tretinoin and Psoriasis

The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.

Topics: Antibodies, Monoclonal, Humanized; Biomarkers; Candidiasis; Cytokines; Dermatomycoses; Humans; Interleukin-17; Mycoses; Patient Selection; Predictive Value of Tests; Psoriasis; Risk; Signal Transduction; Tretinoin; Vitamin A

Vitamin A is required for the proper functioning of many important metabolic and physiologic activities, including vision, gene transcription, the immune system and skin cell differentiation. Both excessive and deficient levels of vitamin A lead to poor functioning of many human systems. The biologically active form, retinoic acid, binds to nuclear receptors that facilitate transcription that ultimately leads to it's physiological effects. Retinoids are derivatives of vitamin A that are medications used to treat acne vulgaris, psoriasis, ichthyosis (and other disorders of keratinization), skin cancer prevention as well as several bone marrow derived neoplasias. Systemic retinoids are teratogenic and have to be prescribed with caution and close oversight. Other potential adverse events are controversial. These include the relationship of retinoid derivatives in sunscreens, their effects on bone mineral density, depression and suicidal ideation and inflammatory bowel disease. These controversies will be discussed in detail.

Topics: Acne Vulgaris; Bone and Bones; Cell Differentiation; Depression; Female; Humans; Ichthyosis; Inflammatory Bowel Diseases; Male; Nutrition Policy; Psoriasis; Retinoids; Sex Factors; Skin; Suicidal Ideation; Sunscreening Agents; Tretinoin; Vitamin A; Vitamins

Talarozole, being developed by Barrier Therapeutics Inc under license from Johnson & Johnson, is a potent and selective inhibitor of cytochrome P450 26-mediated breakdown of endogenous all-trans retinoic acid for the treatment of psoriasis and acne. Phase II clinical trials of an oral formulation of talarozole in patients with psoriasis and with acne, and a phase I clinical trial of a topical formulation have been completed. At the time of publication, Barrier Therapeutics had suspended the development of talarozole as part of a series of cost-cutting initiatives; the company had also been acquired by Stiefel Laboratories Inc. No formal announcement had been made regarding the further development of talarozole.

Topics: Acne Vulgaris; Animals; Benzothiazoles; Clinical Trials as Topic; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Humans; Psoriasis; Structure-Activity Relationship; Tretinoin; Triazoles

Retinoids have been in sharp focus ever since their introduction 30 years ago. They include any drug (s) that bind to retinoid receptors and elicit a biological response. Enormous information on the subject seems to embroil the recent literature. Practically it is impossible to clearly comprehend the undercurrents. The meticulously dispensing text envisages surmounting the perspective reader's predicaments. Accordingly, retinoids and their related facets namely retinoid receptors, classification, mode of action, and the pharmacological diversity have been precisely defined. Commonly used systemic retinoids too have been given a substantial fresh look along with their monitoring. Overall, adverse effects and relative and absolute contraindications have been scrupulously incorporated. Human immuno deficiency virus (HIV) and isoretinoid for acne, in particular, have been highlighted. Micronized isotretinoin formulations have also been taken care so also commonly used topical retinoids. Tretinoin and their newer formulation have also been accounted for along with tretinoin polymer cream. Adapalene, a new chemical entity possessing a unique physico-chemical activity similar to that of tretinoin has also been dealt with. Newer retinoids are likely to be a subject of intrigue. A focus on future potentials of retinoids is its special ingredient. The inclusion of details of rexinoid the most recent introduction in their purview is likely to invoke interest to further consolidate its reckoning in future. All in all the text of the paper should provide an insight into the current rumbling around retinoids.

Topics: Acne Vulgaris; Adapalene; Administration, Cutaneous; Administration, Oral; Chemistry, Pharmaceutical; Humans; Isotretinoin; Naphthalenes; Psoriasis; Receptors, Retinoic Acid; Retinoids; Skin Diseases; Tretinoin

Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes.

Topics: Antineoplastic Agents; Diabetes Mellitus; Humans; Keratolytic Agents; Neoplasms; Psoriasis; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Tretinoin

The retinoids provide an important new way of treating dermatologic disorders. They have also proved to have a role in the prevention of new lesion formation. New retinoids, of which adapalene is one, have recently been synthesized in order to obtain similar or better efficacy while reducing skin irritation potential. These new molecules are currently under clinical investigation. Preliminary results are encouraging. In the near future, an expanded range of topical retinoids should be available.

Topics: Adapalene; Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Isotretinoin; Mice; Models, Biological; Naphthalenes; Psoriasis; Retinoids; Skin Aging; Skin Diseases; Tretinoin

Acitretin (etretin), a second generation monoaromatic retinoid for use in the treatment of severe psoriasis and other dermatoses, is the major active metabolite of etretinate and possesses a similar therapeutic index; i.e. a similar ratio of clinical efficacy to adverse effects. When used alone at a maintenance dosage of 30 to 50mg daily, acitretin is effective in the treatment of psoriasis, causing a reduction in the severity of scaling, erythema and induration. Efficacy appears to be further enhanced by combination with psoralen-ultraviolet A photochemotherapy (PUVA) or ultraviolet B irradiation (UVB). These combinations reduce the time to lesion clearance and reduce the total radiation dose, improving overall safety. Comparative studies have confirmed the equivalence of acitretin and etrtinate with regard to efficacy and toxicity. Adverse reactions are dose-related and generally typical of hypervitaminosis A. Alopecia and mucocutaneous symptoms such as cheilitis and drying of the mucous membranes are particularly prevalent. Hypertriglyceridaemia and elevation of cholesterol levels also occur. Examination of the pharmacokinetic profile of acitretin reveals its main advantage over etretinate. Acitretin is less lipophilic than etretinate, and its lack of sequestration into 'deep' fatty storage sites is reflected in a comparatively short terminal elimination half-life of 50 to 60 hours, compared with 120 days for etretinate. Due to its teratogenic potential, acitretin is strictly contraindicated in women of childbearing potential unless effective contraceptive measures are employed. Etretinate has been identified in plasma samples of some patients treated with acitretin. Thus, acetretin has an established place in the treatment of keratinising disorders, although its use in women of child-bearing potential must be accompanied by effective contraceptive measures, with a further 2-year contraceptive period after therapy completion.

Topics: Acitretin; Animals; Humans; Psoriasis; Tretinoin

Synthetic retinoids that have distinct therapeutic activity on psoriatic plaques act at least in part through the metabolic pathways of natural retinoids. The metabolism of retinol, retinal, and retinoic acid in human epidermis in general and psoriatic plaques in particular has not been previously analyzed. This appears to be an important issue, because enzymatic formation of retinoic acid from retinol within target cells is thought to be the source of biologically active retinoic acid therein and might be subjected to regulation. We found chat the enzymatic system that transforms (3H)retinol into (3H)retinoic acid is detectable in psoriatic plaques (0.33 +/- 0.07 pmol/h/mg protein) but only in trace amounts in normal epidermis. The activity due to alcohol deshydrogenase seems not to be involved in this process. (3H)retinal was found to be either reduced into retinol or oxidized into retinoic acid, depending on the ratio of NAD to NADH (the oxidized arid reduced nicotinamide-adenine dinucleotide, respectively); the former reaction was higher in psoriatic plaques than in normal epidermis.

Topics: Humans; NAD; Psoriasis; Receptors, Retinoic Acid; Retinaldehyde; Retinoids; Skin; Tretinoin; Vitamin A

This is a review of the efficacy of etretinate/acitretin in the treatment of psoriasis and of the currently reported side-effects. The data indicate that retinoids bring significant improvement (if not total clearing) with frequent low-morbidity but rarely serious side-effects. The most serious side-effect of etretinate/acitretin is teratogenicity.

Topics: Abnormalities, Drug-Induced; Acitretin; Adult; Aged; Bone Diseases; Chemical and Drug Induced Liver Injury; Etretinate; Eye Diseases; Female; Humans; Lipids; Male; Middle Aged; Psoriasis; Risk Factors; Skin Diseases; Tretinoin

Retinoids are potent therapuetic agents that have been found to be effective in a variety of skin diseases. They are of benefit in various forms of severe psoriasis. With severe plaque psoriasis, they are used most effectively in combination with other forms of therapy, such as phototherapy. With generalized pustular psoriasis, they are effective monotherapy and are frequently helpful for the control of exfoliative psoriasis. A variety of new retinoid analogs have been studied in clinical investigations. This article discusses important aspects of the use of etretinate, isotretinoin, acitretin, and arotinoid ethyl ester in the treatment of severe forms of psoriasis.

Topics: Acitretin; Etretinate; Humans; Isomerism; Isotretinoin; Psoriasis; Tretinoin

Topics: Adult; Benzoates; Bowen's Disease; Carcinoma, Basal Cell; Child; Etretinate; Female; Humans; Isotretinoin; Male; Precancerous Conditions; Psoriasis; Retinoids; Skin Diseases; Skin Neoplasms; Tretinoin; Xeroderma Pigmentosum

Topics: Acitretin; Administration, Oral; Benzoates; Eczema; Etretinate; Humans; Isotretinoin; Psoriasis; Retinoids; Skin Diseases; Skin Diseases, Vesiculobullous; Tretinoin

The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively non-toxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited.

Topics: Acne Vulgaris; Bone Diseases; Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Isomerism; Isotretinoin; Keratosis; Kinetics; Psoriasis; Skin Diseases; Skin Neoplasms; Tretinoin; Triglycerides; Vitamin A

The retinoids are synthetic derivatives of vitamin A. Isotretinoin (13-cis-retinoic acid) is now being widely used in the United States for severe acne and etretinate is available in Europe and other countries for psoriasis. These drugs are also effective for a number of other skin diseases. This is an attempt to review basic knowledge of retinoids with which the practicing dermatologist should be familiar, to review the current status of studies, and to speculate on the present and future roles of these drugs in dermatology.

Topics: Acne Vulgaris; Etretinate; Humans; Inflammation; Isotretinoin; Keratins; Psoriasis; Retinoids; Sebum; Skin Diseases; Skin Neoplasms; Sweat Gland Diseases; Tretinoin; Vitamin A

Isotretinoin is a new orally active retinoic acid derivative for the treatment of severe refractory nodulocystic acne. The pharmacological profile of isotretinoin suggests that it acts primarily by reducing sebaceous gland size and sebum production, and as a result alters skin surface lipid composition. Bacterial skin microflora is reduced, probably as a result of altered sebaceous factors. Isotretinoin 1 to 2 mg/kg/day for 3 to 4 months produces 60 to 95% clearance of inflammatory lesions in patients with severe, recalcitrant nodulocystic acne, with evidence of continued healing and prolonged remissions in many patients after treatment withdrawal. Doses as low as 0.1 mg/kg/day have also proven successful in the clearance of lesions; however, with such low doses the duration of remission after discontinuation of therapy is usually shorter. Encouraging results have also been seen in small numbers of patients with rosacea, Gram-negative folliculitis, Darier's disease, ichthyosis and pityriasis rubra pilaris, the response in keratinising disorders resembling that with the related drug etretinate. While long term follow-up studies in these patients have not been reported, prolonged remission after withdrawal of isotretinoin in disorders of keratinisation is unlikely, as with other drugs used in these conditions. Isotretinoin is only partially effective in psoriasis, in contrast to etretinate which is very effective in psoriasis but ineffective in severe acne. Some encouraging results have also been reported with isotretinoin in patients with squamous and basal cell carcinomas, but isotretinoin has proven unsuccessful in non-squamous cell epithelial and non-epithelial cancer. Side effects affecting the mucocutaneous system occur in nearly all patients receiving isotretinoin, but rarely lead to drug withdrawal. Raised serum triglyceride levels are also commonly reported. The possibility of long term spinal or skeletal bone toxicity may restrict the use of isotretinoin in severe disorders of keratinisation requiring prolonged administration. Isotretinoin is strictly contraindicated in women of childbearing potential due to its severe teratogenic properties, unless an effective form of contraception is used. Thus, isotretinoin offers an effective advance on the treatment options available in a difficult therapeutic area - those patients with severe, nodulocystic acne not responding to 'traditional' therapy.

Topics: Acne Vulgaris; Animals; Anti-Inflammatory Agents; Carcinogens; Cell Differentiation; Cell Division; Humans; Immunity; Isotretinoin; Kinetics; Mutagens; Psoriasis; Rosacea; Sebaceous Glands; Skin; Skin Absorption; Skin Diseases; Skin Neoplasms; Teratogens; Tissue Distribution; Tretinoin

Topics: Acne Vulgaris; Adolescent; Child; Child, Preschool; Darier Disease; Etretinate; Female; Humans; Ichthyosis; Infant; Isomerism; Isotretinoin; Keratins; Keratoderma, Palmoplantar; Male; Pityriasis Rubra Pilaris; Psoriasis; Skin Diseases; Skin Diseases, Vesiculobullous; Tretinoin

Oral retinoids obviously influence dermal components such as cutaneous capillaries and dermal inflammatory cells in addition to their well-known action on keratinizing epithelia. On this basis, they act as an anti-inflammatory drug. In particular, they reduce the elevated skin temperature, inhibit the motility of neutrophils and eosinophils and their migration into the epidermis, decrease DNA synthesis of human lymphocytes by blocking their response to lectins and stimulate Langerhans cells, monocytes and macrophages in various in vitro and in vivo models. These data indicate that oral retinoids may not only normalize disorders of keratinization but also exert distinct therapeutic effects on various skin diseases with dermal inflammatory involvement regardless of their particular aetiology. In some respects, retinoids resemble corticosteroids, acting as a modified hormone. Preliminary clinical experiences with oral retinoid treatment in skin diseases such as cutaneous disseminated LE, bullous pemphigoid, Duhring's disease, pemphigus, Behçet's disease and necrotizing vasculitis with eosinophilia support these data. Monotherapy or combined administration of oral retinoids with corticosteroids in low doses seems therapeutically beneficial in these disorders.

Topics: Acitretin; Administration, Oral; Animals; Anti-Inflammatory Agents; Etretinate; Granulocytes; Humans; Isotretinoin; Leukocyte Count; Lymphocytes; Macrophages; Mice; Psoriasis; Skin Diseases; Skin Temperature; Tretinoin

Etretinate (Ro 10-9359) is a new aromatic retinoic acid derivative for the treatment of severe psoriasis and other dyskeratoses. The pharmacological profile of etretinate suggests that it acts by normalizing pathological changes in epidermal and dermal skin, particularly inhibiting hyperkeratinization and cell differentiation, although its specific mode of action in different disorders remains to be elucidated. Etretinate is rapidly and presystemically metabolised to an active metabolite which appears in plasma at about the same time as parent drug. A 'deep' storage compartment with a very extended elimination half-life gives rise to detectable plasma levels of drug for at least 3 to 4 months after discontinuation of long term therapy. Studies suggest that etretinate at an initial dose of 1 mg/kg/day, reducible during maintenance therapy, is an effective alternative to PUVA and other conventional therapy in severe psoriasis. Its greatest immediate value is in the control of eruptive and treatment-resistant psoriasis, and in its potential for use in combination with other therapy to improve the response. In Darier's disease it appears to be the treatment of choice, and preliminary studies also suggest its usefulness in ichthyosis, and most other dyskeratoses and possibly in basal cell carcinoma. Side effects affecting the mucocutaneous system occur in nearly all patients, but rarely lead to drug withdrawal. When withdrawal does become necessary, the primary reason is usually hair loss. A few paradoxical observations of raised and lowered liver enzyme levels have been reported, and also a few cases of suspected liver damage. Etretinate is strictly contraindicated in women of child-bearing potential due to its severe teratogenic properties.

Topics: Acne Vulgaris; Alanine Transaminase; Antineoplastic Agents; Cell Division; Etretinate; Humans; Lipids; Liver; Neoplasms, Experimental; Psoriasis; PUVA Therapy; Skin; Skin Diseases; Tretinoin

The synthetic retinoids are a new class of drugs which are highly effective in the treatment of a broad spectrum of dermatologic disease. In this report 15 patients with chronic disorders of keratinization and one patient with severe cystic acne were treated with oral isotretinoin. The degree of clinical response and duration of post-treatment remission varied with the different disorders. Acute side effects were predominantly limited to the skin and mucous membranes and were reversible after discontinuation of treatment in these patients. Acute retinoid toxicity and the potential for developing chronic toxicity are reviewed. In an attempt to facilitate the monitoring of dermatologic patients treated with oral synthetic retinoids, we present our current guidelines for the use of these agents.

Topics: Acne Vulgaris; Adolescent; Animals; Bone Diseases; Child; Child, Preschool; Etretinate; Humans; Isomerism; Isotretinoin; Joint Diseases; Keratosis; Mice; Psoriasis; Skin Diseases; Tretinoin

Topics: Acne Vulgaris; Administration, Oral; Adolescent; Dermatitis, Exfoliative; Half-Life; Humans; Ichthyosis; Isotretinoin; Neoplasms; Pityriasis Rubra Pilaris; Psoriasis; Tretinoin

The Vitamin A. derivatives known as Retinoids, are among the most exciting pharmacological agents used in the last few years. They strongly influence the keratinizing epithelia, have an antipromoting effect upon experimentally induced tumors and have immunomodulatory activities. Teratogenicity seems to be the most worrisome effect of the retinoids. However, it is reasonable to assume their release for physicians prescription in the near future. This review is intended to provide a general background for their correct use by dermatologists.

Topics: Animals; Carcinogens; Darier Disease; Humans; Ichthyosis; Mice; Neoplasms; Psoriasis; Rats; Skin Diseases; T-Lymphocytes; Tretinoin; Vitamin A; Vitamin A Deficiency

International studies evaluating the efficacy of etretinate (Ro 10-9359) in psoriatic patients are reviewed. Double-blind, placebo controlled studies uniformly have demonstrated the therapeutic effect of the retinoid. Both single therapy and combination therapy studies confirm the efficacy of this new form of treatment, especially in patients with the rarer and more severe forms of psoriasis.

Topics: Anthralin; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Etretinate; Humans; Psoriasis; PUVA Therapy; Tretinoin; Ultraviolet Therapy

Topical vitamin A acid (VAA) has various mechanisms of action which may be responsible for its therapeutic success in many different disorders. Although the absorption, metabolism, and excretion of VAA are not completely understood, VAA appears to remain mainly on the skin surface. The question of carcinogenicity is unresolved, and more research is needed to clarify this problem. This article reviews the literature regarding the therapeutic uses of VAA and summarizes various investigators' experiences with VAA.

Topics: Acne Vulgaris; Animals; Callosities; Cocarcinogenesis; Fox-Fordyce Disease; Humans; Ichthyosis; Keloid; Keratoacanthoma; Keratosis; Lichen Planus; Melanoma; Melanosis; Molluscum Contagiosum; Nevus; Psoriasis; Skin Absorption; Skin Diseases; Skin Neoplasms; Tretinoin

Vitamin A, Vitamin A acid (retinoic acid) and their synthetic derivatives were variously applied in the management of psoriasis with different therapeutic results. Obviously, they influence the proliferation rate and the differentiation of human keratinizing epithelia and have beneficial effects on skin diseases with disturbances of keratinization, including psoriasis. Systemic application of Vitamin A has been yet largely abandonned since high dosages leading to clearing develop evident systemic toxicity. The anti-psoriatic effect of Vitamin A acid is either moderate or restricted, because of side effects. Only its combined local application with topical corticosteroids may be considered. Oral application of newly synthesized retinoids, however, was beneficial in psoriasis, particularly in erythrodermic or pustular types. With this group of retinoids new pathways were opened in dermatotherapy which may help to replace cytostatic drugs in these cases. Additionally, oral retinoid treatment may be introduced as an adjuvans in the management of widespread psoriasis, in order to enhance the effect of anthralin, PUVA or UVB treatments.

Topics: Female; In Vitro Techniques; Male; Psoriasis; Skin; Tretinoin; Vitamin A

Psoriasis is a chronic, relapsing dermatosis characterised by scaling, erythema, and less commonly pustulation. Although the clinical spectrum is broad and the nature of the underlying defect responsible for the production of psoriasis uncertain, all currently available effective remedies are capable of inhibiting epidermal mitosis and this remains the most widely accepted concept in the management of psoriasis.

Topics: Administration, Topical; Adrenal Cortex Hormones; Age Factors; Anthralin; Ficusin; Glycogen; Hair; Humans; Hydroxyurea; Methotrexate; Mitosis; Mucous Membrane; Nails; Psoriasis; Skin; Tars; Tretinoin; Ultraviolet Therapy

Topics: Animals; Cell Division; Cyclic AMP; Cyclic GMP; DNA; Fibroblasts; Humans; Hyperplasia; Lymphocytes; Phorbol Esters; Prostaglandins E; Psoriasis; Salivary Glands; Skin; Tretinoin; Ultraviolet Rays

The future of a drug depends upon what it can do in the hands of the practitioner. Medicine is practiced on the basis of probabilities, and treatment must be selected which has the best chance of helping the patient, with the least amount of harm. There are many new drugs available for dermatologic therapy in other developed countries which are not available in this country, due to peculiarities of federal drug regulations.

Topics: Acne Vulgaris; Adrenal Cortex Hormones; Antifungal Agents; Antineoplastic Agents; Carotenoids; Dermatologic Agents; Fluorouracil; Herpesviridae Infections; Humans; Keratolytic Agents; Photosensitivity Disorders; Psoriasis; Skin Diseases; Tretinoin; United States; United States Food and Drug Administration; Vitamin E; Vitiligo

Notwithstanding the intense interest in systemic cytotoxic therapy in recent years, the great majority in psoriatics are likely to go on needing topical therapy with tar, dithranol or corticosteroids, and a welcome trend is the spreading of interest in day care centres such as those in Paris (GRUPPER), Stockholm (THYRESSON), Stanford (FARBER) and San Francisco (CRAM) evolving from the out-patient regimes advocated by INGRAM in Leeds a generation ago.

Topics: Adrenal Cortex Hormones; Anthralin; Azathioprine; Azauridine; Fluorouracil; Humans; Hydroxyurea; Lomustine; Mechlorethamine; Methotrexate; Psoriasis; Tars; Tretinoin; Ultraviolet Therapy

To assess the efficacy, safety, and cost-effectiveness of all-trans retinoic acid/Clobetasol Propionate Compound Ointment and calcipotriol/betamethasone dipropionate ointment in the treatment of mild-to-moderate patients with psoriasis vulgaris. This was a randomized, single-blind, multicenter clinical trial. A total of 240 patients were randomized to receive twice-daily all-trans retinoic acid/Clobetasol Propionate Compound Ointment (treatment group) or once-daily calcipotriol/betamethasone dipropionate ointment (control group) for 4 weeks. The efficacy, safety, and cost-effectiveness were assessed at Weeks 2 and 4. After 4 weeks, both groups showed a significant clinical improvement compared to baseline (88.33% vs. 89.83%, respectively, p = .7112). But PASI 75 response in the treatment group was superior to the control group (44.12% vs. 28.57%, respectively, p = .0200), at Week 4. SSRI improvement rate in the treatment group was also superior to control group (67.11% vs. 59.43%, respectively, p = .0119) at Week 4. All-trans retinoic acid/Clobetasol Propionate Compound Ointment showed a significant clinical improvement in erythema, infiltration, and scales of skin lesions and PASI score compared to baseline. 1.67% of patients (treatment group) reported adverse reactions compared to 2.50% (control group) with no statistical significance. In addition, the cost-effectiveness assessment showed a higher cost-effectiveness of the treatment group compared to the control group in 4 weeks (199.25 vs. 801.51). All-trans retinoic acid/Clobetasol Propionate Compound Ointment was effective and safe in the treatment of psoriasis vulgaris with similar efficacy as calcipotriol/betamethasone dipropionate ointment and lower treatment costs.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Betamethasone; Calcitriol; Clobetasol; Cost-Benefit Analysis; Dermatologic Agents; Drug Combinations; Female; Humans; Keratolytic Agents; Male; Middle Aged; Ointments; Psoriasis; Severity of Illness Index; Single-Blind Method; Tretinoin; Young Adult

Palmoplantar pustulosis (PPP) is an inflammatory, debilitating skin disease. Topical drugs and systemic immunosuppressive agents are often ineffective. Previous uncontrolled studies have suggested that alitretinoin could be a meaningful treatment option for PPP.. The primary objective was to determine response to alitretinoin for the treatment of PPP based on the Palmoplantar Pustulosis Area and Severity Index (PPPASI) after 24 weeks of treatment.. A phase II, randomized, double-blind, placebo-controlled, multicentre study. Adult patients with PPP (with or without psoriasis) refractory to topical therapy and standard skin care were randomized 2:1 to alitretinoin 30 mg once daily or placebo for up to 24 weeks. The primary end point was PPPASI at week 24 (or the last visit in case of early withdrawal). Secondary end points included: percentage change from baseline in the modified Psoriasis Area and Severity Index (mPASI); percentage of patients with ≥ 50% or 75% improvement in PPPASI or mPASI scores from baseline; change in pustule count on the palms and soles; change in the Nail Psoriasis Severity Index and safety and tolerability assessments.. Thirty-three patients were randomized: 24 patients to alitretinoin 30 mg and nine to placebo. Overall, there were no significant differences between alitretinoin 30 mg and placebo for any end point. The safety profile was consistent with that seen in patients with chronic severe hand eczema refractory to potent topical corticosteroids.. Although the results were unexpected based on previous studies of alitretinoin in the treatment of PPP, this study provided no evidence to support further exploration of alitretinoin in the treatment of severe PPP.

Topics: Administration, Cutaneous; Administration, Oral; Alitretinoin; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Foot Dermatoses; Hand Dermatoses; Humans; Male; Middle Aged; Psoriasis; Severity of Illness Index; Treatment Outcome; Tretinoin

The novel systemic all-trans retinoic acid metabolism blocking agent (RAMBA) R115866 (Rambazole(TM); Barrier Therapeutics, Geel, Belgium; further referred to as rambazole) increases intracellular levels of endogenous all-trans retinoic acid (RA). Well-known effects of RA are normalization of aberrant epithelial growth and differentiation. Hence, rambazole might be beneficial in the treatment of plaque psoriasis.. The dynamics of epidermal proliferation, keratinization, lesional T-cell subsets and cells expressing natural killer (NK)-receptors in plaque psoriasis were assessed during treatment with rambazole, as part of a phase IIa open-label clinical trial.. Six patients were treated with rambazole, 1 mg, once daily, for 8 weeks. At weeks 0, 2 and 8, psoriatic plaque severity scores (SUM) and biopsies from a target lesion were assessed. Epidermal proliferation (Ki67), keratinization markers (K10, K13, K19), T-cell subsets (CD3, CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+, GITR+) and cells expressing NK-receptors (CD94, CD161) were immunohistochemically stained and quantified with image analysis.. At week 2 the mean SUM-score was virtually equal to baseline, which was accompanied immunohistochemically by equal epidermal hyperproliferation, a nonsignificant decrease in K10 positive epidermis and, overall, a nonsignificant increase in immunocyte subsets. At week 8, in contrast, plaque severity was reduced by 34% from baseline (P < 0.05). Improvements were also detected for epidermal proliferation (-63%; P < 0.01) and K10 expression (+29%; P < 0.01), compared with baseline. No induction of retinoid-specific keratinization (K13, K19) was observed. A nonsignificant reduction of all pathogenic T-cell subsets and cells expressing NK-receptors was observed at week 8 of treatment (P > 0.05).. Clinical efficacy of rambazole is primarily the result of restoring proliferation (Ki67) and differentiation (K10) of epidermal keratinocytes. Secondly, relevant T-cell subsets and cells expressing NK-receptors showed nonsignificant reductions after 8 weeks of treatment with rambazole.

