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PubMed1989

[Retinoids: the new status. Maintenance therapy, disorders of resorption in "non-responders", interactions and interferences with drugs, treatment of children and bone toxicity, acitetin and 13-cis-acitretin].

Oral retinoids are now well-established drugs for the systemic treatment of skin diseases. For etretinate to be effective on a long-term basis it is recommended that maintenance therapy should be continued for 3-6 months after clinical signs of the disease have disappeared. In "non-responders" with psoriasis the blood levels of etretinate may be low and increasing the dose to 1.5 mg/kg body weight per day will be necessary and helpful in some cases. The interaction of drugs should also be considered carefully in non-responding individuals. Children usually respond well to treatment, but they also often require higher dose levels. Bone toxicity with premature epiphyseal closure and hyperostoses may be seen during isotretinoin administration and, more rarely, in patients receiving etretinate, but the risk is relatively low. Teratogenicity is a major concern in young females being treated for acne with isotretinoin, since 70 embryopathies have been recorded worldwide.

Acitretin↗
PubMed1989

Pustulosis palmo-plantaris. Clinical and histological changes during etretin (acitretin) therapy.

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.

Acitretin↗
PubMedDate not supplied

The frequent use of oral retinoids in combination with other treatments for psoriasis: a retrospective analysis.

BACKGROUND: Combination treatment in psoriasis may be common, logical, and appropriate, even if not well tested or well documented by clinical trials. While oral retinoids such as acitretin can be used as monotherapy, efficacy can be further augmented by combination use with other agents. Similarly, because of its safety profile, acitretin can be added in low doses to help patients who have not achieved adequate control with other psoriasis treatments. OBJECTIVE: The purpose of this study was to assess how oral retinoids are used in combination with other drugs to treat psoriasis. METHODS: We assessed the use of acitretin and other oral retinoids for the treatment of psoriasis using two sources of information: nationally representative survey data from the National Ambulatory Medical Care Survey (NAMCS) and local data obtained by chart review of 518 patients seen in a university dermatology clinic. RESULTS: In the NAMCS, oral retinoids were prescribed with other psoriasis medications at 71% of visits. In the chart review, combination use was even more frequent (96% of subjects were on combination treatment) and included combinations of acitretin with topicals, phototherapy, and other systemic treatments. Adverse events were reported in 53% of patients treated with acitretin, although none were severe. CONCLUSION: Use of acitretin in combination with many other psoriasis treatments is a common practice. Mucocutaneous side effects of oral retinoids are common but with appropriate dosing are generally mild.

Acitretin↗
PubMed2001

Therapeutic strategies: rotational therapy and combinations.

Long-term management of psoriasis requires an individualized approach. Some treatments such as calcipotriol, methotrexate and acitretin may be used as maintenance treatment for many months. However, most anti-psoriasis treatments should be prescribed for restricted periods of time. Rotational treatment is a practical approach to reduce the cumulative toxicity of anti-psoriasis treatments. The selection of a treatment is based on the clinical presentation of psoriasis and whether contraindications might exist. Combination treatment is another approach, which is used by the majority of patients. Useful combinations are calcipotriol-acitretin, calcipotriol-cyclosporin, calcipotriol-PUVA, calcipotriol-topical corticosteroids, dithranol-UVB, dithranol-tar, coaltar-UVB, acitretin-UVB and acitretin-PUVA. Combinations which are contraindicated are coaltar-PUVA, UVB-cyclosporin, PUVA-cyclosporin and methotrexate-acitretin. Combined use of UVB-methotrexate, UVB-PUVA; PUVA-methotrexate; methotrexate-cyclosporin and cyclosporin-acitretin require careful monitoring and might be helpful in patients with severe and recalcitrant psoriasis. Depending on the individual presentation of psoriasis, previous anti-psoriatic treatments and side-effects, treatment adjustments are made.

Acitretin↗
PubMed2004

A controlled study of comparative efficacy of oral retinoids and topical betamethasone/salicylic acid for chronic hyperkeratotic palmoplantar dermatitis.

