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The metabolism of acitretin and isoacitretin in the in situ isolated perfused rat liver.

1. The metabolism of acitretin and its 13-cis isomer, isoacitretin, has been investigated in the in situ isolated perfused rat liver in order to differentiate the action of the liver from that of the gut on the metabolism of these isomers. 2. Acitretin undergoes alpha-oxidation, chain shortening O-demethylation, and glucuronidation in the perfused rat liver. 3. Isoacitretin undergoes glucuronidation as the major, almost exclusive, route of metabolism in the perfused rat liver. 4. The difference in the hepatic metabolism of the cis and trans isomers of this retinoid may explain the differences in their pharmacokinetics, and may help in understanding the pharmacokinetics of related retinoids.

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A double-blind comparison of acitretin and etretinate in the treatment of Darier's disease.

The objective of this double-blind study was to compare the therapeutic effects of acitretin with those of etretinate in patients with Darier's disease. Twenty-six patients (10 males and 16 females) were included in the study. Patients were treated with 30 mg daily for the first 4 weeks and with an individually adjusted dose (10-50 mg/day) for the subsequent 12 weeks. Remission or marked improvement was obtained in 10 of the 13 acitretin-treated patients and in 8 of the 11 etretinate-treated patients who completed the 16-week treatment. The usual mucocutaneous adverse reactions of retinoids were observed in all but one patient. There were no significant differences between treatment groups with regard to the incidence of these reactions.

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Efficacy and skeletal side effects of two years' acitretin treatment.

In this prospective study, 51 patients suffering from psoriasis and ichthyosis were treated with acitretin for 2 years. The average dose was 0.5 mg/kg/day. We have evaluated the efficacy and side effects, focusing on skeletal side effects. X-ray examinations were done before treatment and after 1 and 2 years. Forty-five patients completed the study. Acitretin had a good clinical effect, with 75% improvement in 35 of the patients. Apart from the well-known side effects affecting the mucous membranes, one patient developed biopsy- proven toxic hepatitis. In 2 patients we observed unusual skeletal calcifications located in the forearms and in the hip. These were considered to be caused by the drug. In this study, which included patients up to 71 years, only radiographs of the pelvis and the forearms were of value as routine follow-up films.

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Acitretin and AIDS-related Reiter's disease.

A patient with AIDS presented with Reiter's syndrome. Arthritis and skin lesions responded poorly to nonsteroidal anti-inflammatory drugs and topical corticosteroid therapy. Dramatic improvement was seen 2 weeks after acitretine was added. When Reiter's syndrome recurred 11 months later despite treatment with highly active anti-retroviral drugs and an undetectable plasmatic viral load, acitretin without NSAID or topical treatment was again administered and was rapidly effective.

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The treatment of psoriasis with etretinate and acitretin: a follow up of actual use.

The present study is a retrospective search on the actual use of systemic retinoids in the treatment of psoriasis. The design of the study was inclusion of the patients in whom retinoid treatment was initiated from 1981 up to 1989. The analysis was carried out in 1999, after at least 10 years of follow up. In total 94 patients were included, who were treated with etretinate or acitretin, out of a cohort of 2,000 patients with psoriasis at the Nijmegen Department of Dermatology. The majority of the patients were older than 40 years, 31% were suffering from pustular psoriasis, 6% from erythrodermic psoriasis and 17% from psoriasis arthropatica. Most patients had had psoriasis for more than 5 years and in 56% of them retinoids were the first systemic treatment. Continuous treatment for more than one year was recorded in 33% of the patients. During long-term follow up of at least 10 years, 25% of them were included again for acitretin treatment. Therefore, prolonged treatment actually had occurred in approximately half of the patients. In contrast to the common belief, erythrodermic psoriasis proved to be not the typically "low-dose" - and pustular psoriasis was not the typically "high dose" indication. The present study, however, reconfirmed the high efficacy of systemic retinoids in pustular- and erythrodermic psoriasis. It was also reconfirmed that systemic retinoids are not effective in arthropathic psoriasis. The occurrence of side effects largely followed the controlled investigations. At least 10 years' follow up had not revealed serious side effects. In those patients (n = 30) who completed the entire survey in the Nijmegen centre 19 patients were treated with at least one course of photo(chemo)therapy and 9 patients were treated subsequently with methotrexate.