Topics: Administration, Oral; Adult; Benzothiazoles; Cell Proliferation; Dermatologic Agents; Female; Humans; Immunohistochemistry; Keratolytic Agents; Male; Middle Aged; Psoriasis; Tretinoin; Triazoles

Treatment of common skin diseases such as psoriasis is complicated by differences between individuals in response to topical drug treatment and photochemotherapy. Individuality in hepatic expression of drug-metabolising enzymes is an important determinant of systemic drug handling; we investigated whether similar variation in cutaneous gene expression contributes to individuality in response to topical therapies.. We used quantitative real-time RT-PCR to demonstrate the expression in skin of a recently identified cytochrome P450, CYP2S1, in healthy volunteers (n=27) and patients with psoriasis (n=29). We also investigated regulation of CYP2S1 by ultraviolet radiation, psoralen-ultraviolet A (PUVA), and topical drugs used to treat psoriasis.. We found that CYP2S1 is expressed in skin and showed pronounced individuality in constitutive expression of the enzyme and its induction after ultraviolet irradiation or topical drug treatment. Cutaneous expression of CYP2S1 was induced by ultraviolet radiation, PUVA, coal tar, and all-trans retinoic acid; expression was significantly higher in lesional psoriatic skin than in adjacent non-lesional skin (geometric mean 3.38 [95% CI 2.64-4.34] times higher; p<0.0001), which implies that topical drugs are differentially metabolised in psoriatic plaque and non-lesional skin. We showed that all-trans retinoic acid is metabolised by CYP2S1, which has higher cutaneous expression than CYP26, previously described as the specific cutaneous P450 retinoic-acid-metabolising enzyme.. These findings increase our understanding of the interaction between therapeutic agents and the skin and suggest a functional role for CYP2S1 in the metabolism of topical drugs and in mediating the response to photochemotherapy in psoriasis.

Topics: Coal Tar; Cytochrome P-450 Enzyme System; Enzyme Induction; Gene Expression Regulation, Enzymologic; Humans; Oxygenases; Polymerase Chain Reaction; Psoriasis; PUVA Therapy; RNA, Messenger; Skin; Tretinoin; Ultraviolet Therapy

Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti-inflammatory effects. Recent work shows that topical all-trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8-week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0.1%, and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid/tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19% reduction in epidermal thickness, in corticosteroid-treated perilesional skin, as compared with a slight (1%) increase in corticosteroid/tretinoin-treated perilesional areas (P = 0.067). Western blot analysis showed a 55% reduction in procollagen I aminopropeptide in perilesional skin treated corticosteroid alone, as compared with a 45% reduction in corticosteroid/tretinoin-treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.

Topics: Administration, Topical; Adult; Aged; Anti-Inflammatory Agents; Atrophy; Betamethasone; Blotting, Western; Double-Blind Method; Drug Therapy, Combination; Epidermis; Female; Glucocorticoids; Humans; Male; Middle Aged; Psoriasis; Tretinoin

Retinoids derived from retinol or beta-carotene are inactivated, among other ways, by enzymes belonging to the P450 cytochrome group. Liarozole, an imidazole-containing compound, is known to be a potent inhibitor of the cytochrome P450-mediated metabolism of all-trans retinoic acid. As a result, increased levels of this retinoid are found in skin and plasma. Therefore, in the treatment of psoriasis, therapeutic effects may be expected with liarozole which are similar to those observed with synthetic retinoids. In an open study, oral liarozole was given at a daily dose of 75 mg b.i.d., for 12 weeks to 31 patients with severe psoriasis. After 1 month, this dosage could be increased to 150 mg b.i.d. if there was no improvement or only moderate improvement. Initially, the effect of liarozole was mainly on scaling. A decrease in the Psoriasis Area and Severity Index (PASI) score of 45% at week 4, of 69% at week 8 and of 77% at week 12 was obtained, compared with baseline. A further decrease in the PASI score of up to 87% was observed in the 16 patients who were allowed to continue treatment for a maximum period of 12 months. An excellent or good improvement was noted in 77% of the patients within 12 weeks of starting treatment. This response rate had increased to 88% by the last follow-up visit. Nearly all patients (29 of 31) experienced adverse reactions, such as dry oral mucosa, headache and itching. These were mostly mild and transient, but four patients dropped out of the study because of an adverse event. Haematological, biochemical and cardiovascular parameters were not significantly influenced by liarozole. Six patients showed an increase in triglycerides, which normalized in three of four patients during further treatment. The results of this pilot study suggest that, at doses of 75-150 mg b.i.d., liarozole is an active antipsoriatic drug, and may be a useful addition to the existing therapeutic armamentarium. Controlled studies should be performed to compare liarozole with standard oral treatments.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites; Arthritis, Psoriatic; Female; Humans; Imidazoles; Male; Middle Aged; Psoriasis; Severity of Illness Index; Treatment Outcome; Tretinoin

UVB radiation is beneficial for the treatment of psoriasis vulgaris. Patients with recalcitrant disease, however, are slow to respond to UVB phototherapy with and without the use of coal tars or emollients. Etretinate and, more recently, acitretin have proved useful, but clinical improvement is slow when they are used as monotherapy in plaque psoriasis. Each drug also produces side effects, some of which are dose related. This study was designed to compare results of treatment with UVB combined with either acitretin (50 mg/day) or placebo to determine if psoriasis would respond faster and to less cumulative exposure to UVB and acitretin. The psoriatic disease cleared to a greater degree in patients treated with acitretin-UVB with fewer treatments and smaller amounts of UVB radiation than in patients treated with either placebo-UVB or acitretin alone.

Topics: Acitretin; Adult; Aged; Combined Modality Therapy; Double-Blind Method; Female; Humans; Male; Middle Aged; Psoriasis; Tretinoin; Ultraviolet Therapy

Both etretinate and its principal metabolite, acitretin, are efficacious in the treatment of psoriasis. Because patients with severe psoriasis often require chronic therapy, this study was undertaken to determine the efficacy, tolerability, and safety of acitretin in patients on continuous treatment for 12 months. The initial daily dose of 50 mg was taken for 4 weeks. Thereafter the dose was increased or decreased by 10 mg at monthly intervals (10 to 70 mg) to produce the optimal response with minimal toxicity. Seventy percent of the patients who completed 12 months of treatment showed marked improvement. All patients experienced adverse reactions; dry lips, hair loss, skin peeling, pruritus, and nail disorders were the most frequent. Fourteen patients were withdrawn from the study because of one or more intolerable adverse reactions.

Topics: Acitretin; Adult; Aged; Female; Humans; Male; Middle Aged; Psoriasis; Tretinoin

In a randomized, double-blind comparative study 60 patients with severe, widespread psoriasis were treated either with photochemotherapy (PUVA) alone or in combination with acitretin. Forty-eight patients completed the study; of these, 25 received placebo combined with PUVA and 23 received acitretin with PUVA. Marked or complete clearing of psoriasis occurred in 80% of the patients (20 of 25) without acitretin and in 96% of the patients (22 of 23) with adjunctive acitretin administration. The mean cumulative UVA dose given to patients in the acitretin-PUVA group was 42% less than that required for patients in the placebo-PUVA group. We conclude that acitretin substantially augments the efficacy of photochemotherapy in the treatment of severe psoriasis.

Topics: Acitretin; Adolescent; Adult; Aged; Aspartate Aminotransferases; Cholesterol; Double-Blind Method; Drug Combinations; Drug Synergism; Female; Humans; Male; Methoxsalen; Middle Aged; Placebos; Psoriasis; PUVA Therapy; Radiation Dosage; Time Factors; Tretinoin; Triglycerides

Compared with the antipsoriatic retinoid etretinate, the new aromatic retinoid acitretin represents an important advance due to its rapid elimination kinetics. Since in psoriasis vulgaris retinoids are used predominantly in combination regimens, we investigated the therapeutic efficacy of acitretin and UV-B compared with placebo and UV-B in a double-blind, randomized multicenter trial in 82 patients with severe psoriasis. They were treated with 35 mg of the study medication during the first 4 weeks of therapy and 25 mg thereafter, concomitantly with UV-B irradiation in increasing energy doses. Forty patients who underwent therapy with acitretin and UV-B and 38 patients who underwent therapy with placebo and UV-B were evaluated for efficacy. The target variables--psoriasis severity index and total UV-B dose--were reported at intervals of 2 weeks over a maximum period of 8 weeks. At the end of treatment, the psoriasis severity index decrease was 79% in the acitretin and UV-B group and 35% in the placebo and UV-B group. The response rate, defined as greater than or equal to a 75% decrease of the psoriasis severity index, was 60% for the combination treatment and only 24% for the control treatment. This treatment response was achieved with markedly lower cumulative UV-B energy. The median cumulative UV-B energy applied to reach 75% clinical improvement was 11.8 J/cm2 vs 6.9 J/cm2. Side effects showed a similar pattern in both groups. Our data show that the acitretin dramatically improves the results of UV-B treatment in patients with severe psoriasis. In addition, it markedly decreases the effective cumulative UV-B dose, thereby reducing the potential long-term hazards of UV irradiation. We conclude that the acitretin plus UV-B combination treatment represents a highly effective therapeutic regimen in severe psoriasis.

Topics: Acitretin; Adolescent; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Drug Tolerance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multicenter Studies as Topic; Placebos; Psoriasis; Radiation Dosage; Random Allocation; Time Factors; Tretinoin; Ultraviolet Therapy

The purpose of this double-blind study was to compare the therapeutic effects of a low initial dosage of acitretin, increased at 2-week intervals (group 1: 10, 30, 50 mg/day) with a high initial dosage decreased at similar intervals (group 3: 50, 30, 10 mg/day) and with a constant dosage (group 2: 30 mg/day) in 66 patients (47 men and 19 women) with severe psoriasis. At the end of the double-blind phase, the mean percent improvement, calculated by the Psoriasis Area and Severity Index score, was as follows: 62.7% in group 1, 55.9% in group 2 and 67.1% in group 3. The double-blind phase of 6 weeks was followed by an open phase of 6 weeks, during which the patients were treated either with 10, 30 or 50 mg/day, according to the therapeutic response. At the end of treatment (12 weeks), a mean improvement of more than 80% was obtained in all three groups. Hypervitaminosis A signs and symptoms were observed in all patients. The frequency and severity of these adverse reactions were shown to be dose-dependent. This study shows that a low dose progressively increased is advisable because of similar activity and better acceptability.

Topics: Acitretin; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Psoriasis; Tretinoin

Acitretin, the principal and free acid metabolite of etretinate, was used to treat patients with stable, plaque-type psoriasis. For the first 8 weeks, 38 patients received placebo or acitretin, 10, 25, 50, or 75 mg daily, in a double-blind manner. After the double-blind phase, the patients were allowed to continue for a total of 6 months of acitretin therapy at an average dosage of 50 mg/day. When the patients flared after stopping therapy, an additional 6-month course of acitretin therapy was offered. Acitretin, which was as effective as etretinate, had to be given at a dosage of 50 mg/day or more to obtain a significant benefit. Side effects frequently occurred in patients receiving acitretin, 25 mg/day or more, but were generally mild and did not warrant discontinuation of therapy. They were similar to those of etretinate therapy; cheilitis, peeling of palms and soles, and alopecia occurred most frequently. The most common abnormal laboratory test results were elevations in serum triglycerides and, to a lesser extent, serum cholesterol and liver transaminase levels. Acitretin, in view of its much shorter half-life and similar efficacy and side-effect profile compared with etretinate, may be a preferable therapy for psoriasis, especially in women of childbearing age.

Topics: Acitretin; Adult; Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Humans; Lipids; Male; Middle Aged; Psoriasis; Time Factors; Tretinoin

The administration of UVB phototherapy and low-dose acitretin (0.34-0.44 mg/kg body weight) was compared with the effect of acitretin alone and UVB phototherapy alone in 41 patients with plaque-type psoriasis. Of these patients, 32 received standard UVB phototherapy without acitretin. The other nine were treated with acitretin and the effect of UVB irradiation (Sylvania UV 21-tubes), applied to one half of the body, was assessed. Clearance was defined as 80-100% improvement and this occurred in eight out of the nine patients (89%) treated with acitretin-UVB (ReUVB) and, in two of them (23%), on the untreated side. Clearance occurred in 20 of the 32 (62.5%) patients given UVB alone. The improvement score was significantly higher for the ReUVB side than the acitretin side. Patients treated with ReUVB showed a statistically higher therapeutic score (95-100% clearance) than those receiving UVB alone. However, taking 80-100% improvement as the criterion, no significant difference was found. The number of treatments to clearance was significantly less for the patients treated with ReUVB than for the UVB (19.3 as compared with 24.9). The total UVB dose and the number of minimal erythema doses (MEDs) could be reduced by approximately 20% in the ReUVB group relative to the UVB group.

Topics: Acitretin; Adult; Combined Modality Therapy; Female; Humans; Male; Middle Aged; Psoriasis; Radiotherapy Dosage; Tretinoin; Ultraviolet Therapy

Thirty-four patients with extensive psoriasis were treated in a double-blind parallel fashion with either acitretin plus bath PUVA (trimethylpsoralen bath + UVA) or etretinate plus bath PUVA. Each group consisted of 17 patients. The dose of retinoid was 40 mg/day during the 2-week monotherapy phase and subsequently 20 mg/day during the combination treatment. Bath PUVA was given three times a week starting with a UVA dose of 0.06 J/cm2. Remission (greater than 90% improvement) was achieved in all patients in 6-10 weeks. There were no significant differences in clinical response between the two groups; the mean +/- SD PASI score (psoriasis area and severity index) before treatment was 22.6 +/- 7.1 in the acitretin-PUVA group and 19.4 +/- 7.8 in the etretinate-PUVA group. The corresponding figures after treatment were 0.6 +/- 0.6 and 1.0 +/- 0.5, respectively. Side-effects related to retinoid treatment were frequent in both groups but they were usually mild and well-tolerated. There was only one case of diffuse alopecia after 8 weeks in the etretinate-PUVA group. Scaling of the palms and soles was seen in six patients in the acitretin-group but only in two patients in the etretinate-group. Triglycerides were elevated in about half of the patients in both groups. The present study shows that acitretin is as effective as etretinate in the combination with bath PUVA.

Topics: Acitretin; Adult; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Etretinate; Female; Humans; Male; Psoriasis; PUVA Therapy; Random Allocation; Tretinoin

Acitretin, the active metabolite of etretinate, has the clinical advantage of a much shorter terminal elimination half-life. We report the results of a double-blind, placebo-controlled trial of acitretin (Soriatane) in 15 patients with moderate to severe psoriasis. Patients received 25 mg or 50 mg daily of acitretin or placebo in a double-blind fashion for 8 weeks and then were given 25 to 75 mg acitretin daily during an open study. Only two placebo patients completed the double-blind phase; one patient's psoriasis worsened, and one showed no significant change. All 15 patients then completed at least 8 weeks with 25 to 75 mg acitretin daily, with a moderate change in erythema, scaling, and induration (mean 28% to 37% improvement) but with minimal change in the percentage of body surface area involved. Prolonged treatment (greater than or equal to 20 weeks) with acitretin resulted in further significant improvement and a 44% reduction of involved surface area from baseline.

Topics: Acitretin; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Psoriasis; Tretinoin

We examined the clinical and histological effects of etretin in pustulosis palmo-plantaris (PPP) in a multicentre study. 30 patients with PPP were treated with etretin in a double-blind study. After a 4-week interval of either etretin (50 mg/day) or placebo (randomized), all patients received etretin during a second period of 20 weeks (the dosage was individually varied). The effect of etretin was verified clinically and by immunhistochemical methods. The number of pustules in a 4 cm2 reference area diminished within the first 4 weeks from 8.5 to 1.9 (etretin group) and from 9.0 to 6.2 (placebo group). Within a maximum of 24 weeks 16% of the patients showed a complete remission, 44% a pronounced improvement, and 22% little improvement. The state of 2% of the patients deteriorated. Immunhistologically, the number of granulocytes was reduced in the inflammatory infiltrate and in the pustules. Etretin is therefore a retinoid, which is easily controlled and effective in PPP.

Topics: Acitretin; Adult; Aged; Double-Blind Method; Female; Germany; Humans; Male; Middle Aged; Multicenter Studies as Topic; Psoriasis; Random Allocation; Tretinoin

Topics: Acitretin; Adult; Double-Blind Method; Etretinate; Humans; Male; Middle Aged; Psoriasis; Random Allocation; Tretinoin

The efficacy and tolerability of acitretin (etretin) in severe psoriasis was compared with that of etretinate in a double-blind randomized study for 12 weeks. A total of 127 patients received acitretin and 41 received etretinate. The initial daily dose was 40 mg/day over 4 weeks and was subsequently adjusted according to individual response. From week 5-12 the mean daily dose was 42.9 mg of acitretin (0.58 mg/kg) versus 49.2 mg of etretinate (0.65 mg/kg). Acitretin gave a PASI score reduction from baseline of 70.5% and etretinate a reduction of 68.4% (mean values). Acitretin tended to give more discomfort than etretinate, particularly with regard to hair loss and peeling of palms and soles. The differences found between acitretin and etretinate may be related to higher maximum plasma concentrations of acitretin. The considerably shorter half-life of acitretin, gives it a great advantage over etretinate with regard to risk of teratogenicity after cessation of treatment.

Topics: Acitretin; Double-Blind Method; Etretinate; Female; Humans; Male; Multicenter Studies as Topic; Psoriasis; Random Allocation; Tretinoin

Acitretin, the free acid of etretinate, is less lipophilic and has a much shorter terminal half-life than the parent compound. The present double-blind, randomized study compared the therapeutic effectiveness and the tolerability of acitretin (n = 127) and etretinate (n = 41) in psoriasis. Patients were treated with 40 mg daily for the first 4 weeks and with an individually adjusted dose for the subsequent 8 weeks. The average daily doses of acitretin (0.54 mg/kg/day) and etretinate (0.65 mg/kg/day) were similar. The PASI (Psoriasis Area and Severity Index) scores improved in parallel in the 2 treatment groups. At the completion of the study, the PASI score improvement was 75.8% for acitretin and 70.8% for etretinate. Both acitretin and etretinate resulted in mucocutaneous side effects. Assessments of tolerability by investigators and patients showed a statistically significant difference in favour of etretinate. These results demonstrate that acitretin and etretinate have similar therapeutic effectiveness in psoriasis. Although the tolerance to acitretin was lower than to etretinate, acitretin offers the important advantage of a much shorter period of potential teratogenicity and is, therefore, to be preferred in women of childbearing potential.

Topics: Acitretin; Adolescent; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Psoriasis; Random Allocation; Tretinoin

Six patients with persistent palmoplantar pustulosis were treated with acitretin, and the clinical response was compared with the effect on the intra-epidermal accumulation of polymorphonuclear PMN leukocytes. A prompt improvement of pustule formation and subsequently decreased scaling and erythema was seen in all patients. Following discontinuation of therapy, a relapse occurred within 2 weeks. With dosages of 45 or 55 mg/day, the clinical scores were only slightly better than with 25 or 35 mg/day. In patients using 25 mg acitretin a day, the leukotriene B4-induced intra-epidermal accumulation of polymorphonuclear leukocytes was not affected. However, a dosage of 35 mg/day resulted in a significant inhibition of PMN accumulation, dosages of 45 and 55 mg/day causing an even more pronounced inhibition of this process. Although the effect of different dosages of acitretin is not clearly expressed in the severity scores, the dose-dependent effect on PMN chemotaxis in vivo might be of relevance when combination therapies are considered, in order to achieve a complete clinical clearance.

Topics: Acitretin; Adult; Chemotaxis, Leukocyte; Clinical Trials as Topic; Drug Tolerance; Female; Foot Dermatoses; Hand Dermatoses; Humans; Male; Middle Aged; Neutrophils; Psoriasis; Skin Diseases, Vesiculobullous; Tretinoin

Acitretin, a metabolite of etretinate, was given to 38 patients for the treatment of psoriasis. During the first 8 weeks patients received either placebo, 10 mg, 25 mg, 50 mg, or 75 mg of acitretin daily in a double-blind manner. The dosages of 10 mg and 25 mg daily did not achieve any statistically significant improvement in psoriasis over placebo; however, both the 50 and 75 mg dosages were statistically significantly better than placebo. Side effects were primarily mucocutaneous and occurred in most patients receiving 25 mg or more of acitretin daily. After the double-blind period, patients continued treatment in an open fashion until they had received a total of 24 weeks of acitretin therapy. Most patients received 50 mg of acitretin daily, which adequately cleared their psoriasis. After approximately 3 months without acitretin, most patients required retreatment. Subsequent 24-week courses of therapy were generally effective and well tolerated. The most common laboratory abnormalities were elevations of triglyceride, cholesterol, and liver transaminase levels. The efficacy and side effects of acitretin appear to be similar to those of etretinate; the principal advantage of acitretin is its shorter half-life. Although acitretin is a potent teratogen, its rapid elimination makes it a viable treatment for psoriasis among women of childbearing potential.

Topics: Acitretin; Adult; Cheilitis; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Psoriasis; Tretinoin

175 patients with severe psoriasis of different types were treated with 10, 25, or 50 mg acitretin and compared with patients receiving 50 mg etretinate over a period of 8 weeks in a randomized, double-blind multicenter study in the Federal Republic of Germany. Plasma concentrations of etretinate and its metabolite acitretin were measured during therapy and also 3 weeks after cessation of treatment. After 4 weeks of treatment, a trend toward clinical improvement was shown in all groups with increasing dosage. Those groups receiving the lower acitretin doses (i.e., 10 and 25 mg/day) had more dropouts than the groups taking 50 mg acitretin or 50 mg etretinate. Complete remissions before the end of therapy occurred only among those receiving higher doses. Enlargement of psoriatic lesions, however, could be observed during treatment with both retinoids, despite improvement of other parameters, as measured by psoriasis area and severity index (PASI) and psoriasis severity index (PSI). After 8 weeks, a significant improvement was calculated by the PASI score and by a newly defined, corrected PASI score for all four dose regimens compared with baseline levels. A greater than 50% PSI score improvement was seen in 50% of patients treated with 10 mg acitretin, 40.5% with 25 mg acitretin, 53.8% with 50 mg acitretin, and 61.1% with 50 mg etretinate. No statistical differences were found among these groups at any time during the 8-week period. No new or unexpected side effects occurred during acitretin treatment. Moreover, cholesterol levels did not significantly change. Three weeks after cessation of drug administration, the plasma concentrations of acitretin were below the sensitivity level of the assay, whereas etretinate was still quantifiable. It is interesting that acitretin plasma concentrations during therapy with 50 mg acitretin were markedly lower (means = 18 ng/ml) than were acitretin levels during treatment with 50 mg etretinate (means = 36 ng/ml).

Topics: Acitretin; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Psoriasis; Random Allocation; Tretinoin

A randomized double-blind study was designed with 65 patients in order to clarify two points: (1) does addition of a retinoid to psoralen-ultra violet A photochemotherapy (PUVA) of severe psoriasis decrease the UVA energy required to achieve remission, and (2) is there a difference between two retinoids, i.e. etretinate and acitretin. Acitretin-PUVA treatment was significantly superior to placebo-PUVA with respect to several items (decrease in lesional scores after 6 weeks of therapy, number of PUVA exposures, and total dose of UVA until remission). There were also differences between the etretinate-PUVA and placebo-PUVA groups, but only the decrease in lesional scores reached statistical significance.

Topics: Acitretin; Adult; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Psoriasis; PUVA Therapy; Random Allocation; Remission Induction; Tretinoin

A randomized double-blind parallel trial comparing acitretin and etretinate was performed in 20 patients with severe psoriasis during a treatment period of 12 weeks. The initial dose was 30 mg/day for 4 weeks, and the mean dose at the end of the study was slightly lower in the acitretin group when compared to the etretinate group (30.7 mg/day and 33.4 mg/day, respectively). Follow-up examinations were carried out every 2 weeks, and the efficacy of treatment was evaluated by using the PASI score. Percentage improvement in the PASI score was 50% at week 10 in both groups, and the difference between them at week 12 was insignificant. Both quantitatively and qualitatively, acitretin and etretinate do not significantly differ.

Topics: Acitretin; Adult; Aged; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Psoriasis; Time Factors; Tretinoin

Eighty patients with severe psoriasis were treated in a double-blind fashion with either an initial dose of 10 mg, 25 mg or 50 mg of etretin daily or with placebo. Follow-up examinations were carried out monthly and the efficacy of treatment was evaluated by using the PASI score. Adverse effects of the treatment were recorded monthly; liver enzymes, cholesterol and triglycerides were measured. After 2 months of treatment the maintenance dose was reduced in some of the patients either because of complete remission or adverse effects. After 2 months treatment, groups receiving 25 mg/day and 50 mg/day showed significantly lower PASI scores than the placebo group. The 10 mg/day group showed a response intermediate between the 25 mg and 50 mg groups and the placebo group. Thus, the optimal initial dose seems to be approximately 25 mg/day and the maintenance dose somewhat lower. Six months after the start of treatment there were no significant differences between the four groups; the last follow-up examination took place during the summer and some of the patients probably experienced spontaneous improvement. Although clinical adverse effects were frequent in all groups, severe side effects, namely hair loss and paronychia, occurred frequently only among patients treated with an initial dose of 50 mg of etretin daily. The effect of treatment on liver enzymes, cholesterol and triglycerides was minimal.

Topics: Acitretin; Alanine Transaminase; Aspartate Aminotransferases; Cholesterol; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Female; gamma-Glutamyltransferase; Humans; Male; Middle Aged; Psoriasis; Tretinoin; Triglycerides

We have investigated the clinical responses of 21 patients with severe psoriasis to therapy with etretin, a metabolite of etretinate. In a preliminary double-blind dose-finding study, the optimum dose of etretin was determined to be 50 mg/d (mean, 0.66 mg/kg/d). In an open study, patients receiving etretin therapy were followed up for a minimum of six months. An excellent or good response (greater than 50% clearance) was obtained in 18 of 21 patients. The incidence of mucocutaneous side effects from etretin therapy was similar to that previously reported with etretinate therapy. As a group, patients who received etretin therapy for six or more months showed no significant aberrations from normal levels of serum lipids or serum liver enzymes. However, five patients had mild elevation of liver enzymes or blood lipids, which were corrected by dose reduction. Etretin showed equivalent efficacy to that previously reported with etretinate in severe recalcitrant plaque psoriasis vulgaris. Taken with the reportedly more rapid clearance of etretin from the body, there may be clinical advantages of the use of etretin over the use of etretinate.

