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Altered proliferation, synthetic activity, and differentiation of cultured human sebocytes in the absence of vitamin A and their modulation by synthetic retinoids.

Human sebocytes maintained in medium containing delipidized serum were studied for ultrastructural characteristics, cell proliferation, lipid synthesis, immunophenotype, and keratin expression before and after the addition of the synthetic retinoids isotretinoin and acitretin (10(-8)-10(-5) M). Compared to the properties of sebocytes cultured in normal sebocyte medium (1-2 x 10(-7) M vitamin A), the use of delipidized serum (undetectable amounts of vitamin A) resulted in prominent decrease of i) proliferation; ii) number of intracellular lipid droplets and synthesis of total lipids, especially triglycerides, squalene, and wax esters; and iii) labeling with monoclonal antibodies identifying progressive and late-stage sebocyte differentiation. Intercellular spaces narrowed and cell-to-cell contacts were established by abundant desmosomes. Lanosterol was induced. Keratins 14, 16, 17, and 18 were upregulated and the keratin 16: keratin 4 ratio, negatively correlating with sebocyte differentiation, increased. Addition of isotretinoin and acitretin exerted a biphasic effect. At concentrations < or = 10(-7) M, both compounds enhanced sebocyte proliferation and synthesis of total lipids, especially triglycerides and cholesterol, and decreased lanosterol, keratin 16, and the keratin 16:keratin 4 ratio. In contrast, retinoid concentrations > 10(-7) M inhibited sebocyte proliferation in a dose-dependent manner. Our findings indicate that vitamin A is essential for proliferation, synthetic activity, and differentiation of human sebocytes in vitro. Synthetic retinoids partially reinstate the altered functions of sebocytes maintained in medium containing delipidized serum. In contrast to the previously shown isotretinoin-specific response of cultured sebocytes in the presence of vitamin A, similar effects of isotretinoin and acitretin were obtained in its absence. This suggests different interactions of synthetic retinoids with vitamin A, possibly influencing their efficacy on the sebaceous gland.

Antigens↗

Fanconi's anaemia associated with multicentric Bowen's disease and decreased NK cytotoxicity.

We report a patient with Fanconi's anaemia and multiple lesions of vulvo-anal Bowen's disease. She was thrombocytopenic and lymphopenic, and NK-mediated cytotoxicity was undetectable. The vulvar lesions did not contain papillomavirus DNA. In vitro studies showed a possible benefit from acitretin treatment on bone marrow stem cells. However, low-dose acitretin given for 14 months did not prevent the development of an anal squamous carcinoma. Acitretin therapy was, however, associated with a sustained rise in the platelet count.

Adult↗

Oral retinoids--efficacy and toxicity in psoriasis.

Psoriasis is a disease of unknown aetiology, affecting approximately 1-3% of the population. In most cases involving relatively localized disease, patients are best managed with either topical therapy alone or topical therapy in combination with UV-phototherapy. However, approximately 35% of patients do not respond well to these conventional treatments or have moderate-to-severe disease requiring more aggressive forms of therapy. The second-generation retinoids, etretinate and its metabolite acitretin, are important additions to the armamentarium of agents used to treat these recalcitrant or severe forms of the disease. Generalized pustular psoriasis generally responds well to high-dose (0.7-1 mg/kg/day) oral retinoid monotherapy. In contrast, increasing small doses of the retinoid are recommended initially in erythrodermic psoriasis in order not to provoke the disease. Long-term clinical experience favours a combination treatment of the retinoid with either topical and/or UV irradiation in chronic plaque-like psoriasis. Both oral retinoids have comparable efficacy and tolerability profiles, and the relapse rates for both drugs are similar. The toxicities associated with both short- and long-term treatment with oral retinoids are significant and include mucocutaneous effects, adverse modulation of serum lipid chemistries, elevation of liver enzymes, and after long-term chronic dosing, skeletal and ligamentous calcification, and hyperostosis. Both etretinate and acitretin, like all retinoids, are known teratogens in animal models, and documented evidence exists for teratogenic activity in humans as well. Consequently, women of childbearing age are strongly advised to avoid pregnancy during treatment and up to 5 years following cessation of therapy with both etretinate and the carboxylic acid metabolite acitretin.

