Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.
In contrast to results indicating that adolescents may be less sensitive than adults to ethanol's hypothermic effect when ethanol is administered via bolus injection/intubation, adolescents appear more sensitive and develop tolerance to ethanol's hypothermic effects more slowly than adults when ethanol is administered at a more moderate rate via vapor inhalation.
Background-Despite the fact that adolescent rats have repeatedly been found to consume more ethanol than adult rats in a variety of ethanol access paradigms, the exact cause of the increase in ethanol consumption during adolescence is not known. One possibility is that age differences in sensitivity to ethanol's rewarding effects may contribute to the elevated intake seen among adolescents. Human studies have shown that autonomic effects of ethanol, particularly ethanolinduced tachycardia, are correlated with the positive hedonic properties of the drug and, hence, may serve as a biomarker for reward.
A two-injection paradigm was used to assess acute (within-session) tolerance to ethanol in telemetry-implanted adolescent and adult rats. Male rats were intragastrically pretreated with either 1.0 g/kg of ethanol or water and then challenged with 2.0 g/kg of ethanol or water when blood alcohol levels (BALs) of ethanol-pretreated animals were anticipated to approach zero. Adults showed more rapid and sustained ethanol-induced hypothermia than adolescents. Acute tolerance to ethanol-induced hypothermia did not emerge clearly with the two-injection paradigm; ethanol-pretreated animals of both ages generally did not differ from those pretreated with water in their hypothermic response to ethanol despite higher BALs after the second intubation. Housing condition (paired or isolated) had little influence on ethanol-induced hypothermia. The adolescent attenuation of ethanol-induced hypothermia in this experiment was not associated with greater expression of within-session (acute) tolerance.
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