500 results on '"Tyndale RF"'
Search Results
2. Lack of associations of CHRNA5-A3-B4 genetic variants with smoking cessation treatment outcomes in Caucasian smokers despite associations with baseline smoking
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Benowitz, Neal, Tyndale, RF, Zhu, AZX, George, TP, Paul, C, Hawk, L, Schnoll, R, Swan, GE, Benowitz, NL, Heitjan, DF, and Lerman, C
- Abstract
© 2015 Tyndale et al.CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant as
- Published
- 2015
3. Association of CHRNA5-A3-B4 SNP rs2036527 With Smoking Cessation Therapy Response in African-American Smokers
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Benowitz, Neal, Zhu, AZX, Zhou, Q, Cox, LS, David, SP, Ahluwalia, JS, Benowitz, NL, and Tyndale, RF
- Abstract
Associations between CHRNA5-A3-B4 variants and smoking behaviors exist; however, the association with smoking abstinence is less understood, particularly that among African Americans. In 1,295 African Americans enrolled in two clinical trials, we investiga
- Published
- 2014
4. Association of CHRNA5-A3-B4 SNP rs2036527 with smoking cessation therapy response in African-American smokers
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Zhu, AZX, Zhou, Q, Cox, LS, David, SP, Ahluwalia, JS, Benowitz, NL, and Tyndale, RF
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Pharmacology & Pharmacy ,Pharmacology and Pharmaceutical Sciences - Abstract
Associations between CHRNA5-A3-B4 variants and smoking behaviors exist; however, the association with smoking abstinence is less understood, particularly that among African Americans. In 1,295 African Americans enrolled in two clinical trials, we investigated the association between CHRNA5-A3-B4 and smoking abstinence. The rs2056527(A) allele was associated with lower abstinence with active pharmacotherapy (during treatment: odds ratio (OR) = 0.42, P < 0.001; end of treatment (EOT): OR = 0.55, P = 0.004), or with nicotine gum alone (during treatment: OR = 0.31, P < 0.001; EOT: OR = 0.51, P = 0.02), but not significantly with bupropion, although similar directions and magnitudes were observed (during treatment: OR = 0.54, P = 0.05; EOT: OR = 0.59, P = 0.08). In addition, the rs588765(T) allele was associated with abstinence with gum during treatment (OR = 2.31, P < 0.01). The SNP rs16969968 occurred at a low frequency and was not consistently associated with abstinence. CHRNA5-A3-B4 variants were not associated with tobacco consumption, and adjustments for smoking behaviors did not alter the associations with smoking abstinence. Together, our data suggest that among African Americans, CHRNA5-A3-B4 variants are not associated with baseline smoking but can influence smoking abstinence during active pharmacotherapy.
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- 2014
5. Genetic and pharmacokinetic determinants of response to transdermal nicotine in white, black, and Asian nonsmokers
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Benowitz, Neal, Dempsey, Delia, Dempsey, DA, St, G, Jacob, P, Tyndale, RF, and Benowitz, NL
- Abstract
The aim of the study was to examine genetic, pharmacokinetic, and demographic factors that influence sensitivity to nicotine in never-smokers. Sixty never-smokers, balanced for gender and race (white, black, and Asian), wore 7-mg nicotine skin patches for
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- 2013
6. CYP2A6 genotype but not age determines cotinine half-life in infants and children
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Benowitz, Neal, Fuentes-Afflick, Elena, Dempsey, Delia, Dempsey, DA, Sambol, NC, Jacob, P, Hoffmann, E, Tyndale, RF, and Benowitz, NL
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The formation of cotinine, the main proximate metabolite and a biomarker of nicotine exposure, is mediated primarily by cytochrome P450 (CYP)2A6. Our aim was to determine whether higher cotinine levels in young children exposed to secondhand smoke (SHS) ar
- Published
- 2013
7. Variation in Trans-3′-Hydroxycotinine Glucuronidation Does Not Alter the Nicotine Metabolite Ratio or Nicotine Intake
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Benowitz, Neal, Zhu, AZX, Zhou, Q, Cox, LS, Ahluwalia, JS, Benowitz, NL, and Tyndale, RF
- Abstract
Background: CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the "nicotine metabolite ratio", NMR) is an in vivo marker for the rate
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- 2013
8. CYP2B6 and Bupropion's Smoking‐Cessation Pharmacology: The Role of Hydroxybupropion