BACKGROUND: Chronic hyperkeratotic dermatitis of the palms and soles represents a severe multi-etiological problem, too often faced with ineffective or tedious topical remedies. METHODS: A single-blind, matched-sample design investigation was carried out of 42 patients with chronic hyperkeratotic palmoplantar dermatitis, who were administered acitretin 25-50 mg/day for 1 month, which was controlled versus a conventional topical treatment (betamethasone/salicylic acid ointment). Therapeutic improvement was expressed with the reduction of severity score (expressed on a 0-10 scale). RESULTS: Acitretin was significantly better than the conventional treatment after 30 days (two sided p<0.0001). Moreover, improvement significantly persisted 5 months after suspension of acitretin (p<0.0001), while this was not the case after suspension of the control treatment (p=0.3019). Lesions improved more rapidly with acitretin than with the control treatment (p<0.0002). Some cases of loss of sensitization in patch-test-positive patients were observed. Side effects were minimal or absent, and patients expressed overtly their preference for acitretin treatment. CONCLUSION: After evaluating the former literature, the risks and the benefits, as well as the overt superiority of retinoid treatment, the authors conclude that acitretin should be considered a first choice treatment for this fastidious condition.

Acitretin↗
PubMed2005

Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials.

BACKGROUND: The increased incidence of skin cancers after solid organ transplantation is well recognized. Skin cancers developing in transplant recipients are more aggressive in behaviour. Therapeutic options to reduce and/or delay the development of cutaneous neoplasms are therefore of interest. OBJECTIVES: The objective of this review was to summarize the available medical literature from randomized controlled trials on the use of oral retinoids as a preventive agent for skin cancers in the solid organ transplant population. METHODS: Three electronic databases were searched for relevant trials: MEDLINE (1966-October 2003), EMBASE (1980-week 44, 2003) and the Cochrane Controlled Trials Register (third quarter 2003). Randomized or quasi-randomized controlled clinical trials on subjects of any age or ethnic background who had received a solid organ transplant (cardiac, renal, liver, etc.) were evaluated. All titles and abstracts found by the search strategy were independently reviewed by two researchers for inclusion into the review. RESULTS: Eighty-one abstracts were identified through the electronic databases for consideration. Review of the abstracts identified three eligible trials. One cross-over trial involving 23 subjects treated with acitretin 25 mg daily for 12 months reported 46 squamous cell carcinomas (SCCs) developing in six subjects during acitretin treatment vs. 65 SCCs developing in 15 subjects during the drug-free period. Another trial involving 44 subjects treated with acitretin 30 mg daily or placebo for 6 months reported two of 19 subjects developing two SCCs in the treatment group vs. nine of 19 subjects developing 18 new skin cancers (15 SCCs, one Bowen's disease, two basal cell carcinomas) in the placebo group. One dose comparison trial involving 26 renal transplant recipients treated with acitretin did not find a significant difference in numbers of skin cancers developing at the doses examined. The major limitation to the use of acitretin was poor tolerance due to adverse events. Headaches, rash, musculoskeletal symptoms and hyperlipidaemia were the most common causes of withdrawal from treatment. No alterations in renal or liver function were detected during the periods of treatment or follow-up. CONCLUSIONS: The available data from a small number of randomized controlled trials suggest that acitretin may have a role in the management of solid organ transplant recipients with skin cancers. Tolerability of the drug is a major factor limiting its use. Appropriate selection of patients may help improve the risk-benefit ratio.

Acitretin↗
PubMed1990

UV-induced isomerization of oral retinoids in vitro and in vivo in hairless mice.

Ultraviolet (UV) irradiation causes isomerization and destruction of many vitamin A analogues (retinoids). Using high-performance liquid chromatography (HPLC), we investigated in vitro and in vivo the effects of UV irradiation on 2 all-trans aromatic retinoids (etretinate and acitretin) and on 13-cis retinoic acid (isotretinoin). When etretinate and acitretin dissolved in ethanol were irradiated with UVB (280-320 nm; 10-336 mJ/cm2) or UVA (320-400 nm; 1-5 J/cm2), extensive and reproducible cis-isomerizations occurred at the 13-position (cis/trans ratio approximately 1.6 in all experiments) but there was no progressive photodegradation of the molecules. Irradiation of isotretinoin produced only moderate trans-isomerization but the sum of HPLC peak heights fell with increasing UV doses, being 72% of the original value after 336 mJ/cm2 of UVB. Hairless mice were given etretinate (50 mg/kg bw), acitretin (200 mg/kg) or isotretinoin (50 mg/kg) on days 1, 4 and 7 and were irradiated daily for 8 d with 13 mJ/cm2 UVB plus 1 J/cm2 UVA. Samples of serum, dorsal skin and liver were collected and retinoids analyzed by HPLC. In the etretinate and acitretin-treated, irradiated animals the serum concentrations of the 13-cis isomers were 2-6 times higher than in nonirradiated controls. Irradiated epidermis also contained significantly higher concentrations of 13-cis etretinate and 13-cis acitretin than did control epidermis. The serum and epidermal concentrations of all-trans etretinate and acitretin were unchanged or even increased after irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗
PubMed2006

Effects of retinoid therapy on insulin sensitivity, lipid profile and circulating adipocytokines.

