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ISOTRETINOINACCUTANEACNEPREGNANCYCYSTICFETALHEALTHMEDICINE ISOTRETINOIN (ACCUTANE) TREATMENT OF ACNE Isotretinoin (Accutane) treatment of acne ----------------------------------------- It has long been known that vitamin A has a regulatory effect on growth and differentiation of epithelial tissue. Since the 1940's, high doses of vitamin A have been employed in the treatment of severe acne and various disorders of keratinization. Vitamin A's use, however, was limited by its side effects - liver toxicity and pseudotumor cerebri in particular. In an attempt to find a drug with a better therapeutic index than vitamin A, several synthetic retinoids have been developed (1). One of these, isotretinoin (13-cis-retinoic acid), was first synthesized in 1955. It was largely ignored until the results of the first major clinical trial demonstrating its efficacy in the treatment of severe recalcitrant cystic acne were published in 1972 (2). in 1982, isotretinoin was approved in the United States for that single indication only. Its trade name is Accutane. A major feature of this drug is that it produces a prolonged remission in patients with severe cystic acne, many of whom had not responded to other therapies. The most striking discovery, however, is that the remission is often sustained for months or years after the four- to five-month treatment course has been completed. Transport and metabolism of vitamin A (retinol) and isotretinoin Significant differences between vitamin A and isotretinoin with regard to their transport and metabolism account for their difference in toxicity (3). The major source of vitamin A (retinol) is the conversion of dietary plant carotenoids in the intestinal mucosa. Retinol is stored in the liver, which contains over 90% of body stores. Mobilization from the liver is accomplished when retinol is bound to a specific transport protein, retinol binding protein, that delivers it to tissues. Plasma levels of vitamin A tend to remain constant despite wide variations in diet. Extremely high dietary intake (eg. polar bear liver, vitamin A tablets) produces hypervitaminosis A. Hypervitaminosis A results in greatly increased hepatic stores and subsequent toxicity. In contrast, isotretinoin binds to serum albumin. Isotretinoin is readily absorbed orally and put into circulation via the portal system. It is not significantly stored in any organ system, and plasma levels vary with the amount ingested. Mode of action of isotretinoin in the treatment of acne Acne is a disease of the pilosebaceous unit. The pathogenesis of acne is believed to include several factors. Among them are excessive sebum production, abnormal keratinization of follicular epithelium, proliferation of 'Propionibacterium acnes', inflammation, and hormonal regulation of sebaceous glands. Isotreinoin affects several of these mechanisms, but its exact mode of action is not known. Isotretinoin causes pronounced but temporary inhibition of sebum production and atrophy of sebaceous glands (4). In general, after two weeks of standard therapy (1mg/kg/day), sebum production is decreased by more than 50% and by the end of a four- to five- month treatment period, it is reduced by greater than 90%. While there are some patients who continue to have decreased sebum production months to years after cessation of therapy, the sebum production of the vast majority returns to the baseline level within a few months. Since sebum production returns to normal in most patients, this is obviously not the sole mechanism for the prolonged remission of acne seen in these individuals. Many of these patients continue to improve even after therapy is discontinued (5). Some investigators believe that isotretinoin inhibits follicular keratinization in patients with acne. They postulate that this prevents the formation of comedomes (whiteheads and blackheads), the precursors of inflammatory acne lesions. Isotretinoin does decrease the quantity of 'Propionbacterium acnes' in treated patients. This organism is normal flora within the follicles. Increased numbers of these bacteria in patients with acne produce various chemotactic factors and enzymes that may increase inflammation. The decreased number of these bacteria in isotretinoin-treated patients is thought to be a result of decreased sebum production, producing a poor environment for the proliferation of this organism. Therefore, the decreased bacterial counts are thought to be secondary, and not the primary mechanism of action of Accutane. Clinical side effects Mucocutaneous side effects are the most common seen in isotretinoin treatment (6). More than 90% of people treated experience cheilitis, usually within the first two weeks of treatment. This is most easily treated with bland emolliation. A generalized xerosis is very common, but frequently acne patients view this as a beneficial rather than adverse effect. Should xerosis become problematic, the use of a noncomedogenic emollient lotion can be employed. Frequently patients develop nose bleeds and non-infectious conjunctivitis. Symptomatic treatment of these problems is all that is indicated. Less than 30% of patients notice temporary thinning of the hair. Less than 10% of these have clinically apparent hair loss, and hair density returns to normal after treatment is discontinued. Approximately 20% of patients on isotretinoin have musculo- skeletal pains. These tend to be minor, and are relieved by non- steroidal anti-inflammatory agents. More worrisome are the skeletal abnormalities seen in patients on long term isotretinoin treatment for various keratinizing disorders (7). These patients however , were usually treated with higher doses of 2mg/kg/day for more than two years. The ossification disorder seen in these patients resembles diffuse idiopathic skeletal hypostosis. Children being treated for these disoreders had x-ray findings suggesting premature closure of the epiphyses of the knees. More recently, in a small prospective study of patients on doses of 2 mg/kg/day of isotretinoin for the treatment of keratinizing disorders, radiologically documented skeletal changes were noted after only 6-12 months of therapy. These changes consisted of slightly increased bone formation in areas of ligament