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Biomedical subjects

Caryn Lerman

Publications and source records attributed to Caryn Lerman.

At least 19 recordsLinked to original sources
PubMed2024

Fine-mapping the CYP2A6 regional association with nicotine metabolism among African American smokers.

The nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine) is a stable biomarker for CYP2A6 enzyme activity and nicotine clearance, with demonstrated clinical utility in personalizing smoking cessation treatment. Common genetic variation in the CYP2A6 region is strongly associated with NMR in smokers. Here, we investigated this regional association in more detail. We evaluated the association of CYP2A6 single-nucleotide polymorphisms (SNPs) and * alleles with NMR among African American smokers (N = 953) from two clinical trials of smoking cessation. Stepwise conditional analysis and Bayesian fine-mapping were undertaken. Putative causal variants were incorporated into an existing African ancestry-specific genetic risk score (GRS) for NMR, and the performance of the updated GRS was evaluated in both African American (n = 953) and European ancestry smokers (n = 933) from these clinical trials. Five independent associations with NMR in the CYP2A6 region were identified using stepwise conditional analysis, including the deletion variant CYP2A6*4 (beta = -0.90, p = 1.55 × 10-11). Six putative causal variants were identified using Bayesian fine-mapping (posterior probability, PP = 0.67), with the top causal configuration including CYP2A6*4, rs116670633, CYP2A6*9, rs28399451, rs8192720, and rs10853742 (PP = 0.09). Incorporating these putative causal variants into an existing ancestry-specific GRS resulted in comparable prediction of NMR within African American smokers, and improved trans-ancestry portability of the GRS to European smokers. Our findings suggest that both * alleles and SNPs underlie the association of the CYP2A6 region with NMR among African American smokers, identify a shortlist of variants that may causally influence nicotine clearance, and suggest that portability of GRSs across populations can be improved through inclusion of putative causal variants.

Adult↗
PubMed2007

CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial.

BACKGROUND: CYP2B6 is the primary enzyme involved in bupropion (Zyban; GlaxoSmithKline, Research Triangle Park, North Carolina) metabolism. Genetic polymorphisms in CYP2B6, such as CYP2B6*6, can alter bupropion metabolism and may affect bupropion treatment outcome. METHODS: Subjects participated in a smoking cessation clinical trial of bupropion versus placebo. The main outcome was a 7-day point prevalence abstinence rate measured 10 weeks after the start of treatment (i.e., end of treatment) and at the 6-month follow-up; secondary outcomes were severity of adverse effects, withdrawal, and urge to smoke. Subjects were haplotyped for the CYP2B6*6 variants. RESULTS: Among smokers in the CYP2B6*6 group (CYP2B6*1/*6 or CYP2B6*6/*6 genotype, n = 147, 45% of the population), bupropion produced significantly higher abstinence rates than placebo at the end of treatment (32.5% vs. 14.3%, p = .01) and at the 6-month follow-up (31.2% vs. 12.9%, p = .008). In contrast, bupropion was no more effective than placebo for smokers in the CYP2B6*1 group (CYP2B6*1/*1, n = 179) at the end of treatment (31.0% vs. 31.6%, p = .93) or at the 6-month follow-up (22.0% vs. 21.5%, p = .94). There was a significant genotype by treatment interaction at the end of treatment (odds ratio [OR] = 2.97, confidence interval [CI] = 1.05-8.40, p = .04), which was similar at 6-month follow-up (OR = 2.98, CI = .98-9.06, p = .05). CONCLUSIONS: These data suggest that smokers with the CYP2B6*6 genotype have a higher liability to relapse on placebo and that they may be good candidates for bupropion treatment for smoking cessation.

Adult↗
PubMed2006

New lower nicotine cigarettes can produce compensatory smoking and increased carbon monoxide exposure.

Potential reduced exposure products (PREPs) are marketed as a means to reduce exposure to tobacco toxicants. Quest cigarettes, a new type of PREP, use genetically modified tobacco to provide a nicotine step-down approach, and are available as 0.6, 0.3 and 0.05 mg nicotine cigarettes. However, these cigarettes deliver equivalent levels of tar (10 mg). Prior research on low nicotine cigarettes suggests smokers will compensate for lower nicotine delivery by increasing their puffing behavior to extract more nicotine. This study tested the hypothesis that compensatory smoking will occur with this PREP as nicotine levels decrease, increasing exposure to tobacco toxins. Fifty smokers completed a within-subject human laboratory study investigating the effect of cigarette nicotine level on smoking behavior. Cigarette nicotine level was double-blinded and order of presentation counter-balanced. Breath carbon monoxide (CO) boost was used as a biomarker of smoke exposure; total puff volume to assess smoking behavior. Total puff volume was greatest for the 0.05 mg nicotine cigarette and CO boost was moderately greater after smoking the 0.3 and 0.05 mg cigarettes compared to the 0.6 mg nicotine cigarette. These data provide novel behavioral and biochemical evidence of compensatory smoking when smoking lower nicotine cigarettes. Although marketed as a PREP, increases in CO boost suggest this product can potentially be a harm-increasing product.