Topics: Acitretin; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psoriasis; Random Allocation; Time Factors; Tretinoin

Etretin, an aromatic retinoic acid derivative, has recently been introduced as a possible substitute for etretinate in the treatment of severe psoriasis and other dyskeratoses. A total of nine patients with psoriasis of either sex in the age range 23-76 years was investigated after single dose oral drug administration, six were given 40 mg of etretin and three 40 mg of etretinate. A newly developed reversed-phase HPLC method was applied for simultaneous determination of etretin and etretinate in plasma. In patients receiving etretinate, the lag-time i.e. the time elapsing until appearance of first-order drug absorption was 1.24 +/- 0.27 for the parent drug and 0.69 hrs +/- 0.16 (mean value +/- S.D.) for its metabolite, etretin. Absorption half-times were 0.86 +/- 0.04 and 0.55 hrs +/- 0.09, respectively. The patients receiving etretin showed a lag-time of 0.42 hrs +/- 0.23 and an absorption half-time of 0.33 hrs +/- 0.28. This suggests that a fraction of etretinate is rapidly hydrolysed to etretin during the absorption process. The mean half-times of the distributory phases of disposition for etretinate and etretin were about 1 and 1.3 hrs and the apparent terminal half-lives were 6.57 +/- 2.09 and 5.52 hrs +/- 1.76, respectively. Assuming 40% systemic availability for both drugs the mean apparent volumes of distributions were calculated to be 1.50 +/- 0.46 and 1.31 l X kg-1 +/- 0.53 and mean plasma clearances were 177.8 +/- 105.8 and 175.9 ml X kg-1 X hr-1 +/- 81.4 for etretinate and etretin, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acitretin; Adult; Aged; Drug Administration Schedule; Etretinate; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Psoriasis; Random Allocation; Tretinoin

Eight patients with psoriasis (seven with plaque-type and one with palmoplantar pustular psoriasis) were treated with the synthetic retinoid etretin, the active metabolite of etretinate. An initial 8-week double-blind phase of the study with dosages of 0, 25, or 50 mg/day was followed by an open phase in which variable dosages of 25, 50, or 75 mg/day were used to achieve an optimal clinical response. All patients completed a minimum of 6 months of therapy. A good or an excellent response (at least 50% clearing) after 8 months of treatment was noted in six of the eight patients. One patient had a poor response (less than 50% clearing), and one patient continued to have worsening of psoriatic involvement during treatment. The best response occurred in those patients with the most extensive initial plaque involvement or palmoplantar pustulosis. The clinical side effects were similar to those reported with use of etretinate and seemed to be related to the dose. The laboratory abnormalities--primarily mild intermittent elevations of liver enzymes and elevations in serum lipids--were similar to those described in previous reports about etretinate. Both etretin and etretinate are potent teratogens. Because of its shorter half-life, etretin will likely be preferred, especially in female patients of childbearing potential.

Topics: Acitretin; Adult; Aged; Alopecia; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Psoriasis; Random Allocation; Tretinoin

Synthetic retinoids were first evaluated 15 years ago for systemic treatment of psoriasis in the Federal Republic of Germany. Etretinate was introduced 2 years ago into the market for systemic treatment of all severe types of the disease. Today etretinate is administered as monotherapy and/or combined with other modalities (anthralin, tar, topical corticosteroids, selective UV therapy, RePUVA), which leads to successful clearing in most cases. Nevertheless, thorough consideration of the risk-benefit ratio is required in each individual patient. The advantages and disadvantages are presented that should be taken into consideration. As a rule, severe cases of psoriasis are admitted to the hospital; initial treatment is given and then continued on an outpatient basis. In some patients, particularly those with pustular eruptions and/or erythroderma, low-dosage oral etretinate may be continued for prophylactic reasons over several months or years. Since the amount of hospitalization is reduced, the overall treatment costs are reduced in spite of the high cost of the drug. The main disadvantage of oral retinoids is their teratogenicity, although no severe cases of retinoid toxicity have been reported in the last 2 years in the Federal Republic of Germany since their introduction. As a successor drug to etretinate, its free aromatic acid, Ro 10-1670 is now under clinical investigation. It seems to be clinically effective, is rapidly eliminated, and requires only 4 weeks contraception after discontinuation of oral administration. Arotinoids then follow.

Topics: Abnormalities, Drug-Induced; Acitretin; Benzoates; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Etretinate; Humans; Lipids; Long-Term Care; Prognosis; Psoriasis; Retinoids; Risk; Skin; Tretinoin

Topics: Humans; Isomerism; Isotretinoin; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

Since etretinate, an aromatic retinoid useful in the treatment of psoriasis and other skin disorders is lipid-soluble, it may be poorly absorbed in the absence of a fat load. We therefore studied serum concentrations of etretinate and its major metabolite (Ro 10-1670) after the controlled administration of etretinate. After an overnight fast, 6 Darier's disease and 4 psoriatic patients received a 1 mg/kg morning dose of etretinate with water or 1 pint of whole milk (fat load). There was a 260% increase (p less than 0.0005) in the mean of each patient's increase in the baseline-corrected peak serum concentration of etretinate after administration with milk (115 +/- 15 micrograms/dl) compared to after administration with water (32 +/- 4 micrograms/dl). Over a 24-h period there was an overall 296 +/- 26% (p less than 0.0005) increase in serum etretinate after administration with milk compared to water in 5 patients with Darier's disease. In contrast to the serum etretinate, there was a 17% mean decrease (p less than 0.025) in the corrected peak serum concentration of Ro 10-1670 in all 10 patients after administration of etretinate with milk compared to water. The net result of these alterations is that the mean corrected serum concentration of etretinate is higher than Ro 10-1670 at all time points measured after milk administration. In contrast, after administration of etretinate with water the major retinoid in the serum is Ro 10-1670. Establishing the clinical significance of these alterations may require controlled clinical trials.

Topics: Acitretin; Animals; Darier Disease; Etretinate; Humans; Milk; Psoriasis; Tretinoin; Water

Topics: Etretinate; Humans; Isomerism; Isotretinoin; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

Oral administration of the aromatic retinoid etretinate is effective therapy for psoriasis and other epidermal hyperproliferative disorders. Since polyamine metabolism is known to be important in cell growth and differentiation, we measured urinary levels of the polyamines putrescine, spermidine, and spermine as a reflection of cutaneous polyamine metabolism in 19 psoriatic patients treated with etretinate for 16 weeks. Using thin-layer chromatography, polyamine determinations were performed on urine collected pretherapy, during therapy, and 8 weeks after therapy was concluded. Good to excellent clearing of psoriasis occurred in 18 of 19 patients. All urinary polyamines showed a downward trend in the first week of therapy, prior to significant clinical improvement. At week 16 of therapy, the greatest reduction in mean urinary polyamine content occurred. Mean putrescine levels decreased from pretherapy to week 16 by 27% (p less than 0.001), mean spermidine values fell by 34% (p less than 0.001), and mean spermine levels declined by 37% (p = 0.005). These data are consistent with the hypothesis that etretinate inhibits polyamine biosynthesis.

Topics: Adult; Aged; Etretinate; Female; Humans; Male; Middle Aged; Polyamines; Psoriasis; Tretinoin

Orally administered retinoids are synthetic derivatives of vitamin A. This new group of drugs (not yet available for general use in the United States) has been effective in experimental trials for treatment of a wide range of skin diseases. The current status of two of these drugs, isotretinoin (13-cis-retinoic acid) and etretinate (Ro 10-9359), is herein reviewed.

Topics: Acne Vulgaris; Administration, Oral; Child; Clinical Trials as Topic; Facial Dermatoses; Female; Humans; Isomerism; Isotretinoin; Keratins; Keratitis; Neoplasms; Psoriasis; Skin Diseases; Tretinoin; Xerostomia

Topics: Administration, Oral; Administration, Topical; Adolescent; Adult; Aged; Betamethasone; Betamethasone Valerate; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Etretinate; Female; Humans; Male; Middle Aged; Psoriasis; Random Allocation; Tretinoin

Topics: Darier Disease; Etretinate; Female; Humans; Male; Microscopy, Electron; Polyamines; Psoriasis; PUVA Therapy; Skin; Tretinoin; Vitamin A

International studies evaluating the efficacy of etretinate (Ro 10-9359) in psoriatic patients are reviewed. Double-blind, placebo controlled studies uniformly have demonstrated the therapeutic effect of the retinoid. Both single therapy and combination therapy studies confirm the efficacy of this new form of treatment, especially in patients with the rarer and more severe forms of psoriasis.

Topics: Anthralin; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Etretinate; Humans; Psoriasis; PUVA Therapy; Tretinoin; Ultraviolet Therapy

We investigated changes in serum triglyceride, cholesterol, and high-density lipoprotein cholesterol (HDLC) levels during etretinate administration in 21 patients with psoriasis. Mean serum triglyceride and cholesterol values showed a statistically significant increase during etretinate therapy compared with placebo treatment; mean HDLC levels did not change. During etretinate therapy, elevations out of the normal range occurred in 77% of the patients for serum triglycerides and 25% for serum cholesterol. Eight weeks after discontinuation of the drug regimen, patients' mean serum triglyceride and cholesterol levels were not statistically different from those found prior to therapy. Nevertheless, eight weeks after therapy had been stopped, six (32%) of 19 patients had cholesterol values that were still 20% or more above their baseline levels; the prolonged etretinate excretion time could have been responsible. The mechanisms for the etretinate-induced lipid elevations are unknown.

Topics: Adult; Aged; Body Weight; Cholesterol; Cholesterol, HDL; Double-Blind Method; Etretinate; Female; Humans; Lipids; Lipoproteins, HDL; Male; Middle Aged; Psoriasis; Random Allocation; Tretinoin; Triglycerides

Eighty ambulatory adult patients with severe psoriasis were included in our 14-week study to compare the clinical effects of treatment with an aromatic retinoid (Tigason), combination treatment with aromatic retinoid plus PUVA (RePUVA), and PUVA alone. RePUVA was given by two different modifications: either 4 weeks of pretreatment with retinoid followed by 6 weeks of PUVA treatment, or 10 weeks of retinoid treatment with concomitant PUVA treatment during the last 6 weeks. The latter modification of RePUVA proved to be significantly more effective than the other treatments (P less than 0.01) as regards complete remission. With respect to the number of patients with good or excellent improvement (75-100% improvement) there was no marked difference between RePUVA and PUVA treatments. Retinoid alone proved to be the least effective, showing, however, a good to excellent result in 65% of patients. Besides the increase in efficacy, another advantage achieved by RePUVA was a highly significant (P less than 0.001) reduction of total UVA doses to about one third as compared to PUVA therapy.

Topics: Adult; Clinical Trials as Topic; Drug Therapy, Combination; Etretinate; Female; Humans; Male; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

In an open trial, eight patients with psoriasis took part in a four-month study to evaluate the effect of a new oral synthetic retinoid Ro-10-9359 (Tigason). All patients improved on the treatment, although one had side effects severe enough to force dosage reduction with less satisfactory control.

Topics: Administration, Oral; Adult; Aged; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Psoriasis; Time Factors; Tretinoin; Xerostomia

The authors discuss results observed in 126 patients affected with severe psoriasis covering more than 40% of the whole body area, some of them representing failures of oral photochemotherapy (PUVA). They were treated according to 5 different schedules, 3 of them combining aromatic retinoid Ro 10-9359 (AR) with PUVA therapy. The most effective results were obtained with a schedule entailing initial treatment for a 2-week period with AR only, followed on the 15th day by the adjunction of classic PUVA therapy with progressive daily decrease of AR dosage (schedule C). It was possible to reduce the frequency and duration of PUVA treatments and the amount of energy used although to a lesser degree than described by other authors. Even more important, far longer remissions were obtained than with PUVA therapy alone, even where the ratio of clearing was identical. This combination therapy made it possible to recover over 70% of the complete or relative failures of PUVA monotherapy. Thus the combination of AR + PUVA therapy (RE-PUVA) as in this schedule appears to be the most important improvement ot PUVA since its introduction as a therapy for psoriasis.

Topics: Adult; Aged; Etretinate; Female; Humans; Male; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

Topics: Adolescent; Adult; Aged; Ambulatory Care; Balneology; Female; Humans; Male; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy; Sodium Chloride; Tretinoin

Ninety-seven patients with severe psoriasis took part in a 1-year study to evaluate the effect of a new oral synthetic retinoid (Ro 10-9359). The trial was performed in a double-blind cross-over fashion. The treatment started with either 100 mg daily of Ro10-9359 or placebo and the maintenance dose was in most cases 50 mg. Follow-up examinations were performed monthly and the parameters erythema, desquamation, infiltration and extent of the lesions were followed. Throughout the study there was a significant to highly significant preference for Ro 10-9359 shown by all parameters. More patients were in complete remission after Ro 10-9359 periods than after placebo periods. The side-effects of Ro 10-9359 on uninvolved skin and mucous membranes seemed to be largely dose-dependent. Twenty-three patients interrupted the study, four of them because of side-effects, mainly alopecia. Laboratory examinations revealed no aberrations which could be attributed to the therapy. One patient developed hepatitis during a placebo period.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Humans; Male; Psoriasis; Tretinoin

In a multicentre double-blind trial the effect of three therapy regimens was studied for 6 weeks in ninety psoriasis patients: (1) aromatic retinoid (Ro 10-9359) orally (0.50-0.66 mg/kg body weight) and placebo cream topically; (2) aromatic retinoid (Ro 10-9359) (same dosage) with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream; (3) placebo capsules with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream. Regimen 1 had virtually no effect and regimen 2 gave better results than regimen 3 for almost all parameters, although statistical significance was reached for only some of them. The 6 week double-blind period was followed by an open study in which all patients were treated according to regimen 2. The clinical result could be maintained up to the end of the study (18 weeks), when more than 60% of the patients showed good to excellant (80-100%) improvement. Most of the side-effects of retinoid were mild and relatively rare. It is concluded that the combination of the aromatic retinoid (Ro 10-9359) given in low dosage orally with corticosteroids topically is as effective as therapy with the retinoid in high dosage alone, but with markedly less side-effects.

Topics: Administration, Oral; Administration, Topical; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Etretinate; Female; Humans; Male; Psoriasis; Tretinoin; Triamcinolone Acetonide

The combined application of an oral retinoid (Ro 10-9359) and phototherapy with predominantly UVB radiation (Selective Ultraviolet Phototherapy=SUP) is a new, highly effective method of treating psoriasis. It has few side effects and can be performed on an out-patient basis. With the aid of this combined treatment we achieved good or very good improvement in 19 out of 23 patients with generalized psoriasis (=82.6%). The average number of radiation sessions required to achieve this was 22.9, and the mean total therapeutic dose (TTD) was 73 J/cm2. In a control group of 40 psoriasis patients, who received only radiation therapy, we achieved good or very good results in only 60% with an average of 26 radiation sessions and 94 J/cm2 TTD. The effect of the oral retinoid and UVB radiation therapy is apparently additive, since the retinoid does not increase the sensitivity of the skin to light.

Topics: Administration, Oral; Drug Evaluation; Humans; Photochemotherapy; Psoriasis; Tretinoin; Ultraviolet Therapy; Vitamin A

Oral administration of an aromatic retinoid has a marked beneficial effect on psoriasis and does not produce significant changes in liver function or the blood count when given at a dose of 25 mgm three times a day for six weeks. This effect does not occur unless the drug has produced dermatological side-effects and this may inhibit its future acceptance but the present findings indicate that, at least in the less developed parts of the world where many Western treatments are unacceptable for various reasons, oral retinoids are a useful and relatively safe addition to the present range of medications available for psoriasis.

Topics: Administration, Oral; Adult; Clinical Trials as Topic; Double-Blind Method; Etretinate; Female; Humans; Male; Middle Aged; Placebos; Psoriasis; Random Allocation; Tretinoin; Vitamin A

Topics: Administration, Oral; Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Humans; Keratoderma, Palmoplantar; Middle Aged; Psoriasis; Tretinoin; Vitamin A

Ro 10-9359 is a retinoic acid derivative, selected for study because of a better tolerance than retinoic acid, shown in animal experiments. Doses of 25 mg b.i.d., 25 mg t.i.d. and 50 mg b.i.d. were administered orally to 27 patients suffering from severe chronic generalized psoriasis. The clinical efficacy was evaluated by means of a new index, psoriasis area and severity index (PASI) based on severity and area of psoriatic lesions. At doses of 25 mg t.i.d. or 50 mg b.i.d. Ro 10--9359 proved to be an extremely potent antipsoriatic drug. A more than 90% reduction of psoriatic lesions could be seen in 10 patients out of 20 after 4-8 weeks of treatment. This good effect lasted about 5 weeks after treatment. Side effects were frequent, but mostly mild and completely reversible after termination of treatment.

Topics: Administration, Oral; Adult; Chemical Phenomena; Chemistry; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psoriasis; Tretinoin; Vitamin A

Topics: Administration, Oral; Clinical Trials as Topic; Drug Evaluation; Humans; Psoriasis; Skin; Tretinoin; Vitamin A

Topics: Administration, Oral; Adult; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Psoriasis; Skin; Tretinoin; Vitamin A

Topics: Administration, Oral; Adult; Clinical Trials as Topic; Drug Evaluation; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psoriasis; Skin; Tretinoin; Vitamin A

Topics: Clinical Trials as Topic; Drug Evaluation; Follow-Up Studies; Humans; Psoriasis; Tretinoin; Vitamin A

The effectiveness of photochemotherapy can be substantially increased by the concomitant administration of an oral aromatic retinoid. 134 patients with severe plaque-type or palmoplantar psoriasis were given various combined treatment schedules. In the initial (clearing) phase a significant synergistic effect was achieved if retinoid administration was started before photochemotherapy, and if the dose was 1.0 mg/kg body-weight. This shortened by half the time required in a control group given photochemotherapy alone (7.7 +/- 4.5 irradiation sessions within 14.1 +/- 8.6 days), and reduction of the total UVA energy necessary for complete clearing to one third (32.4 +/- 40.0 J/cm2). After clearing the patients received standard photochemotherapy maintanance treatment. The incidence of relapses observed during a 10-month follow-up was the same as that in patients cleared and maintained with photochemotherapy alone. Short courses of retinoid treatment in addition to photochemotherapy were highly effective in clearing patients who had failed to do so or had not been maintained in a cleared state on standard photochemotherapy.

Topics: Administration, Oral; Clinical Trials as Topic; Follow-Up Studies; Humans; Methoxsalen; Psoriasis; Recurrence; Tretinoin; Ultraviolet Therapy; Vitamin A

In a multi-centre study 291 patients with psoriasis were treated with (a) oral doses of the recently developed retinoid Ro 10-9359, (b) classical local dithranol application, and (c) both. In a preliminary evaluation of 203 patients treated orally excellent or good results were obtained in 120 (61%), no response in 31 (15.8%). The initial dose was 1.0 mg/kg body-weight daily, i.e. 50-75 mg, which was then reduced to 25-50 mg daily. A clinical response was noted after 2-3 weeks. Particularly, severe erythrodermic and pustular forms of the disease responded surprisingly well to the drug so that cytostatic agents were avoided. Under long-term administration, however, relapses were still seen. Most side-effects were reasonably well tolerated. But in 14% of patients the drug had to be discontinued because of hair loss, paronychia or slight elevation of transaminases (up to 40 U/I). This new drug is thus a potent antipsoriatic agent: it is effective, easily controlled and causes only moderate side-effects.

Topics: Administration, Oral; Adolescent; Adult; Anthralin; Child; Female; Humans; Male; Middle Aged; Psoriasis; Recurrence; Remission, Spontaneous; Time Factors; Tretinoin; Vitamin A

In the study presented, an evaluation has been made of the results achieved in a group of 32 psoriatic patients treated with a derivative of the retinoid acid, i.e. Ro 10-9359, taken orally. The therapy used was considered highly favourable in 28 cases and favourable in 3. It is considered that the treatment is effective independently of the time of evolution and of the extension of seriousness of the disease with no effects on the visceral or humoral sectors. All the information included in the present study allows to assert that the treatment of psoriasis with this derivative of the retinoid acid represents a significant progress as compared with the corticoids or cythostatics therapy.

Topics: Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Infant; Male; Middle Aged; Psoriasis; Tretinoin; Vitamin A

Topics: Administration, Oral; Clinical Trials as Topic; Humans; Psoriasis; Tretinoin; Vitamin A

The effect of urea-lactic acid ointment on the scales of ichthyotic skin was assessed using the 'cell swelling' technique of Christophers & Kligman. The thickness of the horny layer and of the scales was reduced both by the ointment and by the base. The formation of scales was shown to differ from that in psoriasis where the scale forms at the apex of th a rete peg and is symmetrical whereas in ichthyosis the separation of the scale may be at an entirely different depth at one margin. There is an increase in the number of 'T' cells in X-linked recessive ichthyosis.

Topics: Adolescent; Adult; Aged; Female; Humans; Ichthyosis; Lactates; Male; Middle Aged; Ointment Bases; Psoriasis; Skin; Tretinoin; Urea

The sequential application of tretinoin and a corticosteroid ointment was considerably more effective in the treatment of plaque-type psoriasis than either drug alone in a pilot study. The best results were obtained with 0.3% tretinoin followed by a potent corticosteroid ointment. Combined therapy was particularly efficacious in steroid-resistant psoriasis, including that on the palms, elbows, and knees. Irritancy from the high-strength tretinoin was a potentially troublesome side-effect. Care must be taken to avoid drug contact on areas that are easily irritated.

Topics: Administration, Topical; Adrenal Cortex Hormones; Adult; Clinical Trials as Topic; Dexamethasone; Drug Combinations; Drug Therapy, Combination; Fluocinonide; Humans; Middle Aged; Ointments; Psoriasis; Tretinoin; Vitamin A

The retinoic acid derivative Ro 10-9359 has been tested in 24 patients with psoriasis. In all patients the therapeutic activity was good to excellent. The symptoms of the hypervitaminosis A syndrome were slight to marked. The ratio between the therapeutic effectiveness and the side effects was favourable only in cases with severe psoriasis.

Topics: Administration, Oral; Clinical Trials as Topic; Drug Evaluation; Hair; Humans; Nails; Placebos; Psoriasis; Time Factors; Tretinoin; Vitamin A

Whey acidic protein four-disulfide core domain protein 12 (WFDC12) has been implicated in the pathogenesis of psoriasis but the specific molecular mechanism is not clearly defined. In this study, we found the expression of WFDC12 protein closely correlated with psoriasis. WFDC12 in keratinocyte might increase infiltration of Langerhans cells (LCs) and monocyte-derived dendritic cells (moDDCs), up-regulating the co-stimulation molecular CD40/CD86. Th1 cells in lymph nodes were higher in K14-WFDC12 transgenic psoiasis-like mice. Meanwhile, the mRNA of IL-12 and IFN-γ in the lesion skin was significantly increased in transgenic mice. Moreover, we found that the expression of the proteins that participated in the retinoic acid-related pathway and immune signaling pathway was more changed in the lesion skin of K14-WFDC12 transgenic psoriasis-like mice. Collectively, the results implied that WFDC12 might affect the activation of the retinoic acid signaling pathway and regulate the infiltration of DC cells in the skin lesions and lymph nodes, thereby inducing Th1 cells differentiation and increasing the secretion of IFN-γ to exacerbate psoriasis in mice.

Topics: Animals; Disease Models, Animal; Interleukin-12; Mice; Mice, Transgenic; Milk Proteins; Psoriasis; RNA, Messenger; Tretinoin

Psoriasis is a chronic skin disease characterized by thickening and disorganization of the skin's protective barrier. Although current models replicate some aspects of the disease, development of therapeutic strategies have been hindered by absence of more relevant models. This study aimed to develop and characterize an

Topics: Cell Differentiation; Cell Line; Cell Proliferation; Cytokines; Fibroblasts; Humans; Keratolytic Agents; Psoriasis; Tretinoin

This study was to develop a combination of zedoary turmeric oil (ZTO) and tretinoin (TRE)-loaded liposomal gel as a topical drug delivery system. We used a combination of single-factor experiment and orthogonal experiment to systematically optimize encapsulation process of the compound liposomes. The optimized liposome vesicles were incorporated into Carbopol gel matrix and studied by continuous

Topics: Animals; Curcuma; Gels; Liposomes; Mice; Particle Size; Psoriasis; Tretinoin

Psoriasis is a chronic immune-mediated inflammatory skin disease without effective treatment. The utilization of all trans-retinoic acid (TRA) and betamethasone (BT) for the treatment of psoriasis is still facing difficulties, due to their relatively poor stability, limited skin permeation, and systemic side effects. Flexible liposomes are excellent in deeper skin permeation and reducing the side effects of drugs, which is promising for effective treatment of skin disorders. This work aimed to establish dual-loaded flexible liposomal gel for enhanced therapeutic efficiency of psoriasis based on TRA and BT.. Flexible liposomes co-loaded with TRA and BT were successfully prepared in our study. The characterization examination revealed that flexible liposomes featured nano-sized particles (around 70 nm), high drug encapsulation efficiency (> 98%) and sustained drug release behaviors. Flexible liposomes remarkably increased the drug skin permeation and retention as compared with free drugs. Results on HaCaT cells suggested that flexible liposomes were nontoxic, and its cellular uptake has a time-dependent manner. In vivo studies suggested the topical application of TRA and BT dual-loaded liposomal gel had the best ability to reduce the thickness of epidermal and the level of cytokines (TNF-α and IL-6), largely alleviating the symptoms of psoriasis.. Flexible liposomal gel dual-loaded with TRA and BT exerted a synergistic effect, which is a promising topical therapeutic for the treatment of psoriasis.

Topics: Animals; Betamethasone; Cell Survival; Cytokines; Dermatologic Agents; Disease Models, Animal; Gels; HaCaT Cells; Humans; Liposomes; Mice, Inbred BALB C; Particle Size; Pliability; Psoriasis; Rats; Rats, Sprague-Dawley; Tretinoin

Psoriasis vulgaris is a common skin inflammatory disease characterized by recurrent flare episodes associated with scaly well-demarcated skin plaques. Skin biopsies from psoriatic patients with high PASI score (22.67 ± 8.67) and from HD were used to study APN/CD13. APN/CD13 is over-expressed in LP and nLP compare to HD skins and fibroblasts. This over-expression is positively correlated with specific enzymatic activity enhancement. However, discrepancies between APN/CD13 expression in LP and nLP prompt us to focus our study on APN/CD13 modulation. Calcitonin Gene Related Peptide (CGRP), a neuropeptide, positively modulated expression and activity of APN/CD13. CGRP consistently induced IL4 secretion, which is also involved in the increase of APN/CD13 expression and activity, which is significantly reversed using IL-4 blocking antibody. Surprisingly, retinoic acid altered the APN/CD13 enzymatic activity only in nLP fibroblasts without modification of APN/CD13 expression. APN/CD13 is over-expressed on psoriatic fibroblasts and exerted high level of activity compare to HD fibroblasts. Taken together, several factors such as CGRP and IL-4 acted on positive regulation of APN/CD13 expression and activity. This study highlighted the interest of APN/CD13 as a new potential target, which should be investigated in psoriasis.

