published by J. SZMUSZKOVICZ, "Synthesis of N-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 MASHKOVSKY et al., in Farmakol. Toksikol., 26, n 1, 10, 1963, said methods being of course in each case adapted to the particular compounds sought. The term "melatonin" is used hereafter to designate both the actual melatonin and the chemical homologues or derivatives thereof. Current Treatment of Psoriasis: Prior Art Topically, treatment consists of the cautious application of corticosteroids (Christiansen et al., 1985), coal tar (Downing & BR< Bauer, 1948), Lasar's paste and anthralens (dithranol) (Champion, 1981). As a treatment, ultraviolet light exposure to the involved skin of different intensities and wavelengths (UVB, UBA) can be considered topical in its exterior application to the psoriatic lesions. Standard treatments for psoriasis include coal tar (Downing & BR< Bauer, 1948) with studies now determining that quinoline or isoquinoline ingredients of coal tar may be the active principal (Foreman et al., 1984). The current most popular treatment utilizes ultraviolet light (UVB) combined with methoxypsoralen given orally (PUVA), a program that has risks related to cutaneous carcinogenesis and skin and/or eye sensitization to light (Parker et al., 1984). Other forms of systemic treatment include corticosteroids, including dehydroepiandrosterone, and the anti-mitotics methotrexate, hydroxyurea, razoxane, mycophenolic acid, cytosine arabinoside and alkylating agents (Champion, 1981). The latter are mutagenic and perhaps carcinogenic while all anti-mitotics can be suppressive of white counts and the immune response. While methotrexate, the most popular of the anti-metabolite mitotic inhibitors produces a significant incidence of liver fibrosis depending on dose and time of exposure (Ashton et al., 1982). Most recently, the retinoics, which are vitamin A precursors and ornithine decarboxylase inhibitors useful in acne have shown benefit in psoriasis alone or when combined with PUVA (Parker et al., 1984). The retinoics are skin drying and teratogenic and must be avoided during pregnancy. In addition to ultraviolet light as an external energy treatment, ultrasound and hyperthermia have also been reported to be of value (Champion, 1981). Dialysis (Whittier et al., 1983) and plasmapheresis (Schuster et al., 1985), based on the removal of a psoriatic blood factor(s), represent expensive intensive technological approaches with controversial therapeutic benefit. No treatment is satisfactory in that remission rates vary and all treatments have drawbacks related to side effects ranging from systemic toxicity, thinning of skin (Salde Classus, 1983) staining of skin and clothing, eye and skin sensitization to sunlight (Farber & BR< Epstein, 1982) and to long term risks related to cancer induction (Champion, 1981) or liver damage. The etiology of psoriasis is unknown as is its underlying pattern of pathophysiology. Most emphasis regarding etiology has stressed the action of the inflammatory or immune system in the etiology of the disease. Although specific injury to the skin can induce psoriatic lesions: (the Koebner reaction) and streptococcal infection can precipitate psoriasis, the underlying causal relationships are still speculative. While genetic predisposition is seen in idiotypic hereditable patterns, i.e., HLA B27 (the same pattern is seen in ankylosing spondylitis and Reiter's syndrome) the actual molecular mechanisms are not defined (Russell et al., 1972; Gazit et al., 1978; Morhenn et al., 1979). Regarding the fundamental pathology of the disease, it is generally recognized that the mitotic rate of psoriatic skin and the normal skin areas of psoriatics shows greater skin proliferative activity. The cell cycle is shortened (Grove, 1979; Chopra and Flaxman,, 1974) although the S phase of DNA synthesis may be delayed (Steigleder and Pullman, 1979). There is evidence for a basic defect in cell kinetics with more cell division in psoriatics, but a lack of understanding as to what triggers the difference between normals and psoriatics or, psoriatic involved skin and normal skin in the psoriatic patient is not clearly defined. Krueger (1981) has presented an excellent review seeking to establish the pattern of abnormality and the etiologic or interrelated factors involved in triggering the hyperplastic cutaneous event. Review of pathology and pathophysiology has presented evidence of cutaneous monocyte/macrophage and langerhans (white) cell aberrations in psoriasis as well as changes in neutrophil infiltration and leukotriene or prostaglandin relationships (Krueger, 1981). Observations have been made regarding angiogenesis and changes in clotting factors or