OBJECTIVE: In vitro and in vivo models indicate that all-trans retinoic acids influence glucose and lipid metabolism. We aimed to evaluate the effects of chronic treatment with acitretin, an all-trans retinoic acid, on glucose metabolism, lipid profile and adiponectin and resistin levels. DESIGN: Ten normoglycemic, normolipemic patients affected with psoriasis vulgaris were studied before and after 1 and 3 months of oral treatment with 35 microg of acitretin. METHODS: Glucose metabolism, lipid profile, and adiponectin and resistin levels were evaluated in basal conditions and after acitretin treatment. Ten healthy subjects matched for age, body mass index (BMI) and insulin sensitivity were studied as controls. RESULTS: One-month acitretin treatment reduced psoriasis activity, insulin sensitivity, evaluated as QUICKI values (0.364 +/- 0.034 versus 0.329 +/- 0.051; P < 0.05) and HOMA-IR index (1.53 +/- 0.73 versus 2.59 +/- 1.41; P < 0.05), and high-density lipoprotein (HDL)-cholesterol levels (45.2 +/- 11.7 versus 39.4 +/- 10.4 mg/dl; P = 0.01). The impairment in glucose and lipid homeostasis was transient and not associated to BMI variations. Adiponectin levels did not change during the treatment, while resistin levels, which were higher in untreated patients than in controls (9.4 +/- 4.4 versus 6.2 +/- 2.1 ng/ml; P = 0.05), fell within the normal range after 1 and 3 months of therapy. The normalization of resistin levels occurred without significant changes in circulating tumor necrosis factor alpha (TNFalpha) levels, which persisted elevated throughout the treatment. CONCLUSIONS: Treatment with a low dose of acitretin induced a mild, transient reduction of insulin sensitivity and HDL-cholesterol levels that was not related to modifications of adiponectin, resistin and TNFalpha levels. Although the role of resistin in humans remains elusive, the levels of this adipocytokine seem to be affected, at least in part, by retinoids.

Acitretin↗
PubMedDate not supplied

Kinetics of tissue distribution and elimination of retinoid drugs in the rat. II. Etretinate.

Rats were injected with single intravenous doses of etretinate (6 mg/kg), and concentrations of the drug and its metabolites, acitretin and 13-cis-acitretin, were determined in plasma and nine tissues up to 96 hr. A newly developed sensitive method for the determination by HPLC of the three retinoids in tissues was used. Etretinate rapidly appeared in most tissues and underwent a redistribution from highly perfused organs into muscle, skin, and ultimately, adipose tissue. Tissue/plasma concentration ratios ranged from 14 to 1, with the highest value in adipose tissue. In this tissue, maximum concentration was reached after 1.5 hr and remained practically constant up to 96 hr. Etretinate was rapidly hydrolyzed to form acitretin at concentrations that surpassed those of the parent drug in plasma, liver, kidney, and brain. After 6 hr, approximately 45% of etretinate had been metabolized to acitretin and approximately 40% to unidentified metabolites. These metabolites were not observed in tissues after 6 hr postdose. The parent drug was not observed 12 hr postdose, except for 6% of the dose remaining in adipose tissue. Etretinate elimination, in most tissues, was biphasic with terminal half-lives of 41 hr in skin, 1-6 hr in other lean tissues, and 1.7 hr in plasma. A volume of distribution of 1.7 liters/kg was determined, and a clearance of 12 ml.min-1.kg-1. Etretinate is characterized by rapid metabolism, transient storage in skin, and prolonged storage at a low level in adipose tissue as a deep compartment. A comparison of the pharmacokinetics of the closely related retinoids, etretinate and acitretin, disclose very pronounced differences.

Acitretin↗
PubMed2001

Drugs for discoid lupus erythematosus.

