WO1987000432A2 - Compositions contenant de la melatonine ou ses homologues, leurs utilisations pour le traitement du psoriasis vulgaris et/ou des affections apparentees - Google Patents

Compositions contenant de la melatonine ou ses homologues, leurs utilisations pour le traitement du psoriasis vulgaris et/ou des affections apparentees Download PDF

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WO1987000432A2
WO1987000432A2 PCT/EP1986/000418 EP8600418W WO8700432A2 WO 1987000432 A2 WO1987000432 A2 WO 1987000432A2 EP 8600418 W EP8600418 W EP 8600418W WO 8700432 A2 WO8700432 A2 WO 8700432A2
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melatonin
psoriasis
composition
treatment
skin
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PCT/EP1986/000418
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WO1987000432A3 (fr
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Walter Pierpaoli
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Cellena (Cell Engineering) A.G.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404Indoles, e.g. pindolol
    • A61K31/405Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin

Definitions

  • 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 epidermal 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 1-2% 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.
  • 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 al., 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.
  • LH luteinizing hormone
  • 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.
  • 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 al., 1977).
  • Melatonin N-acetyl-methoxytryptamine
  • 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 et. al., 1983; Stetson & Watson-Whitmyre, 1984).
  • 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).
  • 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).
  • 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).
  • 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 llpid and brown adipose 'tissue mass and thermogenic capacity (Bartness & Wade, 1984).
  • 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 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 Img/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.
  • 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).
  • melatonin The inhibiting effects of 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 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).
  • 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.
  • compositions of the invention consist of melatonin itself.
  • 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:
  • R 1 and R 2 identical or different from each other are H, NH 2 , 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 NH 2 .
  • 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:
  • compositions of the invention are 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxy- tryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxy melatonin.
  • melatonin is used hereafter to designate both the actual melatonin and the chemical homologues or derivatives thereof.
  • Treatment consists of the cautious application of corticosteroids (Christiansen et al., 1985), coal tar (Downing & Bauer, 1948), Lasar's paste and anthralens (dithranol) (Champion, 1981).
  • UVB ultraviolet light exposure to the involved skin of different intensities and wavelengths
  • UBA ultraviolet light exposure to the involved skin of different intensities and wavelengths
  • UVB ultraviolet light
  • PUVA methoxypsoralen given orally
  • systemic treatment include corticosteroids, including dehydroepiandrosterone, and the anti-mitotics methotrexate, hydroxyurea, razoxane, mycophenolic acid, cytosine arabinoside and alkylating agents (Champion, 1981).
  • corticosteroids including dehydroepiandrosterone
  • anti-mitotics methotrexate, hydroxyurea, razoxane, mycophenolic acid, cytosine arabinoside and alkylating agents Champion, 1981
  • 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).
  • 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.
  • 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 relation- ships (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 proteases 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 fact that melatonin values are lower in psoriatics (Schloot et al., 1981).
  • 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.
  • the composition is in a form suitable for topical application for humans.
  • 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.
  • compositions in which melatonin is- associated with a lipophilic substance both being dissolved in an appropriate solvent.
  • 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.
  • 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.
  • compositions for psoriasis can also be used in a therapeutic environment or application, in addition to cosmetic application.
  • 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.
  • topical preparations relative concentrations of 10 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.
  • compositions of the invention in the evening and prior to going to sleep when melatonin endogenous production is at a higher level.
  • 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.
  • 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 vehicle which makes said composition suitable for topical application for preventing or reversing the pruritic, inflammatory, hyperkeratotic or arthritic manifestations of psoriasis.
  • compositions in which melatonin is associated with a lipophylic substance can be used in an appropriate solvent.
  • 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.
  • 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.
  • psoriasis is a skin disease of distinctive quality associated with epidermal hyperplasia producing hyperkeratotic skin plaques of unsightly character (PInkus & 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.
  • 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.
  • compositions in which melatonin is associated with a lipophylic substance 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.
  • 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.
  • 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.
  • the amount of active ingredients may be more or less depending on the patient's response and the degree of treatment needed.
  • 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.
  • 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.
  • 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.
