Acne, cystic isotretinoin

Isotretinoin COOH Topical 0.05% cream Oral 0.251.0 mg/kg/ d Cystic acne, recalcitrant nodular acne Rosacea gram-negative folliculitis pyoderma faciale hidradenitis suppurativa cancer prevention... 

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (18 years of age and older), the exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicated that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. 

Excretion - Following oral administration of an 80 mg dose of C-isotretinoin as a liquid suspension, C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects underfed conditions, the mean elimination half-lives of isotretinoin and 4-oxo-isotretinoin were approximately 21 and 24 hours, respectively. After single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne. 

Isotretinoin, or 13-cis-retinoic acid, and etretinate are available for oral administration. Isotretinoin is a synthetic retinoid that is used for sever cystic acne, recalcitrant to standard therapies. Its mechanism of action is not well understood but involves the inhibition of sebaceous gland size and function. 

Pseudotumor cerebri is another potential complication of chronic use of these agents, particularly in individuals treated for severe cystic acne with simultaneous use of isotretinoin. This complication can be induced within several days of initiation of therapy and usually resolves with cessation of treatment. 

Isotretinoin (Accutane) is a synthetic retinoid currently restricted to the oral treatment of severe cystic acne that is recalcitrant to standard therapies. The precise mechanism of action of isotretinoin in cystic acne is not known, although it appears to act by inhibiting sebaceous gland size and function. The drug is well absorbed, extensively bound to plasma albumin, and has an elimination half-life of 10-20 hours. 

Most patients with cystic acne respond to 1-2 mg/kg, given in two divided doses daily for 4-5 months. If severe cystic acne persists following this initial treatment, after a period of 2 months, a second course of therapy may be initiated. Common adverse effects resemble hypervitaminosis A and include dryness and itching of the skin and mucous membranes. Less common side effects are headache, corneal opacities, pseudotumor cerebri, inflammatory bowel disease, anorexia, alopecia, and muscle and joint pains. These effects are all reversible on discontinuance of therapy. Skeletal hyperostosis has been observed in patients receiving isotretinoin with premature closure of epiphyses noted in children... 

A change in dreaming pattern has been reported in two patients, occurring within 2-3 weeks after the start of treatment with isotretinoin 40 mg/day for cystic acne (684). One patient also reported increased irritability and bouts of depression. In both patients all the symptoms abated after 4-5 weeks without a change in isotretinoin dosage. 

Retinoids in Dermatology 13-Qs-retinoic acid (isotretinoin, Accutane ) is used orally, and all-trans-retinoic acid (Tretinoin ) topically, for treatment of severely disfiguring cystic acne. Etretinate (the trimethoxyphenyl analog of retinoic acid) and tazarotene (a receptor-specific retinoid) are used topically for the treatment of psoriasis. They are effective in cases in which other therapy has failed, and at lower levels than are required for the control of tumor development in experimental animals, although they have heen associated with hirth defects (Section 2.5.1.1 fohnson and Chandrarama, 1999). 

An analogue of vitamin A, isotretinoin (Accutane), or 13-cfs-retinoic acid, is used for control of severe recalcitrant cystic acne and other keratinizing dermatoses. Oral administration of 1 to 2 mg/kg body weight daily temporarily suppresses sebaceous gland activity, changes surfece lipid composition of the skin, and inhibits kera-tinization. The therapeutic effect is resolution of lesions and, in most patients, prolonged remission of the disease. 

Isotretinoin, or 13-cw-retinoic acid, is widely used for the treatment of recalcitrant cystic acne. Although this drug more commonly affects the external tissues of the eye, causing ocular surface dryness, there is sufficient evidence to designate that this agent has a certain retinotoxic effect, causing nyctalopia. It also has a probably/likely designation for reversible decreases in color vision. 

Excessive use of vitamin A can result in ocular dryness, loss of lashes, night blindness, and even intracranial hypertension, the latter of which is similar to that occurring with the other forms of vitamin A such as isotretinoin, approved for the treatment of cystic acne. With large doses, increased intracranial pressure is considered certain. ... 

