Bupropion for smoking cessation during pregnancy

摘要 拟议研究的目标是提供关于生物制剂的临床前和临床信息。 安非他酮缓释剂（SR）辅助戒烟的处置、有效性和安全性 孕妇大多数吸烟和怀孕的妇女都知道已知的风险 但由于尼古丁的成瘾性而无法戒烟。行为干预有一个适度的， 但对戒烟有持续的有益效果。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 未批准用于妊娠患者，因为其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- 已显示术语安全性特征。因此，我们提出了一个前瞻性，安慰剂对照随机 安非他酮缓释片用于妊娠期戒烟的临床试验。妊娠引起的母体变化 生理学和/或编码肝酶的基因中常见的单核苷酸多态性（SNP CYP 2B 6可能改变妊娠期安非他酮的代谢，因此， 母体循环，影响是功效。此外，我们实验室最近的调查显示， 安非他酮穿过胎盘从母体到胎儿的循环， 内切酶我们的数据表明，此外，胎盘代谢酶（羰基还原酶），以及 作为其外排转运蛋白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中起重要作用，从而影响胎儿对药物的暴露。 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。为了检验安非他酮缓释片的初步疗效和安全性， 将研究以下具体目标：（1）检查安非他酮SR是否减少尼古丁戒断 症状，增加戒烟率，并且与安慰剂相比具有有利的安全性;（2）确定 妊娠诱导的变化对安非他酮缓释剂在不同阶段的药代动力学（PK）的影响 妊娠期和产后在同一个人;（3）确定常见的单核苷酸的效果 CYP 2B 6编码基因中的多态性（SNP）对其在安非他酮生物转化中的活性的影响， 对妊娠期7天时点戒烟率的影响;（4）确定长期暴露于 安非他酮缓释剂对胎盘羰基还原酶表达和活性的影响;（5）测定安非他酮缓释剂对胎盘羰基还原酶表达和活性的影响。 慢性暴露于安非他酮SR对胎盘外排转运蛋白P-gp和 BCRP。 总之，所获得的信息对于评价安非他酮作为潜在药物用于以下疾病是必要的： 帮助怀孕期间戒烟。

ABSTRACT 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.