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Zhu, AZX, Cox, LS, Nollen, N, Faseru, B, Okuyemi, KS, Ahluwalia, JS, Benowitz, NL, and Tyndale, RF
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Tobacco Smoke and Health ,Tobacco ,Clinical Research ,Substance Misuse ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Cancer ,Black or African American ,Antidepressive Agents ,Second-Generation ,Aryl Hydrocarbon Hydroxylases ,Bupropion ,Cytochrome P-450 CYP2B6 ,Double-Blind Method ,Humans ,Kinetics ,Logistic Models ,Odds Ratio ,Oxidoreductases ,N-Demethylating ,Predictive Value of Tests ,Smoking ,Smoking Cessation ,Treatment Outcome ,Pharmacology & Pharmacy ,Pharmacology and pharmaceutical sciences - Abstract
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. Among the treatment-adherent individuals, higher hydroxybupropion concentrations (per μg/ml) resulted in better smoking-cessation outcomes (week 3, 7, and 26 odds ratio (OR) = 2.82, 2.96, and 2.37, respectively, P = 0.005-0.040); this was not observed with bupropion levels (OR = 1.00-1.03, P = 0.59-0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6-mediated hydroxybupropion formation. These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 μg/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion's cessation outcomes.
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- 2012
9. Gender-stratified gene and gene-treatment interactions in smoking cessation
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Benowitz, Neal, Lee, W, Bergen, AW, Swan, GE, Li, D, Liu, J, Thomas, P, Tyndale, RF, Benowitz, NL, Lerman, C, and Conti, DV
- Abstract
We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and
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- 2012
10. Design, baseline characteristics, and retention of African American light smokers into a randomized trial involving biological data
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Cox, LS, Faseru, B, Mayo, MS, Krebill, R, Snow, TS, Bronars, CA, Nollen, NL, Choi, WS, Okuyemi, KS, Salzman, GA, Benowitz, NL, Tyndale, RF, and Ahluwalia, JS
- Abstract
Background: African Americans experience significant tobacco-related health disparities despite the fact that over half of African American smokers are light smokers (use ≤10 cigarettes per day). African Americans have been under-represented in smoking cessation research, and few studies have evaluated treatment for light smokers. This paper describes the study design, measures, and baseline characteristics from Kick It at Swope III (KIS-III), the first treatment study of bupropion for African American light smokers.Methods: Five hundred forty African American light smokers were randomly assigned to receive bupropion (150mg bid) (n = 270) or placebo (n = 270) for 7 weeks. All participants received written materials and health education counseling. Participants responded to survey items and provided blood samples for evaluation of phenotype and genotype of CYP2A6 and CYP2B6 enzymes involved in nicotine and bupropion metabolism. Primary outcome was cotinine-verified 7-day point prevalence smoking abstinence at Week 26 follow-up.Results: Of 2,628 individuals screened, 540 were eligible, consented, and randomized to treatment. Participants had a mean age of 46.5 years and 66.1% were women. Participants smoked an average of 8.0 cigarettes per day, had a mean exhaled carbon monoxide of 16.4ppm (range 1-55) and a mean serum cotinine of 275.8ng/ml. The mean Fagerström Test for Nicotine Dependence was 3.2, and 72.2% of participants smoked within 30 minutes of waking. The average number of quit attempts in the past year was 3.7 and 24.2% reported using pharmacotherapy in their most recent quit attempt. Motivation and confidence to quit were high.Conclusion: KIS-III is the first study designed to examine both nicotine and bupropion metabolism, evaluating CYP2A6 and CYP2B6 phenotype and genotype in conjunction with psychosocial factors, in the context of treatment of African American light smokers. Of 1629 smokers screened for study participation, only 18 (1.1%) were ineligible to participate in the study because they refused blood draws, demonstrating the feasibility of recruiting and enrolling African American light smokers into a clinical treatment trial involving biological data collection and genetic analyses. Future evaluation of individual factors associated with treatment outcome will contribute to advancing tailored tobacco use treatment with the goal of enhancing treatment and reducing health disparities for African American light smokers. © 2011 Cox et al; licensee BioMed Central Ltd.