BACKGROUND: Discoid lupus erythematosus is a chronic form of cutaneous (skin) lupus which can cause permanent scarring if treatment is inadequate. Many drugs have been used to treat this disease and some of these are potentially very toxic. OBJECTIVES: To assess the effects of drugs for discoid lupus erythematosus. SEARCH STRATEGY: We searched the Cochrane Clinical Trials Register (December 1999), MEDLINE (January 1966 to December 1999), EMBASE (January 1980 to January 2000), and the reference lists of relevant reviews. Index Medicus (1956 to 1966) was handsearched and 7 experts in the field were approached for information about unpublished trials. SELECTION CRITERIA: Randomised trials of drugs to treat people with discoid lupus erythematosus. Drugs included in the search were azathioprine, chloroquine, clofazimine, corticosteroids, (oral and topical), dapsone, gold, interferon alpha-2a, methotrexate, phenytoin, retinoids, sulphasalazine and thalidomide. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined each retrieved study for eligibility. MAIN RESULTS: Two trials involving 136 participants were included. In a cross-over study of twelve weeks duration fluocinonide 0.05% cream (a potent topical corticosteroid), appeared to be markedly better than hydrocortisone 1% cream ( a mild corticosteroid). Clearing or excellent improvement was seen in 27% of people using fluocinonide and in 10% of those using hydrocortisone, giving a 17% absolute benefit in favour of fluocinonide (95% CI 4.5 to 29.5% and NNT 6). In the second trial, hydroxychloroquine was compared with acitretin in 58 people. There was marked improvement or clearing in 46% of people using acitretin and in 50% of those on hydroxychloroquine, a nonsignificant 4% absolute gain with hydroxychloroquine (95%CI -23% to 30%). The adverse effects were more frequent and more severe in the acitretin group. REVIEWER'S CONCLUSIONS: Fluocinonide cream may be more effective than hydrocortisone in treating people with discoid lupus erythematosus. Hydroxychloroquine and acitretin appear to be of equal efficacy, although adverse effects are more frequent and more severe with acitretin. There is not enough reliable evidence about other drugs used to treat discoid lupus erythematosus.

Dermatologic Agents↗
PubMed1999

Systemic sequential therapy of psoriasis: a new paradigm for improved therapeutic results.

Sequential therapy is a treatment strategy involving the use of specific therapeutic agents in a deliberate sequence to optimize the therapeutic outcome. The rationale for this strategy in psoriasis is that it is a chronic disease requiring long-term maintenance therapy as well as quick relief of symptoms and that some therapies available for psoriasis are better suited for rapid clearance while others are more appropriate for long-term maintenance. Sequential therapy involves 3 main steps: (1) the clearing, or "quick-fix" phase; (2) the transitional phase; and (3) the maintenance phase. In the example of sequential systemic therapy described in this article, an acute exacerbation of psoriasis is brought under control promptly with the use of cyclosporine at maximum dermatologic dose (5 mg/kg daily). After 1 month, the transitional phase is initiated with the gradual introduction of acitretin as a maintenance agent. Once the maximum tolerated dose of acitretin has been established, cyclosporine is gradually tapered and acitretin is continued for long-term maintenance with phototherapy (UVB or PUVA) added for improved control if needed. The author proposes sequential therapy with cyclosporine and acitretin as a viable option for patients with psoriasis who require systemic therapy and desire an alternative to methotrexate.

Acitretin↗
PubMed2005

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells.

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 microM) or R116010 (1 or 10 microM) in combination with either 10 microM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.

Acitretin↗
PubMed1989

Synthetic retinoids inhibit the antigen presenting properties of epidermal cells in vitro.

The clinical efficacy of retinoids in benign and malignant skin diseases involving immune mechanisms suggests that they affect the immunologic functions of the epidermis. However, these effects have yet to be demonstrated. The action of vitamin A (retinol) and the synthetic retinoids, isotretinoin, etretinate, acitretin, and arotinoid-free acid have been studied on the lymphocyte proliferation induced by phytohemagglutinin (PHA), by the mixed lymphocyte reaction (MLR), and the mixed epidermal cell-lymphocyte reaction (MECLR). The results for PHA-induced proliferations were highly variable for all the retinoids. However, in MECLR, the synthetic retinoids consistently reduced the proliferation by 20%-30%. This occurred at therapeutic drug concentrations of about 10(-7)M. In MLR, a minor decrease of 10%-15% was only found for higher concentrations (10(-5)M). Retinol induced no effect in either reaction. Further analysis of acitretin on MECLR showed that it reduced lymphocyte proliferation in a dose-dependent fashion. This reduction was combined with a decrease in cytotoxic T-lymphocyte induction (CTL). Addition of 10(-6)M acitretin at various times also revealed that its presence at cell culture initiation was necessary to inhibit proliferation significantly. Furthermore, cell treatments prior to MECLR showed that exposure of epidermal cells to acitretin was essential to produce this inhibition, suggesting that it acts directly on epidermal cells. Consequently, it is suggested that the specific inhibitory effect of synthetic retinoids on lymphocyte activation in MECLR may partly account for their therapeutic action on the skin.

Acitretin↗