RESUMO
BACKGROUND: Polymorphism of the DRD2 gene (rs1800497), previously termed Taq1A, includes the A1 and A2 alleles. The A1⺠genotype (A1/A1, A1/A2) has been associated with smoking dependence. The present study determined which polymorphism of the DRD2 gene had a salutary outcome in administration of rimonabant, a drug used in smoking cessation and obesity studies. METHODS: Seventy-six (76) smokers enrolled into a double-blind, placebo-versus-rimonabant, 10-week smoking cessation drug trial. Subjects provided a blood sample to determine whether they had the DRD2 A1⺠genotype (A1/A1, A1/A2) or the DRD2 A1â» genotype (A2/A2). Smoking cessation (or continuation) was monitored on a weekly basis with on-site carbon monoxide (CO) monitoring. RESULTS: Smokers in the rimonabant A1â» group were significantly more successful in completely stopping smoking compared to subjects in the placebo A1â» group (P < 0.05). However, there was no difference in smoking cessation when the rimonabant A1⺠group was compared to the placebo A1⺠group. With respect to quantified verifiable/objective smoking cessation outcomes, exhaled CO (parts per million) was monitored during each week of the study. The rimonabant A1â» group compared to the placebo A1â» group was quantifiably smoking less at weeks 5, 6, and 7 (P < 0.05), at week 8 (P < 0.01), and at weeks 9 and 10 (P < 0.001). No significant difference was found in exhaled CO levels between rimonabant A1⺠group and the placebo A1⺠group in any of the weeks studied. CONCLUSIONS: These findings further support the rationale for incorporating genotyping into clinical trials, particularly smoking cessation trials. Rimonabant demonstrated early and sustained smoking cessation efficacy only in noncarriers of the A1 allele. These results also underscore the risks of heterogeneity contributing to type 2 errors, when analyzing (phase 2 or 3) data. The potential clinical, regulatory, and commercial benefits associated with expediting and enhancing drug development, vis-à-vis the integration of biomarkers in clinical research, is supported by our findings.
Assuntos
Loci Gênicos/genética , Piperidinas/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genética , Pirazóis/uso terapêutico , Receptores de Dopamina D2/genética , Abandono do Hábito de Fumar , Monóxido de Carbono , Humanos , Projetos Piloto , Rimonabanto , Resultado do TratamentoRESUMO
A combination of sustained release (SR) naltrexone (32 mg/day) and bupropion SR (360 mg/day) plus behavioral counseling was evaluated for the treatment of smoking cessation and mitigation of nicotine withdrawal and weight gain. Thirty overweight or obese nicotine-dependent subjects were enrolled in a 24-week, open-label study; 85% and 63% completed 12 and 2 4weeks, respectively. The target quit date was Week 4. Week 4-12 continuous abstinence rate was 48%, 78% of subjects achieved CO < or = 10 ppm, serum cotinine decreased from 185 to 48 microg/L, and tobacco use decreased from 129 to 14 cigarettes/week. Similar results were seen at Week 24. Body weight was essentially unchanged (Week 12: -0.1%; Week 24: +0.4%). Except for a transient significant increase 1 week after the target quit date (p<0.05), nicotine withdrawal scores did not change. The most common adverse events were nausea, insomnia, and constipation. These tended to be transient and mild or moderate in severity. In overweight or obese smokers, naltrexone/bupropion combination therapy with behavioral counseling was associated with decreased nicotine use, limited nicotine withdrawal symptoms, and no significant weight gain.