  • oral or even parenteral administration may be held more effective to achieve the purpose sought, alone or combined with topical melatonin.
  • 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 30% 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.
  • Non-ionic hydrophilic ointment 98.9%
  • Non-ionic hydrophilic ointment (Ung.hydrophilicum nonionogen:
  • 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 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.
  • Treatment Topical melatonin 0.1% every two days in the evening.
  • Topical melatonin 0.1% every day in the evening.
  • melatonin 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 perodicity.
  • 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.
  • 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).
  • 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.
  • melatonin Reconstitution of immunity, following these agents, is achieved by evening injections of melatonin.
  • melatonin antagonizes the in vivo de'pression 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.
  • 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.
  • melatonin may be a natural inhibitor or mediator of prostaglandin activity on proliferation or inflammation.
  • 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.
  • melatonin may act on the prolifer- ative 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.
  • 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 proteases 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.
  • Melatonin is a major anti-growth hormone or growth hormone-inhibitory 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.
  • Gupta D Modulation of basal and GRF stimulated GH secretion by melatonin and visa versa in male rats.
  • Psoriasis is associated with increased mitotic cycling, for the hyperkeratotic involved skin (Gelfant BR: J. Dermatol. 95: 577-590, 1976) .
  • melatonin has a trophic circadian action inhibiting the hyperplasia of psoriatic skin.
  • Melatonin as an indole containing structure, is structurally similar to indole containing prostaglandin inhibitors which have anti-inflammatory action.
  • melatonin produces methyl acetyl-5-methoxy kynurenamine, a brain metabolite with potent prostaglandin synthesis inhibiting activity which may explain its action on psoriasis (Kelly et al., 1986).
  • 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.
  • the following references together with other references which are mentioned hereinbefore relate to studies on various animals in the treatment of various conditions and are herein incorporated by references.
  • Birau N Melatonin in human serum: Progress In screening investigation and clinic. Adv. Biosciences 29: 297-326, in: Melatonin-Current Status and Perspectives. Ed. N. Birau, WE. Schloot, Pergamon Press, NY, 1981.
  • Blask DE The pineal, and oncostatic gland? In: The Pineal Gland, ed. R. J. Reiter, Raven Press, New York, 1984, pp. 276-277. 9. Bloomfield FJ, Young MM: Enhanced release of inflammatory mediators from lithium-stimulated neutrophils in psoriasis. Br. J. Dermatol. 104: 9-13, 1983.
  • Burns JK Administration of melatonin to non-human primates and to women with breast carcinoma. J. Physiol. 229: 38-39, 1973.
  • Cardinali DP Molecular biology of melatonin: Assessment of the "micro- tubule hypothesis of melatonin action". p. 247-256. In: Melatonin- Current Status and Perspectus Ed. N. Birau, W. Schloot. Pergamon Press, NY, 1981.
  • Fiske VM, Parker KL, Ulmer RA, et al. 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.
  • Gazit E, et al HLA antigens in patients with psoriasis. Tissue antigens 12: 195-199, 1978.
  • Kaur, S, Kuman B, Kaur I Psoriasis-as a side effect of beta adrenergic blocking agent -propanalol. Indian Heart J. 35: 1983.
  • Kennaway DJ, Gilmore TA, Beamark RF Effect of melatonin feeding on serum prolactin and gonadotropin levels and the onset of seasonal estrous cyclicity in sheep. Endocrinology 110: 1766-1772, 1982.
  • Kennaway DJ, Gilmore TA Effect of melatonin implants in ewe lambs. J. Reprod. Fert. 70: 39-45, 1984.
  • Krueger GG Psoriasis: Current concepts of its etiology and pathogenesis. In: THE YEAR BOOK OF DERMATOLOGY pp. 13-70, ed. R.L. Dobson, B.H. Thiers. Year Book Med. Pubs. Chicago, 1982.
  • Lincoln G Melatonin as a seasonal time cue: The commercial story. Nature 302: 755, 1983.
  • Marangos PJ, Patel J, Hirata F, et al Inhibition of diazepam binding by tryptophan derivatives including melatonin and its brain metabolite N-acetyl-5-methoxy kynurenamlne. Life Sciences 29: 259-267, 1981.
  • Pettfirborg LJ, Reiter RJ Effect of photoperiod and subcutaneous melatonin implants on the reproductive status of adult white footed nice (percomycus leucopus) J. Androl. 2: 222-224, 1981.
  • Radosevic-Stasic B Jonjig L, Polic D, et al: Immune response of rats after pharmacologic pinealectomy. Period Biolog. 85: 119-121, 1983.
  • Raikhlin NT, Kvetnoy IM, Tolkachev VN Melatonin may be synthesized in enterochromaffin cells. Nature 225: 344-345, 1975.
  • Reiter RJ Reproductive effects of the pineal gland and pineal indoles in the Syrian hamster and the albino rat. In: The Pineal Gland ed. R. J. Reiter, V. II: 45-81, CRC Press, 1981.
  • Reiter RJ The Pineal Gland: An intermediary between the environment and the endocrine system. Pschoneuroendocrinology 8: 31-40, 1983b.
  • Tamarkin L, et al "Melatonin: A coordinating signal for mammalian reproduction”. Science: 227: 714-720, 1985.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Le procédé ci-décrit concerne la fabrication de compositions utiles pour soigner le psoriasis chez les êtres vivants, y compris les humains. Lesdites compositions contiennent un dérivé actif de l'indolamine, de préférence la mélatonine. Certaines compositions préférées destinées à un usage local consistent en des lotions, mousses ou aérosols, tandis que des compositions destinées à une ingestion orale consistent en des comprimés, gélules ou capsules et produits similaires. Le traitement est mis en oeuvre par application locale avec massages légers uniquement, ou en combinaison avec un dosage oral qui peut être utilisé seul ou en combinaison avec le traitement topique.
PCT/EP1986/000418 1985-07-16 1986-07-16 Compositions contenant de la melatonine ou ses homologues, leurs utilisations pour le traitement du psoriasis vulgaris et/ou des affections apparentees WO1987000432A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB858517958A GB8517958D0 (en) 1985-07-16 1985-07-16 Compositions containing melatonin/homologues
GB8517958 1985-07-16

