Biomarkers for smoking cessation.

One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development.

Nicotine kinetics in zebra finches in vivo and in vitro.

Nicotine enhances cognitive performance, and in the zebra finch (Taeniopygia guttata), which is a well-established model of cognition, the effects of nicotine on song production have been reported. Nicotine and cotinine plasma levels were assessed in vivo after subcutaneous injection of 0.18 mg/kg nicotine, a dose that elicits changes in song production.

CYP2A6 slow nicotine metabolism is associated with increased quitting by adolescent smokers.

Variation in the CYP2A6 gene, which decreases the rate of nicotine metabolic inactivation, is associated with higher adult smoking cessation rates during clinical trials. We hypothesized that slow metabolism is associated with increased quitting during adolescence. White adolescent smokers (N=308, aged 12-17, 36.

Effect of a nicotine vaccine on nicotine binding to β2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

Objective: Nicotine promotes smoking partly by binding to β2-containing nicotinic acetylcholine receptors (β2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of β2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty.

The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.

Background: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure.

Methods: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6.

Nicotine-motivated behavior in Caenorhabditis elegans requires the nicotinic acetylcholine receptor subunits acr-5 and acr-15.

Signaling at nicotinic acetylcholine receptors in Caenorhabditis elegans controls many behaviors, including egg-laying and locomotor activity. Here, we show that C. elegans approaches a point source of nicotine in a time-, concentration- and age-dependent manner.

Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state.

Background: Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6.

Objectives: To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants.

Methods: In a genotype-guided study of 42 healthy individuals, we measured the plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion, and erythrohydrobupropion after 7 days of sustained-release bupropion dosing.

Infusion of brain-derived neurotrophic factor into the ventral tegmental area switches the substrates mediating ethanol motivation.

Recent work has shown that infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) promotes a switch in the mechanisms mediating morphine motivation, from a dopamine-independent to a dopamine-dependent pathway. Here we showed that a single infusion of intra-VTA BDNF also promoted a switch in the mechanisms mediating ethanol motivation, from a dopamine-dependent to a dopamine-independent pathway (exactly opposite to that seen with morphine). We suggest that intra-VTA BDNF, via its actions on TrkB receptors, precipitates a switch similar to that which occurs naturally when mice transit from a drug-naive, non-deprived state to a drug-deprived state.

Predictors of cessation in African American light smokers enrolled in a bupropion clinical trial.

Background: This is the first study to examine predictors of successful cessation in African American (AA) light smokers treated within a placebo-controlled trial of bupropion.

Methods: We analyzed data from a randomized, double-blind, placebo-controlled trial of bupropion and health education for 540 African American light smokers. African American light smokers (≤10 cigarettes per day, cpd) were randomly assigned to receive 150mg bid bupropion SR (n=270) or placebo (n=270) for 7weeks.

Nicotinic acetylcholine receptor variation and response to smoking cessation therapies.

Objective: To evaluate the association of nicotinic acetylcholine receptor (nAChR) single nucleotide polymorphism (SNP) with 7-day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.

Materials And Methods: We quantified association of four SNPs at three nAChRs with abstinence in eight randomized clinical trials. Participants were 2633 outpatient treatment-seeking, self-identified European ancestry individuals smoking at least 10 cigarettes/day, recruited through advertisement, prescribed pharmacotherapy, and provided with behavioral therapy.

The DRD4 exon III VNTR, bupropion, and associations with prospective abstinence.

Introduction: DRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive-behavioral mood management therapy.

Methods: We used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies.

Cytochrome P450-mediated drug metabolism in the brain.

Cytochrome P450 enzymes (CYPs) metabolize many drugs that act on the central nervous system (CNS), such as antidepressants and antipsychotics; drugs of abuse; endogenous neurochemicals, such as serotonin and dopamine; neurotoxins; and carcinogens. This takes place primarily in the liver, but metabolism can also occur in extrahepatic organs, including the brain. This is important for CNS-acting drugs, as variation in brain CYP-mediated metabolism may be a contributing factor when plasma levels do not predict drug response.

Imaging changes in synaptic acetylcholine availability in living human subjects.

Unlabelled: In vivo estimation of β(2)-nicotinic acetylcholine receptor availability with molecular neuroimaging is complicated by competition between the endogenous neurotransmitter acetylcholine and the radioligand (123)I-3-[2(S)-2-azetidinylmethoxy]pyridine ((123)I-5-IA). We examined whether binding of (123)I-5-IA is sensitive to increases in extracellular levels of acetylcholine in humans, as suggested in nonhuman primates.