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- 2011
11. Designer Drugs 2.0
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Huestis, MA and Tyndale, RF
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- 2017
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12. Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects
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Faulkner, P, Ghahremani, DG, Tyndale, RF, Cox, CM, Kazanjian, AS, Paterson, N, Lotfipour, S, Hellemann, GS, Petersen, N, Vigil, C, and London, ED
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Adult ,Male ,Nicotine ,Adolescent ,Medical and Health Sciences ,Drug Abuse ,Dose-Response Relationship ,Young Adult ,Substance Misuse ,Clinical Research ,Tobacco ,Humans ,Attention ,Cotinine ,Craving ,Cancer ,Psychiatry ,Tobacco Smoke and Health ,Smoking ,Psychology and Cognitive Sciences ,Substance Abuse ,Consumer Behavior ,Substance Withdrawal Syndrome ,Affect ,Good Health and Well Being ,Female ,Drug ,Drug Abuse (NIDA only) - Abstract
© 2017 American College of Neuropsychopharmacology. All rights reserved. The use of cigarettes delivering different nicotine doses allows evaluation of the contribution of nicotine to the smoking experience. We compared responses of 46 young adult smokers to research cigarettes, delivering 0.027, 0.110, 0.231, or 0.763 mg nicotine, and conventional cigarettes. On five separate days, craving, withdrawal, affect, and sustained attention were measured after overnight abstinence and again after smoking. Participants also rated each cigarette, and the nicotine metabolite ratio (NMR) was used to identify participants as normal or slow metabolizers. All cigarettes equally alleviated craving, withdrawal, and negative affect in the whole sample, but normal metabolizers reported greater reductions of craving and withdrawal than slow metabolizers, with dose-dependent effects. Only conventional cigarettes and, to a lesser degree, 0.763-mg nicotine research cigarettes increased sustained attention. Finally, there were no differences between ratings of lower-dose cigarettes, but the 0.763-mg cigarettes and (even more so) conventional cigarettes were rated more favorably than lower-dose cigarettes. The findings indicate that smoking-induced relief of craving and withdrawal reflects primarily non-nicotine effects in slow metabolizers, but depends on nicotine dose in normal metabolizers. By contrast, relief of withdrawal-related attentional deficits and cigarette ratings depend on nicotine dose regardless of metabolizer status. These findings have bearing on the use of reduced-nicotine cigarettes to facilitate smoking cessation and on policy regarding regulation of nicotine content in cigarettes. They suggest that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to
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- 2017
13. Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: A randomised, double-blind placebo-controlled trial
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Lerman, C, Schnoll, RA, Hawk, LW, Cinciripini, P, George, TP, Wileyto, EP, Swan, GE, Benowitz, NL, Heitjan, DF, and Tyndale, RF
- Abstract
© 2015 Elsevier Ltd. Background: Substantial variability exists in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimise treatment choice for individual smokers might improve treatment outcomes. We tested whether a genetically informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3'-hydroxycotinine:cotinine), predicts response to nicotine patch or varenicline for smoking cessation. Methods: We undertook NMR-stratified multicentre, randomised, placebo-controlled clinical trial from Nov 16, 2010, to Sept 12, 2014, at four sites. Smokers seeking treatment were randomly assigned by baseline NMR status and study site, in blocks of 12 patients (1:1:1 ratio), to 11 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioural counselling. Participants and investigators were masked to group allocation and NMR status. An intention-to-treat analysis was done. Participants were followed up for 12 months after the target quit date. The primary endpoint was biochemically verified 7 day point prevalence abstinence at the end of treatment to estimate the pharmacological effect of treatment by NMR. The trial is registered at ClinicalTrials.gov, number NCT01314001. Findings: 1246 participants (662 slow metabolisers of nicotine, 584 normal