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WO1987000432A2 true WO1987000432A2 (fr) 1987-01-29
WO1987000432A3 WO1987000432A3 (fr) 1987-05-21

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EP (1) EP0229131A1 (fr)
AU (1) AU6142186A (fr)
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WO (1) WO1987000432A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337627A2 (fr) * 1988-04-13 1989-10-18 Pfizer Inc. Dérivés du 2-oxindole-1-carboxamide, substitués en position 3, utilisés comme inhibiteurs de la biosynthèse de l'interleukine-1
EP0438856A2 (fr) * 1989-10-31 1991-07-31 Shiseido Company Limited Utilisation de la mélatonine pour protéger la peau contre les effets des rayons U-V
WO1992006955A1 (fr) * 1990-10-17 1992-04-30 Pulitzer Italiana S.R.L. Derive de melatonine presentant une activite therapeutique en dermatologie
US5146710A (en) * 1991-02-20 1992-09-15 Caldwell Wesley A Parking space control
US5192790A (en) * 1989-10-13 1993-03-09 Pfizer Inc. 3-substituted-2-oxindole derivatives as inhibitors of interleukin-1 biosynthesis
WO1993007870A1 (fr) * 1991-10-18 1993-04-29 Alza Corporation Dispositif pour l'administration transdermique de melatonine
EP0578620A1 (fr) * 1992-06-24 1994-01-12 I.F.L.O. S.a.s. di Giorgio e Aldo Laguzzi Composés pharmaceutiques pour la délivrance transdermale de la mélatonine et/ou ses analogues
WO1995002404A1 (fr) * 1993-07-12 1995-01-26 Minnesota Mining And Manufacturing Company Systeme d'apport transdermique de melatonine
EP0711553A1 (fr) * 1994-08-09 1996-05-15 Mario Cagnoni Utilisation de la melatonine dans le traitement des symptÔmes articulaires de l'arthrite rhumatoide
WO1997006779A1 (fr) * 1995-08-11 1997-02-27 Kistler Gonzague S Protection contre les dommages cutanes induits par rayonnements ultraviolets (uv) a l'aide d'un traitement topique faisant appel a de la melatonine (n-acetyl-5-methoxytryptamine)
FR2741802A1 (fr) * 1995-12-04 1997-06-06 Oreal Utilisation de melatonine pour traiter les peaux sensibles
EP0820766A2 (fr) * 1996-07-25 1998-01-28 L'oreal Nouvelles compositions topiques comprenant de très faibles doses de mélatonine ou ses dérivés et leur utilisation en cosmétique
FR2753095A1 (fr) * 1996-09-06 1998-03-13 Oreal Utilisation de la melatonine comme agent anti-inflammatoire dans une composition cosmetique ou pharmaceutique
US5932608A (en) * 1996-07-25 1999-08-03 Societe L'oreal S.A. Melatonin derivative dermocosmetic compositions for whitening/depigmenting the skin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Advances in the Biosciences, Volume 29, Melatonin: Current Status and Perspectives, 1981, W. SCHLOOT et al.: "Genetics of Melatonin", pages 269-285 see page 272, last but one paragraph cited in the application *
IRCS Med. Sci., Volume 13, No. 1, 1985, N. BIRAU: "Advances in Human Melatonin Research - Physiological and Clinical Aspects", pages 1-5 see page 4, lines 10-11 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337627A2 (fr) * 1988-04-13 1989-10-18 Pfizer Inc. Dérivés du 2-oxindole-1-carboxamide, substitués en position 3, utilisés comme inhibiteurs de la biosynthèse de l'interleukine-1