Adult↗
PubMed2006

Catechol-O-methyltransferase (COMT) gene variants predict response to bupropion therapy for tobacco dependence.

BACKGROUND: Although bupropion is efficacious for smoking cessation, only a minority of smokers are able to quit. Pharmacogenetic research may improve treatment outcomes through discovery of DNA sequences predictive of successful pharmacotherapy for subgroups of smokers. We investigated variants in the catechol-O-methyltransferase (COMT) gene in a smoking cessation trial of bupropion. METHODS: A double-blind, placebo-controlled, 10-week trial of bupropion and counseling (with a 6-month follow-up period) was conducted at two university-based smoking cessation research programs. Abstinence was biochemically verified at the end of treatment and at 6 months after the target quit date. RESULTS: At the end of the treatment phase, statistically significant interaction effects indicated that COMT haplotypes of two SNPs (rs737865 and rs165599) predicted the efficacy of bupropion compared with placebo. This interaction effect was attenuated at 6-month follow-up. CONCLUSIONS: COMT haplotypes at rs737865 and rs165599 may predict a favorable outcome for bupropion treatment for smoking cessation. European-American smokers with a G allele at both SNPs may not benefit from bupropion treatment. Small numbers of some COMT haplotypes limit interpretation of response. If study findings are confirmed in additional large studies, COMT genotyping could be applied to identify likely responders to bupropion treatment for smoking cessation.

Adult↗
PubMed2006

Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation.

BACKGROUND: Nicotine is metabolized to cotinine, and cotinine is metabolized to 3'-hydroxycotinine (3-HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3-HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation. METHODS: By use of an open-label design, 480 treatment-seeking smokers were randomly assigned to 8 weeks of transdermal nicotine or nicotine nasal spray use, plus behavioral group counseling. Assessments included demographics, smoking history, body mass index, and plasma nicotine, cotinine, and 3-HC concentrations, as well as CYP2A6 genotypes. Smoking cessation was biochemically verified at the end of treatment and at 6-month follow-up. RESULTS: The rate of nicotine metabolism, as indicated by pretreatment 3-HC/cotinine ratio derived from cigarette smoking, predicted the effectiveness of transdermal nicotine at both time points. The odds of abstinence were reduced by almost 30% with each increasing quartile of metabolite ratio (odds ratio, 0.72 [95% confidence interval, 0.57-0.90]; P=.005). Higher metabolite ratios also predicted lower nicotine concentrations (beta=-1.72, t(179)=-3.31, P<.001), as well as more severe cravings for cigarettes after 1 week of treatment (beta=0.32, t(190)=2.91, P=.004). The metabolite ratio did not predict cessation with use of nicotine nasal spray (odds ratio, 1.05 [95% confidence interval, 0.83-1.33]; P=.68). CONCLUSION: The nicotine metabolite ratio might be useful in screening smokers to determine likely success with a standard dose of transdermal nicotine.

Administration, Cutaneous↗
PubMed2006

Evaluating smokers' reactions to advertising for new lower nicotine quest cigarettes.

Quest cigarettes are a relatively new (2003) product that has been marketed as a way for smokers to gradually reduce the nicotine they receive from cigarettes in order to, according to marketing materials, become nicotine free. However, despite lower levels of nicotine, Quest cigarettes do not have reduced tar levels and, thus, still pose health hazards. This study evaluated beliefs about Quest cigarettes following exposure to a single print advertisement among 200 regular smokers who had never heard of the brand itself. Descriptively, smokers made several specific false inferences about Quest cigarettes after exposure (i.e., lower in tar, healthier, less likely to cause cancer). Two individual-differences variables, need for cognition and perceived vulnerability, moderated smokers' health beliefs about Quest cigarettes.

Adult↗
PubMed2006

No evidence for a major role of polymorphisms during bupropion treatment.

