TREATMENT OF AGED SKIN WITH ORAL 13-CIS-RETINOIC ACID

Abstract: Various disorders of the human skin, particularly facial skin, of elderly individuals, may be treated with low doses of 13-cis-retinoic acid by oral administration in amounts which are non-toxic and non-teratogenic. The disorders are those which appear in the elderly and are complicated by excessive sun exposure (photoaging), including sebaceous gland hyperplasia, follicular Demodex infestation, bacterial and fungi-induced folliculitis, rosacea-like and seborrheic-like dermatoses and dandruff-like scalp conditions. The treatment is effective at doses of as low as 1-5 mg daily or every other day, and is preferably used with women beyond childbearing potential, and males over about 50 years of age. The treatment also retards and reverses hyperkeratosis, epidermal atrophy, and other skin changes of the elderly.

Description: TREATMENT OF AGED SKIN WITH ORAL 13-CIS-RETINOIC ACID Fiel of the Invention The present invention relates to the treatment of various associated disorders of the skin which are typical of many elderly persons. More particularly, the invention is directed to the treatment of such disorders with low oral doses of 13-ciε-retinoic acid. Background of the Invention Many older persons (i.e., generally over 50 years of age and referred to herein as "the elderly") have "problem" skin deriving from multiple influences. These increase steadily with age, and all are worsened by years of earlier excessive exposure to sunlight. The sun is a significant contributor to chronic skin problems which are very prevalent in the aging population. These skin problems are most vividly expressed in the most exposed areas of the skin, and especially on the face, an area rich in blood vessels, follicles, and sebarceous glands. The face -is also a highly permeable region with a poor barrier layer, allowing ready penetration of potentially toxic chemicals originating in soaps, cosmetics, fragrances, -toiletries, etα. - The face is Tinder continuous chemical assault, as well as radiation insults. The end result is abnormal skin, a consequence of multiple factors acting in combination. One can recognize the following clinical disorders: 1) Rosacea-like syndromes with persistent redness, papules, and solid edema-like swellings; 2) Hyperplasia of the sebaceous glands; 3) A seborrheic-like dermatitis, peculiar to the elderly; 4) Pityrosporon-i.ndu.ced folliculitis; 5) Infestation by Demodex mites, with mite-associated folliculitis, erythema, and scaling; 6) ^ Enlarged, roughened nose (rhinophyma) ; 7) Overgrowth of P. acnes, an anaerobic bacteria living in the follicles; 8) Flat, keratotic and pigmented εeborrheic keratoseε; 9) Rough, scaly lesions of the actinic keratoseε type; 10) Scaly, flaky, dandruff-like conditions of the scalp; and 11) Trichostasiε spinulosa—follicular i pactionε on nose, cheeks, temples and nape of the neck. Changes take place against a background of photoaged skin showing yellowing, wrinkling, dryness, dilated vessels and comedones. U.S. Patent 4,603,146 of Albert . Kligman discloses the use of vitamin A acid (retinoic acid or tretinoin) as a topical medication for sun-damaged skin of adults, usually starting about middle age, which acts to reverse and retard the effects of photoaging through its actions on the damaged connective tissue and abnormal epidermis. Further, pending U.S. Patent- Application Serial No. 886,595 of Albert M. Kligman for "Methods for Treatment of Sunda aged Human Skin with Retinoidε" discloses the topical use of various retinoic acid derivatives, including 13-ciε-retinoic acid, for treating -photoaged skin. 13-cis-retinoic acid, more commonly referred to simply as cis-retinoic acid or isotretinoin or by the trademarks "ACCUTANE" (in U.S.) or "ROACCUTAN" (in -Europe) , is,an FDA-approved oral medication for the treatment of severe, refractory acne vulgaris, in particular acne conglobata. Cis-retinoic acid is also used, but not FDA-approved, for the treatment of certain chronic, uncurable inflammatory and scaling disorders, viz 7 psoriasis, tchthyosiε, Darier's diseaεe, lupuε erythematosus, granulomatous rosacea, etc. Orally adminiεtered isotretinoin also has anti- tumor activity in very high doεeε and can bring about at leaεt partial regreεεion of actinic keratoseε, keratoacanthomaε, and basal cell carcinomas. In such/prior art .treatmentε