Differential hepatotoxicity of two oral retinoids (etretinate and isotretinoin) in a patient with palmoplantar psoriasis

A phase I study was carried out with the new aromatic retinoic acid analogue DCE, all-trans-9-(2,6-dichloro-4-methoxy-m-tolyl)-3,7-dimethyl-2,4,6,8- nonatetraenacetylester. Data from preclinical studies show that DCE has a promising anti-tumor effect. Data from others investigators show that when DCE was given to patients in daily doses, the dose-limiting toxicity. This toxicity was comprising considerable muco-cutaneous toxicity, occurred at 40 mg/day. To avoid this dose-limiting toxicity, a weekly oral treatment schedule was tested for toxicity in this study. The starting dose was 40 mg/m2 body surface, and a modified Fibonacci scheme was used for the dose escalations. A total of 20 patients entered this study, and all were evaluable for toxicity. The highest dose was 300 mg/m2. In three patients, completely reversible WHO grade 1 liver toxicity was observed. In contrast to daily doses, a once-a-week schedule produced no mucocutaneous toxicity. Pharmacokinetic measurements showed that absorption was highly unpredictable and did not increase with dose increments. Given the results of the pharmacokinetic determinations, we concluded that escalating the DCE dose would not lead to a recommendable dose for further phase II studies, and the study was subsequently discontinued.

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Adverse Effects of Retinoids

David

1988

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Oral retinoids, synthetic derivatives of vitamin A, have been used in the treatment of various dermatoses over the last decade. The most useful drugs have been isotretinoin (13-cis-retinoic acid) for nodulocystic acne and etretinate for psoriasis vulgaris. Retinoids are also effective in the treatment of papulosquamous dermatoses other than psoriasis (i.e. inherited disorders of keratinisation), cutaneous T-cell lymphoma and in chemotherapy and chemoprevention of cancer. However, systemic administration of these compounds is frequently associated with mucocutaneous side effects, liver toxicity and abnormalities of serum lipid profiles, which might be related to an increased risk of coronary heart disease. Of particular concern is the teratogenic effect of all retinoids, which limits their use in women of child-bearing potential. Chronic toxicities from long term therapy with retinoids may result in skeletal abnormalities, usually mimicking diffuse idiopathic hyperostosis syndrome. Furthermore, the chronic use of retinoids in children may inhibit their growth due to premature epiphyseal closure. In contrast to other side effects of retinoids which are dose dependent and reversible upon withdrawal of the drug, it seems unlikely that bone abnormalities will resolve after discontinuation of the medication. In view of the wide spectrum of toxicities, treatment with retinoids requires appropriate selection of patients, careful consideration of the benefit to risk ratio for each individual, periodic monitoring of clinical response and laboratory tests. Clinicians should use special management techniques in order to prevent or minimize slide effects. Extensive investigations are currently being conducted in an attempt to develop new retinoids which will improve the therapeutic efficacy and reduce unwanted reactions.

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Differential hepatotoxicity of two oral retinoids (etretinate and isotretinoin) in a patient with palmoplantar psoriasis

Cited by 17 publications

References 6 publications

Retinoids — Present Status

Retinoids — Present Status

A phase 1 and pharmacokinetic study using the aromatic retinoic acid analogue dichloroetretinate (Ro 12-7554)

Adverse Effects of Retinoids

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