humoral factors in psoriatics effecting the function of white blood cells on the immune response. Cellular mediators including cyclic nucleotides, polyamines, prostaglandins and pro teasers have been invoked as related to psoriatic changes, as have unique antigenic determinates in psoriatic skin, but no one has defined the pathophysiologic patterns that clearly relate in an integrated manner to cause and affect. Nowhere in reviews or specific research in psoriasis has anyone suggested that melatonin is a therapeutic or controlling factor in psoriasis apart from the fact that melatonin values are lower in psoriatics (Schloot et al., 1981). According to the above authors treatment with psoralen (8-methoxy-psoralen) raises serum melatonin concentration which could act as a factor in normalizing psoriatics. Thus, the invention is based on the discovery that melatonin, particularly when applied externally to the skin, for instance in the form of compositions suitable for local topical use, provides efficient relief in psoriasis-afflicted patients. Description 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 therapeutic or cosmetic liquid applicable externally. Such composition is then of a particular utility for preventing, attenuating or curing psoriasis. In regard to the application of melatonin for the control of psoriasis vulgaris, it is advantageous to use compositions in which melatonin is associated with a lipophilic substance, both being dissolved in an appropriate solvent. For instance, the melatonin homologues are used in the form of a solution in a water-ethanol mixture containing from 10% to 30% v/v or more of ethanol. Alternatively, it can be administered as a cream or ointment. However, the amount of active ingredients in the composition may be more or less, depending on the specific conditions to be treated and the degree of treatment needed. The compositions for psoriasis can also be used in a therapeutic environment or application, in addition to cosmetic application. Whatever the use of the topical composition or lotion for attenuating reversing or preventing psoriasis, the concentration of the active compound therein should be sufficient for providing a good local topical absorption of the active principle. The compositions can also be in a form suitable for oral administration in combination with topical treatment. These oral compositions then containing an effective amount of melatonin at pre-selected levels of concentration. By way of example, there may be mentioned in topical preparations, relative concentrations of 10 4 per cent to about 1% in weight, of the melatonin or melatonin derivatives in lotions or other liquid solutions of 10 4 percent to 1% 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 Company, Easton, PA., 1965, which is incorporated herein by reference. Generally, it is advantageous to apply or use the compositions of the invention in the evening and prior to going to sleep when melatonin endogenous production is at a higher level. However, this is not a limiting condition for the use of melatonin compositions. The compositions can also be in a form suitable for oral administration these compositions then containing an effective amount of the active compound to produce the same effects. The relative innocuity and character of toxic side effects of melatonin are well known. By way of example, relative concentrations of 10 4 per cent to above 1% in weight of the melatonin or melatonin derivatives in lotions or other liquid solutions of 10 4 percent to 1% 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 orally administrable compositions being dosed accordingly. A third embodiment of the invention relates to compositions containing an effective amount of melatonin associated with a veh'icle which makes said composition suitable for topical application for preventing or reversing the pruritic, inflammatory, hyperkeratotic or arthritic manifestations of psoriasis. The other components of such compositions can be the usual ones. As discussed previously, it is advantageous to use compositions in which meblatonin is associated with a lipophylic substance, both being dissolved in an appropriate solvent. For instance, the melatonin homologues are used in the form of a solution in a water-ethanol mixture containing from 10% to 30% v/v or more of ethanol. However, the amount of active ingredients in the composition can be more or less depending upon the patient, the conditions of the psoriatic skin and the effect desired. As discussed previously, psoriasis is a skin disease of -distinctive quality associated with epidermal hyperplasia producing hyperkeratotic skin plaques of unsightly character (Pinkus & BR< Mehregan, 