the recommended oral doses for acne are generally in the range of 40 to 80 mg daily (0.5-2.0mg/kg body weight per day), and higher doεeε, sometimes as much as 200 mg per day, are often given for other chronic, disabling disorders. At these high dosages adverse εide reactionε occur in all patients and are recognized as the general signε of hypervitaminoεiε A, namely dry skin, conjunctivitis, cheilitiε, nasal bleeding, fragile skin, hair loss, pruritus, muscle painε, hyperoεtoεis of bone, calcification of ligaments, gastrointestinal upsets, pseudotumor cerebri and others. In a certain proportion of patients taking oral isotretinoin, blood tests show potentially serious abnormalities, viz, increased cholesterol, reduction of high density lipoproteinε (which protect againεt coronary heart disease) , increased levels of triglycerides, elevation " of hepatic enzymes, xantho a formation and others. Moreover, cis-retinoic acid has been found to be extremely teratogenic. Lower doεeε of cis-retinoic acid in the range of 0.05 or O.lmg/kg body weight per day, have been reported to be beneficial in acne conglobata (nodulo-cyεtic acne). Corlin, R. et al., "13-cis- retinoic acid. Low Doεage Oral Use in Acne Papulopustuloεa. Reεultε of a Multicenter Study," Hautarzt 35:623-629 (1984); Ward, A. et al., "Iεotretinoin. A Review of its Pharmaceutical Properties and Therapeutic Efficacy in Acne and Other Skin Diεorderε," Drugs 28:6-37. (1984). The latter - publication =notes- that the pharmacological profile of isotretinoin suggests that it acts primarily by reducing sebaceouε gland size and sebum production, and as a result alters the composition of the surface lipids. The foliicular microflora are also reduced, owing to diminished sebum production. The reference also reports encouraging preliminary results in small numbers of patients with rosacea, gram-negative folliculitiε, Darier'ε disease, ichthyoεiε and pityriaεiε rubra " pilariε. The response in keratinizing disorders resembles that of the related drug etretinate, another retinoic acid derivative. Plewig, G. et al., "Effects of Two Retinoids in Animal Experiments and After Clinical Application in Acne Patients: 13-Ciε-Retinoic Acid Ro4-3780 and " Ai-omatic Retinoid Rol0-9359, π Petinoids, Pages 219- 235 (Springer-Verlag 1981) discloεeε clinical εtudieε of εixty patients with severe ("untreatable") acne uεing oral doεeε of- 13-ciε-retinoid acid ranging from -D-J5.to 2.0 mg kg body weight. .The authors repotted a dramatic but dose-dependent responεe in all patientε, where with lower doεeε the improvement showed delayed onset. An anti-inflammatory response was said to be demonstrated. Brief Summary of the Invention According to the present invention, a number of skin disorders most often found in elderly persons (over 50 years of age) may be improved, moderated, and partially reversed by the oral administration of unusually low doses of 13-ciε-retinoic acid. These doses are therapeutically effective, but lack cutaneous or εyεtemic toxicity, and are probably non- teratogenic as well. The disorders that respond to the very low doses are often non-descript, repreεenting mixtures of conditions that are not clearly classified in modern dermatological textbooks and are aggravated by photoaging. This new oral medication is a true treatment modality, not just of photoda aged skin, but of a group of associated conditions in the elderly. Specific indications against which the preεent invention iε therapeutically effective include: 1) Sebaceous gland enlargement, giving the skin a knobby, pebbly texture, sometimeε taking the form of circumεcribed growthε, resembling localized tumors, viz. circumscribed sebaceous hyperplasia of the forehead; 5 2) ----- Demodex infestation of follicles, with ensuing folliculitis, perifollicular erythema, and scaling; 3) Horny impactions of follicles leading to conεpicuouε poreε and retention of 10 " fine hairε and horn (follicular hyperkeratosis) , retention of comedo¬ like follicular plugs (trichostaεis εpinulosa) , particularly on the nose, cheekε, temples and nape of the neck; 15 4) Leakage of sebum out of follicles whose walls have been weakened by a dense growth of yeast-like fungi Pityrosporon species and especially anaerobic P. acnesr producing papules and puεtuleε. .,20 Unlike acne, these do not originate from ruptured comedones. This reaction iε a folliculitiε due to