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PubMed2006

New roles for systemic retinoids.

Acitretin, the only oral retinoid indicated for the treatment of psoriasis, has shown activity when used in combination, rotational, and sequential therapy regimens with other therapies. When used with phototherapy, significantly greater activity has been observed at lower doses than with either approach as monotherapy. While initial anecdotal evidence is promising, clinical trials are needed to evaluate whether sequential or rotational use of biologic agents with acitretin may yield improved efficacy and an acceptable safety profile with decreased risk of immunosuppression. Acitretin and other retinoids also work as chemopreventative agents in psoriasis patients with extensive exposure to psoralen ultraviolet A (PUVA) and in solid-organ transplant patients where a number of studies have reported decreased numbers of squamous cell cancers when treated with acitretin.

Acitretin↗
PubMed2005

[Use of topical cutaneous N-acetylcysteine in the treatment of major bilateral ectropion in an infant with lamellar ichthyosis].

PURPOSE: To report for the first time bilateral ectropion treatment in an infant with severe lamellar ichthyosis associating N-acetylcysteine applied directly to the skin and oral acitretin. METHODS: An 8-week-old male child with major bilateral ectropion due to lamellar ichthyosis was given treatment associating oral acitretin (Soriatane) and topical N-acetylcysteine. Though the precorneal tear film quality could be maintained, after 1 month of initial treatment with acitretin only, bilateral upper eyelid ectropion remained threatening for the child's cornea. The adjunction of topical N-acetylcysteine enabled a complete regression of ectropion. No complementary surgery was needed and the eyelids remained well positioned. CONCLUSION: Topical N-acetylcysteine has been proved to have an antiproliferative effect on keratinocytes in vitro and in vivo. It may be useful in the treatment of major forms of ectropion in children with lamellar ichthyosis. Its association with conventional acitretin treatment may prevent unnecessary surgery.

Acetylcysteine↗
PubMed1996

Multiple retinoids alter liver bile salt-independent retinyl ester-hydrolase activity, serum vitamin A and serum retinol-binding protein of rats.

Liver bile salt-independent retinyl ester hydrolase (BSI-REH) has been suggested to play a significant role in the hydrolysis of chylomicron derived retinyl esters. Studies were conducted to investigate the individual effects of N-(4-hydroxyphenyl)retinamide (HPR), retinoic acid, 13-cis-retinoic acid, Acitretin and Temarotene on BSI-REH, serum retinol, and serum retinol-binding protein (RBP) concentrations. We have demonstrated that micromolar concentrations of HPR, retinoic acid, 13-cis-retinoic acid or Acitretin significantly reduced the in vitro hydrolysis of retinyl palmitate. In contrast, Temarotene stimulated retinyl palmitate hydrolysis by BSI-REH. Retinoic acid and 13-cis-retinoic acid produced transient, but significant, depressions of both serum retinol and RBP concentrations, when the individual retinoids were administered orally to rats. The duration of the depression was shorter than we previously observed with acute HPR administration. Furthermore, Acitretin appeared to function with bimodal activity, producing significant depression of serum retinol at 2 h and 24 h. No effect of Acitretin or Temarotene on serum RBP concentration was observed. The alterations observed in BSI-REH activity, serum retinol and RBP concentrations provide evidence that these retinoids can alter liver retinyl ester hydrolysis, but the effects observed on serum retinol concentration can only be partially explained by the BSI-REH activity.

Animals↗
PubMed1997

Inhibition of plasma membrane NADH oxidase activity and growth of HeLa cells by natural and synthetic retinoids.

Several retinoids, both natural and synthetic, were evaluated for their ability to modulate NADH oxidase activity of plasma membranes of cultured HeLa cells and the growth of HeLa cells in culture. Both NADH oxidase activity and the growth of cells were inhibited by the naturally-occurring retinoids all trans-retinoic acid (tretinoin) and retinol as well as by the synthetic retinoids, trans-acitretin, 13-cis-acitretin, etretinate and arotonoid ethylester (Ro 13-6298). For all retinoids tested, inhibition of NADH oxidase activity and inhibition of growth were correlated closely. With tretinoin, etretinate and arotonoid ethylester, NADH oxidase activity and cell growth were inhibited in parallel in proportion to the logarithm of retinoid concentration over the range of concentrations 10(-8) to 10(-5) M. Approximately 70% inhibition of both NADH oxidase activity and growth was reached at 10 microM. With retinol, trans-acitretin and 13-cis-acitretin, inhibition of NADH oxidase activity and growth also were correlated but maximum inhibition of both was about 40% at 10 microM. The possibility is suggested that inhibition of the plasma membrane NADH oxidase activity by retinoids may be related to their mechanism of inhibition of growth of HeLa cells in culture.