Topics: Adult; Aged; Calcitonin Gene-Related Peptide; Case-Control Studies; CD13 Antigens; Cells, Cultured; Female; Fibroblasts; Humans; Interleukin-4; Male; Middle Aged; Psoriasis; Skin; Time Factors; Tretinoin; Up-Regulation

Topics: Alitretinoin; Exanthema; Humans; Psoriasis; Skin Diseases, Vesiculobullous; Tretinoin

Chronic itch with secondary scratch lesions such as prurigo has a major impact on quality of life. Due to its relapsing nature and often unknown origin, its treatment is challenging.. We sought to demonstrate that alitretinoin can be an efficacious and well-tolerated treatment in a patient suffering from chronic itch with concomitant prurigo and psoriatic lesions.. Case report.. After 1 month of alitretinoin treatment (30 mg daily), itch as well as prurigo and psoriasis lesions decreased markedly. Three cycles of alitretinoin were administered, as each cessation of treatment led to relapse of the symptoms after 6-8 weeks. Tapering of the alitretinoin dose (30 mg every second day) after the third cycle allowed to maintain the effects for over 18 months.. Treatment of refractory prurigo with alitretinoin might be an efficacious alternative to standard therapies. In case of relapse, retreatment with alitretinoin reinduces a further long-lasting response.

Topics: Alitretinoin; Antineoplastic Agents; Female; Humans; Middle Aged; Prurigo; Pruritus; Psoriasis; Retreatment; Tretinoin

Psoriasis is a chronic inflammatory skin disease and topical therapy remains a key role for treatment. The aim of this study is to evaluate the influence of psoriasis-like lesions on the cutaneous permeation of anti-psoriatic drugs.. We first set up imiquimod-induced dermatitis in mice that closely resembles human psoriasis lesions. The development of the lesions is based on the IL-23/IL17A axis for phenotypical and histological characteristics. Four drugs, 5-aminolevulinic acid (ALA), tacrolimus, calcipotriol, and retinoic acid, were used to evaluate percutaneous absorption.. The most hydrophilic molecule, ALA, revealed the greatest enhancement on skin absorption after imiquimod treatment. Imiquimod increased the skin deposition and flux of ALA by 5.6 to 14.4-fold, respectively, compared to normal skin. The follicular accumulation of ALA was also increased 3.8-fold. The extremely lipophilic drug retinoic acid showed a 1.7- and 3.8-fold increase in skin deposition and flux, respectively. Tacrolimus flux was enhanced from 2 to 21 μg/cm2/h by imiquimod intervention. However, imiquimod did not promote skin deposition of this macrolide. The lipophilicity, but not the molecular size, dominated drug permeation enhancement by psoriatic lesions. The in vivo percutaneous absorption of ALA and rhodamine B examined by confocal microscopy confirmed the deficient resistance of epidermal barrier for facilitating cutaneous delivery of drugs via psoriasis-like skin.. We established the topical delivery profiles of anti-psoriatic drugs via imiquimod-treated psoriasis-like skin.

Topics: Aminolevulinic Acid; Aminoquinolines; Animals; Cytokines; Disease Models, Animal; Female; Imiquimod; Mice; Psoriasis; Skin; Skin Absorption; Tacrolimus; Tretinoin

To analyze the clinical characteristics and combined use of chemical and traditional Chinese medicine (TCM) medicine of hospitalized patients with psoriasis base on real world database, 2 991 cases of hospitalized patients with psoriasis in hospital information system (HIS) database from 16 hospitals in China were analyzed for general hospitalization information, combined diseases and combined use of drugs et al. The results showed that half of inpatients aged 18-45 years old. The most common syndrome of TCM was intrinsic blood heat. More than 1/3 inpatients' hospitalization time was 18-25 days, and the average expense of hospitalization was 6 989. 20 RMB. The top five combined diseases were hypertension, non-alcoholic fatty liver disease, diabetes, upper respiratory tract infection and lipoprotein disorders. Medicine information analysis showed 599 chemical medicines and 341 TCMs were used and combined use of drugs was common in clinical practice. Licorice extract medicine was the most common combined TCM with western medicine; in the next two places were compound Qingdai capsule and tripterygium glycosides. The most common combined use of chemical medicines were Vitamin C, calcium gluconate, ketotifen, cetirizine, retinoic acid and external use glucocorticoid. Anti-inflammatory and liver protection, clearing heat and toxic materials, activating blood and dissolving stasis were the most common combined TCM medicine with western medicine, while the most common combined chemical medicine with TCM were anti-allergic, anti-infection, glucocorticoid and retinoic acid. In conclusion, half of hospitalized patients of psoriasis were young adults. The main type of combined diseases was metabolic disorders and upper respiratory infections. Combined use of chemical medicine and TCM was common in clinical practice. Licorice extract medicine was the most common combined TCM with western medicine.

Topics: Adolescent; Adult; Aged; Ascorbic Acid; Calcium Gluconate; Cetirizine; China; Drugs, Chinese Herbal; Female; Glucocorticoids; Humans; Ketotifen; Male; Medicine, Chinese Traditional; Middle Aged; Psoriasis; Tretinoin; Young Adult

Interleukin (IL)-1 family comprise 11 members that play an important role in immune regulation and inflammatory process. Retinoids exert complex effects on the immune system, having anti-inflammatory effects in chronic dermatological diseases. Vitamin D (vitD) and analogs have been shown to suppress TNF-α-induced IL-1α in human keratinocytes (KCs). In the present study, we investigated IL-1 family members in psoriasis and the effects of vitD and retinoic acid (RA) on these members. We analyzed IL-1 family members gene expression in psoriatic skin and in ex vivo skin organ culture exposed to TNF-α, IL-17 or broadband UVB; afterwards, treatment with vitD or RA was performed and IL-1 family members mRNA was evaluated. Similarly, KCs were stimulated with IL-17 and subsequently treated with vitD. IL-1 family members were enhanced in psoriatic skin and in ex vivo skin organ cultures after pro-inflammatory stimuli (TNF-α, IL-17 and UVB). RA and vitD were able to suppress this enhancement.

Topics: Bone Density Conservation Agents; Cells, Cultured; Gene Expression; Humans; Inflammation; Interleukin-1; Interleukin-17; Keratinocytes; Keratolytic Agents; Organ Culture Techniques; Psoriasis; RNA, Messenger; Skin; Tretinoin; Tumor Necrosis Factor-alpha; Ultraviolet Rays; Vitamin D

Tretinoin (TRE) is a widely used retinoid for the topical treatment of acne, psoriasis, skin cancer and photoaging. Despite unmatchable efficacy, it is associated with several vexatious side effects like marked skin erythema, peeling and irritation, eventually leading to poor patient compliance. Its photo-instability and high lipophilicity also pose challenges in the development of a suitable topical product. The present study, therefore, aims to develop biocompatible lipid-based nanocarriers of TRE to improve its skin delivery, photostability, biocompatibility and pharmacodynamic efficacy. The TRE-loaded liposomes, ethosomes, solid lipid nanoparticles (SLNs) and nanostructured lipidic carriers (NLCs) were prepared and characterized for micromeritics, surface charge, percent drug efficiency and morphology. Bioadhesive hydrogels of the developed systems were also evaluated for rheological characterization, photostability, ex vivo skin permeation and retention employing porcine skin, and anti-psoriatic activity in mouse tail model. Nanoparticulate carriers (SLNs, NLCs) offered enhanced photostability, skin transport and anti-psoriatic activity vis-à-vis the vesicular carriers (liposomes, ethosomes) and the marketed product. However, all the developed nanocarriers were found to be more biocompatible and effective than the marketed product. These encouraging findings can guide in proper selection of topical carriers among diversity of such available carriers systems.

Topics: Animals; Dermatologic Agents; Drug Carriers; Drug Stability; Ethanol; Female; In Vitro Techniques; Lipids; Mice; Nanostructures; Psoriasis; Skin Absorption; Sunlight; Tretinoin

Topics: Adult; Female; Gingiva; Humans; Mouthwashes; Mucositis; Palate, Hard; Psoriasis; Tretinoin

Topics: Acitretin; Adolescent; Alitretinoin; Antibodies, Monoclonal; Dermatologic Agents; Drug Therapy, Combination; Humans; Infliximab; Male; Psoriasis; Severity of Illness Index; Treatment Outcome; Tretinoin; Tumor Necrosis Factor-alpha

Palmoplantar pustular psoriasis is often recalcitrant to therapy. Here we evaluated the therapeutic effect of alitretinoin in patients with recalcitrant palmoplantar pustular psoriasis and investigated subsequent immunopathological alterations.. Seven patients with palmoplantar pustular psoriasis were treated with oral alitretinoin 30 mg once daily for 12 weeks. Efficacy was assessed by palmoplantar pustular psoriasis area and severity index (PPPASI), visual analogue scales (VAS) on intensity of pain and pruritus and an overall patient assessment. Immunohistochemical staining for neutrophil elastase, CD3, CD4, CD8, CD1a CD11c, CD303,CD68, CD69, CD208 and HLA-DR was on lesional skin biopsies obtained before and after 12 weeks of treatment.. PPPASI and VAS for pruritus and pain decreased significantly after 12 weeks of treatment with alitretinoin. The overall patient assessment ranged from 60% to 90% clinical improvement. In correlation with clinical improvement a significant reduction, particularly of neutrophils, macrophages and dendritic cells, was also observed in the skin sections. Alitretinoin was well tolerated except for headache during the first month of treatment in two patients. Limitations of the study are a missing control group and the concomitant usage of topical therapy.. Our findings suggest that alitretinoin may represent a new and promising therapy for recalcitrant palmo-plantar psoriasis and warrants further controlled studies to confirm efficacy and safety of alitretinoin in this disease.

Topics: Adult; Aged; Alitretinoin; Antineoplastic Agents; Female; Humans; Inflammation; Male; Middle Aged; Psoriasis; Treatment Outcome; Tretinoin; Young Adult

Psoriasis is a skin disease characterized by the presence of red plaques on the skin. This pathology is well-known to be a retinoid-sensitive disease. Previous investigations have shown that retinoids can modulate epidermal proliferation with an antiproliferative potential in hyperproliferative skins. The aim of this study was to compare the development of psoriatic substitutes cultured in a retinoic acid supplemented medium with those cultured in medium receiving no supplement, to define the effects of this growth factor on keratinocyte proliferation and differentiation. The self-assembly method was used to create substitutes. Characterization of the psoriatic substitutes was performed by histological and immunolabeling analyses. Results showed that psoriatic keratinocyte substitutes cultured with retinoic acid have a thinner epidermis compared with psoriatic keratinocyte substitutes cultured without this supplement. Further, the expression of all tested cell differentiation markers was restored in psoriatic keratinocyte substitutes cultured in presence of retinoic acid. No significant change in epidermal thickness or in the expression of late differentiation markers was observed in healthy keratinocyte substitutes cultured with or without retinoic acid; however, some changes were reported for proliferation and early differentiation markers. Results suggest that retinoic acid can modulate epidermal differentiation and proliferation with an antiproliferative potential in psoriatic substitutes such as observed in psoriatic skin in vivo.

Topics: Adult; Aged; Biomarkers; Cell Differentiation; Cell Proliferation; Epidermis; Female; Humans; Keratinocytes; Male; Middle Aged; Models, Biological; Psoriasis; Skin; Transcription Factors; Tretinoin; Tumor Suppressor Proteins

Psoriasis lesions accumulate protoporphyrin IX (PpIX) with a variable distribution within plaques due to variations in hyperkeratosis causing differences in penetration of cream or light.. To study the effects of different keratolytic pretreatments in PpIX-induced fluorescence diagnosis (FDAP) and during photodynamic therapy (PDT).. Two psoriasis plaques of 10 patients were treated with either topical retinoic acid or with a hydrocolloid dressing. The hydrocolloid dressing gave the best results. Subsequently, two different contralateral plaques of eight patients were pretreated with a hydrocolloid dressing or the standard pretreatment, salicylic acid in petrolatum, during the 6 weeks of PDT. Biopsies were investigated with respect to stratum corneum thickness, proliferation, differentiation and inflammation.. Irritation and point bleedings were noticed after retinoic acid. A hydrocolloid dressing induced the best clinical improvement. Therefore, it was used as alternative pretreatment for psoriasis prior to PDT. We observed significant clinical and immunohistochemical improvement of psoriasis in the salicylic acid as well as the hydrocolloid dressing pretreated plaques.. Salicylic acid in petrolatum and a hydrocolloid dressing prior to FDAP and PDT induce improvement of hyperkeratosis. Thus, a hydrocolloid dressing is a good alternative to the current keratolytic pretreatment regime.

Topics: Administration, Topical; Aged; Aminolevulinic Acid; Analysis of Variance; Bandages, Hydrocolloid; Biopsy, Needle; Female; Fluorescence; Humans; Immunohistochemistry; Keratolytic Agents; Male; Middle Aged; Photochemotherapy; Pilot Projects; Probability; Protoporphyrins; Psoriasis; Skin Absorption; Treatment Outcome; Tretinoin

Psoriasis is a type I interferon-driven T cell-mediated disease characterized by the recruitment of plasmacytoid dendritic cells (pDC) into the skin. The molecules involved in pDC accumulation in psoriasis lesions are unknown. Chemerin is the only inflammatory chemotactic factor that is directly active on human blood pDC in vitro. The aim of this study was to evaluate the role of the chemerin/ChemR23 axis in the recruitment of pDC in psoriasis skin. Prepsoriatic skin adjacent to active lesions and early lesions were characterized by a strong expression of chemerin in the dermis and by the presence of CD15(+) neutrophils and CD123(+)/BDCA-2(+)/ChemR23(+) pDC. Conversely, skin from chronic plaques showed low chemerin expression, segregation of neutrophils to epidermal microabscesses, and few pDC in the dermis. Chemerin expression was localized mainly in fibroblasts, mast cells, and endothelial cells. Fibroblasts cultured from skin of psoriatic lesions expressed higher levels of chemerin messenger RNA and protein than fibroblasts from uninvolved psoriatic skin or healthy donors and promoted pDC migration in vitro in a chemerin-dependent manner. Therefore, chemerin expression specifically marks the early phases of evolving skin psoriatic lesions and is temporally strictly associated with pDC. These results support a role for the chemerin/ChemR23 axis in the early phases of psoriasis development.

Topics: Adult; Antibodies, Monoclonal; Antigens, CD; Blotting, Western; Calcitriol; CD8-Positive T-Lymphocytes; Cells, Cultured; Chemokine CXCL10; Chemokines; Chemotaxis, Leukocyte; Culture Media, Conditioned; Dendritic Cells; Dermatitis, Atopic; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression; Humans; Intercellular Adhesion Molecule-1; Intercellular Signaling Peptides and Proteins; Lectins, C-Type; Membrane Glycoproteins; Neutrophils; Psoriasis; Receptors, Chemokine; Receptors, Immunologic; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tretinoin

Retinoids (RA) have been used as therapeutic agents for numerous skin diseases, from psoriasis to acne and wrinkles. While RA is known to inhibit keratinocyte differentiation, the molecular effects of RA in epidermis have not been comprehensively defined. To identify the transcriptional targets of RA in primary human epidermal keratinocytes, we compared the transcriptional profiles of cells grown in the presence or absence of all-trans retinoic acid for 1, 4, 24, 48, and 72 h, using large DNA microarrays. As expected, RA suppresses the protein markers of cornification; however the genes responsible for biosynthesis of epidermal lipids, long-chain fatty acids, cholesterol, and sphingolipids, are also suppressed. Importantly, the pathways of RA synthesis, esterification and metabolism are activated by RA; therefore, RA regulates its own bioavailability. Unexpectedly, RA regulates many genes associated with the cell cycle and programmed cell death. This led us to reveal novel effects of RA on keratinocyte proliferation and apoptosis. The response to RA is very fast: 315 genes were regulated already after 1 h. More than one-third of RA-regulated genes function in signal transduction and regulation of transcription. Using in silico analysis, we identified a set of over-represented transcription factor binding sites in the RA-regulated genes. Many psoriasis-related genes are regulated by RA, some induced, others suppressed. These results comprehensively document the transcriptional changes caused by RA in keratinocytes, add new insights into the molecular mechanism influenced by RA in the epidermis and demonstrate the hypothesis-generating power of DNA microarray analysis.

Topics: Cell Differentiation; Cells, Cultured; Epidermal Cells; Gene Expression Profiling; Gene Expression Regulation; Humans; Keratinocytes; Keratins; Keratolytic Agents; Lipid Metabolism; Multigene Family; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Psoriasis; Receptors, Retinoic Acid; Transcription, Genetic; Tretinoin

Oral acitretin is currently indicated for the treatment of severe psoriasis in adults, but its use is limited by systemic side effects and teratogenicity. Topical administration of acitretin may lessen the risk of systemic toxicity while increasing local bioavailability in the skin. The effects of topical acitretin on reconstructed human epidermis (RHE) and Rhino mice were investigated and compared to those of currently marketed topical retinoids: tretinoin and tazarotene. In acitretin-treated RHE cultures, there was a reduction in keratohyalin granules and filaggrin expression in the stratum granulosum, a loss of keratin 10 expression in the stratum spinosum, and an increase in keratin 19 expression in all viable cell layers. All retinoids showed similar signs of activity in RHE cultures. Furthermore, the release of pro-inflammatory cytokines IL-1alpha and IL-8 in RHE cultures was less pronounced with acitretin compared to tretinoin- and tazarotene-containing formulations, suggesting that acitretin may be less irritating. In Rhino mice, acitretin induced a local, dose-dependent reduction in utricle diameter after seven daily dermal doses. A similar effect was observed in tretinoin- and tazarotene-treated mice. Our data suggest that topical application of acitretin may have a therapeutic benefit in the local management of keratinization disorders.

Topics: Acitretin; Administration, Topical; Animals; Disease Models, Animal; Epidermis; Female; Filaggrin Proteins; Humans; Interleukin-1alpha; Interleukin-8; Keratin-10; Keratin-19; Keratolytic Agents; Male; Mice; Mice, Hairless; Nicotinic Acids; Psoriasis; Tretinoin

Vascular endothelial growth factor (VEGF) promotes angiogenesis, and elevated levels are found in plaques of psoriasis. Two VEGF polymorphisms, +405 and -460, are associated with early-onset psoriasis and are close to the functional activator protein-1 site (+419) through which retinoids, an established systemic therapy for psoriasis, can block production of VEGF. We report that peripheral blood mononuclear cells (PBMCs) and epidermal keratinocytes (KC) from patients with psoriasis demonstrate differential, genotype-dependent, regulation of VEGF. For PBMCs, VEGF genotype distinguishes two groups of patients with psoriasis - "high and low VEGF producers" (P < 0.001). In contrast, KC production of VEGF is not genotype dependent. However, the effects of all-trans retinoic acid (RA) on cellular expression of VEGF are determined by both cell type and genotype. RA inhibits KC production of VEGF in a genotype-dependent manner (P < 0.005) whereas RA stimulates PBMCs production irrespective of VEGF genotype (P < 0.001). We also report that the -460 VEGF polymorphism appears to have a clinical pharmacogenetic role in predicting response or non-response of psoriasis to acitretin (P = 0.01). In future, determination of VEGF gene polymorphisms and thus individual patient VEGF "signatures" may be used as a prognostic factor for psoriasis susceptibility/severity and as a means for optimizing treatment response.

Topics: Acitretin; Cells, Cultured; Female; Gene Expression Regulation; Genotype; Humans; Keratinocytes; Leukocytes, Mononuclear; Male; Polymorphism, Genetic; Psoriasis; Retinoids; Tretinoin; Vascular Endothelial Growth Factor A

Caspase-14 is a nonapoptotic caspase family member whose expression in the epidermis is confined to the suprabasal layers, which consist of differentiating keratinocytes. Proteolytic activation of this caspase is observed in the later stages of epidermal differentiation. In psoriatic skin, a dramatic decrease in caspase-14 expression in the parakeratotic plugs was observed. Topical treatment of psoriatic lesions with a vitamin D3 analogue resulted in a decrease of the psoriatic phenotype and an increase in caspase-14 expression in the parakeratotic plugs. To investigate whether vitamin D3 directly affects caspase-14 expression levels, we used keratinocyte cell cultures. 1alpha,25-Dihydroxycholecalciferol, the biologically active form of vitamin D3, increased caspase-14 expression, whereas retinoic acid inhibited it. Moreover, retinoic acid repressed the vitamin D3-induced caspase-14 expression level. In addition, the use of organotypic skin cultures demonstrated that 1alpha,25-dihydroxycholecalciferol enhanced epidermal differentiation and caspase-14 activation, whereas retinoic acid completely blocked caspase-14 processing. Our data indicate that caspase-14 plays an important role in terminal epidermal differentiation, and its absence may contribute to the psoriatic phenotype.

Topics: Adolescent; Adult; Aged; Apoptosis; Caspase 14; Caspase Inhibitors; Caspases; Cell Differentiation; Cholecalciferol; Enzyme Activation; Epidermis; Female; Humans; Keratinocytes; Male; Middle Aged; Organ Culture Techniques; Phenotype; Psoriasis; Thymidine; Tretinoin

Therapeutic retinoids have profound effects on psoriatic skin pathology but their interactions with various retinoid-binding proteins in lesional vs non-lesional skin have not been investigated. Using quantitative real-time PCR the mRNA expression of cellular retinol-binding protein I (CRBPI) and retinoic acid-binding protein I/II (CRABPI/CRABPII) was studied in psoriatic and healthy control (=normal) skin after 4 days of occlusive RA/vehicle treatment (n=6). Untreated psoriatic lesions showed a markedly elevated CRABPII/CRABPI ratio, while the CRBPI level was reduced in lesional and non-lesional skin as compared to normal skin. In RA-treated normal and non-lesional skin, the mRNA expression of CRBPI was unaltered while that of CRABPI and CRABPII was reduced by approximately 80% and increased approximately 5-fold, respectively, as compared to vehicle-treated skin. In contrast, lesional skin exposed to RA showed an almost 90% increase in CRBPI transcripts but unaltered expression of CRABPI and CRABPII, yet, the mRNA expression of several inflammatory mediators, e.g. inducible nitric oxide synthase, interferon-gamma and interleukin-1beta, was clearly reduced. Immunohistochemistry localized CRABPII to suprabasal keratinocytes in normal skin and revealed markedly elevated levels in lesional skin. RA treatment induced CRABPII protein expression in normal and non-lesional skin, to similar levels as in untreated lesions. The results indicate that the effects of RA differ in normal/non-lesional psoriatic skin and lesional skin. Whether the high expression of CRABPII in psoriatic skin lesions is due to increased amounts of endogenous retinoids in lesional skin or reflects an abnormal regulation of the CRABPII gene in psoriasis remains to be studied.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Antibodies; Cells, Cultured; Female; Humans; Keratinocytes; Male; Middle Aged; Psoriasis; Receptors, Retinoic Acid; Reference Values; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Skin; Tretinoin

Retinoids are a fascinating class of compounds that exert control over cellular function from the time of conception to death. They play a critical role in such vital processes as fetal morphogenesis, cellular differentiation and apoptosis. Over the years synthetic retinoids have provided dermatologists with a spectrum of medications that have profound therapeutic effects on a variety of recalcitrant skin disorders. Moreover, retinoids are an expanding component of the treatment arsenal against hematologic and solid malignancies. Retinoids are poised to offer exciting new therapeutic options in the field of endocrinology for the treatment of diabetes and lipid disorders. Researchers and clinicians are only beginning to unveil the therapeutic potential of this class of medications. The development of new retinoid compounds targeting specific receptors promises a wealth of new therapies for the new millennium.

Topics: Acne Vulgaris; Humans; Keratosis; Leukemia, Promyelocytic, Acute; Lymphoma, T-Cell, Cutaneous; Psoriasis; Skin Neoplasms; Treatment Outcome; Tretinoin; Vitamin A

Telomerase activity is usually detected in most tumor tissues but not in normal tissues. Recently, there is increasing evidence that telomerase activity is associated with cell proliferation without malignancy, whereas there is little information about telomerase activity and its relationship with cell proliferation in chronic hyperproliferative skin diseases. Thus, we studied telomerase activity in skins from 10 patients with psoriasis and compared telomerase activity with the expression of Ki-67, a proliferation marker, using immunohistochemical staining. The effect of retinoic acid on the telomerase activity in HaCaT cells was also evaluated. Telomerase activity was detected in 7 (70%) of 10 lesional skins of psoriasis and none of the nonlesional skin. Telomerase activity in lesional skin was significantly associated with Ki-67 labelling index. Retinoic acid treatment on HaCaT cells inhibited telomerase activity, which correlated with inhibition of cell proliferation by the agent. The results of our study represent another example that shows telomerase activity correlates with cellular proliferation. Further studies on the regulation of the telomerase are needed to understand the cellular factors involved in controlling telomerase activity.

Topics: Cell Division; Cell Line; Enzyme Inhibitors; Humans; Ki-67 Antigen; Psoriasis; Skin; Telomerase; Tretinoin

To describe the clinical characteristics and treatments of children with psoriasis.. Retrospective, descriptive.. The medical records were studied of all 38 children with psoriasis who visited the outpatient clinic for Dermatology of the University Hospital/Wilhelmina Children's Hospital Utrecht, the Netherlands, for the first time between 1 January 1995 and 31 December 1997.. The 38 children accounted for 3.6% of all children in whom a diagnosis was made. There were 19 boys and 19 girls. 79% had psoriasis vulgaris and 11% psoriasis guttata. Average age of onset was 6.8 years for girls and 9.3 years for boys. Family history was positive in 42%. The limbs were affected most. Nail changes were seen in 11%. Provoking factors were stress, infections, summertime and injuries of the skin. In almost all patients in the outpatient department local mono- and/or combination therapy of corticosteroids in cream or ointment with salicylic acid and tar was given.

Topics: Adolescent; Adrenal Cortex Hormones; Anthralin; Anti-Inflammatory Agents; Aspirin; Calcitriol; Child; Cyclosporine; Dermatologic Agents; Female; Genetic Predisposition to Disease; Humans; Male; Phototherapy; Psoriasis; Retrospective Studies; Tars; Treatment Outcome; Tretinoin

Fibroblast cultures were established from the skin of normal and psoriatic subjects. The response to 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] of each kind of cells was assessed by measuring tritiated thymidine incorporation into DNA as an index of cell proliferation. We found that both types of cells responded with a similar dose- and time-dependent inhibition of thymidine incorporation. We also studied the response of the mRNA encoding the proto-oncogene c-myc, since its level is associated to the proliferative state in many cell types. Psoriatic fibroblasts contained higher basal amounts of c-myc RNA than control fibroblasts. Addition of 1,25-(OH)2D3 to the culture medium induced a time-dependent increase of c-myc RNA in psoriatic fibroblasts but not in controls. As a control, retinoic acid had no effect in any of the two cell types. It is concluded that in primary normal human fibroblasts, c-myc RNA levels are not correlated with the proliferative state, and that there is an altered expression of this proto-oncogene in psoriasis.

