Bupropion for smoking cessation during pregnancy

描述（由申请人提供）：拟议研究的目的是提供安非他酮缓释片（SR）作为孕妇戒烟辅助的生物倾向、疗效和安全性的临床前和临床信息。大多数吸烟并怀孕的妇女都意识到已知的风险，但由于尼古丁的成瘾性，她们无法戒烟。行为干预对戒烟有适度但持续的有益效果。然而，它对重度吸烟者效果最差。另外，对于非怀孕的吸烟者来说，药物戒烟是安全有效的，但它们不被批准用于怀孕患者，因为它们的安全性和有效性尚未得到证实。安非他酮SR已成功用于非怀孕吸烟者的戒烟，其长期安全性已被证明。因此，我们建议进行一项前瞻性、安慰剂对照的安非他酮SR用于妊娠期戒烟的随机临床试验。妊娠引起的母体生理变化和/或编码肝酶CYP2B6基因的常见单核苷酸多态性（snp）可能改变妊娠期间安非他酮的代谢，从而改变其在母体循环中的浓度，影响其疗效。此外，我们实验室最近的研究表明，安非他酮通过胎盘从母体到胎儿的循环，并被组织的酶代谢。此外，我们的数据表明，胎盘代谢酶（羰基还原酶）及其外排转运蛋白p -糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）在调节胎盘对安非他酮的处置以及胎儿对该药物的暴露方面发挥着重要作用。这项调查的假设是安非他酮是一种安全有效的药物，可以帮助怀孕期间戒烟。为了验证安非他酮SR的初步有效性和安全性，将研究以下具体目标：(1)与安慰剂相比，检查安非他酮SR是否能减轻尼古丁戒断症状，增加戒烟率，并具有良好的安全性；(2)测定妊娠变化对同一个体不同妊娠阶段和产后安非他酮SR药代动力学（PK）的影响；(3)测定CYP2B6基因常见单核苷酸多态性（snp）对安非他酮生物转化活性和妊娠期7天点流行戒断率的影响；(4)测定长期暴露于安非他酮SR对胎盘羰基还原酶表达和活性的影响；(5)确定长期暴露于安非他酮SR对胎盘外排转运体P-gp和BCRP表达和活性的影响。总之，所获得的信息对于评价安非他酮作为一种潜在的帮助怀孕期间戒烟的药物是必要的。

DESCRIPTION (provided by applicant): The goal of the proposed investigations is to provide preclinical and clinical information on the bio- disposition, efficacy, and safety of bupropion sustained release (SR) as an aid for smoking cessation in pregnant women. The majority of women who are smokers and become pregnant are aware of the known risks but are unable to quit smoking due to the addictive nature of nicotine. Behavioral interventions have a modest, but consistent, beneficial effect on smoking cessation. However, it is least effective in heavier smokers. Alternatively, medications are safe and effective for smoking cessation in nonpregnant smokers, but they are not approved for pregnant patients because their safety and efficacy have not been established. Bupropion SR has been successfully used for smoking cessation in nonpregnant smokers, and its long- term safety profile has been shown. Therefore, we propose a prospective, placebo-controlled randomized clinical trial of bupropion SR for smoking cessation during pregnancy. Pregnancy-induced changes in maternal physiology and/or common single nucleotide polymorphisms (SNPs) in the gene encoding the hepatic enzyme CYP2B6 might alter the metabolism of bupropion during pregnancy and, consequently, its concentration in maternal circulation, affecting is efficacy. Moreover, recent investigations in our laboratory revealed that bupropion crosses the placenta from the maternal to the fetal circuit and is metabolized by the tissue's enzymes. Our data indicate, furthermore, that placental metabolizing enzymes (carbonyl reductases), as well as its efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistant Protein (BCRP), have an important role in regulating placental disposition of bupropion and, consequently, fetal exposure to the drug. The hypothesis for this investigation is that bupropion is a safe and effective medication that can aid in smoking cessation during pregnancy. To examine the preliminary efficacy and safety of bupropion SR, the following specific aims will be investigated: (1) Examine whether bupropion SR reduces nicotine withdrawal symptoms, increases quit rates, and has a favorable safety profile compared to placebo; (2) Determine the effect of pregnancy-induced changes on the pharmacokinetics (PK) of bupropion SR at different stages of gestation and postpartum in the same individual; (3) Determine the effect of common single nucleotide polymorphisms (SNPs) in the gene encoding CYP2B6 on its activity in the biotransformation of bupropion and on 7-day point prevalence abstinence rates in pregnancy; (4) Determine the effects of chronic exposure to bupropion SR on the expression and activity of the placental carbonyl reductases; (5) Determine the effects of chronic exposure to bupropion SR on the expression and activity of the placental efflux transporters P-gp and BCRP. In summary, The information obtained is necessary for evaluating bupropion as a potential medication for aiding in smoking cessation during pregnancy. PUBLIC HEALTH RELEVANCE: The goal of this investigation is to examine preliminary safety and efficacy of bupropion SR to help pregnant women stop smoking. We will determine whether bupropion SR reduces cigarette cravings and withdrawal symptoms during pregnancy. This research is necessary for the development of medications to treat pregnant smokers which will, in turn, improve infant health.