Bupropion for smoking cessation during pregnancy

描述(由申请人提供)：拟议研究的目标是提供有关安非他酮缓释(SR)作为孕妇戒烟辅助药物的生物处置、有效性和安全性的临床前和临床信息。大多数吸烟并怀孕的女性都意识到了已知的风险，但由于尼古丁的成瘾性质，她们无法戒烟。行为干预对戒烟有温和但持续的有益效果。然而，它对吸烟量较大的人效果最差。或者，在非怀孕吸烟者中，药物是安全有效的戒烟药物，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SR已成功用于非妊娠吸烟者的戒烟，并显示了其长期安全性。因此，我们提出了一项孕期应用安非他酮SR戒烟的前瞻性、安慰剂对照随机临床试验。妊娠引起的母体生理改变和/或编码肝脏酶CYP2B6基因的常见单核苷酸多态(SNPs)可能会改变孕期安非他酮的代谢，从而影响其在母体循环中的浓度，从而影响疗效。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进入胎儿循环，并通过组织的酶进行代谢。我们的数据进一步表明，胎盘代谢酶(羰基还原酶)及其外流转运体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中起着重要作用，从而调节胎儿对安非他酮的暴露。这项研究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。为了检验安非他酮SR的初步疗效和安全性，我们将研究以下具体目标：(1)检测安非他酮SR是否能减少尼古丁戒断症状、增加戒烟率，并且与安慰剂相比是否具有良好的安全性；(2)确定妊娠引起的变化对安非他酮SR在孕期和产后不同阶段的药代动力学(PK)的影响；(3)确定编码CYP2B6基因的常见单核苷酸多态性(SNPs)对其在安非他酮生物转化中的活性以及对妊娠7天点戒断率的影响；(4)确定慢性暴露于安非他酮SR对胎盘羰基还原酶表达和活性的影响：(5)确定慢性暴露于安非他酮SR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怀孕期间帮助戒烟的潜在药物是必要的。 公共卫生相关性：这项调查的目标是检查安非他酮SR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SR是否可以减少怀孕期间的香烟渴望和戒断症状。这项研究对于开发治疗怀孕吸烟者的药物是必要的，这将反过来改善婴儿的健康。

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.