Administration, Oral↗

Novel therapies for psoriasis.

The T cell-driven immunopathogenesis of psoriasis has been well recognized since cyclosporine first revolutionized the treatment of psoriasis 20 years ago. Almost all investigative and clinical research subsequently, has concentrated on elucidating the specifics of antigen presentation, T cell interaction and the production of specific cytokines. The role of the keratinocyte, previously thought to be the primary target cell in psoriasis pathogenesis, has been relegated to a secondary role and the mechanism of action of systemic methotrexate in psoriasis has been challenged, the primary role of the T lymphocyte is now well known. While psoriasis has traditionally been treated "ab initio" with topical medications (corticosteroids, vitamin D(3), and retinoid derivatives), either singly, in combination, or with ultraviolet B (UVB) or psoralens and ultraviolet A (PUVA) therapy, the role of systemic medications has assumed greater prominence. Thus, three systemic medications currently are approved worldwide for the treatment of moderate to severe forms of psoriasis, namely cyclosporine, methotrexate and acitretin. The first two are likely to give significant clearing (greater than 75%) in the majority of cases, whereas acitretin is significantly less effective as monotherapy, but may approach methotrexate and cyclosporine in efficacy, if combined with PUVA or UVB phototherapy. The main limitations of these three drugs remain organ toxicity, especially hepatic toxicity with methotrexate, hypertension and nephrotoxicity with cyclosporine, and teratogenicity and mucocutaneous toxicity with acitretin. Thus, the need for more specific systemic therapy, targeting the T lymphocyte. This has become the major area of clinical research interest over the past 5 years, with the promise of longer-term disease control (improved remissions) and less organ toxicities. Currently, there are over 15 of these "biologic" drugs in various stages of development and clinical trials, either by the subcutaneous, intramuscular or intravenous route. The three main variables are the rapidity of onset, percentages of improvement and remission rates. Without exception, these new systemic agents appear to be remarkably free of systemic organ toxicities (liver, renal, bone-marrow, etc.), with adverse effects being limited to mild flu-like symptoms with the anticipated increase in infections (e.g., herpes simplex) being either equal to placebo or only marginally increased. Not all these agents under evaluation give clinical responses equal to methotrexate or cyclosporine (75% or greater clearing in 75% of cases). In addition, response rates may be slower with some therapies versus others. However, the need for intermittent administration even by the injectable route, longer remissions, lack of systemic organ toxicities and the potential for safer usage in females of child-bearing age, make a compelling argument for widespread acceptance by both patients and the dermatological community. Other modalities under clinical evaluation include vitamin D and retinoid drugs, topically and systemically, with effects on nuclear receptors, as well as more specific wavelengths (308 to 311 nm) of UVB phototherapy with application for more localized forms of psoriasis. For the 2 to 3% of the worldwide population of patients with psoriasis the future has never looked brighter.

Adrenal Cortex Hormones↗

[Treatment with retinoids].

Aromatic retinoids are synthetic vitamin A derivatives that are particularly active in the treatment of severe psoriasis. They have two pharmacodynamic properties: a regulating effect on epidermal differentiation, and an immunomodulating effect, notably on some functions of granulocytes. Two compounds from this group are now available: etretinate (Tigason) and its active metabolite and future successor acitretin (Soriatane). Retinoids are indicated in pustular psoriasis, erythrodermic psoriasis and extensive psoriasis vulgaris. The mean daily dose in adults is 30 to 50 mg for etretinate and 30 to 35 mg for acitretin. The dose-dependent cutaneous and mucosal side-effects consist of dryness of mucous membranes, desquamation of the extremities and fragility of the skin. Laboratory tests for liver function and lipids must be performed regularly. Because of their teratogenicity, retinoids are strictly contra-indicated in pregnant women and otherwise require and efficient contraception pursued for at least two years after withdrawal of etretinate or acitretin therapy.

Humans↗

Identification of etretinate metabolites in human bile.

