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PubMed1992

Ad hoc tracing of a cohort of patients exposed to acitretine (Neotigason) on a nation-wide scale.

Etretinate has been detected in the blood of women taking acitretine. Because of the proven teratogenic effects of etretinate it was decided to try to trace all users of acitretine in The Netherlands via all drug dispensing outlets (1450 community pharmacies, 95 hospital pharmacies and 636 general practitioners). A request for information on the date of birth, sex, type of prescriber, and the number of capsules dispensed yielded a response rate of 87%. In 61% of all the responding dispensing outlets a prescription for acitretine had been filled. Of these 1153 outlets, 40% had dispensed acitretine to one patient and 52% had dispensed it to 2-5 patients. The 2717 patients comprised 1500 men (55%) and 1217 women, with mean ages of 48 and 53 y, respectively. As against 45% of all the male users, 31% of all the women were in the child-bearing age (15-45 y). The average numbers of dispensed capsules was 167 to users of 10 mg capsules, and 107 to users of the 25 mg capsules. In more than 80% of cases acitretine had been prescribed by dermatologists. Because the large majority of inhabitants in The Netherlands use one community pharmacy, and because most of them have automated records, it is possible to trace a cohort of users quickly and almost completely. Because most large-scale problems with adverse reactions are discovered within the first 2 years of marketing, at a time when exposure and morbidity registries are still collecting information, ad hoc formation of a cohort in this way may be a useful resource for postmarketing surveillance.

Acitretin↗
PubMed1990

Uptake of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, delivered to cultured human fibroblasts by serum proteins. Lack of evidence for perturbation of LDL catabolism.

Etretinate or acitretin are efficiently delivered to cultured human fibroblasts in the presence of low density lipoproteins, high density lipoproteins or human serum albumin. In contrast to acitretin, delivery of etretinate to fibroblasts is more efficiently achieved with human serum albumin than with lipoproteins. The uptake of etretinate and acitretin via low density lipoproteins delivery, does not take place via the low density lipoprotein-receptor endocytotic pathway but mostly through a passive exchange with the plasma membrane. However, in contrast to acitretin, the exchange of etretinate seems to occur alter binding of etretinate-loaded low density lipoproteins to the apolipoprotein B receptors. No differences are observed in binding, internalization and degradation of native, etretinate-loaded low density lipoproteins and acitretin-loaded low density lipoproteins, suggesting that the presence of these retinoids in low density lipoproteins does not alter their processing by the cells. Furthermore, the presence of these retinoids in the cells does not notably affect, under our experimental conditions, the catabolism of native low density lipoproteins.

Acitretin↗
PubMed1995

Vulvo-vaginal candidiasis associated with acitretin.

The aim of this study was to estimate the risk of vulvo-vaginal candidiasis among the users of acitretin. The incidence rate ratio of vulvo-vaginal candidiasis was estimated in a cohort of acitretin users by using prescription sequence analysis. Study subjects were 196 women between 15 and 45 years of age, exposed to acitretin in 1990. Prescriptions of drugs for treatment of vulvo-vaginal candidiasis were used as proxy for the occurrence of vulvo-vaginal candidiasis. Validation of the proxy drug was performed by record linkage of pharmacy and medical records. In addition to the risk estimation by incidence rate ratios a case-crossover study with patient-stratified logistic regression analysis was performed to control for distortion due to individual differences in contribution of exposure time. The positive predictive value of the proxy drug for vulvo-vaginal candidiasis ranged between 57 and 100%, the sensitivity was 87% and the specificity estimated 99%. The crude incidence rate ratio for vulvo-vaginal candidiasis following acitretin exposure was 2.8 (CI95%: 1.1-7.1). The pooled Mantel-Haenszel incidence rate ratio was 3.3 (CI95%: 1.1-9.6) after stratification for accumulated level of exposure. Patient-stratified analysis on the subgroup of cases (n = 15) revealed an odds ratio of 6.5 (CI95%: 2.3-18.2). This study strongly suggests that the higher occurrence of vulvo-vaginal candidiasis during acitretin exposure is attributable to the drug.

Acitretin↗
PubMed1990

High-performance liquid chromatographic determination of etretinate and all-trans- and 13-cis-acitretin in human plasma.