This study evaluated the ability of polymorphisms in five candidate genes to predict weight gain among patients taking bupropion or placebo in a smoking cessation trial. Five hundred fifty-three smokers were enrolled into a randomized double-blind, placebo-controlled trial and followed for 12 months. Five candidate genes [DRD2 Taq1 (rs1800497), DRD2-141 (rs1799732), C957T (rs6277), COMT (rs4818), and SLC6A3] were genotyped. Weights at baseline, at end of treatment, and after 6 and 12 months of follow-up were self-reported. Smoking abstinence at each endpoint was self-reported and confirmed biochemically. A self-reported average weight gain after 12 months of 1.1 +/- 6.0 kg (mean +/- standard deviation) in the bupropion group and 1.8 +/- 4.8 kg in the placebo group was noted. For subjects with biochemically confirmed abstinence from smoking, the HL genotype (alleles coding Val at codon 108 are denoted as H, and those coding Met are denoted as L) at the COMT locus and A1A1 genotype at the DRD2 Taq1 locus were associated with less weight gain at the end of treatment. The TC genotype at the C957T locus was associated with increased weight gain at 6 months of follow-up. However, no polymorphisms or their interactions with bupropion consistently and significantly predicted baseline BMI or weight change during treatment for all study subjects. Overall, our results do not support a major role for these five candidate genes in weight gain after smoking cessation.

Adult↗
PubMed2006

Role of functional genetic variation in the dopamine D2 receptor (DRD2) in response to bupropion and nicotine replacement therapy for tobacco dependence: results of two randomized clinical trials.

Although bupropion and nicotine replacement therapy (NRT) are efficacious tobacco dependence treatments, there is substantial interindividual variability in therapeutic response and most smokers relapse. Pharmacogenetics research may improve treatment outcomes by identifying genetic variants predictive of therapeutic response. We investigated the roles of two functional genetic variants in the dopamine D2 receptor (DRD2) gene in response to pharmacotherapy for tobacco dependence among participants in two randomized clinical trials with a 6-month follow-up period: a double-blind placebo-controlled trial of bupropion (n=414) and an open label trial of transdermal nicotine vs nicotine nasal spray (n=368). At the end of the treatment phase, a statistically significant (p=0.01) interaction between the DRD2 - 141C Ins/Del genotype and treatment indicated a more favorable response to bupropion among smokers homozygous for the Ins C allele compared to those carrying a Del C allele. By contrast, smokers carrying the Del C allele had statistically significantly (p=0.006) higher quit rates on NRT compared to those homozygous for the Ins C allele, independent of NRT type. The C957T variant was also associated (p=0.03) with abstinence following NRT. These results suggest that bupropion may be the preferred pharmacologic treatment for smokers homozygous for the DRD2 - 141 Ins C allele, while NRT may be more beneficial for those who carry the Del C allele. Study findings require confirmation in additional larger samples before they are applied in practice.

Administration, Intranasal↗
PubMed2006

A randomized controlled trial of financial incentives for smoking cessation.

BACKGROUND: Although 435,000 Americans die each year of tobacco-related illness, only approximately 3% of smokers quit each year. Financial incentives have been shown to be effective in modifying behavior within highly structured settings, such as drug treatment programs, but this has not been shown in treating chronic disease in less structured settings. The objective of this study was to determine whether modest financial incentives increase the rate of smoking cessation program enrollment, completion, and quit rates in a outpatient clinical setting. METHODS: 179 smokers at the Philadelphia Veterans Affairs Medical Center who reported smoking at least 10 cigarettes per day were randomized into incentive and non-incentive groups. Both groups were offered a free five-class smoking cessation program at the Philadelphia Veterans Affairs Medical Center. The incentive group was also offered $20 for each class attended and $100 if they quit smoking 30 days post program completion. Self-reported smoking cessation was confirmed with urine cotinine tests. RESULTS: The incentive group had higher rates of program enrollment (43.3% versus 20.2%; P<0.001) and completion (25.8% versus 12.2%; P=0.02). Quit rates at 75 days were 16.3% in the incentive group versus 4.6% in the control group (P=0.01). At 6 months, quit rates in the incentive group were not significantly higher (6.5%) than in the control group (4.6%; P>0.20). CONCLUSION: Modest financial incentives are associated with significantly higher rates of smoking cessation program enrollment and completion and short-term quit rates. Future studies should consider including an incentive for longer-term cessation.

Cotinine↗
PubMed2006

Current and emerging pharmacotherapies for treating tobacco dependence.