The metabolites of etretinate (Tegison) were investigated in bile obtained from two patients with biliary T-tubes. Bile samples were collected for 5 days after administration of a single, oral 100-mg dose of 14C-labeled etretinate. Radioactivity measurements indicated that the two patients excreted 9.6% and 8.0% of the dose in the 5-day bile. The etretinate metabolites in the bile were present mainly as beta-glucuronidase-labile conjugates. HPLC analyses of the beta-glucuronidase-treated bile samples showed no measurable concentrations (less than 10 ng/ml) of etretinate or the 13-cis acid, isoacitretin. Acitretin, the free acid of etretinate, was present and accounted for about 0.9% of the biliary radioactivity. The major portion of the radioactivity in the extracts of the beta-glucuronidase-treated bile samples consisted of two metabolites with shortened side chains. One was identified as the 11, 12-dihydro-13, 14, 15, 20-tetranor phenolic derivative of acitretin, which was previously identified as a human urinary metabolite. The other metabolite was identified as the 11, 12, 13, 14-tetrahydro-15-nor phenolic derivative of acitretin, which has not been previously identified as a metabolite of etretinate.

Adult↗

Use of retinoids in the treatment of psoriasis.

The limitations of conventional therapy for psoriasis are reviewed, and the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosing and therapeutic monitoring of etretinate and other retinoids are described. Traditional treatments for psoriasis include topical application of anthralin and coal tar ointments; systemic therapy with corticosteroids or methotrexate; and systemic or methotrexate; and systemic psoralens combined with exposure to ultraviolet light (PUVA). The topical therapies are beneficial but aesthetically displeasing to patients; the systemic treatments are associated with severe adverse reactions. Etretinate provides another option in the treatment of psoriasis. Etretinate and acitretin, an investigational retinoid, appear to be effective oral therapies for severe variants of psoriasis, especially pustular psoriasis. Retinoids generally do not offer substantial therapeutic advantages over other treatments for chronic-plaque psoriasis. The most common adverse effects of etretinate are cheilitis, alopecia, desquamation of the skin, drying of mucous membranes, and pruritus. Use of low-dose etretinae in combination with other forms of therapy, such as corticosteroids or PUVA, may minimize the frequency of adverse effects. Etretinate is a known teratogen. Its elimination half-life is prolonged to 100-120 days with long-term use. Acitretin, the carboxylic acid derivative of etretinate, has a much shorter elimination half-life than etretinate (50 hours after multiple doses). Its adverse-effect profile is similar to that of etretinate. Etretinate and acitretin appear to be clinically effective for therapy of severe variants of psoriasis. Etretinate should not be used to treat mild psoriasis because of the high incidence of serious adverse effects.

Humans↗

Teratogenicity of etretinate during early pregnancy in the rat and its correlation with maternal plasma concentrations of the drug.

Sprague-Dawley female rats were treated with a single oral dose of 0 (vehicle), 10, or 25 mg/kg of etretinate (ET), an aromatic retinoid, on gestation day 6, 7, or 8. While treatment on day 8 with both dosages of ET was highly teratogenic, no evidence of embryotoxicity, considered to be treatment related, was observed when the same doses were administered on day 6 or 7. We concluded that the rat embryo is not susceptible to teratogenic effects of ET on gestation day 6 or 7 and that day 8 is the earliest susceptible period for ET teratogenesis. This may well be true of retinoids as a class since we have observed similar results for all-trans- and 13-cis-retinoic acids (unpublished findings). In another study, mated rats were treated with a single oral dose of ET on day 8. No evidence of embryotoxicity was observed at dosages of 1, 3, and 6 mg/kg; in contrast, treatment with 10, 15, or 25 mg/kg of ET resulted in an increasingly greater number of malformed fetuses and resorptions. Plasma concentrations of ET and three metabolites [acitretin (AC), 13-cis-etretinate (13-cis-ET), and 13-cis-acitretin (13-cis-AC)) were determined in mated rats given a single oral non-teratogenic (3 or 6 mg/kg) or teratogenic (10 or 25 mg/kg) dose of ET on gestation day 8. The AUC0----24hr values of ET and AC, the major metabolite and suspected proximal teratogen, were roughly proportional to the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗

Effects of retinoids on the generation of neutrophil-derived reactive oxygen species studied by EPR spin trapping techniques.