metabolisers of nicotine) were enrolled and randomly assigned to the three interventions (408 placebo, 418 nicotine patch, 420 varenicline). At end of treatment, varenicline was more efficacious than nicotine patch in normal metabolisers (OR 2·17, 95% CI 1·38-3·42; p=0·001), but not in slow metabolisers (OR 1·13, 0·74-1·71; p=0·56). In the longitudinal model including all timepoints, the NMR-by-treatment interaction was significant (ratio of odds ratios [ORR] 1·96, 95% CI 1·11-3·46; p=0·02). An NMR-by-treatment interaction showed that slow (. vs normal) metabolisers reported greater overall side-effect severity with varenicline versus placebo (β=-1·06, 95% CI -2·08 to -0·03; p=0·044). Interpretation: Treating normal metabolisers with varenicline and slow metabolisers with nicotine patch could optimise quit rates while minimising side-effects. Funding: National Institutes of Health, Canadian Institutes of Health Research, Abramson Cancer Center, Centre for Addiction and Mental Health Foundation, and Pennsylvania Department of Health.
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- 2015
14. Nicotine metabolite ratio (3-Hydroxycotinine/Cotinine) in plasma and urine by different analytical methods and laboratories: Implications for clinical implementation
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Tanner, JA, Novalen, M, Jatlow, P, Huestis, MA, Murphy, SE, Kaprio, J, Kankaanpää, A, Galanti, L, Stefan, C, George, TP, Benowitz, NL, Lerman, C, and Tyndale, RF
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© 2015 American Association for Cancer Research. Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-30- hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Results: Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios, 0.82-1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR. Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Impact: Together this indicates a reduced need for differential interpretation of plasmaNMRresults based on the approach used, allowing for direct comparison of different studies.
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- 2015
15. Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes
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Zhu, AZX, Zhou, Q, Cox, LS, Ahluwalia, JS, Benowitz, NL, and Tyndale, RF
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health services administration ,mental disorders ,behavior and behavior mechanisms ,psychological phenomena and processes - Abstract
Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics. Bupropion is used clinically to treat depression and to promote smoking cessation. It is metabolized by CYP2B6 to its active metabolite hydroxybupropion, yet alterations in CYP2B6 activity have little impact on bupropion plasma levels. Furthermore, less than 10% of a bupropion dose is excreted as urinary bupropion and its characterized metabolites hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, suggesting that alternative metabolic pathways may exist. In vitro data suggested CYP2C19 could metabolize bupropion. The current study investigated the impact of functional CYP2C19 genetic variants on bupropion pharmacokinetics and treatment outcomes. In 42 healthy volunteers, CYP2C19∗2 (a reduced activity allele) was associated with higher bupropion area under the plasma concentration-time curve (AUC), but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670 hours·ng/ml in individuals with and without CYP2C19∗2, respectively (P = 0.017). CYP2C19∗2 was also associated with higher threohydrobupropion and erythrohydrobupropion AUC (P < 0.005). Adjusting for CYP2B6 genotype did not alter these associations, and CYP2C19 variants did not alter the utility of the hydroxybupropion/bupropion ratio as a measure of CYP2B6 activity. Finally, in a clinical trial of 540 smokers, CYP2C19 genotype was not associated with smoking cessation outcomes, supporting the hypothesis that bupropion response is mediated by hydroxybupropion, which is not altered by CYP2C19. In conclusion, our study reports the first in vivo evidence that reduced CYP2C19 activity significantly increases the steady-state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion. These pharmacokinetic changes were not associated with differences in bupropion's ability to promote smoking cessation in smokers, but may influence the side effects and toxicity associated with bupropion.