Animals↗
PubMed1988

Percutaneous absorption of retinoids: influence of vehicle, light exposure, and dose.

The percutaneous absorption characteristics of isotretinoin, etretinate, tretinoin, and acitretin were investigated in vitro to assess the feasibility of their topical application for dermatological disorders. The influence of vehicle, photodegradation, and dose was examined. Retinoid absorption through monkey skin was highly vehicle dependent and followed the order: propylene glycol = isopropyl alcohol greater than mineral oil greater than diisopropyl adipate greater than polyethylene glycol 400. Peak flux of etretinate (an ester) was less than 50% that of the acid retinoids in both human and monkey skin. Exposure to light caused a 60% degradation of isotretinoin on the surface of the skin, but did not change the amount of drug which penetrated the epidermis. In accord with this result, the amount of isotretinoin and acitretin which penetrated epidermis did not increase in proportion to dose over a 25-fold range of dose in human skin. Dermal concentration at doses of 10 micrograms/cm2 of isotretinoin and acitretin were greater than that reported for shave biopsies of human skin following treatment for several months with clinically effective doses of isotretinoin and etretinate (the parent ester of the acid acitretin).

Absorption↗
PubMed2005

Effects of chronic retinoid administration on pituitary function.

It has been reported that retinoids may affect hypothalamic-pituitary-thyroid axis, causing central hypothyroidism. In the present study, we evaluated pituitary function in 11 male psoriatic patients at baseline and after 1 and 3 months of treatment with acitretin (all-trans retinoic acid, 35 mg/day). Serum LH, FSH, testosterone, cortisol, GH and IGF-I levels were not affected by the treatment. By contrast, we observed a significant decrease in TSH levels (from 0.92 +/- 0.3 to 0.80 +/- 0.3 mU/I, p < 0.05) at 1 month, that reverted to baseline after 3 months. No change in free T4 (FT4) levels occurred, while free T3 (FT3) levels were reduced at 1 and 3 months (from 6.7 +/- 0.5 to 6.2 +/- 0.3 and 6.1 +/- 0.6 pmol/l; p < 0.05, respectively). Moreover, acitretin treatment induced a significant reduction of PRL levels after 3 months (from 182 +/- 70 to 150 +/- 56 mU/l, p < 0.05). During treatment, no change in TSH and PRL response either to TRH or dopamine infusion was observed. In conclusion, we demonstrated that treatment with low dose of acitretin induced a series of hormonal modifications that, in addition to a mild and transient reduction of TSH levels, included a persistent reduction of FT3, probably due to changes in thyroid hormone metabolism, and a decrease in PRL levels.

Acitretin↗
PubMed1991

A newly discovered xenobiotic metabolic pathway: ethyl ester formation.

Formation of etretinate, ethyl ester of acitretin, can be confirmed in vitro and in vivo using acitretin as the substrate. Etretinate was identified by LC/MS. The in vitro incubation was performed using rat and human liver 12,000 g supernatant, and the in vivo experiment was conducted in rats after oral dosing of acitretin. The ethyl ester formation was greatly enhanced by addition of or dosing with ethanol.

Acitretin↗
PubMed1995

Extensive extraspinal hyperostoses after long-term oral retinoid treatment in a patient with pityriasis rubra pilaris.

We describe a patient with severe pityriasis rubra pilaris in whom extensive extraspinal hyperostoses developed after 13 years of oral retinoid treatment. The most prominent abnormality was a bridging exostosis between the left acetabulum and collum. X-ray examinations of the spine during retinoid therapy showed no abnormalities. During oral retinoid treatment, it is important to ask the patient on a regular basis about any skeletal pains or mobility restriction. Normal spinal x-ray results are no guarantee that a patient is free of hyperostoses. Discontinuation of acitretin therapy resulted in a severe exacerbation of the patient's pityriasis rubra pilaris after 2 weeks. The clinical response to administration of azathioprine was clearly inferior to that of acitretin. However, low-dose oral methotrexate therapy appeared to be a good alternative in this patient, with a clinical result comparable to acitretin and no side effects after 6 months of therapy.