A high-performance liquid chromatographic procedure is described for the simultaneous determination of etretinate (Tigason), all-trans-acitretin (Neotigason) and 13-cis-acitretin in human plasma. The compounds are extracted from the plasma with n-hexane under acidic conditions. Quantification is performed on a normal-phase column (CP-Spher Si, 5 microns), followed by UV detection at 350 nm. The limit of quantification is 3 ng/ml. The day-to-day precision was 6.7, 13.6 and 9.1% for etretinate (means = 53 ng/ml), all-trans-acitretin (means = 95 ng/ml) and 13-cis-acitretin (means = 149 ng/ml), respectively (n = 13 for each compound). The within-day precision of nine determinations was 3.2, 11.7 and 6.5%, respectively, with mean concentrations of 128.53 and 261 ng/ml, respectively. The method was also applied to the study of the long-term pharmacokinetic behaviour of etretinate in psoriatic patients previously treated with etretinate but now on therapy with all-trans-acitretin.

Acitretin↗
PubMed1999

Acitretin: optimal dosing strategies.

Acitretin is an oral synthetic retinoid effective in the treatment of psoriasis. As monotherapy, acitretin has been shown to be most effective in treating pustular and erythrodermic types of the disease. Monotherapy with acitretin for plaque-type psoriasis is often less successful; however, its use in combination with other therapies is highly effective in treating this form of the disease. Dose-response studies have established the effective dose range of acitretin as well as the dose-dependence of its side effects. Because both efficacy and side effects can vary substantially among individual patients, proper dosing of acitretin requires a balance between optimizing response and minimizing toxicity for each patient. Optimal dosing for individual patients may be achieved through a dose-escalation strategy involving initiation of therapy at low doses (10 to 25 mg/day) and, if necessary, gradually increasing the dose as tolerated until optimal response is achieved.

Acitretin↗
PubMed1998

The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin.

The imidazole derivative liarozole is a potent inhibitor of cytochrome P450-dependent 4-hydroxylation of endogenous all-trans retinoic acid, thereby increasing the levels of all-trans retinoic acid in both plasma and skin. As part of a large, double-blind, randomized clinical study, we investigated the cell biological alterations in uninvolved and lesional skin of 20 patients with severe plaque psoriasis, who were treated with either liarozole or acitretin. The extent and severity of the skin lesions, as recorded by the Psoriasis Area and Severity Index score, was significantly reduced (P </=0.05) after 12 weeks of treatment in both the acitretin- and the liarozole-treated group. A significant decrease in the markers for inflammation (neutrophils), epidermal proliferation (Ki-67-positive cells), normal differentiation (transglutaminase) and abnormal differentiation [cytokeratin 16 and skin-derived antileucoproteinase (SKALP), also known as elafin] was seen in both groups. No significant differences were noted in clinical scores or cell biological scores between the liarozole- and acitretin-treated group. None of the markers returned to the levels seen in uninvolved skin or in normal human skin. The expression of epidermal fatty acid binding protein (E-FABP) was only minimally decreased after 12 weeks of treatment, a substantial part of the stratum spinosum remaining positive. SKALP levels in serum fell in both groups with similar kinetics and showed a statistically significant correlation with clinical scores. A remarkable finding in the uninvolved skin of patients treated with liarozole or acitretin was the distinct focal expression of SKALP in the granular layer and the expression of E-FABP in the spinous layers, which is not found in normal human skin. Although the mechanism of action differs fundamentally, liarozole and acitretin show similar effects with respect to clinical effects and cell biological changes in the lesional and non-lesional skin.

Acitretin↗
PubMed2006

Effects of acitretin on spermatogenesis of rats.

In this experimental study the possible effects of the acitretin on the spermatogenesis of the rats were investigated histopathologically. Thirty-nine male adult Wistar albino rats were divided into 3 groups as two experimental groups and one control group. The first group consisting 14 rats were applied orally standard dose (0.75 mg/kg/day) acitretin and the second group consisting 16 rats were applied high dose (1.5 mg/kg/day) acitretin. Acitretin was given within dimetil sulphoxide (DMSO), which was diluted with saline solution as a ratio of 1/10, in order to increase its solubility. The control group consisting 9 rats were given only saline solution including DMSO for 8 weeks. After 8 weeks of the administration, half of the rats in the first and second groups and the entire control group were sacrificed under deep ether anaesthesia and bilateral orchiectomy was made. The remaining rats were compared with the control group using a similar method at the end of 8 weeks of wash-off period. The orchiectomy materials were histopathologically evaluated under the light microscope for spermatogenesis according to parameters including spermatogenetic activity, spermatogenetic organization, seminiferous tubular diameter, interstitial Leydig cells and fibroblasts. The groups, which were evaluated at the end of the 8(th) and 16(th) weeks, were compared with the control group regarding the mentioned parameters and no statistical significance was observed among the groups. In our study it was concluded that the standard and high doses of acitretin do not have any effect on the spermatogenesis of the rats.