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Efficacy of acitretin in severe psoriasis.

Acitretin (Soriatane, Roche Pharmaceuticals) is an aromatic retinoid, effective in the treatment of severe psoriasis. This study highlights data from two existing clinical trials to capture PASI 50 and PASI 75 responder rates which represent a common metric used in current psoriasis clinical trials. A review of pharmacokinetics, safety and a discussion of relapse rate establish acitretin as an efficacious, convenient, oral treatment for initial and maintenance therapy of severe psoriasis.

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Oral acitretin induces alterations in mouse liver phospholipid composition.

3 and 10 mg/kg/day acitretin, a new synthetic retinoid, were orally administered to two groups of Ng57Bln mice (12 animals each) respectively, over a period of six weeks. Control animals (N = 10) received corresponding quantities of arachis oil. Chromatographic analysis and quantitative determination of the isolated phospholipid classes revealed statistically significant alterations in the liver phospholipid composition of the treated animals under both acitretin dosages, which may be associated with changes in the metabolic activity, ionic transport and cell-cell interaction of the liver cellular components.

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Sequential therapy using cyclosporine and acitretin for treatment of total body psoriasis.

Systemic sequential therapy using cyclosporine and acitretin is a novel strategy that can provide quick resolution and maintenance in refractory cases of psoriasis. We describe the case of a patient with a psoriatic flare over 98% of his body, despite methotrexate therapy. Implementing sequential therapy with cyclosporine and acitretin maximized the benefit of each treatment and allowed for rapid improvement with minimal risk of toxicity.

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Clinical and ultrastructural effects of acitretin in Darier's disease.

Thirteen patients with Darier's disease with a mean extent of the lesions of 29.4 +/- 10% of the total skin area were treated with acitretin (the main metabolite of etretinate) for 16 weeks. The dose was 30 mg/day during the initial 8 weeks and was later adjusted individually to 10-30 mg/day in order to achieve optimal results. Three patients cleared completely, 7 patients showed marked improvement and 3 patients became slightly better during treatment. The mean extent of the lesions after the treatment was 7.3 +/- 8% of the skin area. Despite good clinical clearing, the improvement at the ultrastructural level was incomplete in the 3 patients studied by electron microscopy. Normal stratification did not develop and the size and number of desmosomes remained reduced. The main side effects during treatment were pruritus in 5 patients, diffuse alopecia in 2 patients and marked elevation in serum triglycerides in 4 patients. On the basis of this study, acitretin would seem to be a useful alternative to etretinate for the treatment of Darier's disease.

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[Bazex paraneoplastic acrokeratosis. Treatment with acitretin].

INTRODUCTION: Bazex paraneoplastic acrokeratosis remains a therapeutic challenge when the cancer cannot be treated. We report the third patient in which a complete clearance of the lesions was obtained with oral acitretine. CASE REPORT: A 67 year-old patient had Bazex paraneoplastic acrokeratosis. Despite a complete cancer screening, no cancer was found. A cervical lymph node metastasis was treated with surgery and radiotherapy. Because the cutaneous lesions got worse after this treatment, the patient received oral acitretine. A complete clearing of the lesions was observed within 2 months. DISCUSSION: Only 2 similar cases have been reported to our knowledge. The comparison with these 2 cases supports the efficacy of oral retinoids in this disease. The search and the treatment of the cancer remain compulsory. CONCLUSION: In some definite cases, oral retinoids can be proposed as a treatment of cutaneous lesions in Bazex paraneoplastic acrokeratosis.

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Etretinate may work where acitretin fails.