Acetabulum↗
PubMed1992

Retinoids in psoriasis and disorders of keratinization.

Synthetic retinoids, particularly the aromatic retinoid etretinate (Tigason, Europe; Tegison, United States), have had an established role in the treatment of psoriasis and a variety of ichthyosiform disorders for more than a decade. Isotretinoin (Accutane), which was released at approximately the same time, plays a less important role in these disorders. The mechanism of action of etretinate is still incompletely understood although, like retinoic acid, it is thought to interfere with the terminal differentiation of keratinocytes. The recent detection of nuclear retinoic acid receptors may lead to a unifying theory of retinoid effects and provide the means for more targeted use of this class of compounds. The substantial amount of data on the clinical effectiveness of etretinate was obtained empirically from numerous multicenter trials and individual reports; its indications, dosimetry, pharmacokinetics, and side effects are well established. The main adverse effect associated with etretinate is its teratogenicity (common to all retinoids), which is of particular concern because the lipophilic compound is stored in fat tissue, resulting in an elimination half-life of as many as 120 days. To avoid this problem the much less lipophilic unesterified acid of etretinate, acitretin, has been made available and has now replaced etretinate in many countries. Acitretin represents the active principle of etretinate and has an elimination half-life of 2 days. No significant clinical differences have been observed between these two compounds. Partial in vivo conversion of acitretin into etretinate, however, has been described in some patients. Both compounds are standard treatment for pustular and erythrodermic psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin↗
PubMed1999

Retinoids and psoriasis: novel issues in retinoid pharmacology and implications for psoriasis treatment.

Oral synthetic retinoids have been established as effective systemic therapy for psoriasis since their introduction for clinical use in the 1970s. Acitretin, the free acid of etretinate and its active metabolite, has replaced etretinate as the retinoid of choice for treating psoriasis because of its more favorable pharmacokinetic profile. Despite the demonstrated clinical success of retinoid therapy in psoriasis and other proliferative skin disorders, their mechanism of action has not been fully elucidated. Altered vitamin A metabolism, characterized by an increase in the formation of retinoic acid, has been demonstrated in psoriatic lesions and is potentially influenced by cytokines such as interferon gamma, which is present in high levels in these lesions. Synthetic retinoids such as acitretin may interfere with such cytokine-induced alterations. Studies on nuclear retinoic acid receptors have shown that acitretin activates all 3 receptor subtypes (RAR-alpha, -beta, and -gamma) without measurable receptor binding; this paradox remains unexplained. Further studies on nuclear receptor binding and activity, including possible receptor crosstalk with vitamin D nuclear receptors, promise to enhance understanding of the usefulness of retinoids in treatment of psoriasis.

Acitretin↗
PubMed1998

Inhibition of ribonuclease P activity by retinoids.

The effect of two naturally occurring (retinol and all-trans retinoic acid) and two synthetic (isotretinoin and acitretin) analogs of vitamin A (retinoids) on tRNA biogenesis was investigated employing the RNase P of Dictyostelium discoideum as an in vitro experimental system. RNase P is an ubiquitous and essential enzyme that endonucleolytically cleaves all tRNA precursors to produce the mature 5' end. All retinoids tested revealed a dose-dependent inhibition of RNase P activity, indicating that these compounds may have a direct effect on tRNA biogenesis. Detailed kinetic analysis showed that all retinoids behave as classical competitive inhibitors. The Ki values determined were 1475 microM for retinol, 15 microM for all-trans retinoic acid, 20 microM for isotretinoin, and 8.0 microM for acitretin. On the basis of these values acitretin is a 184, 2.5, and 1.9 times more potent inhibitor, as compared with retinol, isotretinoin, and all-trans retinoic acid, respectively. Taking into account that retinoids share no structural similarities to precursor tRNA, it is suggested that their kinetic behavior reflects allosteric interactions of these compounds with hydrophobic site(s) of D. discoideum RNase P.