Isotretinoin is indicated for the treatment of severe recalcitrant cystic acne. Because of the risks of adverse effects, its use should be reserved for patients who are unresponsive to conventional acne therapies. Treatment should be individu-alixed and modilled depending on the course of the di.sease. The mechanism is believed to involve inhibition of sebaceous gland function and follicular keratinixation. Isotretinoin reduces sebum production, the size of the glantfs. and gland differentiation. 

More than 1500 retinoids have been synthesized. Two in particular, 13-cw-retinoic acid (isotretinoin) and etretinate (Figure 38-4), have generated considerable interest as agents for the treatment of dermatological disorders. 13-cA retinoic acid inhibits sebum production, is the drug of choice for treatment of severe cystic acne, and is useful in the treatment of other forms of acne. Etretinate is used in Europe for treatment of psoriasis and related disorders. 

Isotretinoin, a retinoic acid derivative with antiacne properties, is indicated in the treatment of severe cystic acne ume-sponsive to conventional therapy. In addition, it has been used in keratinization disorders resistant to conventional therapy. 

Abel EA. Isotretinoin treatment of severe cystic acne in a heart transplant patient receiving cyclosporine consideration of drug interactions. JAmAcadDermatal( 99 ) 24,511. 

Interest in the toxicity of the retinoids has resulted from their increased use in the treatment of dermatological disorders (Peck, 1980 Pardini, 1981 Elias and Williams, 1981 Windhorst, 1982 Chapter 16, this volume) and neoplasms (Spom, 1977 Spom and Newton, 1981 Spom, 1982 Bollag, 1979 Lotan, 1980 Newbeme and Rogers, 1981 Chapter 14, this volume). Isotretinoin (13-cw-retinoic acid, Ro 4-3780, Accutane) has become available in the United States for use in the treatment of severe recalcitrant cystic acne in Europe, etretinate (Ro 10-9359, Tegison) is used for treatment of psoriasis. The toxicity of these retinoids has been exhaustively studied in laboratory animals as part of the regulatory approval process. 

The development of biologically active, less-toxic synthetic derivatives of retinoic acid has lead to a major advance in dermatologic therapeutics. Isotretinoin (13-ci y-retinoic acid, Accutane) is the first of these synthetic retinoids to be marketed for the treatment of severe, recalcitrant cystic acne in the United States. 

Windhorst and Nigra (1982) have summarized the clinical results in 523 patients treated with isotretinoin for various disorders of keratinizatioq and cystic acne. Cutaneous and mucous membrane symptoms were by far the most prominent side effects (Table VII). Mucosal effects of isotretinoin have most often included cheilitis, dry nose, conjunctivitis, sore mouth, excessive thirst, and epistaxis. Integumentary effects have included desquamation, pruritus, erythema, skin fragility, finger-tip peeling, and, less frequently, hair loss (Farrell et al., 1980 Gilgor, 1980 Jones et al., 1980 Peck, 1981). Other less-frequent side effects that have been reported included inflammation of urethral meatus. 

Cystic acne is a severe scarring form of acne characterized by the presence of large, deep-dermal, and subcutaneous nodules and cysts. In the initial report demonstrating the effectiveness of isotretinoin in the treatment of cystic acne, a... 

Isotretinoin, therefore, has proved to be the most effective therapy for cystic acne. Most cases of even the greatest severity, being previously treatment-... 

Synthetic retinoids are beneficial in a variety of cutaneous disorders. Isotretinoin is the drug of choice for severe cystic acne. The development of optimum dosage schedules for acne of varying severity and for facial and truncal locations is continuing. 

Metabolism In a prospective controlled study in 74 patients taking isotretinoin for cystic acne, blood concentrations of homocysteine, vitamin B12, and folate were assessed before and after 45 days of isotretinoin therapy [39 ]. The control group consisted of 80 individuals. Homocysteine concentrations were significantly higher in those who took isotretinoin. The vitamins were unaffected, but serum lipids and liver enzymes increased significantly. These effects may have been due to inhibition of cystathionine-beta-synthase, an enzyme required for the metabolism of homocysteine by either the drug or liver dysfunction. Daily supplementation with vitamin B12 and folate can lower plasma concentrations of homocysteine, and the authors therefore recommended the use of these vitamins in patients taking isotretinoin. 

Polat M, Lenk N, Bingol S, Ozta P, nhan MN, Arttiz F, Alii N. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne a prospective controlled study. J Dermatolog Treat 2008 19(4) 229-32. 

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