1966). The disease, apart from its cosmetic and consequent emotional effects on its victims, is associated with extensive scaling and the shedding of large quantities of keratotic skin depending on the degree of skin involvement. Psoriasis incidence involves 1-2% of the population (Krueger, 1981) with the exception of American Indians. Psoriasis is noted for its exacerbating and remitting quality and it is frequently associated with characteristic patterns of crippling inflammatory arthritis or spondylytis. The cause of psoriasis is unknown and the prior art treatments are largely empiric related to inhibiting the hyperplastic growth of the skin or decreasing inflammation and softening and removing the hyperkeratotic epithelium from its underlying dermal base. The basic treatment is to attempt to control the epidermal hyperplasia with both topical and systemic drugs (Champion, 1981). A preferred composition of this invention for treating psoriasis contains an effective amount of melatonin associated with a vehicle which makes said composition suitable for topical application for humans. Advantageously, this composition is made in the form of a lotion, liquid or ointment applicable externally, along with light massage. Such composition is of particular utility for relieving patients from pain and itching and for restoring the damaged or affected skin. As a matter of fact, it has been found that upon applying melatönin locally on a regular basis, the proliferation of psoriatic scales is inhibited and regresses and is followed by reepithelialzation and reemergence of new healthy skin. The other components, particularly vehicles of such compositions can be any of those which can be tolerated by the patients. It is advantageous to use compositions in which melatonin is associated with a lipophylic substance, both being dissolved in an appropriate solvent, for instance in the form of a solution in a water-ethanol mixture containing from 10% to 30% v/v or more of ethanol. By way of example, there may be mentioned merely by way of examples, relative concentrations of 10 % to about 1% in weight, of the melatonin or melatonin derivatives in lotions or other liquid solutions. Preferred relative concentrations of melatonin in ointment compositions are in the same range. However, the amount of active ingredients may be more or less depending on the patient's response and the degree of treatment needed. Other suitable preparations may comprise the following: Melatonin 1.0% in a colorless, greaseless lotion which contains water, aluminum hydroxide, isopropyl stearate, PEG-100 stearate, glyceryl stearate, cetyl alcohol, glycereth-26, isocetyl stearate, glycerin, dimethicone, copolyol, sodium citrate, citric acid, methylparaben, propylparaben, fragrance. Included also among preferred compositions for topical administration are creams or ointments or emulsions or also compositions suitable for the production of foams or sprays, all compositions in which melatonin is associated with corresponding suitable physiologically or dermatologically acceptable vehicles. 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 Company, Easton, PA. 1965, which is incorporated herein by reference. Needless to say that whatever the use of the topical composition or location, the concentration of the active compound therein should be sufficient for providing a good local absorption of the active principle to the desired level. The invention is not limited to topical compositions. The compositions of this invention can also be in a form suitable for oral - or even parenteral administration, these compositions then containing an effective amount of the active compound to produce the same effects. The relative innocuity and absence of toxic side effects of melatonin are well known, particularly as reported in the articles mentioned previously. In some situations, oral or even parenteral administration may be held more effective to achieve the purpose sought, alone or combined with topical melatonin. When oral use is considered, effective daily dosages range from about 0.1 to about 100 mg/kg a day, the orally administrable compositions being dosed accordingly. But, again, the amount of active ingredients may be more or less depending on the response to treatment, the degree of treatment needed, convenience to patient and side effects such as sedation, if any. The beneficial effects of melatonin-containing compositions on psoriasis were observed in psoriatic patients under the following conditions. The melatonin-containing composition used consisted of a solution containing 1 mg/ml of melatonin (produced by FLUKA A.G.) in a 30t alcohol-water mixture. The patients treated exhibited in areas localized