εebum leakage; 5) Flushing and redneεε, aεεociated with dilated vessels, resembling rosacea, accompanied by sensitive skin which stings and burns; 6) Scaling and redness along the sides of the nose and cheekε, also the eyebrows, mimicking and related to εeborrheic dermatitis of younger personε; 7) Flat, brown pigmented keratotic leεionε of the seborrheic keratoεis variety; 8) Rough, εcaly leεions of the actinic keratoεis type; 9) Scaly, flaky, dandruff-like conditions of the scalp; 10) Fine wrinkles caused by dryneεs or loss of moisture from the aged skin; and 11) Accelerated hair loss due to εeborrheic dermatitiε and perhaps other εubclinical inflammatory components of patterned baldness in males and females (androgenic familial alopecia) . The unusually low doses, preferably given in capsule form, are in the range of about 1 to 5 mg -daily or every- other day, and even lower doses are possible for maintenance therapy. Though 1 or 2 mg daily may be below the teratogenic level, the treatment of females should be limited to poεt- ttenopausal and-ibn-childbearing- women (that is, -women of childbearing potential muεt not be given thiε drug) . Maleε over 50 yearε of age are eligible for treatment. Detailed Description of Preferred Embodiments In the practice of the present invention, a therapeutically effective but low dose of 13-ciε- retinoic acid iε administered orally which substantially avoids all the adverse side effects of hypervitaminoεiε A induced by higher, conventional therapeutic doses of cis-retinoic acid in εevere acne and chronic dermatoεeε. The effective doεeε according to the preεent invention are one-tenth to one-twentieth or le ε the doεeε of prior art tr-eatmen ε. .Although conventional doεeε of isotretinoin are prescribed in milligrams per kilogram of body weight, the doseε of the preεent invention are so low that it iε irrelevant to take body weight into account. It has been surprisingly found that doses of about 5 mg or lesε daily, and aε low aε 1 or 2 mg daily or every other day are effective while providing the least danger of toxicity and teratogenicity. Isotretinoin iε available commercially, being sold by Roche Laboratories under the trademark "ACCUTANE." Normally an oily suspension, it may suitably be administered in capsule form containing the required daily or less frequent dose. The oral dosage form may additionally comprise pharmaceutically acceptable diluents, flavoring agents, lubricants, and other suitable excipients which are εtandard in the art. For example, εuitable diluents for inclusion in filled capsules include, but are not limited to lactose, mannitol, calcium carbonate and magnesium carbonate. Other forms of oral administration will be evident to those of ordinary skill in the art. Although no εignε of toxicity or teratogenicity have been found with the low doεes of the preεent invention, the low dose treatment regimen of therpresent.invention should be limited to .older women beyond childbearing potential, non-ovulating, mainly post-menopauεal, ovariectomized or after tubal ligation, to avoid any possible teratogenicity. The treatment may be nεed without-restriction to older men. Thus, in order to maintain the therapeutic effects of the present invention, the treatment must be continued for long periods, such aε εix months to two years, and preferably indefinitely, i.e., a program of maintenance therapy should be used since significant residual effects are not generally obtained at such low dosages. Maintenance doses after achieving a therapeutic benefit may be 1 to 2.5 mg or even less two or three timeε a week. The oral administration of isotretinoin according to the preεent invention may be combined with other therapieε, εuch aε low εtrength topical retinoic acid for even greater effectε in treating and leεεening the complicationε of photoaged skin. While .retinoic acid irritates many patients when applied topically, oral adminiεtration of iεotretinoin iε very well tolerated. Topical tretinoin makes roεacea and εeborrheic dermatitiε worse. A further advantage of oral isotretinoin is that topical retinoic acid has no appreciable effect on enlarged sebaceous glands. Many of the indications for low-dose oral ciε-retinoic acid are different than topical tretinoin. More than one hundred (100) women and men have been treated according to the invention with oral cis-retinoic acid at doεeε of 2.5 