Acitretin↗
PubMed1992

Therapeutic drug monitoring of retinoids.

Retinoids are natural or synthetic compounds related to vitamin A. They are successfully used in the treatment of dermatological disorders. However, one of the limiting factors in the use of retinoids is their huge teratogenic potential. The investigation into the pharmacokinetics and metabolism of retinoids has encountered many difficulties due to lack of suitable techniques to deal with these labile compounds. Because of the teratogenic nature of the retinoids, the sensitivity of the assay is of utmost importance. We report a systematic comparison between two high-performance liquid chromatographic methods used to monitor levels of etretinate and its metabolites acitretin and 13-cis-acitretin in plasma. Our analysis suggests that the column-switching method is superior owing to smaller variability in results and its simplicity. We also describe our therapeutic drug monitoring program for counseling women of reproductive age following etretinate or acitretin exposure. Presently, labeling of etretinate in North America suggests that women should refrain from conception for an undetermined length of time. Assessment of serum concentrations over time is beneficial in defining the length of period to postpone conception.

Acitretin↗
PubMed2006

Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years' experience on 23 patients.

BACKGROUND: Over the last three decades, the oral retinoids etretinate and acitretin have revolutionized the treatment of disorders of keratinization (DOK). Many patients with DOK require life-long treatment with oral retinoids. However, the longest follow-up data of patients with DOK on oral retinoid therapy is 10 years for adults and up to 11 years for children. OBJECTIVES: The aim of our study was to collect long-term retrospective data including disease response, side-effects and pregnancy outcome in a cohort of patients with DOK who were among the first in the world to commence oral retinoids 25 years ago. METHODS: Between 1979 and 1981, 30 patients with DOK were commenced on oral etretinate in our department. Case notes of these patients were reviewed retrospectively, and patients interviewed where possible to obtain the following information: diagnosis, age when treatment commenced, duration of treatment, reason for discontinuation of therapy, side-effects, abnormal investigation results and pregnancy outcomes. RESULTS: Case notes of 23 of the 30 patients were available for review; of these, two patients were deceased and 14 were interviewed. In the 23 patients, the mean age of commencing treatment was 33.5 years (range 4.2-61) and the mean duration of etretinate therapy was 5.2 years (range 1 month to 14 years). Reasons for discontinuing treatment were an overall improvement in the skin disease (six of 23), no benefit +/- side-effects (11 of 23) and noncompliance (one of 23). Two patients died of causes unrelated to their skin disease or treatment, 12 and 4 years after stopping etretinate. Five patients (one female, four males) subsequently changed to acitretin and are currently continuing therapy. The mean total duration of retinoid therapy (etretinate and acitretin) for the four males was 23.7 years (range 20.6-25.1). The female patient continued intermittent courses (due to planned pregnancies) of oral retinoids for a total of 10.1 years over the last 25 years. Abnormal investigation results included elevated serum triglycerides and cholesterol (two of 23), isolated high triglycerides (three of 23), isolated high cholesterol (three of 23), worsening of liver enzymes in a patient with alcohol dependence, and elevated serum alkaline phosphatase (ALP) in healthy adults (three of 23). In two children, the elevated pretreatment ALP levels increased further after commencing etretinate but returned to normal in adulthood while treatment continued. One patient developed diffuse idiopathic skeletal hyperostosis after 21 years of retinoid therapy. One female patient had two early spontaneous abortions 2.75 and 3.2 years after discontinuing etretinate; she subsequently had two normal children. Two other females had normal children 1, 3 and 5 years after stopping etretinate. Two male patients fathered a total of three healthy children while on etretinate. CONCLUSIONS: This study provides the longest available follow-up data of children and adults with DOK on oral retinoid therapy. Such information is essential for clinicians and their patients with DOK embarking on life-long treatment with retinoids.

Acitretin↗
PubMed2007

Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas.

