Bupropion for smoking cessation during pregnancy

描述（由申请方提供）：拟定研究的目的是提供关于安非他酮缓释剂（SR）辅助孕妇戒烟的生物处置、疗效和安全性的临床前和临床信息。大多数吸烟和怀孕的女性都知道已知的风险，但由于尼古丁的成瘾性而无法戒烟。行为干预对戒烟有适度但一致的有益影响。然而，它对重度吸烟者的效果最差。另外，药物对非怀孕吸烟者的戒烟是安全有效的，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确定。 安非他酮缓释剂已成功用于非妊娠吸烟者的戒烟，其长期安全性特征已得到证实。因此，我们提出了一个前瞻性的，安慰剂对照的随机临床试验，安非他酮SR戒烟在怀孕期间。妊娠诱导的母体生理学变化和/或编码肝酶CYP 2B 6的基因中常见的单核苷酸多态性（SNP）可能会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，影响疗效。此外，我们实验室最近的研究表明，安非他酮穿过胎盘从母体到胎儿的电路，并通过组织的酶代谢。此外，我们的数据表明，胎盘代谢酶（羰基还原酶），以及其外排转运蛋白P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP），在调节安非他酮的胎盘处置，因此，胎儿暴露于药物中具有重要作用。 这项调查的假设是，安非他酮是一种安全有效的药物，可以帮助在怀孕期间戒烟。为了检查安非他酮SR的初步疗效和安全性，将研究以下具体目的：（1）检查安非他酮SR是否减少尼古丁戒断症状，增加戒烟率，以及与安慰剂相比是否具有有利的安全性特征;（2）确定妊娠诱导的变化对同一个体在妊娠和产后不同阶段的安非他酮SR药代动力学（PK）的影响;（3）确定编码CYP 2B 6的基因中常见的单核苷酸多态性（SNPs）对其在安非他酮生物转化中的活性和妊娠期7天点流行率戒断率的影响;（4）确定慢性暴露于安非他酮SR对胎盘羰基还原酶的表达和活性的影响;（5）确定安非他酮缓释剂慢性暴露对胎盘外排转运蛋白P-gp和BCRP表达和活性的影响。总之，所获得的信息对于评估安非他酮作为帮助怀孕期间戒烟的潜在药物是必要的。 公共卫生相关性：本研究的目的是检查安非他酮缓释剂帮助孕妇戒烟的初步安全性和有效性。我们将确定安非他酮缓释剂是否能减少怀孕期间的烟瘾和戒断症状。这项研究对于开发治疗怀孕吸烟者的药物是必要的，这反过来又会改善婴儿的健康。

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.