Topics: Adult; Blotting, Northern; Calcitriol; Cell Division; Culture Media; DNA; DNA Probes; Fibroblasts; Gene Expression; Genes, myc; Humans; Male; Proto-Oncogene Mas; Psoriasis; RNA, Messenger; Tretinoin; Triiodothyronine

Previously, we have reported a defect in the cAMP-dependent protein kinases (cAMP-PK) in psoriatic cells (i.e., a decrease in 8-azido-[32P]cAMP binding to the regulatory subunits and a decrease in phosphotransferase activity) which is rapidly reversed with retinoic acid (RA) treatment of these cells. This led us to examine a possible direct interaction between retinoids and the RI and RII regulatory subunits through retinoylation. Retinoylation of RI and RII present in normal and psoriatic human fibroblasts was analysed by [3H]RA treatment of these cells, followed either by chromatographic separation of the regulatory subunits or by their specific immunoprecipitation. These studies indicated that RI and RII can be retinoylated. [3H]RA labeling of the RII subunit was significantly (P < 0.005) greater in psoriatic fibroblasts (nine subjects; mean 7.47 relative units +/- 1.37 SEM) compared to normal fibroblasts (eight subjects; mean 2.46 relative +/- 0.49 SEM). [3H]RA labeling of and the increase in 8-azido-[32P]-binding to the RI and RII subunit in psoriatic fibroblasts showed a similar time course. This suggests that the rapid effect of retinoic acid treatment to enhance 8-azido-[32P]-cAMP binding to the RI and RII in psoriatic fibroblasts may be due, in part, to covalent modification of the regulatory subunits by retinoylation.

Topics: Affinity Labels; Autoradiography; Azides; Blotting, Western; Cell Fractionation; Chromatography; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Fibroblasts; Humans; Phosphorus Radioisotopes; Protein Binding; Psoriasis; Skin; Time Factors; Tretinoin; Tritium

Psoriasis is characterized by hyperproliferation and impared differentiation of epidermal keratinocytes (KCs). Psoriasis can be treated with derivatives of retinoic acid (RA) and vitamin D3. Analogues of vitamin D3 are able to inhibit proliferation and stimulate differentiation of KCs. In contrast, RA inhibits terminal differentiation of KCs. Interactions are known to occur between RA and vitamin D3 signalling pathways. The purpose of the present study was to determine the effect of all-trans RA on the binding of 1,25-dihydroxy-vitamin D3 (1,25 (OH)2D3) to the vitamin D3 receptor (VDR) of cultured human KCs. Cultured KCs from normal adults were incubated with or without RA (10-9-10-7M) for 4-24 h. Cells were then harvested, homogenized and ultrasonicated. The extracted protein was incubated with 3H-1,25 (OH)2D3 (0.015-1.0 nM) with or without 250-fold excess nonradioactive 1,25 (OH)2D3 for 24 h and specific binding was determined by use of the dextran coated charcoal binding assay. Western blot analysis utilizing the monoclonal antibody 9A7 gamma to VDR was performed on protein extracted from the KCs. The bands resulting from Western blot analysis were visualized by enhanced chemiluminescence. From Scatchard analysis it was found that KCs bind 1,25 (OH)2D3 with high affinity (Kd = 0.175 nM). This binding was dose and time dependently inhibited by RA (60% inhibition at 10-7 M after 24 h of incubation). By Western blot analysis, RA had no effect on the amount of protein extracted from KCs at any of the RA concentrations tested. In conclusion, these results show that binding of vitamin D3 to its receptor of human KCs can be inhibited markedly by RA without effecting the amount of protein. These results are in contrast to results with other cell types in which RA upregulates binding of 1,25 (OH)2D3 to the VDR. Because interaction between retinoids and vitamin D3 may occur at different levels during signal transduction, it is not possible to predict from our results whether RA will inhibit the effects of vitamin D3 in vivo.

Topics: Calcitriol; Cells, Cultured; Dose-Response Relationship, Drug; Epidermal Growth Factor; Humans; Keratinocytes; Kinetics; Pituitary Hormones; Protein Binding; Psoriasis; Receptors, Calcitriol; Tretinoin

The environmental contaminant dioxin exerts most of its effects by activating the aryl hydrocarbon receptor (AhR). The AhR is considered to play not only a role in the regulation of xenobiotic metabolism, but also for development, growth, and differentiation. The transcript levels of the AhR and its associated translocator protein (ARNT) were found to increase with ongoing differentiation in the human keratinocyte cell line HaCaT. Correspondingly, in situ hybridization studies in normal human skin revealed an absence of AhR-expression in proliferating basal cells and increasing transcript levels in upper cell layers, in dependence of keratinocyte differentiation. AhR expression in differentiation-deficient hyperproliferative psoriatic skin was markedly decreased. When keratinocytes were continuously treated with 1 microM retinoic acid (RA), the upregulation of AhR- and ARNT-mRNA levels was inhibited as was keratin 4-expression, a marker of HaCaT-keratinocyte differentiation. In contrast, treatment of already differentiated cells with RA did not down-regulate these transcript levels. The mRNA levels of the prevalent retinoic acid receptors in keratinocytes, RAR gamma and RXR alpha, were not influenced by the process of differentiation or by addition of RA. Our data suggest that the regulation of AhR-, ARNT- and keratin 4-expression by RA is indirect and mediated by a yet to be identified factor.

Topics: Aryl Hydrocarbon Receptor Nuclear Translocator; Cell Differentiation; Cell Division; Cells, Cultured; DNA-Binding Proteins; Gene Expression Regulation, Developmental; Humans; Keratinocytes; Keratins; Polychlorinated Dibenzodioxins; Psoriasis; Receptors, Aryl Hydrocarbon; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Retinoid X Receptors; RNA, Messenger; Time Factors; Transcription Factors; Tretinoin

Leukotriene A4 hydrolase is a key enzyme in the biosynthesis of leukotriene B4, a potent pro-inflammatory compound. The purpose of this study was to determine the capacity of antiinflammatory and anti-proliferative compounds to regulate the levels and activity of leukotriene A4 hydrolase in cultured human keratinocytes. The content of leukotriene A4 hydrolase was determined by Western blot analysis, and the activity of leukotriene A4 hydrolase was expressed as the leukotriene B4 formation after incubation of keratinocyte cultures with leukotriene A4. Leukotriene B4 was measured by revered-phase high performance liquid chromatography. Preincubation for 10 min of the cultured keratinocytes with the leukotriene A4 hydrolase inhibitor RP 64699 (0.1-10 microM) caused a significant dose-dependent inhibition of leukotriene B4 formation (IC50 = 0.7 microM). Cyclosporin A (0.1 micrograms/ml and 1.0 micrograms/ml) had no direct effect on leukotriene A4 hydrolase activity, but after incubation for 72 h there was a decrease in the mean leukotriene B4 formation per culture dish (35% and 48%, respectively). The decreased leukotriene B4 formation was caused mainly by a decrease in the mean leukotriene A4 hydrolase content per mg protein (30.1% at 0.1 micrograms/ml cyclosporin A and 40.0% at 1.0 micrograms/ml cyclosporin A), although keratinocyte proliferation was also slightly decreased. Incubations with 1.25-dihydroxyvitamin D3 (10(-7)-10(-10) M), all-trans retinoic acid (10(-6)-10(-10) M), eicosartienoic acid (10(-6)-10(-8) M), dexamethasone (10(-5)-10(-7) M), interferon-gamma (10 and 100 units/ml) or methotrexate (0.1-10 micrograms/ml) had no effect on either the leukotriene B4 formation or the amount of leukotriene A4 hydrolase in keratinocyte cultures. These results show that cyclosporin A, in contrast to other anti-inflammatory and anti-proliferative compounds, inhibits the level of leukotriene A4 hydrolase in keratinocyte cultures. Since similar cyclosporin A concentrations are obtained during treatment of psoriasis with cyclosporin A, the effect on leukotriene A4 hydrolase may play a role in the anti-inflammatory action of cyclosporin A.

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Antineoplastic Agents; Calcitriol; Cells, Cultured; Cyclosporine; Dexamethasone; Down-Regulation; Epoxide Hydrolases; Humans; Interferon-gamma; Keratinocytes; Leukotriene B4; Methotrexate; Psoriasis; Thiophenes; Tretinoin

Previously, we have reported a decrease in the binding of a cAMP analog to the regulatory subunits of cAMP-dependent protein kinase (cAMP-PK), as well as a decrease in cAMP-PK activities, in psoriatic cells. Retinoic acid (RA) treatment of these cells can induce an increase in cAMP-PK toward normal levels. To better define the effect of retinoic acid on the cAMP-PK system in psoriatic fibroblasts, Western blot analysis using an RII alpha specific antibody and in vivo phosphorylation experiments were carried out to determine possible changes in the RII regulatory subunit. Our results indicate a decrease in the binding of the cAMP analog 8-azido-[32P]-cAMP with no change in the level of RII protein in psoriatic fibroblasts. In addition, by two-dimensional gel electrophoresis we observed the presence of a phosphorylated form of RII unique to psoriatic cells which is suppressed by RA treatment. This study suggests an altered posttranslational modification of the cAMP-PKII in psoriatic fibroblasts which can be reversed by exposure of these cells to RA.

Topics: Autoradiography; Azides; Binding Sites; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases; Densitometry; Fibroblasts; Humans; Immunoblotting; Phosphorylation; Precipitin Tests; Protein Processing, Post-Translational; Psoriasis; Tretinoin

A retinoic acid (RA) inducible skin-specific gene transcript (RIS-1) was isolated by differential hybridization screening of a RA-treated human skin cDNA library. The library was constructed from pooled RNA derived from normal adult human skin treated with all trans-RA for 4 h (n = 6) and 12 h (n = 6) in vivo. RIS-1 cDNA corresponded to a 0.6 kb transcript that was barely detectable in normal adult human skin but was significantly induced by 8 h in RA-treated compared to vehicle-treated skin (range 1.1-3.6 fold). Prolonged RA treatment for up to 24 h further increased relative RIS-1 mRNA levels by 1.3-5.5 fold. HPLC analysis of the RA content of 0.1% RA-treated skin in vivo revealed significant levels at 6 h (18.8-120.6 ng RA/g wet weight tissue; approximately 240 nM), immediately preceding the time point at which the increased RIS-1 mRNA level was first seen. This concentration of RA also induced the mRNA levels for cellular RA binding protein II (1.6-19 fold), a marker of RA activity in human skin. RIS-1 mRNA was detected by Northern and dot blotting only in normal skin but not in any other normal human tissues examined, indicating a tissue-specific pattern of gene expression. RIS-1 transcripts were detected at very low levels in untreated cultured human epidermal keratinocytes, while no expression was seen in dermal fibroblasts and melanocytes, the other major cell types in skin. Southern analysis of human and mouse DNA indicated the existence of evolutionarily conserved sequences for RIS-1 between these two species. The polypeptide sequence derived from the partial RIS-1 cDNA was found to be identical to the calcium binding domain found in 'psoriasin', a gene whose expression appears to be increased in the skin of psoriasis patients.

Topics: Calcium-Binding Proteins; Cells, Cultured; Cloning, Molecular; Conserved Sequence; DNA Probes; DNA, Complementary; Gene Expression Regulation; Humans; Keratinocytes; Organ Specificity; Polymorphism, Restriction Fragment Length; Psoriasis; Receptors, Retinoic Acid; RNA, Messenger; S100 Calcium Binding Protein A7; S100 Proteins; Skin; Transcription, Genetic; Tretinoin

PA-FABP (psoriasis-associated fatty acid-binding protein) is a new member of a group of low-molecular-weight proteins that are highly up-regulated in psoriatic skin and that share similarity to fatty acid-binding proteins. In this study we demonstrate that PA-FABP transcripts are expressed in human skin in vivo and that topical application of 0.05% retinoic acid (RA) cream results in a rapid induction of PA-FABP transcripts following treatment for 16 hours and persists at increasing levels after 48 and 96 h of RA treatment. The PA-FABP mRNA response to RA was reduced by approximately 50% when patients concurrently were treated with RA and 0.025% clobetasol propionate (CLO) for 48 and 96 h, whereas treatment with CLO alone resulted in PA-FABP transcript levels not significantly different from vehicle-treated skin. When comparing the effects of a well-known irritant, sodium lauryl sulfate (SLS), to those of RA and its vehicle, 0.05% RA cream but not 2% SLS in RA vehicle caused PA-FABP mRNA induction after 16 h. SLS treatment of human skin for 96 h caused a slight increase in PA-FABP transcripts, but markedly less than that observed in response to RA treatment. Incubation of cultured human keratinocytes or skin fibroblasts with RA for up to 48 h did not significantly induce PA-FABP transcripts. Expression of PA-FABP message in keratinocytes was observed to be induced by calcium and fetal calf serum (FCS), while tetra-decanoyl phorbol acetate (TPA) caused little or no induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Base Sequence; Carrier Proteins; Cells, Cultured; Clobetasol; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Expression; Humans; Keratinocytes; Molecular Probes; Molecular Sequence Data; Neoplasm Proteins; Psoriasis; RNA, Messenger; Skin; Skin Physiological Phenomena; Sodium Dodecyl Sulfate; Tissue Distribution; Tretinoin; Tumor Suppressor Proteins

The expression of cornifin, a putative cross-linked envelope precursor, was investigated in several squamous differentiating tissues by in situ hybridization and immunohistochemical analysis. Cornifin mRNA and protein, which are absent in the normal mucociliary tracheal epithelium, are induced in the suprabasal layers of the squamous metaplastic tracheal epithelium of vitamin A-deficient hamsters. Similar to the induction of squamous metaplasia in vivo, culture of rabbit tracheal cells in the absence of retinoids results in squamous differentiation and expression of cornifin. This induction of cornifin expression is suppressed by retinoic acid and several of its analogs. Cornifin mRNA and protein are also detected in the suprabasal layers of the squamous epithelium of rabbit esophagus and tongue. The distribution of cornifin in human epidermis was compared with that of two other crosslinked envelope precursor proteins, involucrin and loricrin. The localization of cornifin and involucrin is very similar. Both are induced in the spinous layer and appear at an earlier stage during epidermal differentiation than loricrin. The expression of cornifin is greatly increased in psoriatic skin. Cornifin mRNA is barely detectable in normal epidermis, whereas it is present at relatively high levels in the suprabasal layers of psoriatic epidermis. Topical treatment with RA results in thickening of the skin and increases the level of cornifin mRNA and protein in the upper spinous layers of mouse skin. Cornifin expression correlates generally with squamous differentiation in a variety of tissues and is abnormally regulated in psoriatic skin and in skin treated topically with retinoic acid.

Topics: Administration, Topical; Animals; Cells, Cultured; Cornified Envelope Proline-Rich Proteins; Cricetinae; Esophagus; Gene Expression; Humans; Male; Membrane Proteins; Mice; Protein Precursors; Psoriasis; Rabbits; RNA, Messenger; Skin; Trachea; Tracheal Neoplasms; Tretinoin; Vitamin A Deficiency

Using PAGE--Autoradioblotting technique we have characterized an E--FABP in human epidermal cells that is distinct from liver-, heart-, intestine- and adipose tissue-FABPs. FABP radiobinding analysis was performed directly on protein extracts without prior partial purification. E-FABP has a Mr of approximately 15 kDa and binds oleic acid with high affinity but does not bind all-trans-, 13-cis- and 9-cis-retinoic acid nor all-trans-retinol. Expression levels of E-FABP were low in normal epidermis, higher in human cultured keratinocytes and still higher in psoriasis, a disease characterized by abnormal epidermal differentiation. These findings suggest that epidermal cells may have a distinct fatty acid metabolism compared to other tissues.

Topics: Carrier Proteins; Cell Differentiation; Electrophoresis, Polyacrylamide Gel; Epidermis; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Humans; Keratinocytes; Neoplasm Proteins; Oleic Acid; Oleic Acids; Psoriasis; Tretinoin; Tritium; Tumor Suppressor Proteins; Vitamin A

Many of the pleiotropic effects of retinoids are likely to be mediated by nuclear retinoic acid receptors (RAR) acting as ligand-dependent enhancer factors. However, in previous studies we have been unable to document altered RAR expression at the RNA level in response to retinoic acid (RA) treatment or in psoriatic lesions, conditions characterized by marked alterations in keratinocyte proliferation and differentiation, which are either caused by or responsive to RA. In an attempt to identify other potential regulators of RA responsiveness, we have used RNA blot hybridization to study the expression of the cellular retinoic acid binding proteins (CRABP) CRABP-I and CRABP-II, the RAR-gamma isoforms RAR-gamma 1 and RAR-gamma 2, and the low-affinity RAR homologue RXR in normal, RA-treated, and psoriatic human epidermis. CRABP-II is selectively and markedly induced by RA in adult human skin (J Biol Chem 266:17662-17666, 1991). However, in submerged, serum-free keratinocyte cultures, CRABP-II mRNA could not be induced by RA. Comparisons of intact human skin, submerged keratinocyte cultures, and human skin equivalent cultures indicated that induction of CRABP-II by RA requires epidermal stratification, dermal-epidermal interactions, or both. CRABP-II transcripts were also expressed in heat-separated human dermis at levels similar to those found in epidermal keratome biopsies, whereas CRABP-I transcripts were undetectable in dermal RNA. CRABP-II transcripts were markedly elevated in psoriatic lesions, as they were in RA-treated skin. In contrast, CRABP-I mRNA was undetectable and not increased in psoriatic lesions. Expression of RAR-gamma isoforms and RXR was not detectably altered in either psoriatic lesions or in RA-treated skin. Thus, altered expression of CRABP-II appears more likely to regulate the cutaneous actions of RA than does altered expression of CRABP-I, RXR, or RAR-gamma isoforms. From these and other results, a model for regulation of RA action involving sequestration of RA by CRABP-II is proposed.

Topics: Base Sequence; Carrier Proteins; Humans; Isomerism; Molecular Sequence Data; Psoriasis; Receptors, Retinoic Acid; RNA, Messenger; Skin; Tretinoin

The ability of topically applied retinoic acid to improve photoaged skin has stimulated research interest into its mechanism of action. Currently available assay systems are either in-vitro or mouse models, neither of which are truly representative of the in-vivo situation in man. Another drawback is that skin biopsies available from studies using retinoic acid to treat photoageing are of insufficient size to accomplish biochemical and molecular assays. In order to address these problems, a 4-day in-vivo retinoid assay has been developed which serves as a good predictive model for the chronic effects of retinoic acid on skin and helps to characterize the mechanism of action of retinoic acid.

Topics: Carrier Proteins; Humans; Models, Biological; Psoriasis; Receptors, Retinoic Acid; Skin; Skin Aging; Skin Tests; Sunlight; Time Factors; Tretinoin

The purpose of the present study was to determine the concentrations of acitretin and its main metabolite, 13-cis acitretin, in epidermis, subcutis and plasma in twelve psoriatic patients treated with 30 mg acitretin orally daily for 6 months. In addition, endogenous concentrations of vitamin A were monitored. Blood samples and biopsies from normal appearing skin were obtained prior to therapy, after 1 and 6 months of treatment and finally 1 month after cessation of therapy. Using a highly sensitive liquid chromatography method concentrations of synthetic retinoids and endogenous retinoid (retinol, 3,4-didehydroretinol) were analysed in hydrolyzed tissue samples and plasma. Steady-state concentration of acitretin in epidermis (17 +/- 9 ng/g) was reached within 1 month of therapy. There was a significant correlation between the individual plasma trough value and the epidermal concentration of acitretin after 1 month of therapy. The acitretin concentrations in subcutis varied from 15 to 1437 ng/g, but the mean values at 1 and 6 months of therapy were similar (177 and 227 ng/g, respectively). After stopping therapy the acitretin level was below the detection limit in both epidermis and serum within 1 month in 9 out of 12 patients. In contrast, only 3 of the patients were negative for acitretin in subcutis biopsies obtained 1 month after stopping therapy. The occurrence of a presumed tissue contaminator with characteristics similar to 13-cis acitretin prevented quantitation of this metabolite in many subcutis samples. The epidermal, subcutis and serum composition of retinol and 3,4-didehydroretinol remained unchanged during therapy, indicating no or only minimal interaction between acitretin and endogenous vitamin A metabolism.

Topics: Acitretin; Adipose Tissue; Administration, Oral; Adult; Female; Humans; Male; Middle Aged; Psoriasis; Skin; Tretinoin; Vitamin A

Some morphologic changes of the epidermis of psoriatic skin were observed in organ culture in the presence of absence of vitamin A. Normal and uninvolved and involved psoriatic skin areas, punch biopsied in 3-4-mm diameter specimens, were put in serum-free medium containing no vitamin A with or without delipidized fetal calf serum (FCS) and rotation cultured at 60 rpm under an atmosphere consisting of 95% O2 + 5% CO2. The involved psoriatic skin specimens showed well-developed granular layers after 1 d of culture. The values of labeling indices of 3H-thymidine (3H-TdR) incorporated into the epidermal layers of the cultured specimens of the psoriatic skin were nearly constant during culture for as long as 8 d, although the viable epidermal layer gradually became thinner. Addition of tretinoin to the culture caused uninvolved and involved psoriatic skin specimens to become parakeratotic at concentrations as low as about 2.0 x 10(-6) M and 4.0 x 10(-8) M, respectively, suggesting that the involved psoriatic epidermis is much more sensitive, in terms of keratinization, than uninvolved epidermis to the effect of tretinoin.

Topics: Culture Media; Humans; Male; Organ Culture Techniques; Psoriasis; Skin; Tretinoin; Vitamin A; Vitamin A Deficiency

Topical treatment of the mouse tail with antipsoriatic drugs enhances orthokeratotic cell differentiation in the epidermal scales. We developed a new evaluation system for this test which allows quantification of drug efficacy. Drugs were applied topically, once daily, 5 times a week, for 2 weeks. Two hours after the last treatment the animals were sacrificed, longitudinal sections of the tail skin were made and prepared for histological examination (hematoxylin-eosin staining). As indicator of orthokeratosis (OK), the length of the granular layer per scale was measured microscopically with a semiautomatic image evaluation unit and related to the total scale length (= % OK per scale). Drug activity was defined by the increase in the total length of orthokeratotic regions, 100% activity corresponds to a granular layer extending over the whole scale length. In this model dithranol and retinoic acid dose-dependently increased orthokeratosis up to 75 and 79%, respectively. Beech tar, in a concentration of 5% induced a 19% increase in orthokeratosis. Morphometric quantification by image analysis of the conversion of parakeratotic into orthokeratotic regions in mouse tail scales induced by topical drug treatment seems to be a suitable and reliable procedure to investigate new drugs from which antipsoriatic activity may be expected.

Topics: Animals; Anthralin; Drug Evaluation, Preclinical; Male; Mice; Mice, Inbred Strains; Psoriasis; Tail; Tars; Tretinoin

In situ hybridization with full length mouse cellular retinoic acid-binding protein type 1 and cellular retinoic acid-binding protein type 2 cDNA derived RNA probes showed overexpression of cellular retinoic acid-binding protein type 2 mRNA in lesional hyperplastic psoriatic skin whereas cellular retinoic acid-binding protein type 1 mRNA was undetectable. This suggests that the previously reported increase of cellular retinoic acid-binding protein in psoriatic epidermis corresponds to increased translation of cellular retinoic acid-binding protein type 2 gene. Cellular retinoic acid-binding protein types 1 and 2 mRNAs were not detectable in normal epidermis; however, type 2 message was detected in non-hyperplastic, non-lesional skin of psoriatic patients thus before altered epidermal differentiation and hyperplasia are morphologically detectable.

Topics: Antisense Elements (Genetics); Carrier Proteins; Gene Expression; Humans; Nucleic Acid Hybridization; Psoriasis; Receptors, Retinoic Acid; RNA Probes; RNA, Messenger; Tretinoin

The synthetic retinoic acid derivative acitretin has recently been introduced for the treatment of severe psoriasis. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half-life of up to 120 days for this drug. In the presented study, 12 patients with severe psoriasis were treated with 30 mg acitretin daily for a period of 6 months. The maximum plasma concentration of the drug occurred within about 0.9 to 4.6 hours with an apparent absorption half-life ranging from 0.2 to 1.7 hours and with half-lives of the distribution phase within the range of 1.2 to 3.5 hours. After stopping therapy, the terminal elimination half-life of acitretin varied between 16.5 and 111.1 hours (mean: 47.1 hr +/- 29.8 SD), whereas that for the 13-cis-metabolite varied between 36.5 and 249.4 hours (mean: 119.4 hr +/- 73.4 SD). Suction blister fluid concentrations of both the parent drug and metabolite were lower than plasma concentrations. The mean concentration of serum triglycerides was significantly elevated during the course of therapy, but still remained within the normal range. Saliva concentrations of drug and metabolite at steady-state were below 1 ng/mL. It is not possible from the observed half-lives of acitretin and its 13-cis-metabolite to draw any definite conclusion with regard to the anticonceptional period after acitretin therapy in psoriatic patients.

Topics: Acitretin; Adult; Blister; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Psoriasis; Saliva; Tretinoin

Psoriasis is a common skin disease in which retinoids have beneficial effects. It offers a model for the study of benign hyperproliferation with abnormal differentiation. The dermis has a prominent role in the appearance of epidermal lesions. It is therefore of interest to study the factors that modulate dermal cell proliferation. In this study, the role of retinoids in modulating platelet-derived growth factor (PDGF) bioactivity was studied in normal (six subjects) and psoriatic fibroblasts from involved and uninvolved tissues (six patients). Retinoic acid treatment (for 4 d at 10(-6) M) of psoriatic fibroblasts significantly increased the chemotactic effect of PDGF in these cells (p less than 0.01 and p less than 0.05, respectively, in involved and uninvolved skin at 20 ng/ml of platelet-derived growth factor as measured in a modified Boyden Chamber Assay). In the same way, retinoic acid treatment of psoriatic fibroblasts increased the mitogenicity of platelet-derived growth factor in these cells. Retinoic acid treatment has no significant effect on the mitogenic and chemotactic activity of PDGF in normal fibroblasts. The binding of the homodimer BB PDGF to its type-B receptor, which mediates the mitogenic and chemotactic effect of PDGF, was not modified by retinoic acid treatment either in psoriatic and/or normal fibroblasts. These results suggest that retinoic acid may modulate the PDGF bioactivity in psoriatic fibroblasts not by affecting the binding of this ligand to these cells but by influencing a post-receptor event.

Topics: Adult; Cell Division; Cells, Cultured; Chemotaxis; DNA Replication; Fibroblasts; Humans; Kinetics; Platelet-Derived Growth Factor; Psoriasis; Receptors, Cell Surface; Receptors, Platelet-Derived Growth Factor; Reference Values; Skin; Thymidine; Tretinoin

Retinoid transfer into breast milk was studied in a psoriatric woman receiving oral acitretin at a dosage of 40 mg once daily. Concentrations of the parent compound and its main metabolite, 13-cis acitretin, were measured in serum and mature milk during the initial nine days of therapy, using reverse-phase high performance liquid chromatography. At steady-state, trace amounts of the drug and metabolite (30-40 ng/ml) appeared in breast milk corresponding to a milk/serum concentration ratio of about 0.18. Acitretin was almost exclusively distributed in the fatty layers of the milk. Although the estimated amount of the drug consumed by a suckling infant would correspond to only 1.5% of the maternal dose, the toxic potential of acitretin justifies its avoidance in breast-feeding women.