to 5 mg daily for periods ranging from six (6) months to two (2) years. Even lower doseε were εucceεεfully uεed in other patientε. The reεultε obtained were at a slower rate, but after " four (4) to six (6) months, the reεultε were about equivalent to εimilar patientε treated with 40 mg ciε-retinoic acid daily. The following resultε were obtained with these low doεeε for the diεorderε indicated, which are primarily inflammatory disorders of the elderly: (a) Rosacea-like dermatitis Roεacea, or a condition εimilar to it, increaεeε with age and is quite common in women and men past 50. Clinical signs and symptoms include: redness, εcalinesε, papulo-puεtuleε, "sensitive" skin (stinging and burning from fragrances, soaps, astringent , .etc.) , enlarged vessels (telangiectasia) , sometimes with enlargement of the nose (rhinophyma) . Minor forms are usually misεed by physicians. Patients are often flusher-bluεhers with -unstable vascular " systems. Flushing may be induced by heat, cold, wind, emotions, wine, alcoholic spiritε of variouε kindε, hot drinkε, εpices, etc. Photophobia with blepharitis and conjunctivitiε can frequently be found when looked for. Many patientε go from doctor to ' doctor with ^problem εkin," which by hiεtory and inspection can be properly claεεified aε roεacea, a variable εyndrome. Topical retinoic acid aggravates roεacea becauεe of itε irritant effect and cannot be uεed for thiε indication. Low-dose cis-retinoic acid -moderates all .of theεe manifestationε, viz, the eye problems, the pimpleε, the redneεε and bluεhing, the unusual εenεitivity to chemicalε and εunlight. Thiε iε a very strong indication for a problem that iε not properly diagnosed or recognized, even by specialists. Dilated vesεelε, coε etically troublesome, become lesε conεpicuouε. (b) Enlarged sebaceous elands Hyperplasia of εebaceouε glands occurs in various forms including: (1) circumscribed sebaceous hyperplasia of the forehead and (2) whitish- yellowiεh, small nodules, often in linear array, on the neck and face, especially in photodamaged skin, (so-called εtippled εkin-erythroεiε interfollicularis colli) . Sebaceous hyperplasia coarsens facial skin and makes the surface pebbly. One of the most dramatic effects of ciε-retinoic acid orally, unobtainable topically by any other retinoid, iε shrinkage of the sebaceous gland. The enlarged glands in older perεonε do not secrete more εebum; oilineεε iε not the problem. It iε their size that iε aesthetically unpleaεing and unattractive. Low- doεe ciε-retinoic acid according to the present invention reduces the size of enlarged glands, accompanied by a great improvement in skin appearance, texture and smoothneεε. Sebaceous glands of the face and neck involute and regreεε in about two monthε. Alεo, εebaceous benign growths (circumscribed hyperplasia) of the forehead disappear. (c) Elimination of Demodex *~ Demodex folliculorcm iε a mite which strongly colonizes the facial follicleε of older persons. The clinical signs are often subtle and go unrecognized by most physicians, including dermatologists. " - Usually, there is little more than scaling and follicular thickening, some perifollicular erythema, and small papules, asεociated with εenεitive εkin. Hiεtology alwayε shows perifollicular inflammation and sebaceous follicles crowded with mites. Invariably, application of soaps, perfumes, astringents, alcohols, mild acids (e.g., lactic acid) includes intense stinging, owing to the sub-clinical inflammatory reaction. Demodex infestation iε very common, rarely diagnosed, but an important source of discomfort, contributing to a coarεer appearance. It may be aεsociated with small papulo-pustuleε. In εhort, when Demodex are numerouε, typically εo in sundamaged skin, there iε subclinical diεeaεe. Demodex takeε itε nourishment from sebum. It disappears after cis-retinoic acid treatment because of deprivation of lipoid nutrientε. Topical retinoic acid, because it does not cause atrophy of sebaceous glands, has no effect on Demodex infestation. (d) Elimination of resident bacteria end yeasts Propionibacteria are lipid dependent organisms which disappear when sebum secretion is reduced. They make a number of enzymes and products which are potentially harmful to skin, viz, lipases, proteaseε and comedogenic substances which produce horny i pactions within the follicles (pseudo- comedones) . All thiε contributeε to