Tobacco dependence remains the leading cause of death and disease in the US and a major cause of mortality around the world, yet 1 out of 5 American adults smoke and 1.3 billion adults smoke worldwide. Nicotine replacement therapies (NRTs), bupropion and varenicline, are approved by the US FDA as first-line treatments for nicotine dependence. Clonidine and nortriptyline are recommended as second-line treatments by the Agency for Healthcare Research and Quality. Although recent data suggest that varenicline is superior to bupropion for treating nicotine dependence, a majority of smokers fail to maintain long-term abstinence from smoking using FDA-approved pharmacotherapies. Thus, continued investigation of novel medications for nicotine dependence remains a critical priority. Guided by research on multiple neurobiological mechanisms of nicotine dependence, several novel medications that mimic and/or attenuate nicotine's rewarding effects, or reduce nicotine withdrawal, are under investigation. Although existing data are limited or conflicting, there is some evidence for the efficacy of selegiline, fluoxetine, naltrexone and mecamylamine in certain subgroups of smokers. New research directions, such as fast-acting NRTs, the tailored use of NRTs for subtypes of smokers, and pharmacogenetics, hold promise for new treatment approaches and, ultimately, for reducing rates of tobacco use in the US and worldwide.

Animals↗
PubMed2005

Medication screening for smoking cessation: a proposal for new methodologies.

RATIONALE: The purpose of medication screening studies is to quickly and cheaply evaluate the clinical potential of medications, so that promising drugs proceed to large-scale clinical trials and unpromising drugs do not. Screening procedures for smoking cessation medications either are not sufficiently practical or lack clinical validity. Clinical trials have clinical validity but are often impractical as initial tests of efficacy (i.e., screening) or suffer from limited statistical power. The alternative approach of short-term, laboratory-based studies of purported mechanisms of efficacy may overcome some of the practical problems of clinical trials but appear to have limited clinical validity. OBJECTIVES: This commentary identifies some of the limitations of current short-term screening procedures and provides suggestions for improving such studies. RESULTS: Short-term screening studies typically use smokers unmotivated to abstain (i.e., nontreatment seekers) as participants and examine brief medication effects on clinical markers or potential mechanisms of action, including relief of withdrawal and craving during enforced abstinence or on reduction in the reinforcing effects of smoked tobacco. The limitation of these approaches is shown by their insensitivity to effects of nicotine replacement and bupropion, which are effective in clinical trials for smoking cessation. CONCLUSIONS: The clinical validity of short-term screening studies may improve if these studies simulate some clinical trial procedures within practical limitations. Thus, they should recruit smokers motivated to abstain, emphasize smoking abstinence as a primary index of medication response, examine effects over sufficiently long time periods to encompass the drug's mechanism of action, and assess responses in the natural environment. Whether these changes improve the sensitivity of screening studies is testable. Other research aimed specifically at identifying the mechanisms of therapeutic action of a medication may also profit from using this approach of simulating a short-term clinical trial.

Administration, Cutaneous↗
PubMed2005

BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships.

Members of hereditary breast and ovarian cancer (HBOC) families often express concern during genetic counseling about the impact of BRCA1/2 testing on close relatives. Yet whether there are likely to be adverse effects of either the decision to undergo genetic testing or the results of testing on family relationships is unknown. One purpose of this study was to assess the impact on close family relationships. Within a randomized trial of breast cancer genetic counseling methods, members of 13 HBOC families were offered BRCA1/2 testing for a known family mutation. The Family Relationship Index (FRI) of the Family Environment Scale (FES) was used to measure perceived family cohesion, conflict, and expressiveness at baseline and again 6-9 months following the receipt of test results, or at the equivalent time for those who declined testing. Participants (n = 212) completed baseline and follow-up questionnaires. Comparisons were made between testers and non-testers as well as between those who tested positive and negative for the family mutation. One hundred eighty-one participants elected to undergo genetic testing (85%) and 47 (26%) were identified to have a mutation. After adjusting for baseline family relationship scores, counseling intervention, gender and marital status, non-testers reported a greater increase in expressiveness (P = 0.006) and cohesion (P = 0.04) than testers. Individuals who tested positive reported a decrease in expressiveness (P = 0.07), although as a trend. Regardless of test decision or test result, those who were randomized to a client-centered counseling intervention reported a decrease in conflict (P = 0.006). Overall, study results suggest that undergoing genetic testing and learning ones BRCA1/2 status may affect family relationships. Those individuals who declined testing reported feeling closer to family members and more encouraged to express emotions to other family members demonstrating potential benefit from the offer of testing. Since those who tested positive reported feeling less encouraged to express their emotions within the family, we recommend helping clients to identify others with whom they feel comfortable sharing their thoughts and feelings about their positive gene status and increased cancer risk.

BRCA1 Protein↗
PubMed2005

Reduced nicotine reward in obesity: cross-comparison in human and mouse.