A 27-year-old white woman was referred for consultation with regard to the presence of extensive multiple keratotic lesions. She began to develop these lesions at the age of 9 years, with healing of the lesions resulting in scar formation. A biopsy was performed at the age of 16 years, but the patient was unsure of the results. Since then, she had not had any treatment or biopsies, and stated that she had not suffered from any health problems during the intervening period. She was most concerned about the tumors on her heels and soles, which caused difficulty with ambulation. The family history was negative for skin diseases, including melanoma, nonmelanoma skin cancer, psoriasis, and eczema, and positive for Type II diabetes mellitus. A relative reported that the patient's grandfather had similar lesions, but the patient's parents and siblings were healthy. She was married and had one child, a 9-year-old daughter. Her child had no skin lesions. The patient's only medication was Ortho-Tricyclene birth control pills. She had no known drug allergies. Physical examination revealed the presence of multiple lesions on her body (Fig. 1). Her left superior helix contained a well-demarcated, dome-shaped nodule with a rolled, mildly erythematous border with a central hyperkeratotic plug. A similar lesion was present in the scaphoid fossa of the left ear and smaller lesions were scattered on her face. Numerous lesions were present on the arms and legs bilaterally, with the majority of lesions being located on the anterior lower legs. There were also lesions present on the palms and soles. The lesions ranged in size from 5 mm to 3 cm, the largest being a verrucous exophytic nodule on the anterior aspect of her left leg. Overall, there appeared to be two distinct types of lesion. One type appeared round, oval, and symmetric with a central keratotic plug, similar to that on the ear. The other type was larger, more exophytic, and verrucous, including the lesions on the volar surfaces. Also present were numerous, irregularly shaped atrophic scars where previous lesions had healed spontaneously. There were no oral lesions or lesions on her fingernails or toenails, and her teeth and hair were normal. A biopsy was obtained from an early lesion on the right dorsal forearm. Histology revealed an exo-/endophytic growth having a central crater containing keratinous material (Fig. 2). The crater was surrounded by markedly hyperplastic squamous epithelium with large squamous epithelial cells having abundant glassy cytoplasm. Some cells were dyskeratotic. Within the dermis was a dense, chiefly mononuclear inflammatory infiltrate. A buttress of epidermis surrounded the crater. The clinical and pathologic data were consistent with keratoacanthomas. Initial laboratory screenings revealed elevated triglycerides and total cholesterol, 537 mg/dL (normal, < 150 mg/dL) and 225 mg/dL (normal, < 200 mg/dL), respectively, with all other laboratory results within normal limits. In anticipation of starting oral retinoid therapy for her multiple keratoacanthomas, she was referred to her primary care physician for control of hyperlipidemia. After her lipids had been controlled, she was placed on isotretinoin (Accutane) 40 mg/day. There was some interval improvement with regression of some lesions leaving atrophic scars. She was also started on topical application of tazarotene (Tazorac) for all nonresolving lesions. Possible side-effects from the isotretinoin occurred, including dry mouth and eyes. After 8 months of isotretinoin, the patient was switched to acitretin (Soriatane) 25 mg to determine whether it might have a more beneficial effect on the resistant lesions. Many of the larger lesions regressed leaving atrophic scars. The dose of acitretin was subsequently increased to 35 mg because the lesions on her heel and the ball of her foot persisted. Almost all of the lesions resolved, except those on her feet, which are slowly regressing. Currently, the patient is on a regimen of acitretin 25 mg once a day with tazarotene 0.1% gel applied directly to the few residual keratoacanthomas on her feet, which are slowly improving.

Acitretin↗
PubMed1992

Antitumor action of retinoids: inhibition of tumor cell line-induced angiogenesis and prevention of tumors in mice.

Acitretin was shown to inhibit angiogenic response to the tumorigenic SKV cell line bearing HPV16 genome and to sarcoma L-1 cell line, both in vitro and in vivo systems. The lowered angiogenic response to tumor cells was independent of duration and timing of the application of acitretin to animals. Acitretin, but not etretinate, was also found to be effective in the prevention of sarcoma tumors in mice.

Acitretin↗
PubMed1996

Acrodermatitis continua of Hallopeau in a patient with myelodysplastic syndrome.

Acrodermatitis continua of Hallopeau (ACH) is a rare manifestation of pustular psoriasis which may considerably disable affected patients. In this case report we confirm the efficacy of acitretin in the treatment of ACH and, in addition, describe the course of the myelodysplastic syndrome (MDS) from which the patient was suffering. During acitretin treatment, there was a transformation into acute myeloid leukaemia. We discuss the effect of retinoids on the bone marrow of normal subjects, patients with MDS, and patients with acute myeloid leukaemia. Our experience in the present case, and the information from the available literature, lead us to advise against the use of the aromatic retinoids, acitretin and etretinate, in patients with MDS. If such treatment is indicated, intensive haematological supervision is mandatory.