poor εkin texture and tolerance to irritantε. Pityroεporon εpecieε are follicular yeaεtε which induce folliculitis and a weakening of the follicular wall. They are also comedogenic, and add to follicular hyperkeratoεiε. They too are lipophilic organiεmε which disappear when the supply of sebum iε reduced. Oral cis-retinoic acid therapy resultε in follicular debride eht with extruεion of retained horn. Thiε elimination of horny material and velluε hairε alεo improves appearance εince the follicular orificeε become εmaller and are not diεtended with retained productε. A result of eliminating "£ollicular contents, along with εebaceouε gland shrinkage, is that the population of P. acnes. £,_ ovales and Demodex strikingly diminisheε. Sensitivity to external stimuli goes down and the skin- returns tor a ' .πiore normal..state. Before treatment, swabbing the cheek with 10% lactic acid produceε great stinging in many individuals. After treatment, stinging iε abεent or slight, (e) Actinic rhinophyma Clasεical rhinophyma is an uneven enlargement of the nose due to increased deposition of collagen and enlargement of the sebaceous glands, usually an end-stage of chronic rosacea. The latter can reach huge εize with a knobby appearance of the noεe. Ciε-retinoic acid, given orally, greatly reduces the volume of nasal tissue in thiε condition. We have alεo recognized a variant not aεεociated with roεacea which we have called actinic rhinophyma. The noεe becomes chronically reddened, with large, -depressed pores r -variably enlarged, uneven surface, accompanied by oilinesε. It is quite common in males with photodamaged skin. Low-dosage oral ciε-retinoic acid reduceε the nasal enlargement with a marked improvement of the surface topography. Classic rhinophyma also responds to a substantial degree. (f) HyperkeratosJE and abnormal epithelial growths The stratum corneum becomes focally thickened in aged skin, accentuating dryneεs and scaliness. The surface becomes rough, brittle and scaly. Oral cis-retinoic acid according to the invention thins down the horny layer and eliminates keratotic scale. The surface, therefore, becomes very much smoother. Incipient seborrheic keratoseε (benign tumorε) become leεs evident. (g) Epidermal atrophy The viable epidermis becomes thin in the elderly; the cells are smaller and somewhat disorderly. Low dosage ciε-retinoic acid induceε thickening of the epidermis with larger, more normal- looking epidermal cells. A more normal, thicker epidermis contributes to a better textured skin with more fullness. These particular effects are like those of topical retinoic acid, but slower and of lesser magnitude. There occurs acanthoεiε (epidermal thickening) , return to normal patterns, correction of dyεplaεia, atypia, etc. Thiε reεultε in ε oother, -.nicer' skin. Inhibition of tumor promotion iε probable but haε not been proved. We have obεerved that "flareε" of subclinical actinic keratoseε (pre- neoplastic growths) can be resolved. (h) Follicular papules and pustules These are not acne but acneifor lesions. These are scattered pimples which might be a result of Demodex, bacteria (see above) or from cosmetics, soaps, etc. We are not referring to solar comedones either, though these too are reduced. These are inflammatory follicular leεionε of varied origin. With oral cis-retinoic acid treatment according to the invention, they disappear in 2-3 months to the great satisfaction of the userε. (i) Seborrheic-like dermatitis This dermatitis iε very common in older perεonε, especially males. This iε an inflammatory condition which clearε with low-doεe oral ciε- retinoic acid. Scalineεε and redneεε regreεε. As is known in the art, oral ciε-retinoic acid therapy reεultε in profound εuppreεεion of sebum production aε a result of atrophy of the sebaceouε glandε, an effect not attainable by topical retinoic acid. Measurementε of sebum production after 6 months of treatment show 45 to 65% reduction in all patients. Shrinkage of the sebaceous glands iε reversible after stopping use of the drug. Moreover, oral cis-retinoic acid has an anti-inflammatory effect, moderating chronic dermatitis. (j) Fac al lines and wrinkles The der atalogic literature does not recognize that finer alterations in facial texture, * complexion, εcalineεs, etc. are amenable to ciε- retinoic acid orally, at any dose. In fact, prior art treatments of various skin disorders