EP0337627A3 (fr) * 1988-04-13 1991-01-02 Pfizer Inc. Dérivés du 2-oxindole-1-carboxamide, substitués en position 3, utilisés comme inhibiteurs de la biosynthèse de l'interleukine-1
US5192790A (en) * 1989-10-13 1993-03-09 Pfizer Inc. 3-substituted-2-oxindole derivatives as inhibitors of interleukin-1 biosynthesis
EP0438856A2 (fr) * 1989-10-31 1991-07-31 Shiseido Company Limited Utilisation de la mélatonine pour protéger la peau contre les effets des rayons U-V
EP0438856A3 (en) * 1989-10-31 1992-11-25 Shiseido Company Limited Use of melatonin to protect the skin against the influence of uv-rays
WO1992006955A1 (fr) * 1990-10-17 1992-04-30 Pulitzer Italiana S.R.L. Derive de melatonine presentant une activite therapeutique en dermatologie
US5146710A (en) * 1991-02-20 1992-09-15 Caldwell Wesley A Parking space control
US5508039A (en) * 1991-10-18 1996-04-16 Alza Corporation Controlled transdermal administration of melatonin
WO1993007870A1 (fr) * 1991-10-18 1993-04-29 Alza Corporation Dispositif pour l'administration transdermique de melatonine
EP0578620A1 (fr) * 1992-06-24 1994-01-12 I.F.L.O. S.a.s. di Giorgio e Aldo Laguzzi Composés pharmaceutiques pour la délivrance transdermale de la mélatonine et/ou ses analogues
WO1995002404A1 (fr) * 1993-07-12 1995-01-26 Minnesota Mining And Manufacturing Company Systeme d'apport transdermique de melatonine
EP0711553A1 (fr) * 1994-08-09 1996-05-15 Mario Cagnoni Utilisation de la melatonine dans le traitement des symptÔmes articulaires de l'arthrite rhumatoide
US5609877A (en) * 1994-08-09 1997-03-11 Cagnoni; Mario Treatment of the articular symptoms of rheumatoid arthritis
WO1997006779A1 (fr) * 1995-08-11 1997-02-27 Kistler Gonzague S Protection contre les dommages cutanes induits par rayonnements ultraviolets (uv) a l'aide d'un traitement topique faisant appel a de la melatonine (n-acetyl-5-methoxytryptamine)
FR2741802A1 (fr) * 1995-12-04 1997-06-06 Oreal Utilisation de melatonine pour traiter les peaux sensibles
EP0820766A2 (fr) * 1996-07-25 1998-01-28 L'oreal Nouvelles compositions topiques comprenant de très faibles doses de mélatonine ou ses dérivés et leur utilisation en cosmétique
FR2751539A1 (fr) * 1996-07-25 1998-01-30 Oreal Nouvelles compositions topiques comprenant de tres faibles doses de melatonine ou ses derives et leur utilisation en cosmetique
EP0820766A3 (fr) * 1996-07-25 1998-02-04 L'oreal Nouvelles compositions topiques comprenant de très faibles doses de mélatonine ou ses dérivés et leur utilisation en cosmétique
US5932608A (en) * 1996-07-25 1999-08-03 Societe L'oreal S.A. Melatonin derivative dermocosmetic compositions for whitening/depigmenting the skin
US5985293A (en) * 1996-07-25 1999-11-16 Societe L'oreal S.A. Antioxidative dermocosmetic compositions comprising very low dosages of melatonin/analogs
FR2753095A1 (fr) * 1996-09-06 1998-03-13 Oreal Utilisation de la melatonine comme agent anti-inflammatoire dans une composition cosmetique ou pharmaceutique

Also Published As

Publication number Publication date
WO1987000432A3 (fr) 1987-05-21
GB8517958D0 (en) 1985-08-21
EP0229131A1 (fr) 1987-07-22
AU6142186A (en) 1987-02-10

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