Topics: Acitretin; Adult; Chromatography, High Pressure Liquid; Female; Humans; Milk, Human; Psoriasis; Tretinoin

Plasma concentrations of etretinate (E), acitretin (A) and 13-cis-acitretin (13-cis A) were measured using a reverse phase HPLC assay in patients with psoriasis during 24h after the first dose (0.8 mg/kg) and after 3 weeks (group A), and in a second group with various skin diseases (B) under long-term treatment after 3 months. Group A (n = 8) showed median peak plasma concentration levels (Cmax) 578 ng/ml for E. and 161 ng/ml for A 4h after dosing (tmax). The plasma concentration profile of 13-cis A. was plateau-like with Cmax-levels of 138 ng/ml after 4 to 10 hours. In group B treated with 0.3 to 0.4 mg/kg etretinate a trend to increased Cmax-values with 123 ng/ml for E., 44 ng/ml for A. and, more pronounced, 210 ng/ml for 13-cis A. occurred (steady state). In a third group C (n = 17) it was found that after an eight month treatment free period measurements of the 13-cis A. plasma concentration are more sensitive than that of E. or A. Comparing the pharmacokinetics in two patients with the same clinical conditions under E. and A., resp., two fold higher Cmax-values of A. after A. were found than for A. after E. However, 13-cis A. values were higher after E. than after A. Our observations have shown that the metabolisation of A. to 13-cis A. may be disturbed and the clinical efficacy may appear only after dramatic increase of the oral doses. Routine monitoring of plasma concentration profiles of oral retinoids and their metabolites under short or long-term treatment enable us to early identify and understand better the so-called "non-responders", either due to a disturbed metabolism of retinoids or to non-compliance. Furthermore, monitoring of 13-cis A in plasma after cessation of treatment with E. or A. in women in childbearing age seems to be more sensitive than measurement of plasma levels of E. or A. These measurements are helpful for defining the strategy of oral retinoid therapy and for reliable information of females who wish to become pregnant after interrupting the drug.

Topics: Acitretin; Administration, Oral; Adult; Aged; Chromatography, High Pressure Liquid; Etretinate; Female; Humans; Long-Term Care; Male; Middle Aged; Psoriasis; Skin Diseases; Tretinoin

Topics: Acitretin; Etretinate; Humans; Psoriasis; Tretinoin

The synthesis of new 10-acylderivatives of dithranol 1 is described. Compound 1 was reacted with the acid chlorides of all-trans retinoic acid 5, 13-cis-retinoic acid 6 and all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8- tetraenoate 7 in toluene and collidin as a base to give the coupling products 2, 3 and 4. The different structures were confirmed by high resolution 1H- and 13C-NMR spectroscopy. Initial investigations with the enzyme glucose-6-phosphate dehydrogenase indicate that all of them are inhibitors of the protein and therefore might have antipsoriatic activity.

Topics: Acitretin; Anthralin; Isotretinoin; Magnetic Resonance Spectroscopy; Psoriasis; Tretinoin

Fourteen male patients suffering from severe psoriasis were treated with 30 to 50 mg/day acitretin during 12 weeks. At the end of the treatment, 6 patients were in remission and 7 showed a marked improvement of the disease. One patient did not show any change. All patients experienced the usual retinoid side effects.

Topics: Acitretin; Adult; Humans; Male; Middle Aged; Psoriasis; Severity of Illness Index; Tretinoin

A study of the pharmacokinetics of etretinate in 7 psoriatic patients with liver fibrosis or liver cirrhosis is reported. Maximum plasma concentrations occurred within 1.5-4.0 hr. Absorption lag-times ranged from 0.3-2.5 hr, whereas the apparent absorption first order half-times (t1/2ka) were within the range of 0.3-1.2 hr. As judged from the AUC-values corrected for dose and body weight a six-fold interindividual variation existed with regard to the systemic availability of etretinate. Absorption and disposition rates of etretinate in subjects with hepatic fibrosis increasing to cirrhosis were not significantly altered compared with previous results in psoriatic patients with normal liver function.

Topics: Acitretin; Aged; Etretinate; Female; Half-Life; Humans; Liver; Liver Cirrhosis; Male; Middle Aged; Psoriasis; Tretinoin

The aim of the study was to investigate the concentrations of Ro 10-1670 (acitretin) and its isomeric metabolite Ro 13-7652 (cis-acitretin) after multiple oral dosing of acitretin. We used a highly sensitive HPLC method for simultaneous determination of the 2 retinoids with a quantification limit of 2 ng/ml in plasma and 10 ng/g in total skin (epidermis and dermis). In hairless rats receiving orally 8 mg/kg acitretin once daily during 8 days, blood and skin samples were taken at different time points between 5 and 96 h after the last dose. After 96 h, appreciable concentrations of Ro 10-1670, but not Ro 13-7652 could be measured in the skin, whereas both isomers were below the quantification limit in plasma. In psoriatic patients treated with a once daily dose of 30 mg acitretin, blood samples and biopsies were taken after 1 month of treatment (i.e. under steady state conditions). 24 h after the last drug intake, skin concentrations of acitretin were approximately 10 times higher than those observed in plasma. Ro 10-1670 concentrations in the skin were approximately 3-5 times higher than for Ro 13-7652 and concentrations of both isomers were higher in lesional compared to uninvolved skin.

Topics: Acitretin; Administration, Oral; Adult; Aged; Animals; Chromatography, High Pressure Liquid; Humans; Male; Middle Aged; Psoriasis; Rats; Skin; Stereoisomerism; Tretinoin

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Female; Humans; Infant, Newborn; Male; Penis; Pregnancy; Pregnancy Complications; Psoriasis; Teratogens; Tretinoin

The effects of acitretin (free acid of etretinate) on the serum lipoprotein pattern and on the fat elimination in serum of 8 patients with psoriasis and 4 with palmo-plantar pustulosis were studied. The drug was given for 12 weeks; the average daily dose was 40 mg. Lipoprotein analyses and an intravenous fat tolerance test (IVFTT) were performed on three occasions (before, after 8 weeks' treatment, as well as 8 weeks after the end of the treatment). Acitretin increased the triglyceride concentration of the very low density lipoproteins by about 50% (p less than 0.02) and reduced the cholesterol of the high density lipoproteins significantly (p less than 0.001), leading to an increased low density/high density lipoprotein cholesterol ratio (p less than 0.02). The IVFTT indicated a lowering of the fat elimination capacity. All changes reverted to the original values after an 8-week wash-out period. The data suggest that the effects of acitretin on the lipoprotein metabolism resemble those of etretinate and isotretinoin.

Topics: Acitretin; Adult; Apolipoproteins; Cholesterol; Fat Emulsions, Intravenous; Female; Foot Dermatoses; Hand Dermatoses; Humans; Lipids; Lipoproteins; Male; Middle Aged; Psoriasis; Skin Diseases, Vesiculobullous; Tretinoin

Retinoic acid treatment of psoriatic fibroblasts increases the activity of cyclic AMP dependent protein kinase. In this study we report that retinoic acid treatment of cultured psoriatic fibroblasts modifies their subsequent cAMP dependent protein phosphorylation. In the soluble fraction of normal fibroblasts cAMP clearly enhances the in vitro phosphorylation of proteins of MW 37,49,54,56,68,83 kD while retinoic acid treatment of the same cells results in a decrease of the cAMP dependent phosphorylation of the first five of the same proteins. In contrast, in psoriatic fibroblasts from psoriatic patients retinoic acid either has no effect or increases the cAMP dependent phosphorylation of some of these proteins. Moreover the phosphorylation of a protein of MW 54 kD, undetectable in untreated psoriatic cells, is more phosphorylated in the presence of cAMP after retinoic acid treatment. The appearance of this phosphorylated proteins is time dependent and dose dependent upon the addition of retinoic acid. These in vitro phosphorylation results suggest that retinoic acid treatment of psoriatic fibroblasts change the level of cAMP dependent phosphorylation of some cytosolic proteins. These specific phosphorylations could be implicated in a variation of cell functions.

Topics: Cells, Cultured; Cyclic AMP; Fibroblasts; Humans; Kinetics; Molecular Weight; Phosphoproteins; Phosphorylation; Proteins; Psoriasis; Reference Values; Tretinoin

Topics: Adenosine Triphosphate; Binding, Competitive; Carrier Proteins; Cytosol; Epidermis; Humans; Phorbol Esters; Protein Binding; Psoriasis; Receptors, Retinoic Acid; Tetradecanoylphorbol Acetate; Tretinoin

The aromatic retinoic acid derivative etretin has recently been introduced in the treatment of severe psoriasis and other dyskeratoses. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half-life of up to 120 days for this drug. Seven patients of either sex from whom we recently reported single-dose pharmacokinetics have been studied after 1 and 3 months multiple dose administration of the drugs. Four were given etretin and three etretinate. Etretin, both as drug and as metabolite, was absorbed faster than etretinate as judged from t-lag, tm and t 1/2 ka. Etretin as drug was eliminated faster than the metabolite etretin, t 1/2 beta 2.39 +/- 1.16 days compared to 6.51 +/- 2.06 days. In patients receiving etretinate the terminal disposition or elimination half-lives for cisetretin (t 1/2 lambda 3 15.9 +/- 9.9 days) were longer than for the metabolite etretin and exhibit a pronounced interindividual variation from 4.25 to 22.8 days. Similarly, cis-etretin accumulated very marked in comparison to the metabolite etretin of the drug etretinate. Assuming 40% systemic availability for both drugs, the central compartment of distribution constituted about 12-32% in case of etretin and about 0.8-3.6% in case of etretinate of the calculated apparent total volume of distribution at steady state, which showed mean values of 3.5 and 39.6 1.kg.-1, respectively, presumably reflecting the higher lipophilic nature of the latter compound.

Topics: Acitretin; Adult; Aged; Etretinate; Female; Half-Life; Humans; Male; Middle Aged; Psoriasis; Tretinoin

Acitretin (Ro 10-1670, etretin) is the free acid derivative of etretinate. This compound possesses a much shorter half-life of elimination than etretinate and was therefore proposed for clinical development. A total of 635 patients with various dermatoses were studied in 12 main clinical trials performed in Europe and in the United States. It was shown that acitretin is effective in the treatment of psoriasis and other diseases of keratinization. Doses between 25 and 35 mg per day are recommended to initiate treatment since marked improvement or clearing was obtained in the majority of patients within this range. Hypervitaminosis A signs and symptoms have been observed in patients treated with acitretin. It is concluded that the efficacy and safety profile of acitretin resembles that of etretinate.

Topics: Acitretin; Adolescent; Adult; Child; Child, Preschool; Etretinate; Female; Humans; Male; Middle Aged; Psoriasis; Skin; Tretinoin

Although retinoid derivatives are an effective treatment for severe psoriasis, they result in systemic toxicity, including hyperlipidemia. In an attempt to reverse this retinoid-related hyperlipidemia in patients with psoriasis, a prospective 4-week pilot study of fish oil supplementation was carried out in 25 patients with psoriasis vulgaris receiving etretinate (Ro-10-9359) or acitretin (Ro 10-1670). Daily fish oil supplements containing 3 gm of omega-3 fatty acids (1.8 gm of eicosapentaenoic acid 20:5 omega 3, and 1.2 gm of docosahexaenoic acid 22:6 omega 3) were found to be effective in reducing hypertriglyceridemia, with a significant mean reduction from 215.6 +/- 92.5 to 156.9 +/- 58.5 mg/dl (-27%) when compared with controls (203.6 +/- 46.9 to 204.1 +/- 54.3 mg/dl). High-density lipoprotein cholesterol levels increased from 41.4 +/- 10.5 to 46.1 +/- 10.8 mg/dl (+11%), and the ratio of total cholesterol to high-density lipoprotein cholesterol decreased from 6.6 +/- 1.9 to 5.9 +/- 1.7 (-11%). It is concluded that fish oil supplementation may prove a valuable adjunct to ameliorate the lipid changes secondary to retinoids.

Topics: Acitretin; Adult; Aged; Cholesterol; Cholesterol, HDL; Etretinate; Female; Fish Oils; Humans; Hyperlipoproteinemias; Male; Middle Aged; Prothrombin Time; Psoriasis; Tretinoin; Triglycerides

Skeletal effects of retinoids on the spine were studied in two clinical trials. In the first study, spinal radiographs of 96 patients who had been treated with isotretinoin for 4 to 9 months were reviewed. The average age of these patients was 25 years, and during treatment or within 2 1/2 years after the end of treatment, 26% of the patients showed progressive formation of small bony spurs consisting of tiny horizontal excrescences that arose at the anterior margin of one or more vertebral bodies adjacent to the intervertebral disk. In a second study, the radiographs of 241 patients with psoriasis who were treated continually for 1 to 2 years with acitretin were examined. Many of these patients had abnormal radiographs at the start of therapy. These preexisting conditions included psoriatic arthritis, degenerative arthritis, and diffuse idiopathic skeletal hyperostosis. Five percent of the patients showed progression of their abnormalities during the study. The difference in the rate of spur formation in the two groups may be due to multiple factors and not simply to retinoid therapy. Because of the extensive amount of preexisting disease in the psoriasis group compared with the relatively normal appearance of the spine in the isotretinoin group, the underlying disease process may be more important than the retinoid therapy. The development of the spinal spurs was not associated with specific clinical symptoms. Since there was no control group, it is unknown whether the spurs would have developed or progressed in the absence of retinoid therapy.

Topics: Acitretin; Adult; Humans; Isotretinoin; Psoriasis; Spinal Diseases; Time Factors; Tretinoin

In order to study the elimination of Ro 10-1670 (acitretin) and Ro 13-7652, its 13-cis-isomeric metabolite after chronic administration, determination of the residual plasma concentrations of these two compounds were assayed in 9 patients in a range of 22-30 days following cessation of a 2- to 7.5-month course with daily oral doses of 10-50 mg of acitretin. A highly sensitive HPLC method was used (2 ng/ml). Residual plasma concentrations of Ro 10-1670 were below the quantification limit in all cases. Residual plasma concentrations of Ro 13-7652 were below the quantification limit in 7 cases and respectively of 3 and 4 ng/ml in the other 2 cases. These data appear to confirm the absence of storage of acitretin even after an extended course of therapy.

Topics: Acitretin; Adolescent; Adult; Aged; Chromatography, High Pressure Liquid; Female; Humans; Lichen Planus; Male; Middle Aged; Psoriasis; Tretinoin

The major plasma metabolite of acitretin (trans-acitretin) is its 13-cis isomer, cis-acitretin. Interconversion of cis-acitretin to trans-acitretin was demonstrated in man following administration of a single oral dose of cis-acitretin. Plasma concentrations of Ro 13-7652 (cis-acitretin) and Ro 10-1670 (trans-acitretin) were much higher after cis-acitretin administration than after trans-acitretin administration. Surprisingly, these high concentrations were not associated with a clear therapeutic effect in dermatoses (e.g. psoriasis) which are usually responsive to oral retinoids. Interactions between the cis and trans isomers formed in vivo may explain the difference in therapeutic activity of each stereoisomer when administered orally.

Topics: Acitretin; Adult; Aged; Animals; Biotransformation; Dermatitis; Female; Half-Life; Humans; Male; Middle Aged; Psoriasis; Rats; Skin Diseases; Stereoisomerism; Tretinoin

The present investigation focused on the oxidative response of polymorphonuclear neutrophil leukocytes in psoriasis, in particular pustular psoriasis and how this response was affected by different retinoid compounds. In the active phase of pustular psoriasis, the neutrophil chemiluminescence response to the chemotactic peptide f-met-leu-phe and to phorbol myristate acetate was enhanced and correlated to the development of pustules, whereas cells from psoriasis vulgaris patients showed normal chemiluminescence response. Retinoids, particularly tretinoin (= retinoic acid) and isotretinoin caused a pronounced inhibition of the chemiluminescence response only in primed neutrophils in vivo and in vitro, whereas etretinate and the metabolite Ro 10-1670 was less inhibitory. Retinoic acid furthermore inhibited the Fc-mediated phagocytosis, but did not affect C3bi-mediated phagocytosis. These data suggest that the antiinflammatory effect of retinoids may operate by affecting neutrophil activation and function.

Topics: Acitretin; Dermatologic Agents; Etretinate; Female; Humans; In Vitro Techniques; Isotretinoin; Luminescent Measurements; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phagocytosis; Psoriasis; Retinoids; Tetradecanoylphorbol Acetate; Tretinoin

Topics: Acitretin; Chromatography, High Pressure Liquid; Etretinate; Humans; Isomerism; Kinetics; Psoriasis; Tretinoin

Treatment with retinoids results in increased serum triglyceride and cholesterol and reduced HDL-cholesterol; dietary supplementation with fish oil lowers serum lipids. Therefore combining retinoids with fish oil may reduce retinoid hyperlipidaemia. Increased triglyceride due to isotretinoin was reduced by 70% (P less than 0.05) and cholesterol by 45% (P less than 0.05) after addition of fish oil; placebo oil had no effect. These decreases were not associated with changes in levels of HDL-cholesterol or reduction of increased levels of apoprotein B. Increased triglyceride due to etretinate was reversed after the addition of fish oil (P less than 0.01), but cholesterol levels did not change. Therefore fish oil inhibits hypertriglyceridaemia due to isotretinoin and etretinate and reduces increased cholesterol levels due to isotretinoin; this effect is likely to be due to altered lipoprotein composition.

Topics: Acne Vulgaris; Adolescent; Adult; Aged; Cholesterol; Etretinate; Female; Fish Oils; Humans; Hyperlipidemias; Isotretinoin; Male; Middle Aged; Psoriasis; Tretinoin; Triglycerides

Chronic renal failure (CRF) interferes with the catabolism of retinol and is frequently associated with hypervitaminosis A. The effect of CRF on the plasma levels of etretinate (Tigason, Tegison), an aromatic retinoid, was therefore studied in 4 patients who were given the drug as part of a maintenance antipsoriatic regimen. The concentrations of the parent compound and its main metabolites (etretin and isoetretin) were monitored for 24 h after receiving a routine dose of the drug. In comparison with 4 non-CRF patients receiving similar maintenance doses of etretinate, although the CRF patients had higher peak levels of the parent compound (p less than 0.01), the levels of the metabolites were similar or lower. The plasma half-lives for all compounds were approximately the same in each group, indicating that the catabolism of the drug was not affected by CRF. However, elevated etretinate concentrations may increase the drug accumulation in fat tissues and thereby prolong the time required for final elimination of the drug.

Topics: Acitretin; Etretinate; Humans; Kidney Failure, Chronic; Kidney Function Tests; Psoriasis; Tretinoin

The effects of four retinoids, all-trans-retinoic acid (tretinoin), 13-cis-retinoic acid (isotretinoin), R0 10-1670 (etretin) and the arotinoid, R0 15-0778, on fibroblast proliferation and glycosaminoglycans (GAG) secretion in vitro were studied. Fibroblasts lines cultured from normal skin (HSF) were compared with those from lesional (PSA) and non-lesional (PSB) psoriatic skin. In general, the retinoids inhibited proliferation; the action was cytostatic, in rank order tretinoin greater than isotretinoin greater than etretin greater than arotinoid. The psoriatic cells tended to be more sensitive than the HSF lines, overall mean proliferation values (+/- SEM), as a percentage of untreated controls being: HSF 72 ++- 3, PSA 61 +/- 3 and PSB 54 +/- 3. Stimulation of GAG secretion at low concentrations (10(-7) M) of all four retinoids, declined as concentrations increased, and secretion was inhibited at 10(-4)M in PSB fibroblasts. Calculation of effects on GAG secretion due to changes in cell density confirmed the rank order for direct stimulation of secretion as arotinoid greater than etretin greater than isotretinoin greater than tretinoin. Electrophoresis of [3H]-labelled glycosaminoglycans secreted in the presence of 10(-7) M arotinoid showed that it was predominantly hyaluronic acid, as in untreated cells. These data confirm that different retinoids have contrasting levels of effects on mesenchymal cells and suggest a greater sensitivity to drugs in fibroblasts from psoriatic skin.

Topics: Acitretin; Cell Division; Cell Line; Fibroblasts; Glycosaminoglycans; Humans; Isotretinoin; Psoriasis; Retinoids; Skin; Tretinoin

A reproducible method for sequential study of migration out of human skin, phagocytosis and bactericidal activity of neutrophils is described. Untreated psoriatics exhibit an early increase of chemotactic activity (0-8 h, p less than 0.02) and subsequently a strong inhibition of chemotaxis (8-24 h, p less than 0.01), a slight decrease of phagocytosis and a decrease in bactericidal activity (20 mn, p less than 0.02; 30 mn, p less than 0.003); 60 mn, p less than 0.001; 120 mn, p less than 0.001) as compared with controls. After clearing of skin lesions, the early increased chemotactic activity returned to normal values but the subsequent chemotactic inhibition remains as strong as before treatment. Phagocytosis increased to normal values (p less than 0.02) and bactericidal activity also increased but remained significantly low. The abnormalities were more evident in migrating than in circulating neutrophils, underlining the sensitivity of the described method. Using the same method we have shown that the aromatic retinoid etretinate (Ro 10-9359) and its main metabolite (Ro 10-1670) significantly inhibit the migration of neutrophils from the blood to tissues when applied into skin chambers (0.1 mg/ml) or when given orally (1 mg/kg/day) for 8 days to normal volunteers. This pharmacological property could be closely linked to the antipsoriatic properties of these drugs.

Topics: Adult; Cell Migration Inhibition; Cell Movement; Etretinate; Humans; Neutrophils; Phagocytosis; Psoriasis; Tretinoin

Cellular retinol (CRBP)-and retinoic acid (CRABP)-binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients, before and during oral administration of a synthetic retinoid, Etretin (Ro 10-1670). A 200% increase in CRABP levels, measured by the ability of the protein to bind retinoic acid, was observed in the normal skin during treatment. The CRBP levels were not altered during therapy. The results show that CRBP and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors.

Topics: Acitretin; Adult; Aged; Carrier Proteins; Charcoal; Chromatography, Gel; Dextrans; Female; Humans; Male; Middle Aged; Psoriasis; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Skin; Tretinoin

We have previously found an important increase of cellular retinoic acid-binding protein (CRABP) in psoriatic plaques whereas the cellular retinol-binding protein (CRBP) was not elevated compared to normal human skin and nonlesional psoriatic skin. In the present study we analyzed CRABP and CRBP levels in a panel of dermatoses in order to address several questions raised by the above findings. Three observations were made: CRBP showed little or no variations whereas CRABP was either normal (seborrheic keratosis, lichenification, nonlesional psoriatic and nonlesional Darier disease skin) or elevated (psoriatic plaques, lamellar ichthyosis, lesional Darier disease, pityriasis rubra pilaris, keratosis pilaris); high levels of CRABP might indicate a greater sensitivity of the lesions to systemic synthetic retinoids with a carboxyl group in the C15 position, and systemic administration of etretin increased the levels of CRABP but not CRBP. These observations suggest that CRABP might be the receptor for synthetic retinoids in the skin and that its analysis might be useful in monitoring retinoid therapy.

Topics: Acitretin; Adsorption; Carrier Proteins; Charcoal; Chromatography, Gel; Dextrans; Female; Humans; Male; Psoriasis; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Skin; Skin Diseases; Tretinoin

The problematic storage of etretinate in fat during chronic etretinate therapy prompted us to search for other "high-affinity" tissues in 3 patients studied at autopsy. Specimens from eleven organs were analysed for etretinate and its main metabolite, etretin, by high-performance liquid chromatography. The results confirmed an accumulation of etretinate in fat and to a lesser degree in liver. High levels of etretinate were also found in the adrenals and, in one case, this value exceeded that of the fat tissue. Low levels were observed in several other organs, notably the kidneys, brain and testis. With the possible exception of liver and gut, the metabolite did not accumulate in any particular organ. Although the available data is still limited, the risk that the accumulation of etretinate in the adrenals may adversely affect adrenal function must be examined.

Topics: Acitretin; Adipose Tissue; Adrenal Glands; Adult; Aged; Aged, 80 and over; Etretinate; Humans; Ichthyosis; Male; Psoriasis; Tissue Distribution; Tretinoin

Topics: Acitretin; Arachidonic Acid; Arachidonic Acids; Cell Line; Humans; Keratins; Psoriasis; Skin; Tretinoin; Ultraviolet Rays

Retinoids are natural and synthetic analogues of vitamin A. They have a marked influence on the differentiation of epithelial tissues by modifying membrane glycoconjugates and by acting through cytosolic and nuclear mechanisms like steroid hormones. Their clinical and biological toxic effects are numerous, but they are usually benign and reversible. However the possibility of teratogenic effects requires close monitoring of female patients. Etretinate is particularly effective in disorders of keratinisation (psoriasis, ichthyosis) whereas isotretinoin is the best known therapy of severe acne. Moreover the possible role of retinoids in the prevention and treatment of certain cancers gives hopeful prospects.

Topics: Acne Vulgaris; Chemical Phenomena; Chemistry; Etretinate; Humans; Ichthyosis; Isotretinoin; Neoplasms; Psoriasis; PUVA Therapy; Recurrence; Retinoids; Tretinoin

Topics: Adult; Aged; Drug Eruptions; Female; Fenretinide; Humans; Male; Night Blindness; Psoriasis; Tretinoin

Isotretinoin, a synthetic retinoid that has been prescribed for over 500,000 patients with cystic acne, has been associated with both spinal hyperostosis and a disorder similar to diffuse idiopathic skeletal hyperostosis. We describe a syndrome of tendon and ligament calcification, primarily in extraspinal locations, that we have observed after long-term therapy for psoriasis and disorders of keratinization with etretinate, another synthetic retinoid. Of 38 patients who had received etretinate (average dose, 0.8 mg per kilogram of body weight per day; average duration, 60 months), 32 (84 percent) had radiographic evidence of extraspinal tendon and ligament calcification. The most common sites of involvement were the ankles (29 patients [76 percent]), pelvis (20 patients [53 percent]), and knees (16 patients [42 percent]); spine involvement was uncommon in this group of etretinate-treated patients. Involvement tended to be bilateral and multifocal. Fifteen (47 percent) of the 32 affected patients had no bone or joint symptoms at the sites of radiographic abnormality. Thus, tendon and ligament calcification can occur without vertebral involvement as well as in association with it (for example, as part of the spectrum of diffuse idiopathic skeletal hyperostosis). We have identified extraspinal tendon and ligament calcification as a toxic effect that is commonly associated with long-term etretinate therapy.

Topics: Adult; Aged; Calcinosis; Etretinate; Female; Humans; Isotretinoin; Knee Joint; Ligaments; Lupus Erythematosus, Systemic; Male; Middle Aged; Pelvis; Prospective Studies; Psoriasis; Radiography; Skin Diseases; Spinal Diseases; Tendons; Tretinoin

Topics: Anthralin; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblasts; Humans; Models, Biological; Psoriasis; PUVA Therapy; Retinoids; Skin; Tretinoin

A 64-year-old woman developed biopsy-proven hepatitis during oral treatment of severe pustular psoriasis of palms and soles with an aromatic retinoid, etretinate. The elevations in hepatic enzyme levels reappeared when etretinate was reinstituted 18 months later. Analysis of serum and subcutis showed normal therapeutic concentrations of the drug. Isotretinoin therapy, although apparently devoid of hepatotoxicity, was clinically only marginally effective. Evidence compiled from the literature suggests that etretinate-hepatitis is a drug-specific reaction.