at the level of elbows and knees a proliferation of immunerable erythematous papules and plaques, with silvery white keratotic scales. Cotton pads imbibed with the above composition were applied and maintained regularly over-night as occlusive dressings on the psoriatic areas. Two weeks from the beginning of the treatment, the scale proliferation was stopped and shortly thereupon started to regress, with a attendant reduction of itching. It was followed by a reepithelialzation and reemergence below the scales of healthy red elastic new skin. Response only occurred in the involved areas that were topically treated. More recent studies have been conducted using a 0.1% melatonin cream of the following composition. MELATONIN - CREAM 0.1%, 0.01% and 0.001%' Melatonin 0.1% Non-ionic hydrophilic ointment 98.9% (Ung-.hydrophilicum nonionogen. Ph.Helv.VI) Alcohol benzylicus 1.0% Non-ionic hydrophilic ointment (Ung.hydrophilicum nonionogen: Cetanolum; Ol.arach.hydrogennatum; propylenglycolum; Tween 60; Aqua destillata Melatonin was administered as an overnight application. Prior to the present invention, there have been no clinical or laboratory studies with regard to the topical application of melatonin to cutaneous areas in the treatment of psoriasis. The following cases showed response to topical malatonin. In one case, oral bed time melatonin was added and topical application discontinued with continued improvement of the patient. Examples and results in the testing of melatonin in treatment of psoriasis and acne From the clinical testing clear indications emerged showing that the TIME OF ADMINISTRATION and the INITIAL AND MAINTENANCE DOSAGE ARE FUNDAMENTAL FACTORS AFFECTING RESPONSES SEEN. As the night levels of melatonin in humans are in the order of picograms/ml serum, some governing factors in topical administration involve: (1) We have observed that frequently during initial testing with our ointment containing 0.1% melatonin, an initial dramatic improvement of psoriasis was followed by a period of no further changes and eventually, in extreme cases, of excessive topical dosage (in one case accompanied by the use of beta-blockers), increased pruritus and inflammation of the psoriatic lesions develops. This condition was immediately reversed by drastic reduction in the ' dose of melatonin ointment administered. It is thus important that, at most, a negligible amount of melatonin should remain on the skin during daytime. (The opposite in night shift workers) It must be pointed out that cases of psoriasis can differ and that timing of treatment and dosage must be adapted to each patient. (2) The initial dosage selected was necessarily empirical, but once an effect was evident, the amount of ointment or cream was reduced to a topical preparation containing 10 or 100 times less melatonin than initially selected. The psoriatic patient needs to be informed that it is not the quantity, but the DOSAGE and TIMING of melatonin that is fundamental for his therapy. The above discoveries applied especially to patients with psoriasis vulgaris having very large lesions who have suffered from psoriasis for many years. These patients notice a dramatic improvement immediately, but get disappointed if they do not see constant amelioration of their disease. Generally, we observed from the application of melatonin in mild cases of psoriasis, that improvement comes soon while severe cases require a longer treatment before seeing similar improvements. Patient No. 1: B.F., Born 1939, male. History: Psoriasis vulgaris on both elbows for many years. Therapy: Topical melatonin 0.1% daily in the evening. Observations after 14 days: Progressive improvement. Treatment: Topical melatonin 0.1% every two days in the evening. Observations after 9 days: slight increase in scaling; decreased erythema; gradual appearance of islands of healthy skin. Patient No. 2: C.L., Born 1933, female. History: Psoriasis vulgaris on both elbows and on the vulva for 3 years. Therapy: Melatonin 0.1% on the right elbow and placebo (eccipient) on the left one. First, daily appli cation then, every 2 days always in the evening. Observations after 4 weeks: Right elbow clearly better than the left one. Afterwards, the topical treatment was stopped and the patient started taking one capsule of melatonin (2mg) orally every day in the evening. With this therapy, clearcut decrease of erythema and of scaling continued. Patient No. 3: V.B., Born 1948, male. History: Psoriasis pustolosa on palms and soles for 10 yrs. Therapy: Topical melatonin 0.1% every day in the evening. Observation after 20 days: Palms cured, soles: progressive improvement. Therapy: The topical melatonin 0.1% every 2 days in the evening. Observations