A proof-of-concept, randomized, placebo-controlled, multiple cross-overs (n-of-1) study of naftazone in Parkinson's disease

作者：Rascol Olivier^*; Ferreira Joaquim; Negre Pages Laurence; Perez Lloret Santiago; Lacomblez Lucette; Galitzky Monique; Lemarie Jean Christophe; Corvol Jean Christophe; Brotchie Jonathan M; Bossi Laura

来源：Fundamental & Clinical Pharmacology, 2012, 26(4): 557-564.

DOI：10.1111/j.1472-8206.2011.00951.x

• dyskinesia
• glutamate
• naftazone
• n-of-1 trial
• Parkinson's disease

To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinsons disease (PD). Proof-of-concept, randomized, double-blind, placebo-controlled, multiple-cross-over n-of-1 study in patients with PD with wearing-off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single-blind dose-finding phase. Seven patients entered the placebo-controlled phase (four consecutive 28-day cross-overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48-h ON-OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven-point Likert scale to assess patients discomfort caused by dyskinesias (Q1) and disability during OFF-periods (Q2). A responder analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross-over periods) was used. Treatment effects were derived from mixed-effects anova. On diaries, 5/7 patients responded to naftazone for ON-time with troublesome dyskinesia (reduced time, treatment effect: -49 [95% CI: -93/-4] min, P = 0.03), 6/7 regarding ON-time without troublesome dyskinesia (increased time, treatment effect: 35 [-19/88], P = 0.2). No trend was observed for OFF time. There were 7/7 responders regarding UPDRSIII (reduced score, treatment effect: -2.1[-4.5/0.2], P = 0.08). The 7-point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.

• 出版日期2012-8