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- 2014
16. Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: Results from two randomized clinical trials of bupropion
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David, SP, Strong, DR, Leventhal, AM, Lancaster, MA, Mcgeary, JE, Munafò, MR, Bergen, AW, Swan, GE, Benowitz, NL, Tyndale, RF, Conti, DV, Brown, RA, Lerman, C, and Niaura, R
- Abstract
Aims: To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. Design: Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. Setting: Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). Participants: A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. Measurements: Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4VNTR], SLC6A3,3′VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. Findings: Significant associations of the AGES (hazard ratio [HR]=1.10, 95% confidence interval [CI]=1.06-1.14, P=0.009) and of the DRD4VNTR (HR=1.29, 95% CI=1.17-1.41, P=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error=-0.18 [0.07], P=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. Conclusions: A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion. © 2013 Society for the Study of Addiction.
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- 2013
17. Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
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Kalman, LV, primary, Agúndez, JAG, additional, Appell, M Lindqvist, additional, Black, JL, additional, Bell, GC, additional, Boukouvala, S, additional, Bruckner, C, additional, Bruford, E, additional, Caudle, K, additional, Coulthard, SA, additional, Daly, AK, additional, Tredici, AL Del, additional, den Dunnen, JT, additional, Drozda, K, additional, Everts, RE, additional, Flockhart, D, additional, Freimuth, RR, additional, Gaedigk, A, additional, Hachad, H, additional, Hartshorne, T, additional, Ingelman‐Sundberg, M, additional, Klein, TE, additional, Lauschke, VM, additional, Maglott, DR, additional, McLeod, HL, additional, McMillin, GA, additional, Meyer, UA, additional, Müller, DJ, additional, Nickerson, DA, additional, Oetting, WS, additional, Pacanowski, M, additional, Pratt, VM, additional, Relling, MV, additional, Roberts, A, additional, Rubinstein, WS, additional, Sangkuhl, K, additional, Schwab, M, additional, Scott, SA, additional, Sim, SC, additional, Thirumaran, RK, additional, Toji, LH, additional, Tyndale, RF, additional, van Schaik, RHN, additional, Whirl‐Carrillo, M, additional, Yeo, KTJ, additional, and Zanger, UM, additional
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- 2015
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18. CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in alaska native tobacco users
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Zhu, AZX, Renner, CC, Hatsukami, DK, Benowitz, NL, and Tyndale, RF
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Background and aims: Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and β4 nicotinic receptor subunits, are associated with altered smoking behaviors in European Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska Native people. Design, setting and participants: A cross-sectional study of 400 Alaska Native individuals, including 290 tobacco users. Measurements: CHRNA5-A3-B4 genotype, body weight and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE). Findings: Alaska Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African Americans. In 290 Alaska Native tobacco users the 'G' allele of rs578776, which tagged a 30kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and associated significantly with nicotine intake (20% higher plasma cotinine, P
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- 2013
19. Dose-independent kinetics with low level exposure to nicotine and cotinine
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Benowitz, NL, Dempsey, D, Tyndale, RF, St. Helen, G, and Jacob, P
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Adult ,Cytochrome P-450 CYP2A6 ,Male ,Nicotine ,Cross-Over Studies ,Humans ,Female ,Aryl Hydrocarbon Hydroxylases ,Middle Aged ,Cotinine ,Letters to the Editors ,Alleles - Published