Acitretin↗
PubMed2004

Effect of acitretin on wound healing in organ transplant recipients.

BACKGROUND: Systemic retinoids possess significant benefits in cutaneous malignancy chemoprevention; however, retinoids have been associated with excessive granulation tissue and hypertrophic scarring. OBJECTIVE: The objective of this study was to assess wound healing outcomes in organ transplant recipients, both with and without the concomitant use of systemic acitretin chemoprophylaxis. METHODS: Twenty-nine immunosuppressed organ transplant recipients underwent treatment of basal cell or squamous cell carcinoma by Mohs or excisional surgery, with a total of 85 wounds. Wounds were evaluated postoperatively at early (average 12.9 days) and late (average 75.8 days) time points. Endpoints for all wounds included infection, hypertrophic granulation tissue, and hypertrophic scarring. Reconstructed wounds were also evaluated for dehiscence. RESULTS: Eleven patients taking oral acitretin had 41 wounds, of which 33 were reconstructed and 8 healed by second intention. The 18 patients not taking acitretin (control group) had a total of 44 wounds, of which 33 were reconstructed and 11 healed by second intention. There were no statistically significant differences between the acitretin group and the control group in the incidences of infection, dehiscence, hypertrophic granulation tissue, or hypertrophic scarring at early or late evaluation points. CONCLUSIONS: Systemic acitretin chemoprophylaxis does not appear to increase the risk of wound healing complications in organ transplant recipients.

Acitretin↗
PubMed2002

Is there a reproductive safety risk in male patients treated with acitretin (neotigason/soriatane?

Review of preclinical data including genotoxicity assays and a male rat reproduction toxicology study demonstrates that acitretin (Neotigason)/Soriatane) does not affect the reproductive outcome in naive females mated with treated males. Prospective studies of teratogenic risk or impairment of fertility cannot be ethically conducted in humans. However, it is highly unlikely that any fetal malformation could be induced by an ejaculate containing traces of acitretin. Indeed, worldwide postmarketing surveillance has not revealed any cases of retinoid embryopathy associated with paternal treatment with acitretin. Birth defects seen in pregnancies fathered by male acitretin patients were all events expected to occur in the general population at known frequencies. In conclusion, therefore, available data do not appear to indicate any reproductive safety risk due to paternal treatment with acitretin.

Abnormalities, Drug-Induced↗
PubMed1989

Overview of recent clinical pharmacokinetic studies with acitretin (Ro 10-1670, etretin).

Following oral administration of acitretin with food, peak plasma concentrations of unchanged drug (Ro 10-1670) are reached within 4 h. The mean absolute bioavailability of acitretin is 59% with high interpatient variability consistent with that of etretinate. Taking acitretin with food results in an increased and more consistent bioavailability. The drug appears to be extensively distributed throughout the body without unexpected accumulation and the elimination half-life is approximately 50 h. Acitretin has a profound pharmacokinetic advantage over etretinate because it is eliminated more rapidly from the body; etretinate is sequestered into fatty tissue due to its greater lipophilicity creating a deep compartment from which it is only slowly released. Acitretin is eliminated entirely by the metabolism and the resultant metabolites are excreted via the kidney and bile.

Acitretin↗
PubMed1992

A potentially new metabolic pathway: ethyl esterification of acitretin.

1. The acidic retinoid, acitretin, was esterified to etretinate (ethyl ester) by rat and human liver 12,000 g supernatant. The amount of etretinate formed was increased by adding ethanol to the rat preparation. 2. This esterification almost certainly involves enzymic catalysis, and the amounts of etretinate formed were increased by the use of fresh rat liver. 3. Co-administration of acitretin and ethanol to rats resulted in a maximum plasma concentration of etretinate at approximately 1 h after dosing. Secondary maxima were induced by administering ethanol alone at 5 and 8 h after dosing with acitretin. 4. Comparison of acitretin and etretinate concentrations in rat portal and jugular vein plasma after ethanol administration indicated that the ester was formed mainly systematically, rather than during absorption. 5. The results of our study in the rat could indicate that the presence of etretinate in plasma of some patients being treated with acitretin may result from the intake of alcohol.