OBJECTIVE: To study the potential efficacy of retinoids on granulocytes with regard to their role in inflammatory dermatoses. METHODS: We investigated the in vitro effect of acitretin and isotretinoin on the generation of reactive oxygen species (ROS) by stimulated human neutrophils using EPR spin trapping techniques. RESULTS: The effects of the two retinoids on ROS generation by neutrophils were different. Acitretin increased the generation of hydroxyl radicals, whereas isotretinoin showed an antioxidant activity against the superoxide anion. CONCLUSIONS: Our study demonstrates retinoid type-dependent effects on ROS production by stimulated neutrophils.

Acitretin↗

In vitro effects of retinoids on mitogen-induced peripheral blood leucocyte responses.

The aim of the present study was to investigate the influence of three different retinoids, isotretinoin, etretinate and acitretin, on the mitogenic response of peripheral blood mononuclear cells (PBMCs) to PHA and PMA in vitro. All three retinoids at high concentrations (10(-4)M) significantly inhibited the mitogenic response of PBMCs to these mitogens. At lower concentrations (10(-5) M and 10(-6) M) none of the three retinoids had any effect on PBMC proliferation in response to PHA. Interestingly, isotretinoin and etretinate significantly enhanced the PMA-induced stimulation of proliferation, whereas acitretin at 10(-5) M failed to influence the mitogenic response to PMA but enhanced it at 10(-6) M. The enhancing effects of retinoids on the proliferative response of PMA-stimulated PBMCs were reversed by rapamycin (10 ng/ml), an immunosuppressant known to inhibit the phorbol ester-induced protein kinase C pathway of lymphocyte activation. In conclusion, our study indicates that retinoids directly trigger the PMA-induced protein kinase C pathway of lymphocyte activation in a concentration-dependent manner. This observation could explain the findings of previous studies showing an in vivo immunopotentiating effect of retinoids on certain immune functions.

Acitretin↗

[Teratogenic effects of vitamin A and its derivates].

Retinoids, the synthetic derivates of vitamin A, have a key role on cellular differentiation and developmental tissue specificity. Their effects are mediated by nuclear receptors which transactivate homeobox genes. They are teratogenic to animals and they all induce similar malformations dependent on the dose and the duration of exposure. This is a review of the teratogenic effects of vitamin A and its synthetic derivates--isotretinoin, acitretine and topical retinoids--in humans. High dose vitamin A have a potent teratogenic effect and are therefore contra-indicated during pregnancy. Isotretinoin is responsible for a syndrome including malformations of the central nervous system, heart and thymus, together with craniofacial defects. The incidence rate is high and comparable to thalidomide (ie, 25%). This high teratogenic potency justifies a strict limitation of such a prescription in women susceptible to become pregnant. Acitretine, which replaces etretinate because of its long half life of 120 days, might also be teratogenic in humans. In addition, it may be back transformed into etretinate, thus contraindicating pregnancy for 2 years after withdrawal. Finally, despite a low percutaneous resorption, available data on the use of retinoids as topicals are limited and their use during pregnancy is therefore not recommended. Although they are efficient in skin diseases, the use of retinoids in women of the child bearing age is very limited because of their potent teratogenic effect.

Abnormalities, Drug-Induced↗

The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains.

Retinoic acid exerts many of its biological effects by interaction with heterocomplexes of nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). To further examine this interaction, a glutathione S-transferase (GST) fusion protein containing the ligand binding domain of human RXR alpha has been used to copurify the ligand binding domain of human RAR gamma by affinity chromatography over glutathione-agarose. Complexes of recombinant RAR-RXR ligand binding domains retaining full ligand binding capacity were purified, and their interactions with various retinoids were characterized by fluorometric titration and photoaffinity labeling. Analyses of the distribution of limiting amounts of [3H]-all-trans-retinoic acid between cytoplasmic retinoic acid binding proteins, CRABP-I and CRABP-II, and the purified heterocomplexes indicate that all-trans-retinoic acid binds with comparable affinity to CRABP-I and the heterocomplexes, but with approximately 10-fold less affinity to CRABP-II. The aromatic retinoid acitretin, which is used in the treatment of psoriasis, binds relatively poorly to the purified heterocomplexes, although it binds with high affinity to the CRABPs. Acitretin displaces [3H]-all-trans-retinoic acid from the CRABPs and increases retinoic acid occupancy of the heterocomplexes. These results suggest that certain retinoids could potentially perturb the distribution of endogenous retinoic acid between the CRABPs and the nuclear receptors and thus affect retinoid signaling. The purified recombinant complexes should provide a useful model system for further structural analysis of the dimerization interface between the RAR and RXR ligand binding domains.