after 22 days: Continuous progressive improvement. As discussed previously, even when administered per os at very high doses and for a long time, melatonin-has been found to be singularly free of toxicity. Thus, topical use of melatonin does not constitute a danger if one considers that, in humans, pineal secretion of melatonin is a normal physiologic event with typical night time periodicity This activity of melatonin on remission and improvement of psoriatic plaques does thus constitute a valid "physiological" prophylaxis and therapy for humans suffering from psoriasis. Although the invention relates primarily to the topical application of melatonin, it is understood that topical treatment may be desirable in combination with oral or parenteral administration of melatonin depending upon ' the patient and the severity of the condition to be treated. The success of topical melatonin combined with oral administration is seen in the example of Case &num;2, described herein. Melatonin was given as a 2mg capsule in the evening prior to bed time in addition to topical applications. Rationale for the Use of Melatonin in Psoriasis: It may be added, as a way of background of the invention, that the melatonin rationale for the treatment of psoriasis relate to several areas: Melatonin values are low in psoriasis (Birau, 1981; Schloot et al., 1981). Growth (somatotropin) hormone (GH) effects: Starr (1969, 1970) reported on intravenous melatonin inhibiting growth hormone levels in patients with sarcomas as the rationale for melatonin's repotted clinical anti-cancer effects in conjunction with standard radiotherapy or chemotherapy. Growth hormone inhibition has been recently observed by Gupta's group (Kuzmanovic et al., Attanasio et al., 1985). Weber et al. (1981, 1983) have reported that growth hormone is elevated in psoriasis and based on this , have reported significant clinical responses on administration of somatostatin and/or bromcriptine or salbutamol, all of which are inhibitors of growth hormone release and/or could effect melatonin levels. Weber et al. (1983) reports an 80% response rate to these agents in psoriasis with comparative clinical but differing histologic effects as compared to standard PUVA therapy. These observations of Weber are supported by Priestly et al. (1984) who finds a suggestive increase in growth hormone levels in psoriatics. Thus, if, as based on Starr's report and that of Gupta's group (Kuzmanovic et al., Attanasio et al., 1985) melatonin can reduce growth hormone action on skin psoriatic lesions which might be one other rationale for its anti-psoriatic action. In opposition to the role of melatonin and growth hormone, lithium has been reported to induce psoriasis although it produces a fall in growth hormone levels (Seggie et al., 1983. Although nocturnal melatonin levels remain elevated. Lithium, a stimulator of neutrophil functions may produce effects on neutrophils as an etiologic factor in psoriasis (Bloomfield & Yung, 1983). Ghirlada et al. (1983) have also reported response of psoriasis to somatostatin with concomitant decline in epidermal growth factor (EGF). The relation of melatonin to epidermal growth factor(s) EGF, or growth hormone and somatostatin in skin deserves to be elucidated. One feature of the possibility of melatonin involvement reflects on the action of beta blockers as inducers of psoriasis in susceptible individuals. This relates to beta blockade as a factor in inhibiting melatonin production which would explain why beta blockers can induce psoriatic disease in susceptible individuals. The action of beta blockers in inducing psoriasis has been described by a number of investigators (Felix et al., 1974; Cochran et al., 1975; Gaylarde & Garkany, 1975; Leonard, 1975; Neumann et al., 1981; Das et al., 1978; Kaur et al., 1983, Gawkrodger & Beueridge, 1984). The implications are that beta blocker action by lowering melatonin levels may induce psoriatic side effects in susceptible patients. Alternatively, melatonin may mediate monocyte, langerhans, lymphocyte or neutrophil migration into skin as a factor in triggering or controlling epidermal proliferation as a function of melatonin's role in circadian rhythm cycles associated with enhanced melatonin nocturnal production (Pigatto et al., 1985; Raedelli et al., 1982) or the migration and release of prostaglandin or related proliferative or inflammatory substances by formed blood elements into the skin. Pierpaoli (1981) and Maestroni and Pierpaoli (1981) have shown that the circadian melatonin rhythm in nude mice was deficient and melatonin helps the nude mouse to effectively receive T-cell transplants. The immunologic role of the pineal has been confirmed by Radosevic-Stasic