Acitretin (Ro 10-1670, Neotigason), a second-generation monoaromatic retinoid, is the main acid derivative and active metabolite of etretinate (Ro 10-9359, Tigason). Three patients who were unresponsive to treatment with acitretin but who responded to etretinate are reported. Twenty-nine patients in the U.K. are currently receiving etretinate on a named-patient basis. Possible explanations for the functional discrepancy between the two drugs are discussed.

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Glutathione catalysis of interconversion of acitretin and its 13-cis isomer isoacitretin.

The ability of glutathione to catalyze the cis-trans isomerization of acitretin and isoacitretin was explored. Glutathione catalyzed the isomerization reaction in both directions; the reaction rate varied with glutathione concentration, atmospheric exposure condition, and identity of starting isomer. The ability of this widely distributed molecule to catalyze this interconversion nonenzymatically may contribute to the presence of both isomers in vivo after administration of either isomer.

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Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA.

Interferon-alpha combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-alpha antibodies (IFN ab) occur regularly during IFN-alpha treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subcutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg bodyweight) daily or with 5-methoxypsoralen (1.2 mg/kg bodyweight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of beta 2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.

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[Treatment of lichen planus pemphigoides with acitretin and pulsed corticosteroids].

A patient with lichen planus pemphigoides first developed multiple pruritic papules and subsequently, tense blisters on trunk and extremities. Histopathologic examination of a skin biopsy demonstrated both the typical changes of lichen planus and subepidermal blisters as in bullous pemphigoid. Direct immunofluorescence microscopy revealed both cytoid bodies and linear C3 deposits at the dermal-epidermal junction. By indirect immunofluorescence microscopy on 1 M NaCl-split-skin, circulating autoantibodies labeled the epidermal side of the split. Immunoblot analysis showed binding of the antibodies to the cell-derived soluble 120 kD domain of the 180 kD bullous pemphigoid antigen and to a recombinant form of the immunodominant NC16A region of this protein. When treated with pulsed intravenous corticosteroids, the patient continued to develop new papules and blisters, but when oral acitretin was added, the skin lesions cleared. The immunoblot reactivity of the patient's autoantibodies well reflected disease activity, while the indirect immunofluorescence microscopy titers did not.

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Improved quantitation of 13-cis- and all-trans-acitretin in human plasma by normal-phase high-performance liquid chromatography.

A reliable analytical method has been developed for measurement of 13-cis- and all-trans-acitretin (Neotigason) in human plasma by normal-phase high-performance liquid chromatography, with ultraviolet detection. Human plasma was obtained after centrifugation of whole blood samples and deproteinized by ethanolic denaturation. After liquid-liquid extraction with water-n-hexane, and aliquot ws chromatographed on a silica column using isocratic elution with n-hexane-methylsalicylate-acetic acid (200:18:0.6, v/v). The wavelength was set at 360 nm, and for plasma samples a limit of quantification of 3-4 ng/ml was obtained. All manipulations were carried out under dim light conditions to prevent photoisomerization.

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Multiple verrucous carcinomas treated with acitretin.

Cutaneous verrucous carcinoma is a rare variant of low-grade squamous cell carcinoma. It usually involves distal extremities and is often misdiagnosed as giant warts. Multiple cutaneous verrucous carcinomas are rare in the English-language literature. We describe a 41-year-old man with multiple verrucous plaques on both feet and ankles, as well as the left thigh. Immunohistochemical study with proliferating cell nuclear antigen revealed positive staining of the basal and suprabasal layers. The patient's condition was successfully treated with systemic acitretin.

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Acitretin induces capillary leak syndrome in a patient with pustular psoriasis.

Capillary leak syndrome is a rare and potentially life-threatening condition caused by a shift of intravascular fluid and proteins to the interstitial space. We describe a patient with pustular psoriasis in whom capillary leak syndrome developed after the start of acitretin. Immediate withdrawal of retinoic acid is necessary and corticosteroid therapy should be considered.

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