- 2012
20. Cannabinoids: Friend or foe?
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Le Foll, B, primary and Tyndale, RF, additional
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- 2015
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21. Discussion
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Peto, R, Lerman, C, Tyndale, RF, Shiffman, S, Bertrand, D, Walton, R, Clarke, PBS, Jarvis, MJ, Corrigall, WA, Stolerman, I, and West, R
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- 2006
22. Discussion
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Stolerman, I, Walton, R, Bertrand, D, Changeux, J-P, Hajek, P, Clarke, PBS, Peto, R, and Tyndale, RF
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- 2006
23. The human dopamine D5 receptor gene: cloning and characterization of the 5'-flanking and promoter region
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Adriano Marchese, James H. Meador-Woodruff, P. Seeman, Van Tol Hh, Hyman B. Niznik, Brian F. O'Dowd, S.P. Damask, Timothy V. Beischlag, and Tyndale Rf
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DNA, Complementary ,Pseudogene ,Recombinant Fusion Proteins ,Molecular Sequence Data ,Gene Expression ,Biology ,Transfection ,Biochemistry ,Cell Line ,Receptors, Dopamine ,Gene product ,Transcription (biology) ,Transcriptional regulation ,Humans ,Receptors, Dopamine D5 ,RNA, Messenger ,Cloning, Molecular ,Luciferases ,Promoter Regions, Genetic ,Gene ,Transcription factor ,In Situ Hybridization ,Brain Chemistry ,Base Sequence ,Receptors, Dopamine D1 ,Riboprobe ,Promoter ,Molecular biology - Abstract
Genomic and overlapping cDNA clones encompassing the entire 5'-untranslated region of the human D5 receptor gene were cloned and sequenced. Comparison of these human D5 receptor genomic and cDNA clones revealed the presence of two exons separated by a small and variably sized intron (of either 179 or 155 bp). We have determined that the major site of transcription initiation of the D5 gene is 2125 bp upstream from the translational initiation start site. The region 5' to the transcription initiation site lacked conventional TATA and CAAT sequences, but contained several putative binding sites for transcription factors, such as Sp1 and Ap1. Luciferase reporter gene constructs containing D5 gene sequence information up to 500 bp 5' of the transcription initiation site were able to stimulate transcription only in SK-N-SH cells but not in COS-7, CHO, P19EC, NB41A3, and SK-N-MC cell lines. Promoter deletion analysis indicated that the D5 gene promoter contained a positive modulator at 119-182 and a negative modulator 251-500 bases upstream from the site of transcription initiation. In addition, in order to detect the expression of functional D5 receptor mRNAs and not those of its expressed pseudogenes, in situ hybridization analysis of monkey and human brain using a 5' D5-specific riboprobe revealed that D5 receptor mRNA was most abundant in discrete cortical areas (layers II, IV, and VI), the dentate gyrus, and hippocampal subfields with very little message detected in the striatum. Unexpectedly, D5 mRNA antisense riboprobes labeled discrete cell bodies in the pars compacta of the substantia nigra. The characterization of the genomic organization of the D5 receptor gene and of those factors involved in its transcriptional regulation may aid in our understanding of the role this gene product plays in the generation and maintenance of dopamine D1-like receptor-mediated events.
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- 1995
24. Association of Nicotine Metabolite Ratio and CYP2A6 Genotype With Smoking Cessation Treatment in African-American Light Smokers
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Ho, MK, primary, Mwenifumbo, JC, additional, Al Koudsi, N, additional, Okuyemi, KS, additional, Ahluwalia, JS, additional, Benowitz, NL, additional, and Tyndale, RF, additional
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- 2009
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25. Toward Personalized Therapy for Smoking Cessation: A Randomized Placebo-controlled Trial of Bupropion
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Patterson, F, primary, Schnoll, RA, additional, Wileyto, EP, additional, Pinto, A, additional, Epstein, LH, additional, Shields, PG, additional, Hawk, LW, additional, Tyndale, RF, additional, Benowitz, N, additional, and Lerman, C, additional
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- 2008
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26. Few cell lines with GABAA mRNAs have functional receptors
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Hales, TG, primary and Tyndale, RF, additional
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- 1994
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27. Distinctive patterns of GABAA receptor subunit mRNAs in 13 cell lines
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Tyndale, RF, primary, Hales, TG, additional, Olsen, RW, additional, and Tobin, AJ, additional
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- 1994
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28. Oxidation of reduced haloperidol to haloperidol: involvement of human P450IID6 (sparteine/debrisoquine monooxygenase).
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Tyndale, RF, primary, Kalow, W., additional, and Inaba, T., additional
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- 1991
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29. Overview of the pharmacogenomics of cigarette smoking.