with high doεeε of oral ciε-retinoic acid have resulted in a worsening of the appearance and aesthetic quality of the skin, owing to excesεive scaling and dryness. With the oral 13-ciε-retinoic acid treatment according to the invention, effacement of fine wrinkleε haε unexpectedly been observed. While applicantε do not wiεh to be bound by any particular theory, it iε believed that thiε treatment may reεult in a laying down or depositing of glycocollagen or glycoproteinε in the epidermis, and/or possibly a rehydration of the horny layer. This appears to be a ' " "dif er t mechanism from the effacement of lines and wrinkles with topical retinoic acid treatments, (k) Accelerated hair loss Many persons with male and female pattern baldness have εebtorrheic der atitiε which seems to accelerate the process of hair loss. This loss may be present with younger persons with androgenic alopecia, as well aε individualε paεt 50 yearε old - wl_o~.do.-not εhow evidence of patterned alopecia until rather late in life (40 yearε old or more) . The uεe of topical εteroidε to treat εuch dermatitiε appears to slow down the rate of hair shedding. It now appears that treatment according to the preεent invention alεo diminiεheε hair εhedding by clearing εeborrheic dermatitiε. While applicantε do not-'wiεh to be±iound by any particular theory, it appears that there iε a εubclinical inflammatory component to the patterned baldneεε and that the clearing of the εeborrheic dermatitiε occurε partly ,-by suppreεεing sebum on which Pi yrosporum ovale live, and partly due to the anti-inflammatory reεponεe from 13-ciε-retinoic acid. Hence, the invention may be uεed in conjuction with alopecia treatments such as topical minoxidil and/or tretinoin. In summary, the low-dose oral cis-retinoic acid therapy according to the present invention results in the following improvements in the skin: 1) Improved texture of the skin; 2) Reduced mottling-more uniform pigmentation; 3) Elimination of retained skin products , in follicles, viz. hairs and horny material; 4) Control of follicular pustules and papules; 5) Shrinkage of εebaceouε glandε with disappearance of "εtippled neck," knobby εkin and εebaceouε gland hyperplaεia; 6) Reduction of facial εkin oilineεs in perεonε with excessive oilineεε (εeborrhea) to a pleaεant normal εkin appearance; 7) Reduction of naεal deformity in actinic rhinophyma; 8) nhibition of actinic keratoεeε; • - ... - 9) , • Improved skin turgor and elasticity; rr- 10) Elimination of signs of seborrheic- like dermatitis, a common skin condition; and 11) Reduction of microbial population of bacteria and fungi, along with Demodex folliculorum. Aside from the positive benefits described above for oral ciε-retinoic acid therapy, laboratory studies with the present invention show none of the abnormalitieε commonly aεεociated with the higher doεeε (40 to 80 mg) uεed for treating acne. Specifically, the following valueε have remained normal in all εubjectε: • triglycerideε, choleεterol, liver enzymes, SCOT and SGPT- Theεe are elevated in one-third of patientε receiving 80 mg daily. Thiε greatly improveε εafety and eliminateε problemε in patients with a familial or personal history of heart disease, obesity, hypercholesteremia, etc. Adverse muco-cutaneouε reactionε are very common with 40 to 80 mg doεeε. Theεe include dry eyeε, mouth and noεe, cheilitiε, itchy, and red friable skin. All of theεe are absent εo that cloεe monitoring by clinical and laboratory tests iε unneceεεary. Laboratory follow-up of these patients reveals no changes in blood or urinary chemistries. SMA 12's have remained within normal limits. No adverse effects have been encountered, despite careful surveillance for signs of hypervitaminoεiε A. No toxicity of any kind has been encountered, and it is believed that the doses of the invention are below a teratogenic dose as well. Quantitative bacteriology showε a sharp reduction in anaerobic bacteria, principally P. acnes, along with virtual disappearance of yeast- like fungi (P. species) . The latter fungi contribute to seborrheic-like dermatitiε in older perεonε. Cyanocrylate surface biopsies have shown elimination of the mite Demodex folliculorura. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof, and, accordingly reference should be made to the appended claimε, rather than the εpecification, aε indicating t h e .scope of the invention.