Acitretin↗

Effect of sodium lauryl sulfate-induced skin irritation on in vitro percutaneous absorption of four drugs.

The influence of irritant contact dermatitis on percutaneous penetration was investigated for four 14C-labeled compounds with diverse physicochemical properties: hydrocortisone (HC), indomethacin (IM), ibuprofen (IB), and acitretin (AC). Hairless guinea pigs were pretreated in vivo for 24 h with either 0.5% sodium lauryl sulfate (SLS) to induce irritant contact dermatitis or with water (controls). Twenty-four hours after pretreatment animals were sacrificed. Percutaneous penetration was then measured using in vitro diffusion cells and the removed (pretreated) skin. The following parameters were determined: cumulative amount of compound penetrated, steady state flux, lag time, and permeability coefficient, skin concentration per unit area, and the relative amount of drug remaining in the skin (as a percentage of the cumulative amount of compound penetrated through the skin). SLS pretreatment resulted in moderate irritant dermatitis in all animals and increased in vivo transepidermal water loss 4.5 times. Flux was increased in SLS-pretreated skin as compared with controls for all four compounds, with the greatest enhancement for hydrocortisone (HC) (5.9 times), followed by indomethacin (IM) (4.6 times), ibuprofen (IB) (3.9 times), and acitretin (AC) (3.4 times). Skin concentrations increased to a smaller degree from 1.6 times (IB) and 2.6 times (HC) to 3.4 times (IM). However, AC skin concentrations were not different between the two groups. Thus, percutaneous penetration parameters were equivocally influenced by SLS-induced irritation. Increased skin concentrations were paralleled by even higher increases in flux.

Acitretin↗

Cytokine-stimulated human dermal microvascular endothelial cells produce interleukin 6--inhibition by hydrocortisone, dexamethasone, and calcitriol.

The effects of lipopolysaccharide (LPS), recombinant human tumor necrosis factor-alpha (TNF), recombinant human interleukin 1-beta (IL-1 beta), and interferon-gamma (IFN-gamma) on IL-6 production were determined by enzyme-linked immunosorbent assay (ELISA) and by Northern blot analysis in cultured human dermal microvascular endothelial cells (HDMEC). Unstimulated HDMEC did not produce significant amounts of IL-6, whereas lipopolysaccharide (LPS), TNF, and IL-1 beta were potent inducers of HDMEC-derived IL-6 production. Treatment with IFN-gamma had no effect. IL-1 beta stimulation resulted in pronounced IL-6 production after 4 h, followed by complete downregulation at the transcriptional level after 24 h. In contrast, LPS and TNF induced prolonged stimulation of IL-6 production by HDMEC as IL-6 mRNA transcripts were still detected after 24 h treatment and IL-6 protein was markedly increased at this timepoint. The effects of hydrocortisone, dexamethasone, calcitriol, acitretin, and cyclosporin A on TNF- or IL-1 beta-induced IL-6 production by HDMEC were determined by ELISA. Both hydrocortisone and dexamethasone dose-dependently inhibited the cytokine-induced IL-6 production, whereas the inhibition by calcitriol was less pronounced. In contrast, acitretin and cyclosporine A had no influence on cytokine-induced HDMEC IL-6 production. These results disclose dermal endothelial cells as a major source for the pro-inflammatory cytokine IL-6, involved in the regulation of inflammatory skin processes. As IL-6 seems to play a key role in the pathogenesis of psoriasis, the beneficial effects of corticosteroids and calcitriol in this disease may partly be explained by their ability to inhibit HDMEC-derived IL-6 production.

Acitretin↗

Isotretinoin differs from other synthetic retinoids in its modulation of human cellular retinoic acid binding protein (CRABP).