attachment. It is not yet known whether this is reversible. A small number of patients may have a temporary flare of acne at the onset of treatment. Some clinincians feel that this can be minimized by the administration of low dose prednisone or oral antibiotics. Pseudotumor cerebri ( benign intracranial hypertension) has occurred in patients treated with isotretinoin. Patients with headache, nausea, vomitting or visual disturbances should be screened for papilledema. The drug should be stopped immediately if papilledema is present. Patients with visual disturbances should also be checked for corneal opacities. Corneal opacities occur more frequently in those patients receiving higher doses of isotretinoin for keratinizing disorders but has also been reported in patients treated for cystic acne. The opacities resolve six to seven weeks after discontinuation of the drug. There have been rare reports of inflammatory bowel disease in patients treated with isotretinoin. Occasional patients report fatigue or lassitude. Laboratory abnormalities One fourth of patients treated with isotretinoin develop elevated serum triglycerides during their four- to five- month course of treatment for acne. Approximately one eighth have a decrease in the HDL level and one sixteenth have elevated chloresterol. These changes usually resolve after therapy is discontinued. It is important to monitor blood lipids at the onset of therapy and at intervals of two to four weeks until it is seen that there are no significant changes. Minor elevations in triglycerides are best treated by dietary maneuvres. It is not known what role the lipid abnormalities may play in the production of coronary heart disease, but the risk is currently thought to be low since abnormalities return to normal after therapy is stopped. It is perhaps best that patients with high triglyceride elevations be treated with the lowest effective dosage of isotretinoin for a shorter period of time. Triglyceride elevations of greater than 500 mg/dL necessitate discontinuation of the drug, as these patients are at risk for developing acute pancreatitis. A few patients develop mild leukopenia, anemia, or thrombocytosis. Mild pyuria and liver function test abnormalities occasionally occur. These changes appear to be reversible after discontinuation of the drug and are usually not clinically significant. Isotretinoin and pregnancy The most serious side effect of isotretinoin is its teratogenicity. The drug should not be used by women who are pregnant or those who plan to become pregnant during treatment. Contraception is recommended for women taking the drug, beginning one month before treatment, and continuing until one month after discontinuation of treatment. Many physicians obtain a pregnancy test within two weeks prior to starting therapy. Reported fetal abnormalities include hydrocephalus, microcephalus, abnormalities of the external ear (micropinna, small or absent external auditory canals), Micropthalmia and cardiovascular abnormalities. These abnormalities have occured only in children born to mothers exposed to the drug during pregnancy. The package insert recommends that patients who become pregnant discuss with their physician the desirability of continuing the pregnancy. Since the half-life of isotretinoin is less than one to three days, it is believed that there is no risk of teratogenicity during subsequent pregnancies occurring at least one month after treatment has been stopped. While no reproduction studies have been performed on humans taking isotretinoin, studies in rats have not revealed impaired fertility. No significant changes have been seen in the number or mobility of spermatazoa of human males receiving isotretinoin. As it is not known whether isotretinoin is secreted into milk, it is inadvisable to treat nursing mothers with the drug. Dosage and administration Isotretinoin is presently approved by the FDA only for the treatment of severe recalcitrant nodulocystic acne. While dosages of 0.1, 0.5, and 1.0 mg/kg/day orally seem equally effective in inducing a remission of acne, there is a significantly higher relapse rate in patients rate in patients treated at lower doses. As the goal of isotretinoin therapy is not only the clearing of active disease but the indefinite maintenance of clearing, it is recommended that patients be treated with 1 mg/kg/day for 16-20 weeks. Extensive truncal lesions, which do not respond as quickly or completely as facial lesions, may require dosages of 1.5-2.0 mg/kg/day. Isotretinoin is supplied in 10,20, and 20 mg capsules. Most patients are treated with 40 mg twice daily. Patients should be advised not to ingest any vitamin A supplements during their treatment course. Other indications Isotretinoin has also been shown to be effective for a variety of other skin disorders, but it is not yet approved by the FDA for these indications. These include several variants of acne: hidradenitis suppurativa, gram negative folliculitis, and rosacea. Retinoids also have an antineoplastic effect. Several patients with the basal cell nervus syndrome, an autosomal dominant disorder in which patients develop multiple basal cell carcinomas, have been treated. Isotretinoin resulted in reduction in tumor sizes, but usually did not completely destroy the tumors. Retinoids are also being studied for possible future roles in cancer prevention. Isotretinoin and other retinoids ( especially etretinate, an aromatic retinoid not yet available in the US) have been used to treat a wide variety of keratinizing skin disorders, such as psoriasis, keratosis follicularis, ichthyosis, pityriasis rubra pilaris, and others (8). Discussion of this is beyond the scope of this paper. Although the drug is very effective for several of these disorders, the major problem is that long-term treatment is required for these chronic diseases, and long-term safety of retinoids has not been established. Conclusion Isotretinoin (Accutane) is an exceedingly useful drug, producing dramatic prolonged remissions after four to five weeks in most patients with severe nodulocystic acne. Because of its side effects, teratogenicity, and cost (about $600 for a four- to five- month course of treatment), the drug should be reserved for the less than 1% of patients with severe acne.