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.
D eneau/F arber
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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 (