Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N ¼ 511), and results were also stratified by apolipoprotein E (APOE) genotype (n ¼ 323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE e4 allele status and ADAS-Cog (P ¼ 0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE e4-negative patients on 8 mg RSG (P ¼ 0.024; not corrected for multiplicity). APOE e4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P ¼ 0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE e4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE e4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.
The efficacy and safety of lamotrigine (LTG), a new antiepileptic drug (AED), were evaluated in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 98 patients with refractory partial seizures. Each treatment period lasted 14 weeks. Most patients were titrated to a LTG maintenance dose of 400 mg/day. Seizure frequency with LTG decreased by > or = 50%, as compared with placebo, in one fifth of patients. Overall median seizure frequency decreased by 25% with LTG as compared with placebo (p < 0.001). With LTG, the number of seizure days decreased by 18% as compared with placebo (p < 0.01), and investigator global evaluation of overall patient clinical status favored LTG by 2:1 (p = 0.013). Plasma LTG concentrations appeared to be linearly related to dosage. LTG had no clinically important effects on the plasma concentrations of concomitant AEDs. Adverse experiences were generally minor and most frequently were CNS-related (e.g., ataxia, dizziness, diplopia, headache). Most were transient and resolved without discontinuing treatment. Five patients withdrew as a result of adverse experiences while receiving LTG, including 3 patients with rash. One placebo patient was also withdrawn because of rash. The addition of twice-daily LTG to an existing AED regimen was safe, effective, and well tolerated in these medically refractory partial seizure patients.
Behavioural effects of d- and l-nicotine, d- and l-nornicotine and l-cotinine were studied in two paradigms. In experiment 1, rats responded under a multiple fixed-interval (FI) 5 min, fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and time course, l-nicotine and the stereoisomers of nornicotine produced qualitatively similar effects on rates of responding. With increasing doses of drugs, FI response rates first increased and then decreased, while FR response rates only decreased. In contrast, d-nicotine did not significantly increase FI response rates at lower doses, and only decreased FI and FR response rates at higher doses. At doses up to 100 mg/kg, cotinine produced only dose-dependent increases in FI response rates and had no effect on FR response rates. Rate-increasing effects of cotinine were not blocked by mecamylamine. In experiment 2, rats were trained to discriminate between l-nicotine (0.1 mg/kg SC) and saline (0.1 ml/kg SC) in a two-bar, operant conditioning procedure under a tandem variable-interval (VI) 1 min, FR 10 schedule of food presentation. Full generalization was obtained to d-nicotine and to l- and d-nornicotine. Generalization to cotinine occurred only with large doses that contained significant amounts of nicotine present as an impurity. There was no generalization to non-nicotinic drugs (morphine and clenbuterol), even at doses that reduced response rates.(ABSTRACT TRUNCATED AT 250 WORDS)
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