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Etretinate (Tigason, Tegison) and its active metabolite acitretin (Neotigason, Soriatane) are known teratogens. Pregnancy should be avoided during treatment and until 2 years after treatment discontinuation. The question is discussed whether a dose or a blood concentration of the drug below which there is no teratogenic risk can be determined. Animal experimental and human pharmacokinetic data are reviewed. An evaluation of the outcomes of pregnancies which occurred in mothers exposed to etretinate or acitretin was performed. A threshold dose in human therapy below which there is no risk of congenital malformation cannot be determined based on animal experimental data. With regard to pharmacokinetics, there are currently no data suggesting that blood levels of the drug below the detection limit of 2 ng/ml are associated with a teratogenic risk. The most useful information is given by reports in women who were exposed to either retinoid before or during pregnancy. The data indicate that the risk of spontaneous abortion or congenital malformation is high when the drug is administered during the first trimester of pregnancy. After treatment discontinuation, the risk is low since the number of abnormalities seems not to exceed those observed in a general population. There are currently no available data which suggest that the pregnancy warnings are inappropriate in terms of duration of contraception.

The aim of this study was to investigate the possible esterification of acitretin into etretinate by using hepatocytes in primary culture from the rat, monkey, dog and man. With rat and human hepatocytes, etretinate was detectable only when ethanol was co-administered with acitretin. With monkey and dog cells, traces of etretinate were found without ethanol addition, but the esterification of acitretin was highly enhanced by ethanol. The metabolic profile was not changed when cells were pre-incubated with ethanol. Therefore acitretin seems to act rather as a substrate than an enzymatic inducer.

Nearly two decades after the advent of synthetic retinoids for the treatment of many severe and incapacitating dermatologic conditions, the usefulness of these drugs is not universally accepted. The safety profile is well established. Other than teratogenicity, which can be avoided if the recommended precautions for use are followed, serious or unexpected adverse reactions rarely occur. This article concisely addresses some questions about etretinate and acitretin therapy that are most pertinent for the dermatologist.

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.

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.

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.

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.

Sixty patients with palmoplantar pustulosis were treated in a double-blind trial with either acitretin (etretin, Ro 10-1670) or with etretinate. The study consisted of 4 weeks of therapy with three 10 mg capsules/day followed by 8 weeks of therapy with a varying number of capsules given daily according to therapeutic response. At the end of the 12-week treatment period, the mean number of pustules (+/- SEM) had decreased from 57.8 (+/- 8.6) to 3.9 (+/- 1.6) in the acitretin group and from 57.1 (+/- 14.1) to 5.7 (+/- 2.7) in the etretinate group. With regard to influence on erythema, infiltration, scaling, and area involved, similar improvements were obtained in both treatment groups. Adverse reactions of the hypervitaminosis A type were observed with almost the same frequency and severity in both treatment groups. The mean number of 10 mg capsules used daily was comparable in the two groups: 2.82 (range 1.23-4.67) for acitretin and 2.77 (range 1.60-4.82) for etretinate. It can be concluded that acitretin and etretinate do not significantly differ with regard to efficacy and overall safety in the treatment of patients with palmoplantar pustulosis.

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.

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.