Methods: Six healthy subjects (31 ± 4 y) participated in a (123)I-5-IA SPECT study.

CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion.

Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double-blind, placebo controlled, randomized smoking-cessation trial.

Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco-specific nitrosamine exposure and lower tobacco-specific nitrosamine bioactivation.

Nicotine, the psychoactive ingredient in tobacco, is metabolically inactivated by CYP2A6 to cotinine. CYP2A6 also activates procarcinogenic tobacco-specific nitrosamines (TSNA). Genetic variation in CYP2A6 is known to alter smoking quantity and lung cancer risk in heavy smokers.

Tobacco use among southwestern Alaska Native people.

Introduction: We examined the characteristics, attitudes, beliefs, and exposure to tobacco products in a cohort of rural dwelling Alaska Native (AN) people.

Methods: We conducted a study of 400 of AN adult tobacco users and nonusers living in Southwestern Alaska. Questionnaires covered variables such as demographics, tobacco-use history, current tobacco use and dependence scales, general health status, attitudes and beliefs about tobacco, and quitting history.

Differential effects of nicotine treatment and ethanol self-administration on CYP2A6, CYP2B6 and nicotine pharmacokinetics in African green monkeys.

In primates, nicotine is metabolically inactivated in the liver by CYP2A6 and possibly CYP2B6. Changes in the levels of these two enzymes may affect nicotine pharmacokinetics and influence smoking behaviors. This study investigated the independent and combined effects of ethanol self-administration and nicotine treatment (0.

Developmental hippocampal neuroplasticity in a model of nicotine replacement therapy during pregnancy and breastfeeding.

Rationale: The influence of developmental nicotine exposure on the brain represents an important health topic in light of the popularity of nicotine replacement therapy (NRT) as a smoking cessation method during pregnancy.

Objectives: In this study, we used a model of NRT during pregnancy and breastfeeding to explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring. We focused on two dynamic lifelong phenomena in the dentate gyrus (DG) of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP).

High dose transdermal nicotine for fast metabolizers of nicotine: a proof of concept placebo-controlled trial.

Introduction: Smokers with a faster rate of nicotine metabolism, estimated using the ratio of 3'-hydroxycotinine (3-HC) to cotinine, have lower plasma nicotine levels and are more likely to relapse with 21 mg nicotine patch therapy, than smokers with slower rates of nicotine metabolism. Thus, faster metabolizers of nicotine may require a higher nicotine patch dose to achieve cessation.

Methods: This proof of concept randomized placebo-controlled trial evaluated the efficacy and safety of 8 weeks of 42 mg transdermal nicotine versus 21 mg, among 87 fast metabolizers of nicotine (3-HC/cotinine ≥ 0.

CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people.

Objectives: Alaska Native (AN) people have a high prevalence of tobacco use and associated morbidity and mortality when compared with the general USA population. Variations in the CYP2A6 and CYP2B6 genes, encoding enzymes responsible for nicotine metabolic inactivation and procarcinogen activation, have not been characterized in AN and may contribute toward the increased risk.

Methods: AN people (n=400) residing in the Bristol Bay region of South Western Alaska were recruited for a cross-sectional study on tobacco use.

Reproducibility of the nicotine metabolite ratio in cigarette smokers.

Background: The nicotine metabolite ratio (NMR or 3-hydroxycotinine/cotinine) has been used to phenotype CYP2A6-mediated nicotine metabolism. Our objectives were to analyze (i) the stability of NMR in plasma, saliva, and blood in various storage conditions, (ii) the relationship between NMRs derived from blood, plasma, saliva, and urine, and (iii) the reproducibility of plasma NMR in ad libitum cigarette smokers.

Methods: We analyzed data from four clinical studies.

DRD1 associations with smoking abstinence across slow and normal nicotine metabolizers.

Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence; however, further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cut off). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system.

Exposure to nicotine and carcinogens among Southwestern Alaskan Native cigarette smokers and smokeless tobacco users.

Background: The prevalence of tobacco use, both cigarette smoking and smokeless, including iqmik (homemade smokeless tobacco prepared with dried tobacco leaves mixed with alkaline ash), and of tobacco-related cancer is high in Alaskan Native people (AN). To investigate possible mechanisms of increased cancer risk we studied levels of nicotine and tobacco-specific nitrosamines (TSNA) in tobacco products and biomarkers of tobacco toxicant exposure in Southwestern AN people.

Methods: Participants included 163 cigarette smokers, 76 commercial smokeless tobacco, 20 iqmik, 31 dual cigarette smokers and smokeless tobacco, and 110 nontobacco users.