Topics: Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Isotretinoin; Middle Aged; Psoriasis; Tretinoin

Topics: Etretinate; Humans; Isotretinoin; Psoriasis; PUVA Therapy; Retinoids; Skin Diseases; Tretinoin

The clinical response to isotretinoin (13-cis-retinoic acid) in 11 patients with generalized pustular psoriasis was evaluated. Control of pustulation and systemic symptoms was achieved in ten cases, but additional therapy was required to produce complete clearing of all psoriatic lesions. Also, the efficacy of isotretinoin and etretinate in the treatment of chronic plaque psoriasis was compared in 29 patients. Isotretinoin was found to be less effective than etretinate in the treatment of chronic plaque psoriasis.

Topics: Adult; Aged; Biopsy; Chronic Disease; Etretinate; Female; Humans; Isotretinoin; Male; Middle Aged; Psoriasis; Tretinoin

Topics: Adult; Aged; Female; Humans; Isotretinoin; Male; Middle Aged; Psoriasis; Tretinoin

A histologically confirmed, clinically inapparent and reversible hepatitis occurred in 2 patients (1 psoriasis, 1 basal cell nevus syndrome) within the first months after introduction of etretinate therapy. Causes of hepatitis other than etretinate were not found. Reintroduction of etretinate resulted in reactivation and/or persistence of the hepatitis in both patients. These data strongly suggest that the hepatitis in both patients was caused by etretinate. Later the basal cell nevus syndrome patient was given 13-cis-retinoic acid, which caused no liver test disturbances during a follow-up period of 6 months.

Topics: Aged; Basal Cell Nevus Syndrome; Biopsy; Carcinoma, Basal Cell; Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Liver; Middle Aged; Psoriasis; Tretinoin

Topics: Adult; Aged; Cell Membrane; Desmosomes; Epidermis; Etretinate; Freeze Fracturing; Humans; Keratins; Middle Aged; Psoriasis; Tretinoin

The variations in the expression of epidermal keratins occurring during retinoid therapy were studied in patients with psoriasis before and during oral administration of etretinate (aromatic retinoid Ro 10-9359) and compared with normal epidermis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis densitometric readings were performed on keratins extracted from epidermal cells obtained through trypsinization of skin specimens. Epidermal cells were also tested by immunofluorescence (IF) for the presence of BMZ antigens as markers of basal cells and for the presence of TK and KP (67 K, 63 K, and 55 K) with sera with antibodies against BMZ antigens and specific antisera for TK and KP. In psoriasis-involved epidermis, SDS-PAGE anaLysis showed lower amounts of 67 K and increased amounts of 63 K and 55 K, as compared with normal epidermis. Low proportions of cells expressing by IF the 67 K and the 63 K were also noted, with a defective expression of these two KP by suprabasal keratinocytes in psoriasis-involved epidermis. During etretinate administration, a return toward the normal electrophoretic pattern and a correction of the defective cellular expression of these two KP were obtained parallel with clinical improvement. These findings indicate the presence in involved psoriatic epidermis of a population of suprabasal keratinocytes that do not express the high-molecular-weight KP and show a normalization of the relative proportions of the KP with etretinate.

Topics: Adolescent; Adult; Antigens; Electrophoresis, Polyacrylamide Gel; Epidermis; Etretinate; Fluorescent Antibody Technique; Humans; Keratins; Male; Middle Aged; Peptides; Psoriasis; Tretinoin

Topics: Acne Vulgaris; Humans; Isotretinoin; Psoriasis; Tretinoin

Ro12-7554, a chlorinated derivative of etretinate, was evaluated in an open study. 16 patients, 13 suffering from severe psoriasis and 3 from congenital disorders of keratinization previously treated with etretinate, received Ro 12-7554 at a mean daily dosage of 12.3 mg/day. Ro 12-7554 was very similar to etretinate in terms of clinical efficacy and overall safety.

Topics: Adult; Dermatitis, Exfoliative; Drug Evaluation; Etretinate; Female; Humans; Keratosis; Male; Middle Aged; Psoriasis; Skin Diseases, Vesiculobullous; Tretinoin

In our clinical trials of isotretinoin therapy for cystic acne and etretinate treatment of psoriasis, eight patients had growth of excessive granulation tissue. The granulation tissue was found in resolving acne lesions in one patient taking isotretinoin. Among the psoriatic patients taking etretinate, the granulation tissue usually was seen adjacent to nail plates. In two patients, the side effect caused them to stop retinoid therapy. The tissue response did not appear to be related to the daily or cumulative retinoid dose.

Topics: Acne Vulgaris; Adolescent; Adult; Aged; Granulation Tissue; Granuloma; Humans; Isotretinoin; Male; Middle Aged; Psoriasis; Skin Diseases; Tretinoin

Topics: Acitretin; Adolescent; Adult; Etretinate; Female; Humans; Keratoderma, Palmoplantar; Male; Middle Aged; Pityriasis; Psoriasis; Tretinoin

The naturally occurring retinoids (vitamin A alcohol = retinol and all-trans-retinoic acid) have been largely replaced by synthetic retinoids in recent years as systemic drugs for use in dermatology. At the present time, two synthetic retinoids are commercially available: etretinate (Tigason) and isotretinoin (Accutane). These compounds-which have a more favourable therapeutic index than the naturally occurring retinoids-ushered in a new era of dermatological therapy by their potent antikeratinizing, antiseborrhoeic (only isotretinoin) and antineoplastic action. The broadest indications for the use of these retinoids are psoriasis (etretinate) and cystic acne (isotretinoin), whereas the most dramatic effects are encountered in a number of severe ichthyosiform disorders. Another important, although at present not clearly defined role of the retinoids is in the prophylaxis of skin tumours.

Topics: Acne Vulgaris; Etretinate; Humans; Ichthyosis; Isotretinoin; Psoriasis; Retinoids; Skin Diseases; Skin Neoplasms; Tretinoin

Using a monoclonal antibody against human HLA-DR antigens and OKT6, we investigated by indirect immunofluorescence the distribution of Langerhans cells in normal human skin and involved and uninvolved skin from patients with psoriasis before, during, and after systemic aromatic retinoid administration. In parallel, enumeration of HLA-DR and of OKT6+ cells was also performed. In involved psoriatic epidermis the distribution of positive cells was disturbed; OKT6+ cells were reduced in number, as were HLA-DR+ cells which were seen in clusters. In control skin sections, a regular pattern of fluorescent dendritic epidermal cells was noted. In normal-appearing human skin, in nonlesional psoriatic skin, but not in diseased psoriatic skin, the number of OKT6+ cells per epidermal section surface unit was higher than that of HLA-DR expressing cells. Changes in the number and distribution of OKT6 and HLA-DR+ cells in psoriatic involved epidermis were corrected by oral retinoid treatment.

Topics: Adult; Antibodies, Monoclonal; Antigens; Etretinate; Fluorescent Antibody Technique; Histocompatibility Antigens Class II; HLA-DR Antigens; Humans; Langerhans Cells; Male; Psoriasis; Tretinoin

Eight known antipsoriatic drugs of diverse structures were tested on the basis of their structural similarity with arachidonic acid and known inhibitors of lipoxygenase. A correlation was observed between their antipsoriatic activity and lipoxygenase inhibition suggesting that a common underlying mechanism of action might be involved.

Topics: Anthralin; Arachidonate Lipoxygenases; Etretinate; Glycine max; Lipoxygenase Inhibitors; Mycophenolic Acid; Psoriasis; Resorcinols; Salicylates; Tretinoin

Topics: Etretinate; Humans; Isotretinoin; Keratosis; Psoriasis; Skin; Skin Diseases; Tretinoin

Topics: Drug Therapy, Combination; Etretinate; Humans; Male; Methotrexate; Middle Aged; Psoriasis; Tretinoin

A case of toxic hepatitis caused by combination therapy with methotrexate and etretinate in the treatment of severe psoriasis is presented in a 47-year-old woman. The patient had received methotrexate alone for more than 10 years without any signs of severe liver damage. The liver status had been controlled by consecutive liver biopsies. The treatment was discontinued and after 2 months the liver parameters became normal.

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Liver Function Tests; Methotrexate; Middle Aged; Psoriasis; Tretinoin

A prospective study was carried out over 12 months involving twenty patients with psoriasis vulgaris who were treated with all-trans-aromatic derivative of vitamin A, etretinate. Etretinate was found to be an effective therapy for this skin disorder. Arthritis accompanying psoriasis vulgaris in four of seven of our patients was greatly improved by retinoid therapy. Side effects were found to be dose-related and included mucocutaneous abnormalities as well as abnormalities of blood lipids and liver function tests. Maintenance therapy appears to be required in nearly all patients, with relapse occurring within approximately 8 weeks. Polyamine biosynthesis has been determined previously to be accelerated in patients with psoriasis vulgaris. Polyamines (putrescine [Pu], spermidine [Sp], and spermine [Sm] were measured in skin samples of six patients with stable plaque-stage psoriasis before treatment and at 4 weeks during treatment. Pu, Sp, Sm levels, as well as the Sp/Sm ratio, fell. Epidermal DNA synthesis is increased in involved and noninvolved psoriatic skin; it was measured before and during treatment (at 4 weeks) in this study and found not to fall significantly during this period of time. Polyamine levels therefore decreased prior to any significant expected decrease in epidermal DNA synthesis measured in both involved and uninvolved skin.

Topics: Adult; Aged; DNA; Epidermis; Etretinate; Female; Humans; Male; Middle Aged; Polyamines; Prospective Studies; Psoriasis; Skin; Tretinoin; Vitamin A

Because psoriasis is a disease of unknown etiology, all treatments are based on empirical experience and diverse scientific theories. Although there is no present cure for psoriasis, many forms of therapy are effective in control of the disorder. These range from topical medications such as tar, anthralin, corticosteroids; phototherapy and photochemotherapy; systemic medication, including cytotoxic agents; and vitamin A analogues or retinoids. This report focuses on modifications of existing therapies based on advances in basic science knowledge and technology, combination therapies, as well as new therapeutic agents and new approaches to the treatment of psoriasis.

Topics: Anthralin; Coal Tar; Drug Therapy, Combination; Etretinate; Humans; Methotrexate; Psoriasis; PUVA Therapy; Razoxane; Tretinoin; Ultraviolet Therapy

Topics: Etretinate; Humans; Ichthyosis; Psoriasis; Skin Diseases; Tretinoin

New treatment modalities are now available in the management of psoriasis. We report our local studies on these new modalities. Application of dithranol for 1/2 hour is just as effective as when applied for 24 hours. This means less staining of the skin, clothes and no more burns. Oral retinoids gave more than 70% improvement in six of the seven patients with recalcitrant psoriasis. Oral retinoids produced more than 75% improvement in all eight patients with pustular psoriasis. PUVA therapy gave a complete clearance rate of 77% with an average of 25 sessions of treatment and an average total UVA dose of 346 J/cm2. However REPUVA (retinoids and PUVA) produced a complete clearance rate of 73% with an average of 18 sessions of treatment and an average total UVA dose of 142 J/cm2. The newer forms of treatment together with the established therapies have tremendously improved the total management of patients with psoriasis.

Topics: Adolescent; Adult; Aged; Anthralin; Drug Therapy, Combination; Etretinate; Female; Humans; Male; Methotrexate; Middle Aged; Psoriasis; PUVA Therapy; Time Factors; Tretinoin

Treatment of 20 PUVA-resistant patients with aromatic retinoid Ro 10-9359 resulted in a considerable improvement of psoriasis up to total recovery, and potentiated a favorable clinical effect of subsequent PUVA-treatment with reduced 8-MOP dosage. Aromatic retinoid was especially effective in patients with psoriatic eruptions on palms, soles, face, and scalp. The combination of aromatic retinoid with methotrexate was successfully used in the treatment of two patients with a particularly severe course of psoriasis, one having psoriatic erythroderma coupled with psoriatic arthritis and the other psoriatic erythroderma. No side-effects were noted during retinoid treatment in any of the patients examined.

Topics: Drug Resistance; Drug Therapy, Combination; Etretinate; Humans; Methotrexate; Methoxsalen; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

Topics: Adult; Etretinate; Humans; Male; Middle Aged; Nail Diseases; Psoriasis; Tretinoin

Topics: Acne Vulgaris; Humans; Isotretinoin; Keratins; Psoriasis; Skin Diseases; Skin Neoplasms; Tretinoin; Vitamin A

The distribution of fibronectin in psoriatic skin was studied in 6 patients during treatment with oral etretinate using indirect immunofluorescence technique. In untreated lesions fibronectin was clearly visualized in the dermo-epidermal junction (DEJ) and in the walls of papillary capillaries, and showed a reticular or fibrillar pattern in the dermis. In the horny layer there was some fluorescence which we regarded largely as unspecific. In all patients a transient accentuation of fibronectin accumulation in DEJ was seen after 3-7 days of treatment. Except for some decrease in the amount and intensity of capillary fluorescence, no other notable changes occurred in the fibronectin distribution during 4 weeks of treatment.

Topics: Adult; Etretinate; Female; Fibroblasts; Fibronectins; Fluorescent Antibody Technique; Humans; Male; Middle Aged; Psoriasis; Skin; Tretinoin

Etretinate 0.5 mg/kg body weight combined with 0.1% triamcinolone acetonide and 5% salicylic acid in an O/W cream gave more than 70% improvement in 62% of 75 patients. Of this satisfactorily improved group, at least 41% were still in the same condition after 3 years on a maintenance dose of, on average, 0.3 mg/kg body weight etretinate daily and 20 g weekly of a relatively strong corticosteroid cream. The side effects were acceptable and the convenience for the patients is great as compared with other treatment.

Topics: Administration, Oral; Administration, Topical; Alopecia; Atrophy; Etretinate; Follow-Up Studies; Humans; Psoriasis; Skin; Tretinoin

A 67-year-old male patient, with a history of palmar psoriasis for 8 years, developed a rosacea-like eruption during Tigason (Ro-10-9359) treatment. Strict relationship between Tigason intake and skin symptoms was proved by double introduction of the drug and the patient's previous history. This retinoid side effect is very unusual and we are unable to give any explanation for it.

Topics: Aged; Etretinate; Hand; Humans; Male; Psoriasis; Rosacea; Tretinoin

Topics: Acne Vulgaris; Humans; Neoplasms; Psoriasis; Skin Diseases; Tretinoin; Vitamin A

Retinoids possess regulatory influences on growth and differentiation of epithelial tissues. They induce a population of keratinozytes with normal pattern of differentiation, they have antiproliferative properties, and they show antineoplastic effects by inhibition of malignant transformation of cells in vitro. Also the dermis undergoes distinct alterations under oral administration of retinoids. By stimulating T-lymphocytes and by inhibition of neutrophil migration retinoids seem to develop immunmodulating and antiinflammatory effects. The aromatic retinoid Etretinate is therapeutically used in severe forms of psoriasis and in various genodermatoses with disorders of keratinization as for example ichthyosis, dyskeratosis follicularis Darier, and pityriasis rubra pilaris.

Topics: Acne Vulgaris; Administration, Oral; Etretinate; Humans; Isomerism; Isotretinoin; Psoriasis; Rosacea; Skin Diseases; Tretinoin

Alterations in lipid metabolism have been reported under treatment of various skin disorders with oral retinoids. In 36 patients, mostly psoriatics, under administration of aromatic retinoid (Ro 10-9359) in various dosages serum triglycerides and cholesterol were estimated; in 25 out of 36 patients lipid analysis of the lipoproteins and apoproteins A (HDL) and B (LDL) has been performed. To reveal possible similarities of lipid changes under the two main retinoids we determined the same parameter in 10 patients with conglobate acne treated orally with 13-cis-retinoic acid (isotretinoin/Ro 4-3780 1mg/kg b.w.). Under both drugs serum triglyceride and cholesterol levels were significantly increased. In contrast to the results under the aromatic derivate the HDL- and LDL-cholesterol fractions were changed under isotretinoin. The apoprotein A (HDL) was found significantly increased under aromatic retinoid. Elevated serum lipids mostly occurred in patients having risk factors such as preexisting lipid abnormalities, obesity, diabetes mellitus, heavy smoking, alcohol abuse and hyperlipemia-inducing drugs. Patients to be treated with these drugs should be carefully followed up in order to minimize the risk for atheromatosis.

Topics: Acne Vulgaris; Adult; Etretinate; Female; Humans; Lipids; Male; Middle Aged; Psoriasis; Tretinoin

Topics: Acitretin; Adult; Biological Availability; Blister; Etretinate; Exudates and Transudates; Female; Half-Life; Humans; Male; Middle Aged; Psoriasis; Time Factors; Tretinoin

The activity of phospholipase A2 was tested both in rat skin and human psoriatic skin before and after systemic treatment with a retinoic acid derivative: RO 10-9359. An increase of activity was found in the rat skin homogenates when the animals were treated with 3 mg/kg/day of the drug for 8 days, while no effect was found following treatment with 1.5 mg/kg/day for 10 days. On the contrary a decrease of this activity was found in homogenates from both involved and uninvolved skin of psoriatic patients after systemic treatment with 1-1.5 mg/kg/day for 10 days. These different results are discussed also in the light of the clinical effect of RO 10-9359 on psoriasis.

Topics: Adult; Aged; Animals; Arachidonic Acid; Arachidonic Acids; Etretinate; Humans; In Vitro Techniques; Lipid Metabolism; Male; Middle Aged; Mitochondria, Liver; Phospholipases; Phospholipases A; Phospholipases A2; Psoriasis; Rats; Rats, Inbred Strains; Skin; Tretinoin

Clinical, general laboratory evaluation and immunological studies were conducted in 13 patients with active psoriatic arthropathy undergoing long-term treatment with aromatic retinoid (ethyl-all-trans-9-) (4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenate (Ro 10-9359). Evaluations were made at the beginning of treatment and at 3 and 6 months following drug therapy. A significant improvement in the clinical and laboratory parameters of inflammation was noted. In addition, immunological studies revealed certain changes suggesting that the treatment with Ro 10-9359 may effect some basic mechanisms of etiopathogenic significance in this disease. However, some undesirable, mostly dose-dependent adverse reactions affecting the muco-cutaneous tissues limit a wide use of this agent.

Topics: Adult; Arthritis; Etretinate; Humans; Ibuprofen; Immunoglobulins; Lymphocytes; Male; Middle Aged; Psoriasis; Tretinoin

This study reports comparative results of the effects of an aromatic retinoid, etretinate (RO 10-9359), on various disorders of the skin and mucous membranes. One hundred thirteen patients suffering from psoriasis, lichen planus, keratosis follicularis, and various other disorders were treated and examined. The patients received 25 to 100 mg/day of oral etretinate for up to 30 months. Patients with erythrodermic psoriasis, pustular psoriasis, and keratosis follicularis showed the best response. The conditions of patients with psoriasis vulgaris, palmoplantar psoriasis, and lichen planus also improved, but less impressively. The mucous membrane lesions of lichen planus and leukoplakia showed only moderate improvement. The most striking adverse clinical reactions observed were cheilitis (70%), dryness of the mucous membranes (27%), and hair loss (27%).

Topics: Administration, Oral; Adolescent; Adult; Darier Disease; Etretinate; Female; Humans; Lichen Planus; Male; Middle Aged; Mucous Membrane; Psoriasis; Skin Diseases; Tretinoin

Etretinate was used to treat twenty patients who had severe, disabling psoriasis and an increased risk of liver damage. Potential hepatotoxicity was evaluated by obtaining liver biopsies prior to starting therapy and after a 6-month course on a dosage of 0.75 mg/kg/day. In comparing pretreatment biopsies to posttreatment biopsies, five of twenty patients demonstrated a morphologic change in their liver. Three showed progressive fatty metamorphosis, and two showed liver cell necrosis and progressive fibrosis. One of these was due to heavy alcohol intake. Based on our 6-month evaluation, etretinate does not produce a consistent toxic effect on the liver.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Etretinate; Female; Humans; Liver; Liver Diseases; Male; Middle Aged; Psoriasis; Tretinoin

Previous studies of the polyamines and their biosynthetic enzyme ornithine decarboxylase (ODC) in psoriatic skin have revealed several abnormalities, including significantly elevated ODC activity. Retinoids have also been shown to modulate polyamine biosynthesis and inhibit ODC activity after different stimuli in various cell and tissue systems. The effect of etretinate has been studied on ODC activity in involved and uninvolved psoriasis skin. Increased ODC activity was found in pretreatment samples from both involved and uninvolved psoriatic skin compared with normal volunteers. Etretinate treatment significantly reduced ODC activity in both involved and uninvolved skin in psoriatics to a similar level of activity before any improvement in clinical appearance was noted. Inhibition of epidermal ODC activity in psoriasis may represent one mechanism of retinoid action on the abnormal skin psoriasis.

Topics: Carboxy-Lyases; Etretinate; Humans; Ornithine Decarboxylase; Psoriasis; Skin; Tretinoin

During therapy for psoriasis with the oral aromatic retinoid etretinate, a finely granular material was detected by electron microscopic examination of the epidermis of ten patients. Since this amorphous substance has some of the ultrastructural characteristics of mucin, it is called mucus-like material (MLM). MLM occurs occasionally in untreated psoriatic lesions; however, its deposition is enhanced by etretinate therapy. While MLM has not been fully characterized, evidence exists for the possibilities that it represents either cell products (such as mucin, or carbohydrates associated with the cell surface) or an exudate infiltrating the epidermis.

Topics: Etretinate; Histocytochemistry; Humans; Mucus; Psoriasis; Skin; Tretinoin

Topics: Etretinate; Female; Humans; Lipids; Middle Aged; Psoriasis; Tretinoin

Topics: Adult; Aged; Cholesterol; Drug Therapy, Combination; Etretinate; Humans; Male; Methotrexate; Middle Aged; Psoriasis; Tretinoin; Triglycerides

Topics: Administration, Oral; Aged; Etretinate; Female; Foot Dermatoses; Hand Dermatoses; Humans; Psoriasis; Tretinoin

A patient with pustular psoriasis, which was inadequately controlled by high-dose methotrexate and potent topical corticosteroid therapy, was treated with oral methotrexate and the aromatic retinoid etretinate. The patient's psoriasis improved with sustained maximal etretinate therapy and continued high-dose methotrexate therapy. Subsequently, the methotrexate dose was tapered and used of this drug was discontinued. Previously unattainable success in controlling the psoriasis was achieved with continued etretinate treatment. There were no recognizable adverse effects from concurrent therapy. As the methotrexate dose was tapered, the patient noted increased psoriatic arthritic pain, unrelieved at maximal etretinate levels, but improved with indomethacin treatment. Combination therapy with methotrexate and etretinate may be useful in the treatment of severe psoriasis by providing a controlled transition from methotrexate to etretinate therapy alone.

Topics: Drug Therapy, Combination; Etretinate; Humans; Male; Methotrexate; Middle Aged; Psoriasis; Tretinoin

Therapeutic benefits from aromatic retinoid have been described in the treatment of a variety of dermatological disorders. Stress is given on some of them which coexist with ungual abnormalities and the results are reported. These diseases include psoriasis, acropustulosis, keratosis lichenoides chronica. Drug-induced modifications of the epidermal structures of the nail apparatus are emphasized: fragility with onychorrhexis and onychoschizia is the commonest finding. Onychomadesis and nail shedding can be seen. Onycholysis is rare. Painful paronychia which is sometimes accompanied by granulation tissue and ingrowing nails is the most interesting alteration due to this synthetic retinoid and as yet unexplained.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Etretinate; Female; Humans; Keratosis; Lichen Planus; Male; Middle Aged; Nails; Nails, Malformed; Psoriasis; Tretinoin

The chemotactic activity and other functional parameters both granulocytic and seroimmunologic are evaluated in patients with pustular psoriasis before and after treatment with Etretinate. Before treatment these parameters, and in particular the chemotactic activity of neutrophil granulocyte do not reach statistical difference from control subjects. Etretinate determines in all the cases a dramatic and statistically significant reduction of the chemotactic activity of neutrophil chemotaxis.

Topics: Adolescent; Adult; Aged; Chemotaxis, Leukocyte; Etretinate; Female; Humans; Male; Middle Aged; Neutrophils; Psoriasis; Tretinoin

A 51-year-old man with a 10-year history of psoriasis presented with coexistent perforating folliculitis. Several perforating lesions were located within psoriatic plaques. This case is instructive from several viewpoints: (1) it is the second case to appear in the literature, to our knowledge, describing the coexistence of these two conditions; (2) several of the larger lesions resolved during topical therapy with retinoic acid; (3) it demonstrates the histologic difficulties encountered in attempting to classify the major perforating diseases. Possible mechanisms for the development of perforating disease in this patient are discussed, as are the reasons for its apparent response to topical therapy.

Topics: Administration, Topical; Biopsy; Darier Disease; Diagnosis, Differential; Folliculitis; Humans; Male; Middle Aged; Psoriasis; Skin; Tretinoin

Eight patients with psoriasis (pustular, erythrodermic or severe plaque type) were treated successfully with retinoid (Ro 10-9359) or with retinoid followed by PUVA (RePUVA). The histological changes in recovering skin were examined during 14 weeks. Treatment resulted in normalization of keratinocyte differentiation with fine structural changes suggesting decreased metabolic activity and a reduction of mitoses. There was an increase in the number of keratohyalin granules and of tonofilaments and desmosomes and a decrease in leukocytes in the epidermis. The different cell organelles were studied in detail, but the exact mechanism of retinoid action remains unsolved. Although the treatments were clinically highly effective, total normalization of the histological and electron microscopical picture was not achieved.

Topics: Animals; Biopsy; Drug Therapy, Combination; Epidermis; Etretinate; Humans; Mice; Photochemotherapy; Psoriasis; PUVA Therapy; Rabbits; Tretinoin

Topics: Alcoholism; Etretinate; Humans; Male; Middle Aged; Psoriasis; Tretinoin

The influence of the aromatic retinoid Ro 10-9359 on the migration of neutrophilic granulocytes was examined in standardized supravital preparation. For this purpose, leukocytes were taken from 5 psoriasis patients who had been treated with 75 mg of aromatic retinoid for 3 weeks. The examinations showed that the course of granulocyte migration was disturbed: the dormant stage was prolonged up to several hours. Maximum cell motility was already reached in that stage of motion in which the granulocytes maintained a constantly changing and bizarre cell pattern. The migration stage, which is characterized by a directed linear cell movement, was absent. Leukocyte survival time was shortened by 50%, and cell degeneration was abnormal under the influence of the aromatic retinoid.

Topics: Cell Migration Inhibition; Etretinate; Humans; Neutrophils; Psoriasis; Tretinoin

Topics: Administration, Oral; Adult; Cell Count; Eczema; Epidermis; Etretinate; Female; Humans; Langerhans Cells; Lichen Planus; Male; Middle Aged; Psoriasis; Skin Diseases; Tretinoin

Topics: Biological Availability; Etretinate; Female; Follow-Up Studies; Humans; Kinetics; Male; Psoriasis; Time Factors; Tretinoin

Topics: Adult; Etretinate; Female; Humans; Male; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

Topics: Aged; Diagnosis, Differential; Etretinate; Female; Humans; Lymphocyte Activation; Psoriasis; Stevens-Johnson Syndrome; Suppuration; Tretinoin

26 patients with psoriasis and 23 patients with other dermatoses were treated for 28 days with oral retinoid Ro 10-9359. Intradermal tests to seven recall antigens were carried out before and after therapy. Dinitrochlorobenzene (DNCB) sensitization was started at the initiation of retinoid therapy and challenge tests made after 28 days. There was a significant increase in the reactions to recall antigens in all groups after 28 days' retinoid therapy. The reaction to DNCB was increased only in the non-psoriatic group compared with controls. These results demonstrate that the retinoid Ro 10-9359 stimulates cell-mediated immunity in vivo.