et al., 1983. Melatonin has also been found to enhance primary antibody production through an opiatergic mechanism (Maestroni and Pierpaoli, 1986). Melatonin production is inhibited by propranolol and para-chlorophenylalanine which act through beta adrenergic blockade and serotonin inhibition to interfere with primary immune response to sheep RBC's. Reconstitution of immunity, following these agents, is achieved by evening injections of melatonin. In addition, melatonin antagonizes the in vivo depression of corticosterone to the autologous mixed lymphocyte reaction (Maestroni et al., 1986). Melatonin may have primary immunologic modulating action suggesting that it may also have a place in the immunologic control of cutaneous responses that could be pertinent to psoriasis. The theoretical aspect of melatonin's anti-psoriatic action may relate to its inhibition of prostaglandin release (Leach et al., 1982). This is pertinent to the observations that indomethicin related compounds, can relieve the symptoms of psoriasis, i.e., bonoxaprofen (Allen & Littlewood, 1982) and melatonin is an indol containing structure related to prostaglandin synthetase inhibiting non-steroidal anti-inflammatory agents. This is supported by the work of Gimeno et al. (1981) who have shown melatonin at physiologically related concentrations to depress the prostaglandin mediated activity of the rat uterus, platelet ADP induced aggregation by human platelets and release of PGE from the rat medial basal hypothalamus in vitro. Melatonin produces n-acetyl-5-methoxy kynurenamine, a brain metabolite with potent prostaglandin synthesis inhibiting activity which may explain aspects of its activity (Kelly et al., 1984). The above strongly supports the concept that melatonin may be a natural inhibitor or mediator of prostaglandin activity on proliferation or inflammation. Thus, melatonin may reduce the psoriatic reaction in skin as a function of modulation of white cell infiltration or natural prostaglandin metabolism, i.e., by blocking prostaglandin synthesis or release, making it similar in action to synthetic anti-inflammatory indols. The melatonin relationship to prostaglandin or white cell infiltrative or circadian cycles is quite compatible with patterns of genetic susceptibility to psoriasis as is seen in melatonin differences that are familial related or with the decreased production of melatonin observed in psoriasis (Wetterberg et al., 1983; Schloot et al., 1981; Birau, 1981). Melatonin is involved in circadian periodicity and the seasonal response of mammals to the duration of light to darkness in the seasonal'cycle. In that regard, there are diurnal variations in the clinical mitotic cycle of the skin (Scheving, 1959; Schell et al., 1980). In man, epidermal hyperplasia or replacement occurs at night during the sleep cycle. The circadian role of melatonin in man (Wetterberg et al., 1978) is well established with the highest levels produced during sleep and the lowest levels in the morning or afternoon. Melatonin pineal levels decrease with age in rats (Pang et al., 1984) and man (Touitou et al., 1984) and seasonal variations have been found. Regarding the fundamental pathology of the disease, it is generally recognized that the mitotic rate of psoriatic skin and the normal skin areas of psoriatics shows greater skin proliferative activity (Gelfant, 1976). The cell cycle is shortened (Grove, 1979; Chopra and Flaxman, 1974) although the S phase of DNA synthesis may be delayed (Steigleder and Pullman, 1979). There is evidence for a basic defect in cell kinetics with more cell division in psoriatics, but a lack of understanding as to what triggers the difference between normals and psoriatics or, psoriatic involved skin and normal skin in the psoriatic patient is not clearly defined. It is a distinct possibility that the decline in nocturnal production of melatonin can result in increased skin proliferation in psoriatic sites as the skin may be under an inhibitory or controlling influence of melatonin. This is supported by recent work of Mastrioni and Pierpaoli (1986) who have shown the presence of distinct melatonin cytoplasmic receptors in the skin of mice. In regard to the above, melatonin may act on the proliferative capacity of skin in similar fashion to its control of pigment cell morphology which led to its biologic discovery (Reed et al., 1969). Melatonin is reported to act directly on the hypophysis by decreasing microtubulin content (Cardinali, 1981 a,b) thus modifying neurotransmitter uptake and release (Cardinali et al., 1975). Cytoplasmic melatonin receptors have been observed (Cohen et al., 1978) and melatonin trophic action on other than pigment cells may be its