RATIONALE: Tobacco use and obesity lead to significant morbidity and mortality. OBJECTIVE: This study was conducted to investigate the factors maintaining smoking behavior in lean and obese individuals by utilizing a mouse/human cross-validation model of nicotine reward. METHODS: In humans, a cigarette choice paradigm was used to examine the relative reinforcing value of nicotine in obese and non-obese smokers. Conditioned place preference (CPP) for nicotine was assessed in mice fed standard low fat rodent chow and mice rendered obese by a high fat diet. RESULTS: In humans, obese smokers self-administered nicotine via cigarettes significantly less often than non-obese smokers and showed attenuated hedonic effects of nicotine-containing cigarettes compared to denicotinized cigarettes. Similarly, mice exposed to a high fat diet did not exhibit nicotine CPP, relative to control mice. mRNA levels for mu-opiate and leptin receptors were also downregulated in the ventral tegmental area of these mice. CONCLUSIONS: Together, these studies provide the first evidence for reduced nicotine reward in obese subjects and suggest that this may be mediated by dietary influences on the endogenous opioid system.

Animals↗
PubMed2005

Naltrexone reduces the relative reinforcing value of nicotine in a cigarette smoking choice paradigm.

RATIONALE: Human behavioral pharmacology studies can examine how medications that target different neurotransmitter systems influence different aspects of smoking. Naltrexone and bupropion have been shown to alter ad lib smoking behavior; however, medication effects on nicotine reward in a cigarette choice paradigm have yet to be investigated. OBJECTIVE: This study explored the effects of an acute dose of naltrexone, bupropion, or placebo on the relative reinforcing value of nicotine from cigarette smoking using new nicotine and de-nicotinized (Quest, 0.6 and 0.05 mg = "denicotinized") cigarettes. METHODS: In a double-blind, within-subjects design, 26 dependent smokers participated in three experimental cigarette smoking sessions following pretreatment with either naltrexone (50 mg), bupropion (300 mg), or placebo. After medication administration and 2 h of monitored deprivation from cigarettes and food, participants rated their responses to the initial exposure to the cigarettes and then participated in four choice sessions over a 2-h period during which they could take four puffs from either cigarette. RESULTS: The relative reinforcing value of nicotine, as measured by the number of nicotine puffs chosen out of 16, was significantly lower following naltrexone compared to placebo. There were no effects of an acute dose of bupropion on nicotine choices. CONCLUSIONS: These results suggest that naltrexone may reduce the relative reinforcing effects of nicotine via cigarette smoking and support ongoing investigation of opioid antagonists as potential smoking cessation pharmacotherapies.

Adolescent↗
PubMed2005

Treating tobacco dependence: state of the science and new directions.

Despite almost two decades of intensive tobacco control efforts, nearly one quarter of Americans continue to smoke. The two United States Food and Drug Administration-approved medications used to treat tobacco dependence, bupropion and nicotine replacement therapy, are effective for only a fraction of smokers. Investigations of medications approved for affective disorders and other forms of substance abuse, such as fluoxetine and naltrexone, have yielded mixed results as tobacco dependence treatments. A particular challenge in tobacco dependence treatment is the development of effective approaches for smokers with unique needs, such as cancer patients and pregnant women. Despite new developments in these areas, significant gaps in knowledge and practice remain. Basic research in the neurobiologic and genetic basis of nicotine dependence offers promise for the development of novel and more effective treatment approaches. For example, emerging research in pharmacogenetics explores how genetic variation in drug-metabolizing enzymes and drug targets modifies response to pharmacotherapy. These discoveries could someday help practitioners to individualize the type, dosage, and duration of tobacco dependence treatment based on genotype, and maximize the efficacy.

Female↗
PubMed2005

Effects of different nicotine replacement therapies on postcessation psychological responses.

Transdermal nicotine patch (TN) and nicotine nasal spray (NS) are both efficacious forms of smoking cessation treatment, but have different pharmacokinetic properties and modes of action. To understand better psychological responses to treatment, we investigated the effects of TN versus NS on positive affect, negative affect, and withdrawal symptoms during treatment. Participants were randomly assigned to receive TN (n=172) or NS (n=163) plus seven sessions of behavioral counseling, and completed self-report questionnaires at pretreatment and during treatment. TN participants, but not NS participants, reported significant increases in positive affect during treatment. Increases in negative affect and withdrawal were observed, independent of treatment. Only changes in negative affect predicted relapse by the end of the treatment phase. These findings indicate that, although TN may enhance positive affect for smokers in treatment compared with NS, only changes in negative affect predict treatment outcome.

Administration, Cutaneous↗