Isotretinoin differs from acitretin and Ro137410 by its striking sebostatic effect in acne after oral, but not topical, administration. The reason for this is not yet understood. Previous studies indicate that cellular retinoic acid binding protein (CRABP) might be implicated in the action of synthetic retinoids. We, therefore, compared the three retinoids for their ability to increase epidermal CRABP levels after systemic and topical treatment. Oral treatment with acitretin and Ro137410 led to a striking increase of epidermal CRABP (from 2.6 +/- 0.9 to 16.2 +/- 2.9, P less than 0.004 and from 2.5 +/- 1.2 to 21.5 +/- 3.4 pmol/mg protein, P less than 0.004, respectively), while isotretinoin failed to induce a comparable rise (3.2 +/- 1.6 before and 3.7 +/- 0.7 pmol/mg protein after treatment), although it displayed in all patients a striking sebostatic effect. After topical application, the increase of CRABP was comparable for all three compounds. The interaction of isotretinoin with the epidermis seems to be different from other synthetic retinoids only after systemic treatment, a finding that parallels clinical observations.

Acitretin↗

Retinoid augmentation of bioactive interleukin-1 production by murine keratinocytes.

The effect of retinoids on the production of interleukin-1 (IL-1) by murine epidermal keratinocytes was investigated. Freshly isolated keratinocytes were cultured in the presence of etretinate, acitretin, all-trans retinoic acid or 13-cis retinoic acid at concentrations of 8 x 10(-9)-8 x 10(-6) mol/l. Exposure of keratinocytes to retinoids increased IL-1 bioactivity in culture supernatants and cell extracts at concentrations as low as 8 x 10(-9) mol/l, as assessed by T-cell proliferation. Prolongation of the culture period enhanced the augmentative effect of retinoids. All-trans retinoic acid and 13-cis retinoic acid had a greater ability to induce IL-1 production than the two aromatic retinoids, etretinate and acitretin. Treatment with 8-methoxypsoralen plus ultraviolet A radiation and treatment with triamcinolone acetonide both reduced the effect of retinoids on the production of bioactive IL-1.

Acitretin↗

Systemic and topical retinoids in the management of skin cancer in organ transplant recipients.

BACKGROUND: Nonmelanoma skin cancers are the most frequent malignancies in organ transplant patients. Patients who develop multiple new skin cancers may benefit from retinoid chemoprevention. OBJECTIVE: The objective of this study was to advise on the use of retinoids in organ transplant recipients. METHODS: A summary was performed of the existing literature regarding experience with retinoid chemoprevention for skin cancer in organ transplant patients. RESULTS: Systemic retinoids, specifically acitretin, are effective in inhibiting tumor development in organ transplant patients. This effect is only present during therapy, however. Topical retinoids have some effect in the treatment of actinic keratoses. CONCLUSIONS AND RECOMMENDATIONS: Systemic retinoids can be used for chemoprevention of skin cancer. For a good result, long-term treatment with acitretin is necessary. Side effects, however, limit the use of retinoid chemoprevention. It is advised that treatment be started at a low dose, and patients should be monitored regularly for triglyceride and cholesterol levels and transaminases.

Acitretin↗

Antiproliferative effect of retinoid compounds on Kaposi's sarcoma cells.

A panel of retinoid compounds (tretinoin, isotretinoin, acitretin, and RO13-1470) were tested for inhibitory activity against Kaposi's sarcoma cell (KSC) cultures in vitro. Tretinoin was found to be the most effective retinoid tested, inhibiting the growth of KSC in vitro while having no effect on the expression of interleukin-6 and basic fibroblast growth factor, two important cytokines involved in KSC growth. Tretinoin also did not appear to downregulate the expression of receptors for these two cytokines. At low concentrations (10(-9) M), acitretin and tretinoin selectively inhibited growth of early passage KSC. At higher concentrations (10(-6)-10(-5) M), retinoid treatment induced a pattern of DNA degradation and morphological changes in KSC characteristic of apoptosis (programmed cell death). The inhibitory activity of tretinoin on KSC growth was decreased if human serum (but not fetal calf serum) was present in the growth medium, and partially restored by removal of serum lipids. These data suggest that retinoids possess potential as therapeutic agents in Kaposi's sarcoma.

Acitretin↗