Acitretin↗
PubMed1999

Effects of acitretin on the liver.

BACKGROUND: Therapy with aromatic retinoids for psoriasis is associated with abnormal liver function test findings and toxic hepatitis (in 1.5% of patients). OBJECTIVE: Our purpose was to determine the safety of acitretin with respect to liver function, on the basis of biopsy. METHODS: We treated 128 adults (with chronic, stable psoriasis) with oral acitretin (25-75 mg/day) for four 6-month intervals in a prospective, open-label, 2-year multicenter study. Liver biopsies were performed before and after study completion (2 years). RESULTS: Eighty-three available pairs of pretreatment and posttreatment liver biopsies demonstrated no change in 49 patients (59%), improvement in 20 (24%), and worsening in 14 (17%). Of these 14 patients with decrements in biopsy status, most changes were mild. There was no correlation between liver function test abnormalities or cumulative acitretin dose and changes in liver biopsy status. CONCLUSION: Acitretin therapy elicited no biopsy-proven hepatotoxicity in this prospective 2-year study. These findings suggest that periodic liver biopsy may not be necessary with acitretin treatment.

Acitretin↗
PubMed1991

[Acitretin; an example of ad-hoc tracing of users in acute problems with drugs].

Recently etretinate was demonstrated in the blood of women on acitretin. Because of the proven teratogenic effects of etretinate we tried to trace all users of acitretin in the Netherlands via all drug dispensing outlets (1450 community pharmacies, 95 hospital pharmacies and 636 general practitioners). A request for information as regards date of birth, sex, type of prescriber, and number of dispensed capsules was followed by a response rate of 87%. In 61% of all responding outlets a prescription of acitretin had been filled. Of these 1153 outlets 40% had dispensed the drug to one user, whereas 52% had dispensed acitretin to 2-5 patients. The 2717 patients consisted of 1500 men (55%) and 1217 women with mean ages of 48 and 53 years, respectively. Of the women 31% were in the age-group of 15-45 years and of the male users, 45% (p less than 0.0001), whereas in other age groups there was no difference. In 80% of cases acitretin had been prescribed by dermatologists. This study demonstrated that it is possible to trace a cohort of users quickly and almost completely. As most large-scale problems with adverse reactions are discovered in the first 2 years of marketing when exposure and morbidity registries are still collecting information, ad hoc cohort formation may be a useful resource for postmarketing surveillance.

Acitretin↗
PubMed1997

[Ofuji's eosinophilic pustular folliculitis. Efficacy of acitretin].

BACKGROUND: We report the first case of eosinophilic pustular folliculitis (Ofuji's disease) which was successfully treated with acitretin. CASE REPORT: A 50-year old women (HIV negative) had developed over 3 months an erythematopapulous plaque under the left orbit. The clinical and histological diagnosis was eosinophilic pustular folliculitis. Successive treatment with cetirizine then indomethacin was ineffective. Acitretin (0.5 mg/kg/d) was then started and led to cure within 1 month. Six weeks after the patient spontaneously stopped the treatment, the lesion recurred at the same localization. Further treatment with isotretinoin (0.5 mg/kg/d) was then given but did not alter progression of the lesion. Acitretin was then reintroduced at the same dose and again produced rapid cure. Acitretin was then tapered off to 10 mg/d then maintained at this dose as lesions reappeared with further dose reduction. DISCUSSION: It is difficult to treat eosinophilic pustular folliculitis because of the random nature of response to different drugs. General corticosteroids, dapsone and indomethacin are classically proposed but with variable success. Isotretinoin is proposed on the hypothesis of a link with sebaceous secretion, but results have been contradictory. This drug was ineffective in our case. Acitretin did however provide very rapid improvement with an efficacy confirmed at reintroduction. This retinoid which does not have the specific action of isotretinoin could affect follicular keratinocytes which have been shown to be activated in this chronic skin disease.

Acitretin↗
PubMed1995

Severe limb defects and craniofacial anomalies in a fetus conceived during acitretin therapy.