mechanism of action in psoriasis. Although specific injury to the skin can induce psoriatic lesions: (the Koebaer reaction) and streptococcal infection can precipitate psoriasis, the underlying causal relationships are still speculative. While genetic predisposition is seen in idiotypic hereditable patterns, i.e., HLA B27 (the same pattern is seen in ankylosing spondylitis and Reiter's syndrome) the actual molecular mechanisms are not defined (Russell et al., 1972; Gazit et al., 1978; Morhenn et al., 1979). Krueger (1981) has presented an excellent review seeking to establish the pattern of abnormality and the etiologic or interrelated factors involved in triggering the hyperplastic cutaneous event. Review of pathology and pathophysiology has presented evidence of cutaneous monocyte/macrophage and langerhans (white) cell aberrations in psoriasis as well as changes in neutrophil infiltration and leukotriene or prostaglandin relationships (Krueger, 1981). Observations have been made regarding angiogenesis and changes in clotting factors or humoral factors in psoriatics effecting the function of white blood cells on the immune response. Cellular mediators including cyclic nucleotides, polyamines, prostaglandins and pro teasers have been invoked as related to psoriatic changes, as have unique antigenic determinates in psoriatic skin, but no one has defined the pathophysiologic patterns that clearly relate in an integrated manner to cause and effect. Nowhere in reviews or specific research in psoriasis has anyone suggested that melatonin is a therapeutic or controlling factor in psoriasis apart from the observation that melatonin values are lower in psoriatics (Schloot et al., 1981). Summary of Rationale for Topical Use of Melatonin in Psoriasis: Evidence exists in the literature on the derangement of pineal gland-melatonin function in psoriatic patients. This clear-cut evidence has never been taken into consideration for the topical or systemic treatment of psoriasis. The main evidence is illustrated in the following documented studies: (1) Night levels of melatonin are extremely low or at baseline levels in psoriatic patients. N. Birau. Melatonin in human serum: progress in screening investigation and clinic. (N. Birau and WE. Schloot, editors), in "Melatonin: current status and perspectives", p. 297, Pergamon Press, Oxford, 1980. (2) Beta-adrenergic receptors blockers like Propranolol can induce psoriasis in psoriatic disposed individuals. It is known that administration of beta-blockers, especially in the evening, will abrogate the night release of melatonin by acting on its formation or release in the pineal gland. Therefore, persons chronically taking beta-blockers may develop a number of derangements and pathologies which depend on alteration or abrogation of a normal pineal function. Kaur, S., Jumar, B., Kaur, I. and Sharma, BK: Psoriasis, as a side effect of beta adrenergic blocking agent, propranolol. Indian Heart Journal, 35, 1983. Leonard JE: Oxprenolol and psoriasis like eruption. Lancet I: 630, 1975. (3) It is now well documented that psoriatic patients display abnormally high levels of growth hormone in the blood and that the circadian release of the hormone is completely different from that of normal individuals (10 a.m. and 10 p.m. peaks). Treatment with an anti-prolactin agent and growth hormone inhibitory hormone produce both variable but occasionally dramatic effects on psoriasis. Melatonin is a major anti-growth hormone or growth hormone-inhibitor.y factor and this information adds to our hypothesis that lack of melatonin from the pineal gland of psoriatics or its abnormal release leads to derangements of secretion of growth-promoting, pituitary hormones like prolactin and growth hormone. Starr, KW: Hormonal imbalance and the sarcomata. Aust. NZ J. Surg. 39: 142-150, 1969. Kuzmanovic D, Attanasio A, Bombelli M, Gupta D: Modulation of basal and GRF stimulated GH secretion by melatonin and visa versa in male rats. Neuroendocrinology Letters 7: 148, 1985. Attanasio A, Ronke MG, Gupta D: GRF induced changes in serum melatonin and growth hormone in children and adults. Neuroendocrinology Letters 7: 153, 1985. (4) There is a circadian rhythm to the repair and replacement of skin, with the mitotic cycle at its peak during sleep. Scheving LE; The Anat. Rec.. 135: 7-14, 1959. Schell et al., Dermatological 161: 12-21, 1980. Psoriasis is associated with increased mitotic cycling. for the hyperkeratotic involved skin (Gelfant BR: J. Dermatol. 