title: A proof-of-concept, randomized, placebo-controlled, multiple cross-overs (n-of-1) study of naftazone in Parkinson's disease.
abstract: To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson's 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.
authors.affiliation: Department of Clinical Pharmacology, Hospital and University Paul Sabatier of Toulouse, France. rascol@cict.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ferreira
authors.forename: Laurence
authors.initials: L
authors.lastname: Nègre-Pages
authors.forename: Santiago
authors.initials: S
authors.lastname: Perez-Lloret
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Monique
authors.initials: M
authors.lastname: Galitzky
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Lemarié
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
authors.forename: Laura
authors.initials: L
authors.lastname: Bossi
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D020820:Dyskinesias / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D009285:Naphthoquinones / Q000009:adverse effects / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D010865:Pilot Projects; D010919:Placebos; D016037:Single-Blind Method; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D009285:Naphthoquinones; D010919:Placebos; C005272:naftazone