Dermatologica 151: 158-163 (1975)

The Treatment of Psoriasis with Azaribine D a v id G. D eneau and E u g en e M. F arber Department of Dermatology, Stanford University School of Medicine, Stanford, Calif.

Key Words. Azaribine • Triazure • Triacetyl 6-azauridine • Antimetabolite • Chemo­ therapy ■Psoriasis • Treatment • Toxicity Abstract. An open study was made of 25 patients with severe, recalcitrant psoriasis treated with azaribine (6-azauridine triacetate). Most patients received 125 mg/kg/day for a period of 8 weeks. A good to excellent response with 60-100% clearing of lesions was observed in 14 patients and a fair response with 40-60% improvement in another 6 patients. Thus 20 patients (80% of the series) exhibited a favorable clinical response. 16 of these 20 patients relapsed to approximately pretreatment status within 1 month after stopping therapy. The most frequently observed side-effects were mild reversible anemia, fatigue and mild transient gastrointestinal symptoms. 8 patients (32% of the series) exhibited sufficient toxicity to necessitate the discontinuance of therapy. 1 patient experienced an unexplained femoral arterial thrombotic episode while on the drug. Azaribine may find a place in the therapy of severe psoriasis particularly in patients with hepatic disease. However, further studies of its potential for toxicity are indicated.

Introduction The anti-pyrimidine cytotoxic agent 6-azauridine is one of several anti­ metabolites that have been evaluated in the therapy of severe generalized psoriasis in the past decade [1], Studies of the parent compound 6-azauracil in 1956 had demonstrated its antineoplastic properties but it was also found to be significantly neurotoxic [2-4]. In 1957, the ribonucleoside derivative 6-azauridine was shown to be both a more active antineoplastic agent and less neurotoxic when given intravenously [5]. However, oral administration

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Received: July 8, 1975; accepted: August 4, 1975.

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of 6-azauridine produced 6-azauracil, apparently by the action of intestinal bacteria, which was then absorbed and again resulted in neurotoxicity [6], By 1962, the triacetyl derivative of 6-azauridine, azaribine, was shown to be rapidly absorbed with liberation of 6-azauridine which does not readily cross the blood-brain barrier. Intracellularly, 6-azauridine is phosphorylated to 6-azauridylic acid which competitively inhibits the enzyme orotidylic decar­ boxylase. This in turn blocks the de novo synthetic pathway of pyrimidine nucleic acids inhibiting DNA, RNA and coenzyme formation by the cell. More than 90% of an oral dose of azaribine is excreted by the kidneys within 48 h. About 75% is excreted as 6-azauridine with variable lesser quantities of the monoacetyl and diacetyl forms and occasional minute quantities of 6-azauracil [7]. In 1964, T u r n e r and C alabresi [8] reported 10 cases of severe psoriasis treated with azaribine at a dosage level of 270 mg/kg/day with favorable clinical results and mild hematologic toxicity. In 1970, a double-blind cross­ over study on 22 patients was reported by V ogler and O lan sky [9] with similar results at a dosage level of 200 mg/kg/day. More recently, M ilstein et al. [10], in 1973, reported another double-blind crossover study on 27 patients at a dosage level of 125 mg/kg/day. Again the clinical results were favorable and mild anemia and lethargy were the most frequently observed side-effects. This communication reports an open study of 25 psoriatic patients treated with azaribine. Since previous series had been designed more specif­ ically to study therapeutic efficacy, the primary purpose of this series was to monitor possible toxicity.

25 patients with moderate to severe generalized plaque-type psoriasis, unresponsive to conventional therapy were selected for an open study. The group included 11 men and 14 women with an average age of 47 years with a range of 16-73 years. Adequate contraception was advised for women in the child-bearing age group. Although 18 patients had received previous antimetabolite therapy, none had been under such therapy for at least 1 month prior to the study and most for a much longer period. All patients were fully informed of the investigational status of azaribine. No patients with concomitant systemic disease thought to be a contraindication to antimetabolite therapy were included in the study. Initial evaluation included history and physical examination, clinical photographs, complete blood count, urinalysis, chest film and a chemical screening battery including determin­ ations of serum glucose, BUN, uric acid, total bilirubin, alkaline phosphatase, and gluta­ mic oxaloacetic transaminase (SGOT).

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Materials and Methods

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D eneau/F arber

Azaribine was administered orally with 500-mg tablets at doses varying from 60 to 200 mg/kg/day in 3 or 4 divided doses. Most patients received 125 mg/kg/day for a period of 8 weeks. Additional courses of therapy were administered to 5 patients. The patients were instructed to use only bland emollients for topical therapy. At weekly intervals they were examined and complete blood counts obtained. After 8 weeks, the drug was stopped, the chemical screening battery and photographs were repeated and the patients observed for post-treatment changes. Results were judged excellent if 80-100% of the lesions cleared, good if 60-80% cleared, fair if 40-60% cleared and poor if less than 40% of the lesions cleared.

Results

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The results were excellent (80-100% clearing) in 5 patients, good (60-80% clearing) in 9 patients, fair (40-60% clearing) in 6 patients, and poor (

The treatment of psoriasis with azaribine.

An open study was made of 25 patients with severe, recalcitrant psoriasis treated with azaribine (6-azauridine triacetate). Most patients received 125...
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