Topics: Dinitrochlorobenzene; Etretinate; Female; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunoglobulins; Intradermal Tests; Male; Middle Aged; Psoriasis; Skin Diseases; Tretinoin

Topics: Drug Evaluation; Drug Therapy, Combination; Etretinate; Female; Humans; Methotrexate; Middle Aged; Psoriasis; PUVA Therapy; Time Factors; Tretinoin

No significant changes were noted in the serum levels or molar ratios of vitamin A, retinol-binding protein (RBP) and prealbumin even during long-term (up to 15 months) treatment with RO 10-9359 in 19 patients with normal renal function. Nor did any significant alteration occur in the highly significant correlations between vitamin A and RBP, and between RBP and prealbumin. In 3 patients with slightly elevated serum creatinine, some tendency towards an elevation of vitamin A and RBP levels was seen.

Topics: Adult; Etretinate; Female; Humans; Male; Middle Aged; Prealbumin; Psoriasis; Retinol-Binding Proteins; Tretinoin; Vitamin A

The enlarged intercellular space in the lower malpighian layers of untreated psoriasis contains a fine granular and a coarse granular substance. Both types of this substance increase in amount during 2-6 weeks of retinoid (RO 10-9359) therapy. Retinoid stimulates the formation of these substances, which previously have been termed "mucus". After glutaraldehyde-osmium tetroxide fixation their mucoid nature cannot be ascertained more specific cytochemical techniques being needed for this. A darker, more homogeneous substance in the upper spinous intercellular spaces increases in amount during retinoid therapy. Large amounts of keratinosome-derived lamellae are observed at the boundary of the stratum intermedium and the stratum corneum. Even after 14 weeks of treatment with retinoid or retinoid plus PUVA, at clinical remission, the histological and electron microscopical pictures still show some psoriatic changes, i.e. enlarged intercellular spaces with fine or coarse granular substance.

Topics: Adult; Aged; Etretinate; Extracellular Space; Female; Humans; Male; Microscopy, Electron; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy; Skin; Tretinoin

Topics: Acne Vulgaris; Darier Disease; Humans; Ichthyosis; Psoriasis; Skin Diseases; Tretinoin; Vitamin A

Topics: Acne Vulgaris; Animals; Cocarcinogenesis; Etretinate; Humans; Immunity; Isomerism; Isotretinoin; Keratosis; Polyamines; Psoriasis; Skin; Skin Diseases; Teratogens; Tretinoin; Triglycerides; Vitamin A

Topics: Animals; Bile; Biotransformation; Etretinate; Feces; Humans; Kinetics; Liver; Psoriasis; Rats; Tissue Distribution; Tretinoin; Tritium

Combined oral retinoid (RO 10.9359) and PUVA therapy were given to 107 patients with psoriasis, 9 of whom had psoriatic arthropathy. Treatment was started with the retinoid at a dose of 1 mg/kg day and PUVA therapy added after 2 weeks. No other treatment was given. In 100 patients the combined therapy achieved clearing of the lesions, including scalp lesions, in a shorter time and with less total joules/cm2 than a group treated by PUVA alone. The remaining 7 patients were not responding to PUVA alone but achieved clearing when the retinoid was added. Five patients out of 9 with psoriatic arthropathy responded to the combined therapy. Predictable mild side-effects from the retinoid were encountered. The teratogenic risk of retinoid therapy is emphasized. The value of combined retinoid-PUVA therapy in psoriasis is discussed.

Topics: Adolescent; Adult; Aged; Etretinate; Female; Humans; Male; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy; Rheumatic Diseases; Tretinoin

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Etretinate; Female; Humans; Male; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin

Topics: Adult; Edema; Etretinate; Female; Humans; Psoriasis; Tretinoin

26 patients with generalized psoriasis were treated with oral Retinoid (Ro 10-9359; 50-150 mg/day) and radiations (2-5 times per week) with two different light sources emitting UVA and UVB. In 22 patients, remission was seen with only few remaining lesions at the predilection sites within 35 days. There was no obvious difference in the effect of the two light sources. 17 patients remained free from lesions for several months under a low-dose treatment with Ro 10-9359 and 2-8 radiations per month. The side effects of this treatment were negligible. This therapy is especially suited for outdoor patients with generalized psoriasis.

Topics: Etretinate; Humans; Outcome and Process Assessment, Health Care; Psoriasis; Tretinoin; Ultraviolet Therapy

Oral retinoids have been largely introduced in the management of psoriasis. The beneficial effect, however, differs according to the clinical type and requires an appropriate dosimetry: Pustular types respond rapidly and sufficiently to high initial doses (75 mg/d). In psoriatic erythroderma low initial doses (35 mg/d) seem indicated increasing the dose to 50 mg/d after 2-4 weeks. In chronic stationary psoriasis medium doses (50 mg/d) should be given as adjuvant treatment, combined with anthralin or UVB (SUP). In severe cases oral retinoids can be administered with systemic PUVA (RePUVA). Cheilitis, mucosal dryness and hair loss may appear temporarily as dose dependent side-effects. No hepatotoxicity was found. Interactions with serum triglycerides were seen, particularly in patients with diabetes, obesity, alcoholism and elevated triglyceride levels before treatment. Beside the compound Ro 10-9359 new synthetic derivatives are under investigation, either for topical therapy (Ro 11-1430), or for systemic therapy in lower doses (Ro 12-7554). Their mechanisms of action are still unknown. New findings suggest that retinoids may exert an immunomodulatory effect on dermal cells, in addition to their influence on keratinocytes.

Topics: Dose-Response Relationship, Drug; Drug Therapy, Combination; Etretinate; Humans; Psoriasis; PUVA Therapy; Tretinoin

Treatment with an oral aromatic retinoid (etretinate) and with PUVA significantly reduced the elevated levels of putrescine, spermidine and spermine in psoriatic lesions. Both treatments also significantly reduced the spermidine/spermine ratio, which is considered to be an indicator of proliferation activity. Although both regimens produced a roughly parallel reduction of epidermal polyamines the initial fall of putrescine was much more rapid in patients receiving retinoid. This may indicate that one of the primary targets of retinoids could be ornithine decarboxylase.

Topics: Adult; Aged; Etretinate; Humans; Middle Aged; Photochemotherapy; Polyamines; Psoriasis; Putrescine; PUVA Therapy; Skin; Spermidine; Spermine; Tretinoin

Eight patients with psoriasis or Darier's disease were studied during 1-3 months of 'Tigason' treatment (0.7-0.8 mg/kg body weight). The levels of triglycerides and cholesterol in whole serum and in different lipoprotein fractions were repeatedly determined. Before treatment all lipid values were within the normal range. During treatment the values changed gradually and five of the eight patients developed pathological VLDL triglyceride concentrations. A significant increase of VLDL cholesterol and a decrease in the HDL cholesterol was also noted. Until more information is available, prolonged treatment periods with 'Tigason' should perhaps be avoided, at least in high risk patients.

Topics: Cholesterol; Darier Disease; Etretinate; Female; Humans; Lipoproteins; Male; Psoriasis; Tretinoin; Triglycerides

Isolated peripheral mononuclear cells of psoriasis patients with different disease characteristics, e. g. head-localised, quiescent guttata, confluent active widespread and erythrodermic, were cultured in a modified Mishell-Dutton system. Using the plaque-forming cell (PFC) assay, single cell antibody formation was studied, and class distribution monitored, adding pokeweed mitogen (PWM), concanavalin A (ConA), methotrexate (MTX) or Ro-109359/31, as well as autologous sera to the culture. PFC-estimation vs. sheep red blood cells (SRBC) and burro red blood cells (BRBC) revealed a distinct suppression of primarily IgG-PFC in some of the PWM-treated patients' cultures; ConA maximally reduced PFC by only 50%, compared to 100% for normal immune cells. Ro-109359/31 reduced mainly IgG-PFC in the co-cultures with PWM or autologous sera. MTX resulted in a reduction of IgG-PFC and IgM-PFC equally. The results were compared with cultured immune cells from normal individuals. The two antigenically different indicators, the partial abolition of ConA induced suppression, broad-based immunoglobulin elevation in the sera, and the mainly IgG-formation hint at the role of polyclonal B-cell activation in the perpetuation of psoriasis, which can be specifically reduced by Ro-109359/31. Suppressor cell dysfunctions remain to be discussed.

Topics: Antibody Formation; Concanavalin A; Etretinate; Humans; Immunoglobulin G; Immunoglobulin M; Lymphocyte Activation; Lymphocytes; Methotrexate; Pokeweed Mitogens; Psoriasis; Tretinoin

Erythema anulare centrifugum with pustulation (EACP) is an unusual sterile pustulosis, which is believed to represent a rare type of pustular psoriasis. HLA-examination in this patient did not show, however, the typical pattern of vulgar of pustular psoriasis. No other signs of psoriasis were found either, except for the spongiform pustule. The EACP most likely corresponds to a special entity in the large group of psoriatic skin diseases. Oral retinoid therapy revealed full remission of the skin lesions.

Topics: Erythema; Etretinate; Female; Humans; Middle Aged; Psoriasis; Skin; Suppuration; Tretinoin

The effects of the aromatic retinoid RO 10-9359 on the fine structure of psoriatic dermis were investigated by electron microscopy in five patients after 1, 2, and 3 weeks of treatment (I mg/kg/day). Our findings show that aromatic retinoid, additionally to its epidermal effects, exerts a distinct influence on dermal components in psoriasis. Ultrastructural evidence is provided suggesting that this drug stimulates lymphocytes and monocytes, promoting their differentiation into Sézary-like lymphocytic cells, activated macrophages and dermal Langerhans cells. The appearance of these immunocompetent cell lines may modulate the cell-mediated immune response in psoriasis, obviously reflecting a pharmacological action of the drug additional to its definite influence on epidermal keratinization.

Topics: Etretinate; Humans; Immunity, Cellular; Langerhans Cells; Lymphocytes; Macrophages; Microscopy, Electron; Psoriasis; Skin; Tretinoin

In 5 children ranging in age from 8 to 12 years, treatment with Ro 10-9359 for either psoriasis or erythrokeratodermia variabilis for periods of between 11 and 17 months did not cause marked growth retardation and gave excellent therapeutic results.

Topics: Child; Dermatitis, Exfoliative; Etretinate; Female; Humans; Male; Psoriasis; Tretinoin

Topics: Acne Vulgaris; Humans; Psoriasis; Skin Diseases; Tretinoin; Vitamin A

The following treatments for psoriasis are compared with each other: PUVA, UVB, retinoid 10-9359 alone and in combination with 4 mg triamcinolone or UVB. The best results were obtained with UVB alone and with the combination of UVB and retinoid. Based on a survey of various psoriasis therapies during the last 40 years, it is concluded that a final assessment of the value of a new therapy is only possible after some time.

Topics: Etretinate; Humans; Photochemotherapy; Psoriasis; PUVA Therapy; Tretinoin; Triamcinolone; Ultraviolet Therapy

The ever increasing expenditures in health service urgently call for a critical revision of the therapy habitually practiced so far. This also includes the complete utilization of ambulatory therapeutic approaches. Moreover, after many years of clinical practice, the dermatologist in general practice should not forego the manifold therapeutic methods in which he had been trained and by the application of which he has gained particular experience. The dermatologist's small office consisting of a desk and couch must be a matter of the past once and for all. It is just the dermatologist who has the opportunity to try many forms of clinical treatment in general practice.

Topics: Family Practice; Humans; Keratosis; Methotrexate; Methoxsalen; Patient Care Team; Photochemotherapy; Psoriasis; Skin Diseases; Tretinoin

Topics: Acne Vulgaris; Ficusin; Humans; Information Services; Psoriasis; Tretinoin; Ultraviolet Therapy

Dermatitis occurring as a side effect in psoriatic patients during oral administration of the retinoid acid derivative Ro 10-9359 is described. This so-called retinoid dermatitis exhibits a characteristic disseminated pattern. Sites of predilection are the face, the exterior surface of the upper and the interior surface of the lower arms, the superior thoracic aperture, the back of the hands and the flanks. The lesions present as follicular papules and/or vesicles. The histological picture is that of acute non-specific dermatitis. This retinoid dermatitis was observed in 9 our of 23 patients (39%) treated with Ro 10-9359. Other side effect such as erythema, desquamation, itching and, rarely, a burning sensation showed the same distribution. The characteristic dermatitis, as well as the other side effects mentioned, occur dose-dependently within the normal therapeutic range of Ro 10-9359 for psoriasis (0.5--1 mg/kg bodyweight daily).

Topics: Administration, Oral; Adolescent; Adult; Aged; Child; Drug Eruptions; Etretinate; Female; Humans; Male; Middle Aged; Psoriasis; Tretinoin

In a multicentre, cooperative study into the treatment of extensive psoriasis with a new aromatic retinoid (Ro 10--9359) trichogram, liver function tests and the light erythema threshold were investigated. In some of the patients hair loss occurred, usually in the fifth to eighth week after a total dose of 1.9 g retinoid. In all cases this improved an average of six weeks after dose reduction or cessation of treatment. The trichogram in 27 patients showed a diffuse toxic hair loss. In 70% the effluvium was telogenic, in 22% telogen-dystrophic. GPT, GOT, alkaline phosphatase and prothrombin index showed no significant alterations during retinoid treatment. However, in individual cases there was a rise in GOT and GPT up to 80 U/l. Furthermore there was a statistical tendency in rising bilirubin levels. Finally there was no evidence for an increase in light sensitivity after three weeks of retinoid treatment. Measurement of the erythema threshold showed rather more a reduction in light sensitivity under treatment.

Topics: Alanine Transaminase; Alkaline Phosphatase; Alopecia; Aspartate Aminotransferases; Erythema; Humans; Liver; Prothrombin; Psoriasis; Time Factors; Tretinoin; Vitamin A

In a group of 40 patients suffering from wide-spread psoriasis oral administration of a retinoid (Ro 10-9359) was followed by PUVA therapy. The clearance rate was increased by 30% as compared to PUVA alone. Except for cheilitis no side effects were seen. Histological analysis in 20 patients before, during and after therapy revealed an intensification of psoriatic tissue changes after retinoid treatment. Loss of corneal layers, massive exoserosis, and neutrophil migration were prominent features. Mitotic counts were not increased by the pretreatment. The increased susceptibility of diseased skin to PUVA as produced by this drug appears to be based on several factors related to the tissue changes revealed by histology.

Topics: Humans; Methoxsalen; Photochemotherapy; Psoriasis; Skin; Tretinoin; Vitamin A

Numerous laboratory parameters were examined 235 patients with generalized psoriasis treated orally with retinoid and in 35 patients treated topically with anthralin as control. Computer evaluation of the obtained data revealed statistical trends to elevation of the total serum bilirubin level and increasing number of blood monocytes after long-term oral treatment. No other statistically significant changes of the laboratory data were found. Particularly, the liver function tests (transaminases, prothrombin and alkaline phosphatase) showed no significant alterations. Only in a few cases did the retinoid compound have an influence on the GPT and GOT levels. The reasons for this individual sensitivity to the drug remain unknown. No significant alterations were found in the control group treated topically with anthralin.

Topics: Administration, Oral; Administration, Topical; Alanine Transaminase; Alkaline Phosphatase; Anthralin; Aspartate Aminotransferases; Evaluation Studies as Topic; Humans; Leukocyte Count; Liver Function Tests; Monocytes; Psoriasis; Species Specificity; Tretinoin

Topics: Etretinate; Humans; Psoriasis; Tretinoin

Topics: Arthritis; Drug Therapy, Combination; Etretinate; Furocoumarins; Humans; Photochemotherapy; Psoriasis; Tretinoin

Topics: Humans; Psoriasis; Skin Diseases; Tretinoin; Vitamin A

Four patients with active seronegative psoriatic arthropathy were treated with retinoid (Ro 10-9359) in a daily dose of 30 mg for at least four months. Within the first 4--6 weeks of treatment all patients showed marked improvement of arthritis as measured by the number of swollen joints, the Ritchie joint index, morning stiffness and the pain experienced. One patient stopped taking her concomitant medication of nonsteroidal anti-inflammatory agent, while the others were able to reduce the intake of such drugs substantially. None of the patients were taking steroids. The elevated erythrocyte sedimentation rate observed in all patients studied also fell gradually in the course of treatment. With the exception of dry lips observed in two patients, other adverse effect such as extensive mucosa dryness and cheilitis, as commonly seen in patients receiving this agent, were not recorded. In view of these encouraging preliminary results we are now conducting a multicenter control study to substantiate these findings.

Topics: Adult; Aged; Arthritis; Drug Evaluation; Etretinate; Humans; Middle Aged; Pilot Projects; Psoriasis; Tretinoin

Skin psoriasis, a multi- causal disease with unknown mechanism, has several clinical aspects. Besides ordinary psoriasis with mica-like plaques and its special locations, two less known notions are underlined: the localized forms are often less typical (for example: scalp, ears, folds of the hand, foot and nails). They may be relevant to the rhumatologist for the diagnosis the inflammatory forms are often disseminated with pustules and keratosis and constitute another groups where the rhumatologic manifestations are more frequent and more severe. Various forms of treatment are active on the cutaneous symptoms, chronic or relapsing topical therapy with tar, corticoids, nitrogen mustard, photochemytherapy, oral derivatives of retinoic acid, and exceptionally immunosuppressors. Each technic has its advantages, its disadvantages on a short or long term. Therefore each patient should receive the therapy which is adapted to his form of psoriasis, the need and possibilities of the patient. Collaboration is a must and each patient should receive the adequate care making possible an improvement of his condition.

Topics: Adrenal Cortex Hormones; Female; Humans; Male; Mechlorethamine; Photochemotherapy; Psoriasis; Tars; Tretinoin

Topics: Dose-Response Relationship, Radiation; Drug Therapy, Combination; Follow-Up Studies; Humans; Methoxsalen; Photochemotherapy; Psoriasis; Skin; Tretinoin; Ultraviolet Therapy; Vitamin A

Topics: Aged; Coumarins; DNA Repair; Ficusin; Humans; Male; Nucleic Acids; Photochemistry; Psoriasis; Tretinoin; Ultraviolet Therapy

RePUVA is a new therapeutic approach in psoriasis, consisting in oral administration of a retinoid derivative and systemic PUVA treatment. The retinoid (Ro 10-9359) was given daily (50--75 mg) before, simultaneously and, before and simultaneously with PUVA. The overall response was 73%; however, 14 patients resistant to previous standard PUVA treatment also responded surprisingly well to RePUVA. If PUVA-resistent patients were excluded, the overall response was 82.6%. The mean number of treatments required for clearing was 19.4 +/- 6.1, the mean total UVA-dose 57.9 +/- 32.3 J/cm2 and the mean duration of treatment was 55.4 +/- 14.1 days, including pretreatment with retinoid. It seems that RePUVA may be most successful if the retinoid is given before and with PUVA: 33.7 +/- 8.7 J/cm2 in 17.0 +/- 4.7 sessions were then required for clearing. Compared with previous results of our group and recent publications these findings indicate that the RePUVA schedule may reduce the duration of treatment and the total UVA-dose and, therefore, the possible long-term hazards of PUVA management. In addition, RePUVA can be successfully applied in patients resistant to standard PUVA.

Topics: Coumarins; Drug Therapy, Combination; Female; Ficusin; Humans; Male; Photochemotherapy; Psoriasis; Tretinoin; Ultraviolet Therapy; Vitamin A

Topics: Adult; Erythrocytes; Female; Glucose; Humans; Male; Pentosephosphates; Phosphoribosyl Pyrophosphate; Psoriasis; Tretinoin; Vitamin A

Topics: Adult; Furocoumarins; Humans; Male; Middle Aged; Photochemotherapy; Psoriasis; Remission, Spontaneous; Tretinoin; Vitamin A

Topics: Female; Humans; Middle Aged; Psoriasis; Tretinoin; Vitamin A

17 patients with pustular psoriasis, i. e. 9 generalized and 8 localized types, were treated orally with the new aromatic retinoid RO 10-9359. The given dose was 0.5-1.0 mg/kg body weight per day. After 4-8 weeks the result was very good or good in 13 cases. Side effects were moderate; only in one female patient the oral treatment was interrupted because of drug-induced alopecia. Histologic examinations revealed spongiform pustules before treatment and typical features of psoriasis vulgaris after 2 weeks; after 4 weeks most tissue changes had returned to normal. An unusual fine granular mucoid material was seen under the electron microscope in the intercellular spaces of the epidermis, being most likely produced in the keratinocytes.

Topics: Administration, Oral; Adult; Aged; Epidermis; Female; Humans; Intercellular Junctions; Male; Middle Aged; Psoriasis; Tretinoin; Vitamin A

The aromatic retinoic acid derivative Ro 10-9359 was administered orally to 25 severe psoriatic patients (14 with generalized plaques, 7 erythrodermic, 4 pustular). The initial dose was 25 mg/20 kg body weight daily for 4 weeks; afterwards the same posology was given every other day during several months (Max : 18 months). Excellent results were obtained in 16 patients (64 p. 100) particularly in severe erythrodermic and pustular psoriasis. However, under follow-up therapy relapses sometimes occurred leading to temporary resumption of initial posology. The most important side effects are cheilitis, palmoplantar scaling with thinning of the skin, hyperhidrosis and diffuse hair loss. A slight increase of transaminases and of alkaline phosphatases was found in a few patients. The Ro 10-9359 compound is a very useful new therapy of severe psoriasis.

Topics: Administration, Oral; Adult; Alkaline Phosphatase; Alopecia; Cheilitis; Female; Humans; Hyperhidrosis; Male; Psoriasis; Transaminases; Tretinoin; Vitamin A

The light sensitivity was determined on 14 psoriasis patients using two different light sources before, and after a three week period of systemic administration of 75 to 100 mg daily of the aromatic retinoid (ethyl ester of all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid, Ro 10-9359 [1]). The results indicate that with this therapy, the light sensitivity remains unchanged or even decreases; there is thus no contraindication to the simultaneous application of phototherapy and the systemic administration of this retinoic acid derivative.

Topics: Administration, Oral; Etretinate; Humans; Photosensitivity Disorders; Phototherapy; Psoriasis; Tretinoin; Ultraviolet Therapy

The retinoic acid derivative Ro 10-9359, given orally in maximum daily doses of 100 mg to 15 patients with psoriasis vulgaris, led to clearing of the lesions in 8 patients. The average period of treatment was 9 weeks. In 14 patients side-effects were observed, the most important being palmo-plantar desquamation, shivering, thirst and diffuse hair loss. In 2 patients scaling led to withdrawal. In 6 patients abnormal alkaline phosphatase and glutamic-aspartatic transaminase values, partly transient, developed (glutamicaspartatic transaminase, p less than 0.01).

Topics: Alkaline Phosphatase; Aspartate Aminotransferases; Drug Evaluation; Female; Humans; Male; Psoriasis; Time Factors; Tretinoin; Vitamin A

Application of retinoic acid (vitamins which microscopically and histochemically resemble those of psoriasis. In the present studies, the daily application of a 0.1% solution of retinoic acid to the dorsal ear surface of guinea pigs produced a progressive psoriasiform scaling which was apparent grossly and which could be quantitated. Triamcinolone acetonide, hydrocortisone and methotrexate, all known to be useful clinically in the treatment of psoriasis, were examined for their ability to antagonize the development of retinoic-acid-induced scaling. Systemic activity was observed with all three agents; topical activity was obtained with triamcinolone acetonide but not with methotrexate or several of its analogs. On the basis of activity profiles obtained with standard anti-psoriatic compounds, it is suggested that retinoic acid lesions may have utility in identifying the anti-psoriatic potential of new compounds.

Topics: Animals; Guinea Pigs; Hydrocortisone; Methotrexate; Psoriasis; Skin; Tretinoin; Triamcinolone Acetonide; Vitamin A

Topics: Administration, Oral; Adolescent; Adult; Aged; Child; Darier Disease; Female; Humans; Ichthyosis; Keratoderma, Palmoplantar; Keratosis; Leukoplakia; Male; Middle Aged; Pityriasis Rubra Pilaris; Psoriasis; Skin Neoplasms; Tretinoin; Vitamin A

Daily treatment of guinea-pig ear skin with topical 0.5% retinoic acid in acetone produced erythematous scaly dermatitis. Histologic sections revealed bandlike thickening of the epidermis on days 2 to 4, psoriasiform acanthosis, papillomatosis and increased mitotic activity on days 5 to 6. Also seen were dilatation of the upper dermal blood vessels and a fibroblastic, histiocytic reaction in the dermis. Prostaglandin E, cyclic AMP, and cyclic GMP levels were increased in the treated skin and thymidine incorporation was enhanced. Cyclic AMP and GMP levels peaked on day 5 simultaneous with maximal epidermal hyperplasia, increased mitotic activity and dermal reaction. Tritiated thymidine uptake peaked on days 4 and 5, and prostaglandin E levels continued to increase up to day 6. Cyclic AMP phosphodiesterase activity of treated skin on day 5 did not appear to be significantly different from control.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Topical; Animals; Cell Division; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Erythema; Guinea Pigs; Male; Models, Biological; Prostaglandins E; Psoriasis; Skin; Skin Physiological Phenomena; Thymidine; Tretinoin; Vitamin A

Topics: Adult; Aged; Drug Evaluation; Humans; Male; Middle Aged; Psoriasis; Tretinoin; Vitamin A

Topics: Adult; Biopsy; DNA Replication; Female; Humans; Male; Psoriasis; Skin; Tretinoin; Vitamin A

All-trans retinoic acid and its derivative retinoid, two new compounds with expanding therapeutic spectrum in dermatology, were investigated in biochemical assays. Both substances provoke an increase in oxygen consumption of rat skin whereas in human skin only retinoid was found active in this respect. In resting yeast cells, both substances failed to exert any significant influence on oxygen consumption.--Pure G-6-PDH was inhibited by retinoic acid and retinoid in concentrations as low as 5 mug/ml. In human skin homogenates, LDH-, GAPDH-, and G-6-PDH-activities were inhibited by retinoic acid whereas GOT-, LAP-, and ALD-activites remained practically unchanged following an incubation with retinoic acid in concentrations between 1 and 100 mug/ml for 60 min.--The data collected in this study were briefly discussed with regard to the use of retinoic acid and its derivatives in psoriasis.

Topics: Animals; Glucosephosphate Dehydrogenase; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; L-Lactate Dehydrogenase; Oxygen Consumption; Psoriasis; Rats; Skin; Tretinoin; Vitamin A

Topics: Administration, Topical; Humans; Psoriasis; Tretinoin; Vitamin A

Topics: Administration, Topical; Adult; Citrates; Glucosephosphate Dehydrogenase; Humans; L-Lactate Dehydrogenase; NAD; Oxidoreductases; Phosphorylases; Psoriasis; Skin; Tretinoin; Vitamin A