We describe a 20-week-old fetus with multiple congenital anomalies exposed to acitretin in the first trimester of pregnancy. Acitretin and its ethylester etretinate are both vitamin A congeners; drugs of this group are well-known teratogenic agents. Since the marketing of acitretin only one report on human teratogenicity associated with acitretin has been published. The present male fetus showed severe symmetric anomalies of upper and lower limbs, craniofacial anomalies, ear anomalies, and an atrioventricular septal defect (ASD). Although the craniofacial anomalies resemble the abnormalities described in classical "retinoic acid embryopathy," limb anomalies were seldomly reported after maternal use of vitamin A congeners. However, in laboratory animals limb defects were frequently observed after retinoid exposure in utero. This case emphasizes again that extreme care and precaution are needed before prescribing a potentially teratogenic drug to a fertile woman.

Abnormalities, Drug-Induced↗
PubMed2005

Effects of ATRA, acitretin and tazarotene on growth and apoptosis of Tca8113 cells.

To investigate the effects of ATRA, acitretin and tazarotene on the growth and apoptosis of human tongue squamous cell carcinoma cell line Tca8113. The effect of retinoids on growth of Tca8113 cells in vitro was examined by MTT assay and Trypan blue exclusion assay. Cell cycle analysis, early apoptosis analysis with double staining with Annexin V-FITC and PI, and active caspase-3 analysis with the staining of FITC-conjugated monoclonal rabbit anti-active caspase-3 antibody were made by flow cytometer. Streptavidin-biotin complex (SABC) immunocytochemical assays were employed for the detections of Bax/Bcl-2 proteins expressions. Our results showed that the retinoids inhibited growth of Tca8113 cells in a dose- and time-dependent manner with maximal inhibition 24 h after treatment of 10(-5) mol/L. 10(-5) mol/L retinoids altered cell cycle distribution of Tca8113 cells, revealing an increase in G0/G1-phase population, a decrease in S-phase population and the inhibition of G1/S switching. 10(-5) mol/L retinoids significantly induced apoptosis of Tca8113 cells (all P < 0.05), elevated the cells population with detectable active caspase-3 (P < 0.05 for all), increased the number of cells forming Bax and decreased the number of cells forming Bcl-2 significantly (all P < 0.05). Acitretin played a most prominent role among the retinoids. It is concluded that the inhibition of cell cycle progress of Tca8113 cells by ATRA, acitretin and tazarotene is one of the possible mechanisms for proliferation arrest of Tca8113 cells elicited by the retinoids. The retinoids mediate apoptosis in Tca8113 cells that may be caspase-dependent through mitochondria pathway. High concentration retinoids inhibit growth of Tca8113 cells in vitro by interfering with proliferation and inducing apoptosis of cells. Acitretin may be an alternative medicine for the prevention and treatment of tongue squamous cell carcinoma.

Acitretin↗
PubMed1992

Comparative binding of etretinate and acitretin to plasma proteins and erythrocytes.

The interactions of etretinate and its main metabolite acitretin with human plasma proteins have been investigated in vitro by an erythrocyte partitioning technique that allows a quantitative estimation of the plasma and erythrocyte binding. Etretinate was extensively lipoprotein-bound (75% of plasma etretinate), with a binding constant for its main low density lipoprotein carrier of 40 x 10(6) M-1, accounting for 48% of the total plasma-bound drug. Acitretin was mainly albumin-bound (91% of plasma acitretin), with a binding constant of 0.7 x 10(6) M-1. The total plasma binding of both drugs was > 99% and, in blood, the fractions associated with erythrocytes were 14.5 and 8.1% of the total amount for etretinate and acitretin, respectively.

Acitretin↗
PubMed1990

In vitro interactions of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, with human serum lipoproteins and albumin.

Serum lipoproteins are good carriers for the aromatic retinoid Ro 10-9359 (etretinate) and to a lesser extent for its main metabolite in human Ro 10-1670 (acitretin). Up to about 200 and 130 etretinate molecules and 200 and 70 acitretin molecules can bind to one LDL and one HDL, respectively. In contrast human serum albumin only binds about 10 etretinate or 30 acitretin molecules. In whole human serum loaded with the retinoids, lipoproteins carry approx. 67% of total etretinate or approx. 37% of total acitretin. In the particular case of etretinate, low density lipoproteins account for about 30% of the lipoprotein-carried etretinate.

Acitretin↗