Acitretin↗
PubMed2000

Combination regimens of topical calcipotriene in chronic plaque psoriasis: systematic review of efficacy and tolerability.

OBJECTIVE: To examine the efficacy and tolerability of calcipotriene combined with phototherapy or systemic therapies compared with monotherapy for the treatment of chronic plaque psoriasis. DESIGN: Quantitative systematic review of 11 randomized controlled trials involving a total of 756 patients with plaque psoriasis. MAIN OUTCOME MEASURES: Rate ratios (RRs) for marked improvement or clearance in patient and investigator overall assessments of response; mean difference in percentage change in Psoriasis Area and Severity Index; and RRs for clearance in patient and investigator overall assessments of response. Adverse effects were estimated with the RR and the rate difference in terms of withdrawal rate, proportion of patients experiencing adverse events, and proportion of patients with cutaneous and noncutaneous adverse effects. RESULTS: Antipsoriatic effects of acitretin, cyclosporine, and psoralen-UV-A phototherapy were enhanced with the addition of topical calcipotriene using the Psoriasis Area and Severity Index as the outcome, but this is not translated into an increase in the number of patients who achieve at least marked improvement. At the end of treatment, the RRs for marked improvement or clearance in patient assessments were as follows: calcipotriene plus acitretin vs acitretin alone (12 weeks), 1.4 (95% confidence interval [CI], 1.0-1. 9); calcipotriene plus cyclosporine vs cyclosporine alone (6 weeks), 1.2 (95% CI, 0.9-1.6); and calcipotriene plus psoralen-UV-A vs psoralen-UV-A alone (12 weeks), 1.2 (95% CI, 0.9-1.6). Patients were also no more likely to obtain marked improvement or better with calcipotriene plus UV-B therapy than with UV-B therapy alone (RR, 1. 0; 95% CI, 0.8-1.1 at 8 weeks in the patient assessment). There is limited evidence that use of calcipotriene might reduce the cumulative exposure to phototherapy and systemic treatment. During the short duration of these trials, there were no significant differences in withdrawal rates or adverse effects between the combined regimens and their corresponding monotherapy control interventions. CONCLUSIONS: Overall, there is insufficient evidence to support any large effects in favor of combination treatment. In the patient assessments, the results do not show an adjuvant effect, but there is some evidence that use of calcipotriene might reduce cumulative exposure to systemic therapy to obtain clearance. There were no long-term morbidity data on the effectiveness of any of the combinations studied. Given that psoriasis is a chronic recurrent disease for most patients, longer trials are needed to determine whether the addition of topical calcipotriene to systemic therapy improves the risk-benefit ratio by reducing the long-term risk of toxic effects. Equally important is the need to examine the impact of such combinations on the duration of remission after treatment.

Administration, Cutaneous↗
PubMed2003

Retrospective analysis of the treatment of psoriasis of the palms and soles.

In this retrospective analysis, the effect of currently used treatments in 26 patients with psoriasis of the palms and soles were analyzed. In general, patients are treated initially with topical medications including superpotent topical corticosteroids in combination with calcipotriene ointment or tazarotene gel or both. If satisfactory improvement is not achieved in 4-8 weeks, systemic retinoids are added, formerly etretinate and currently acitretin, except in women of childbearing potential. If the latter regimen is not effective within two months, soak PUVA is added to the regimen of oral retinoids and topical medications. If improvement is inadequate, or if the treatment regimen is not tolerated, methotrexate or cyclosporine have been added in the past. The availability of the excimer laser has recently modified our approach so that this therapy is used in combination with acitretin before soak PUVA. With the availability of biologic agents, methotrexate is avoided because of its hepatotoxicity and bone marrow toxicity and cyclosporine is avoided because of its nephrotoxicity. If oral acitretin plus topical therapy is not adequate to control the disease and the excimer laser is not an option because of its limited availability, alefacept, etanercept and infliximab are added when possible. Other biologic agents are likely to be added to this list in the future.

Adult↗