Article

Oral retinoids in the treatment of seborrhoea and acne.

Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Germany.
Dermatology (Impact Factor: 1.69). 02/1998; 196(1):140-7. DOI: 10.1159/000017848
Source: PubMed

ABSTRACT Isotretinoin is an extremely effective drug if given systemically in severe forms of seborrhoea and acne, being the only retinoid with potent sebostatic properties. Its unique activity on the sebaceous gland still remains unclear since isotretinoin barely binds to cellular retinoic-acid-binding proteins and to retinoic acid receptors. Its bioavailability is approximately 25% and can be increased by food 1.5-2 times; after 30 min, the drug is detectable in the blood and maximal concentrations are reached 2-4 h after oral intake. The major metabolites of isotretinoin in blood are 4-hydroxy- and 4-oxo-isotretinoin, while several glucuronides are detectable in the bile. 4-Oxo-isotretinoin is present in plasma in a 2- to 4-fold higher concentration 6 h after a single dose. Steady-state concentrations appear after 1 week. The half-life elimination rate of the parent compound ranges from 7 to 37 h while that of some metabolites does so from 11 to 50 h. Isotretinoin crosses the placenta and is recognized as a strong teratogenic compound. About 10-30% of the drug is metabolized via its isomer tretinoin. Excretion of isotretinoin occurs after conjugation with the faeces or after metabolization with the urine. The epidermal levels of isotretinoin are rather low and no progressive accumulation, either in serum or in the skin, is found. After discontinuation of therapy, isotretinoin disappears from serum and skin within 2-4 weeks. Isotretinoin is the most effective drug in reducing sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocyte differentiation in vivo. The molecular basis for its antisebotrophic activity has not been fully elucidated. Isotretinoin also exhibits anti-inflammatory activities. Systemic isotretinoin is today the regimen of choice in severe seborrhoea, since it reduces sebocyte lipid synthesis by 75% with daily doses as low as 0.1 mg/kg after 4 weeks. Patients who have received oral isotretinoin therapy for seborrhoea do not usually experience a relapse for months or years. In severe acne, a 6- to 12-month treatment with isotretinoin 1 mg/kg/day reduced to 0.5 or 0.2 mg/kg/day according to the response is recommended (cumulative dose of > 120 mg/kg). Contraception is essential during isotretinoin treatment in women of childbearing age 1 month before, during and for 3 months after discontinuation of treatment.

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    • "The laboratory rat was selected as the animal model due to the broad number of assessments sensitive to depressive behaviors in this species. Subsequent to earlier studies which indicated little or no gross toxicity after 13-cis-RA treatment [17] [30], a pharmacokinetic study then determined that a daily oral dose of 7.5 or 15 mg/kg resulted in peak serum levels of ≈577 and 1262 ng/ml, respectively , in male and female rats [32], a level fairly comparable to the 300–800 ng/ml achieved by humans undergoing standard treatment [3] [11] [39] [47] [59] [61]. The half-life for those 7.5 or 15 mg/kg doses was 1–2 h [32]. "
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    ABSTRACT: Reports of depression and/or suicide with ACCUTANE (13-cis-retinoic acid (13-cis-RA)) use prompted studies in a rodent model to ascertain its potential effects. Previously, there were no effects on measures of anhedonia (intake of a saccharin-flavored solution) and depression (forced swim test (FST) behaviors) in rats treated with 7.5 or 22.5 mg/kg 13-cis-RA [S.A. Ferguson, F.J. Cisneros, B. Gough, J.P. Hanig, K.J. Berry, Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats, Toxicol. Sci. 87 (2005) 451-459.]. Here, dose and temporal thresholds were investigated by increasing the maximum 13-cis-RA dose to 30 mg/kg, extending treatment duration, and measuring behaviors repeatedly. Beginning on post-natal day 59, male and female Sprague-Dawley rats were gavaged with soybean oil, 7.5 or 30 mg/kg/day of 13-cis-RA for approximately 19 weeks. FST behaviors were measured after 24, 82, and 131 treatment days and saccharin intake (0.03% solution) was measured at baseline and after 14, 35, 56, and 112 treatment days. Body weight and food intake were not altered by treatment. FST durations of swim, climb/struggle, and immobility were unaffected by 13-cis-RA at any time during treatment. More males than females required "rescue" in the FST but there was no treatment effect on number of rats requiring early removal. 13-cis-RA treatment had no effects on saccharin intake at any time. Given that the 7.5 mg/kg dose produces serum levels which parallel those of humans [S.A. Ferguson, P.H. Siitonen, F.J. Cisneros, B. Gough, J.F. Young, Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all-trans-retinoic acid in male and female adult rats, Basic Clin. Pharmacol. Toxicol 98 (2006) 582-587.], these results are quite relevant. Combined with previous results, these results provide further evidence that 13-cis-RA does not produce behavioral alterations indicative of depression in rats.
    Neurotoxicology and Teratology 11/2007; 29(6):642-51. DOI:10.1016/j.ntt.2007.09.003 · 3.22 Impact Factor
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    • "Our previous work has shown that oral (gavage) treatment with 7.5 mg/kg 13-cis-RA in male and female rats causes little gross toxicity and results in peak serum levels of ≈ 577 ng/ml [6] [17] [18] [25]. Those serum levels are comparable to the 300– 800 ng/ml achieved by humans undergoing standard 13-cis-RA treatment for acne [27] [4] [1] [32] [35] [22]. In the current study, oral treatment of 7.5 or 30 mg/kg 13-cis-RA continued daily for 19 weeks during which three different measures of learning and memory were conducted: the Morris water maze, the 8-arm radial maze, and a dry land maze (the NCTR complex maze). "
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    Neurotoxicology and Teratology 03/2007; 29(2):219-27. DOI:10.1016/j.ntt.2006.10.008 · 3.22 Impact Factor
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    • "Taken together, the C max values for those two reports and the data reported here are relatively similar. The 13-cis-retinoic acid C max values reported here clearly fall within the clinical range of those reported for human beings (Kerr et al. 1982; Brazzell et al. 1983; Almond-Roesler et al. 1998; Nulman et al. 1998; Orfanos & Zouboulis 1998; Hendrix et al. 2004); however, levels of the metabolite, 13-cis-4-oxo-retinoic acid, are much lower than those reported for man (Almond-Roesler et al. 1998; Orfanos & Zouboulis 1998). This may be due to increased glucoronidation in the rat (in which 13-cis-retinoic acid is glucoronidated to 13-cis-retinoic acid glucuronide) relative to the primate in which 13-cis-retinoic acid is oxidized to 13-cis-4- oxo-retinoic acid. "
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    ABSTRACT: Male and female Sprague-Dawley rats were orally gavaged with 13-cis-retinoic acid (7.5 or 15 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg) for 7 consecutive days. Blood was collected out to 8 hr after the last gavage on day 7. HPLC serum concentrations of 13-cis-retinoic acid, all-trans-retinoic acid, and 13-cis-4-oxo-retinoic acid were subjected to model independent pharmacokinetic analyses. Peak serum levels of 563 to 1640 ng/ml were observed for rats treated with 13-cis-retinoic acid at 1.5-2 hr after gavage. Peak serum levels of 183 to 267 ng/ml at 1.5 hr after gavage were observed for all-trans-retinoic acids. The elimination half-life of 13-cis-retinoic acid was about 1.5 hr while the elimination half-life of all-trans-retinoic acid was slightly longer. There were no sex differences for any parameter. Serum levels resulting from the 7.5 mg/kg 13-cis-retinoic acid were similar to those of human Accutane users.
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