Evaluation of the nicotine metabolite ratio in smoking patients treated with varenicline and bupropion.

Background: Smoking is the leading cause of preventable death worldwide. It is responsible for several types of cancer, cardiovascular diseases, and diseases of the reproductive system, among others. Therefore, advances in research are increasingly necessary in order to make smoking cessation treatment more effective. Some studies have investigated the association of the nicotine metabolite ratio (NMR) with general characteristics and treatment outcomes. In the present study, the main aim was to evaluate the NMR in smoking patients from an Assistance Program of a tertiary cardiology hospital. Methodology: Serum samples were collected from 185 patients at T0 (while patients were still smoking and before starting pharmacological treatment). Cotinine and hydroxycotinine analytes were measured using liquid-chromatography tandem mass-spectrometry (LC-MS/MS). By looking at the relationship between hydroxycotinine and cotinine, we can obtain the NMR, with which it is possible to classify patients into slow metabolizers (NMR < 0.31), as well as normal or fast metabolizers (NMR ≥ 0.31). Results: From 185 patients, 55 were considered slow metabolizers and 130 as normal/fast. The metabolite averages were associated with the number of cigarettes smoked per day (p < 0.001 for cotinine and 0.023 hydroxycotinine). However, we were unable to analyze the association of the NMR with general and clinical characteristics of patients under smoking cessation treatment. Conclusion: We were able to evaluate the NMR, and to observe categories of metabolizers in Brazilian patients under pharmacological treatments. Thus, this study can contribute to the indication of a form of analysis, which might form part of the customization of smoking cessation treatments and, consequently, improve the success rates.

Profile of the Nicotinic Cholinergic Receptor Alpha 7 Subunit Gene Expression is Associated with Response to Varenicline Treatment.

INTRODUCTION: Smoking is considered the leading cause of preventable morbidity and mortality worldwide. Studies have sought to identify predictors of response to smoking cessation treatments. The aim of this study was to analyze a possible association of target gene expression for smoking cessation with varenicline. METHODS: We included 74 smokers starting treatment with varenicline. Gene expression analysis was performed through the custom RT² Profiler qPCR array assay, including 17 genes. Times for sample collection were before the start of therapy (T0) and two weeks (T2) and four weeks (T4) after the start of treatment. RESULTS: For gene expression analysis, we selected 14 patients who had success and 13 patients resistant to varenicline treatment. Success was considered to be when a patient achieved tobacco abstinence until the fourth week of treatment and resistant was when a patient had not stopped smoking as of the fourth week of treatment. We observed a significant difference for CHRNA7 gene expression: in the resistant group, samples from T2 and T4 had lower expression compared with T0 (fold change: 0.38, P = 0.007; fold change: 0.67, P = 0.004; respectively). CONCLUSION: This exploratory clinical study, searching for a possible predictor of effectiveness for varenicline, reaffirmed the association of the α7 nAChR subunit for nicotine dependence and smoking therapy effectiveness with varenicline.

Cytochrome P450 2A6 and 2B6 polymorphisms and smoking cessation success in patients treated with varenicline.

BACKGROUND: The identification of variants in genes involved in nicotine metabolism may have implications for the pharmacological therapy of smoking. In the scenario of precision medicine, the aim of this study was to evaluate a possible association of cytochrome P450 2A6 and 2B6 polymorphisms with varenicline pharmacotherapy. METHODS: The present study included 167 patients treated with varenicline in monotherapy who were from a cohort study of 1049 patients (treated with smoking cessation drugs: nicotine replacement therapy, bupropion, varenicline, or combinations of same). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. The CYP2A6 rs1801272 and rs28399433 and CYP2B6 rs8109525 polymorphisms were genotyped by real-time PCR using the TaqMan® platform. RESULTS: Patients with AG or GG genotypes for CYP2B6 rs8109525 had a higher success rate of smoking cessation with varenicline (51.2%) compared with carriers of the AA genotypes (33.3%, P = 0.03, n = 167). The AG or GG genotypes were also associated with a higher odds ratio of success, even in a multivariate analysis adjusting for potential confounders (OR = 2.01; 95%CI = 1.01 to 4.00; P = 0.047). CONCLUSION: CYP2B6 rs8109525 was associated with a higher success rate of smoking cessation with varenicline treatment. This finding may be useful in pharmacogenomic strategies for smoking cessation therapy.

Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women.

BACKGROUND: The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. METHODS: This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. RESULTS: Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P = 0.03, n = 389; P = 0.01, n = 391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR = 1.63; 95% CI = 1.04 to 2.54; P = 0.03 and OR = 1.59, 95% CI = 1.02 to 2.48; P = 0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CONCLUSION: CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine.

CYP2B6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy.

BACKGROUND: Previous studies suggested that polymorphisms in the CYP2B6 gene (which encodes an isoenzyme that metabolizes bupropion) and in the ANKK1 gene (which is located in the ANKK1/DRD2 gene cluster) might influence response to therapy. Thus, the aim of the present study was to evaluate whether the CYP2B6 and ANKK1 polymorphisms are associated with the response to smoking cessation therapies in patients from a smoking cessation assistance program. METHODS: The cohort study enrolled 478 smokers who received behavioral counseling and drug therapy (bupropion, nicotine replacement therapy, and/or varenicline). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerström test for nicotine dependence (FTND) and Issa situational smoking scores were analyzed for nicotine dependence (ND). The ANKK1 rs1800497, CYP2B6*4 (rs2279343), CYP2B6*5 (rs3211371), and CYP2B6*9 (rs3745274) polymorphisms were genotyped by high resolution melting analysis or by restriction fragment length polymorphism. RESULTS: Patients with CYP2B6 rs2279343 wild-type AA genotype had higher success rate (48.0 %) compared with patients carrying AG or GG genotypes (CYP2B6*4 variant) (35.5 %) on bupropion therapy. The AA genotype was associated with higher OR for success during bupropion therapy (OR = 1.92, 95 % CI = 1.08-3.42, p = 0.03) in a multivariate model. We did not observe significant differences in the FTND and Issa scores according to the studied polymorphisms. CONCLUSION: We showed that patients with CYP2B6*4 (rs2279343) variant had lower success rate with bupropion. Likely, the CYP2B6*4 variant, which leads to a rapid predicted metabolic phenotype for the isoenzyme, influences the pharmacological activity of bupropion. Our finding suggests that CYP2B6*4 may be an important genetic marker for individualized bupropion pharmacotherapy.