95: 577-590, 1976) . In view of the decrease in nocturnal levels of melatonin in psoriatics, it may be that melatonin has a trophic circadian action inhibiting the hyperplasia of psoriatic skin. This is supported by recent work (Mastrioni and Pierpaoli, 1986) that mouse skin possesses melatonin cytoplasmic receptors. This should not be surprising in view of melatonin's trophic control of skin pigment cells (Reed et al., Life Sciences, pp. 113-120, 1969). (5) Melatonin permits nude mice to receive T cell transplants (Pierpaoli, 1981) and has a stimulating antibody formation effect on mice through an opiatergic mechanism (Maestroni and Pierpaoli, 1986). The beta blocker, propanalol, which can stimulate reacerbation of psoriasis, blocks melatonin production and interferes with primary immune response in mice to sheep red blood cells. This beta blocker inhibition of immunity is reversed by evening injection of melatonin in mice. Melatonin also antagonizes the in vitro depression of corticosterone to the autologous mixed lymphocyte reaction (Maestroni et al., 1986). If psoriasis is under immune control, this might explain its mechanism of action. (6) Melatonin, as an indole containing structure, is structurally similar to indole containing prostaglandin inhibitors which have anti-inflammatory action. In this regard, melatonin produces methyl acetyl-5-methoxy kynure namine, a brain metabolite with potent prostaglandin synthesis inhibiting activity which may explain its action on psoriasis (Kelly et al., 1986). (7) Melatonin has been shown to decrease microtubulin content in the hypophysis (Cardinali, 1981, a,b). Thus, in similar fashion to its effects on pigment cell morphology, it might have trophic effects on epidermal proliferation in psoriasis. Finally the invention also relates to the use of melatonin or its related homologues for the production of drug compositions suitable for the prevention or treatment of psoriasis in human patients, particularly of the drug compositions for topical and oral uses respectively, as set forth hereabove. 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Claims: WE CLAIM 1. A composition suitable for the treatment or prevention of psoriasis which contains an effective amount of compound of formula: EMI38.1 in which - n is 1 or 2 - R1 and R2, identical or different from each other, are -H, -NH2, -COOH, -OH, acyl comprising from 1 to 4 carbon atoms or alkoxy comprising from 1 to 4 carbon atoms - X is -OH or alkoxy comprising from 1 to 4 carbon atoms - Y is -H, -OH or -tlH2, in association with a suitable pharmaceutical acceptable vehicle. 2. The ccmposition of claim 1 wherein said active compound is melatonin, of formula : EMI38.2 3. The composition of claim 1 wherein sad active compound is selected from the group of compounds consi3- ting of - 5-methoxytryptamine, - 5-methoxytryptophani - 5-methoxytryptophol, - 5-methoxyindole-3-acetic acid, - 6-hydroxy-melatonin. 4. The composition of anyone of claims 1 to 3 which is a composition applicable topically. 5. The composition of claim 4 which is in the form of a solution, an ointment or cream or which is in a form authorizing the production of foams or sprays. 6. The composition of claim S which comprises a concentration of said compound ranging from 10-4 4 to 1 ; weight. 7. A method for the preparation of a pharmaceutical composition for preventing and treating psoriasis in humans by administering to a patient afflicted with said disease an effective amount of a compound of formula EMI39.1 in which - n is 1 or 2 ; - R1 and R2, identical cr 'iferent from each other, are - X, -NH2 -COOH, -OH, acyl comprising from 1 to 4 carbon atoms or alkoxy comprising from 1 to 4 carbon atoms - X is -OH or alkoxy comprising from 1 to 4 .carbon atoms - Y is -H, -OH or -NH2. 8. The method of claim 7, herein said compound bis melatonin of formula EMI39.2 9. The method of claim 7 or 8, wherein said pharmaceutical composition is produced in a form suitable for topical application on the psoriasis-affected site of the patients. io. The Method of claim 9, wherein said method comprises applying said compound topically, in the form of a composition containing an effective amount of the same. 11. The method of claim 7 or 8, wherein said pharmaceutical composition is produced in a form suitable for oral ingestion for the treatment of human patients having psoriasis affected sites on their bodies. 12. The method of claim 7 or 8 wherein said compounds are produced in forms suitable for topical or oral dosage of living creatures having psoriasis affected areas, for the treatment thereof. 13. The method of claim 7 or 8 , wherein said composition is a solution containing said compound or compounds in a concentration ranging from 10 to 1% in weight.

Inventors: PIERPAOLI WALTER, PIERPAOLI, WALTER
Applicants: CELL ENG AG, CELLENA (CELL ENGINEERING) A.G.
Application year: 1986
Main classification: A61K31
IPC codes: A61K31