Claims: CLAIMS 1. A method of retarding and reverεing sebaceous gland hyperplasia, distended and infected sebaceous follicles, and formation of abnormal epithelial growths in human skin, comprising oral administration to said human of 13-cis-retinoic acid in a therapeutically effective amount, said amount being insufficient to be significantly toxic or teratogenic. 2. A method according to Claim 1 wherein the dosage iε not more than about 5 mg daily. 3. A method according to Claim 2 wherein the doεage iε about 1 to 5 mg daily or every other day. 4. A method according to Claim 3 wherein the dosage iε reduced to a maintenance doεe of about 1 to 5 mg two or three timeε a week after achieving therapeutic benefit. 5. A method according to Claim 1 wherein the human being treated iε εelected from the group consisting of women beyond childbearing potential, and males over 50 years of age. 6. A method according to Claim 2 wherein the oral administration is in capsule form. 7. A method for treating disorders of the sebaceous glands and follicles of human skin, said disorders selected ~ from the g oup- consisting of rosacea-like dermatitiε, sebaceous gland hyperplasia, follicular Demodex infestation, bacterial and fungi- induced folliculitis, actinic rhinophyma, hyperkeratosiε, and seborrheic-like dermatitiε, and dandruff-like scalp conditions, said treatment comprising oral administration to said human of 13- ciε-retinoic acid in a therapeutically effective amount, said amount being inεufficient to be significantly toxic or teratogenic. 8. A method according to Claim 7 wherein -' dosage is not jnore than about 5 mg daily. 9. A method according to Claim 8 wherein the doεage iε about 1 to 5 mg daily or every other day. 10. A method according to Claim 9 wherein the doεage iε reduced to a maintenance doεe of about 1 to 5 mg two or three timeε a week after achieving therapeutic benefit. 11. A method according to Claim 7 wherein the human being treated iε selected from the group consisting of women beyond childbearing potential, and males over 50 yearε of age. 12. A method according to Claim 7 wherein the oral administration iε in capsule form. 13. A method for treating disorderε of human εkin over about 50 yearε of age, said disorderε selected from the group consiεting of hyperkeratoεis, epidermal atrophy, and photoaging, said treatment comprising oral administration to said human of 13- cis-retinoic acid in a therapeutically effective amount and for a time effective to thin down the horny layer of the skin, reduce keratotic scale, and induce thickening of the epider iε with large, orderly epidermal cells, but insufficient to be significantly toxic or teratogenic. 14. A method according to Claim 13 wherein the doεage iε not more than about 5 mg daily. 15. A method according to Claim 14 wherein the doεage is about 1 to 5 mg daily or every other day. 16. A method according to Claim 15 wherein the dosage iε reduced to a maintenance doεe of about 1 to 5 mg two or three timeε a week after achieving therapeutic benefit. 17. A method according to Claim 13 wherein the human being:treated is selected from the group consiεting of women beyond childbearing potential, and maleε over 50 yearε of age. 18. A method according to Claim 13 wherein the oral adminiεtration is in capsule form. 19. A method of effacing fine lines and wrinkleε in human εkin co priεing oral adminiεtration to εaid human of 13-ciε-retinoic acid in a therapeutically effective amount, εaid amount being inεufficient to be εignificantly toxic or teratogenic. - " 20. -method of reducing accelerated liair loεε due to dermatitiε or inflammation aεεociated with androgenic alopecia in humanε, comprising oral administration to εaid humanε of 13-ciε-retinoic acid in -a therapeutically effectiv -.amount, εaid amount being inεufficient to be εignificantly toxic or teratogenic.

Inventors: KLIGMAN ALBERT M, PLEWIG GERD, KLIGMAN, ALBERT, M., PLEWIG, GERD
Applicants: DALTEX MEDICAL SCIENCES INC, DALTEX MEDICAL SCIENCES, INC.
Application year: 1988
Main classification: A61K31
IPC codes: A61K8, A61K31, A61Q5, A61Q19