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Ho, MK and Tyndale, RF
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SMOKING , *CANCER , *NICOTINE , *GENETICS , *CIGARETTE smokers , *CAUSES of death , *GENES - Abstract
Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.The Pharmacogenomics Journal (2007) 7, 81–98. doi:10.1038/sj.tpj.6500436; published online 16 January 2007 [ABSTRACT FROM AUTHOR]
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- 2007
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30. The role of CYP2A6 in the emergence of nicotine dependence in adolescents.
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Audrain-McGovern J, Al Koudsi N, Rodriguez D, Wileyto EP, Shields PG, and Tyndale RF
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- 2007
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31. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.
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Robinson KM, Eum S, Desta Z, Tyndale RF, Gaedigk A, Crist RC, Haidar CE, Myers AL, Samer CF, Somogyi AA, Zubiaur P, Iwuchukwu OF, Whirl-Carrillo M, Klein TE, Caudle KE, Donnelly RS, and Kharasch ED
- Subjects
- Humans, Pharmacogenetics, Opiate Substitution Treatment methods, Pharmacogenomic Variants, Methadone pharmacokinetics, Methadone adverse effects, Cytochrome P-450 CYP2B6 genetics, Cytochrome P-450 CYP2B6 metabolism, Analgesics, Opioid pharmacokinetics, Analgesics, Opioid adverse effects, Opioid-Related Disorders drug therapy, Opioid-Related Disorders genetics, Genotype
- Abstract
Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org)., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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32. PharmVar GeneFocus: CYP2A6.
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Langlois AWR, Chenoweth MJ, Twesigomwe D, Scantamburlo G, Whirl-Carrillo M, Sangkuhl K, Klein TE, Nofziger C, Tyndale RF, and Gaedigk A
- Subjects
- Humans, Pharmacogenetics methods, Genetic Variation genetics, Phenotype, Nicotine metabolism, Genotype, Pharmacogenomic Variants, Alleles, Polymorphism, Genetic, Cytochrome P-450 CYP2A6 genetics, Cytochrome P-450 CYP2A6 metabolism
- Abstract
The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the human CYP2A gene locus containing the highly polymorphic CYP2A6 gene. CYP2A6 plays a role in the metabolism of nicotine and various drugs. Thus, genetic variation can substantially contribute to the function of this enzyme and associated efficacy and safety. This GeneFocus provides an overview of the clinical significance of CYP2A6, including its genetic variation and function. We also highlight and discuss caveats in the identification and characterization of allelic variation of this complex pharmacogene, a prerequisite for accurate genotype determination and prediction of phenotype status., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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33. Fine-mapping the CYP2A6 regional association with nicotine metabolism among African American smokers.
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Pouget JG, Giratallah H, Langlois AWR, El-Boraie A, Lerman C, Knight J, Cox LS, Nollen NL, Ahluwalia JS, Benner C, Chenoweth MJ, and Tyndale RF
- Abstract
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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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34. Implementing a Metabolism-informed approach for smoking cessation in an Alaska Tribal health system: study protocol for a single-arm implementation pilot trial.
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Jansen KJ, Tranby BN, Shane AL, Takeno T, Chadwick K, Sinicrope P, Shaw JL, Tyndale RF, Harris JR, Patten CA, and Avey JP
- Abstract
Background: Individualized treatment for commercial tobacco smoking cessation, such as through the utilization of the nicotine metabolite ratio (NMR), offers potential clinical benefit. NMR is a metabolism-informed biomarker that can be used to guide medication selection. NMR testing is particularly promising for tobacco cessation efforts in populations with high rates of smoking, such as some Alaska Native and American Indian (AN/AI) communities. To date, no prior study has evaluated the implementation of NMR-guided tobacco cessation with AN/AI populations., Methods: The present "QUIT" protocol is a two-phase study that will occur at Southcentral Foundation (SCF), an Alaska Native-owned health system, serving 70,000 AN/AI people, based in Anchorage, Alaska. In Phase one, qualitative interviews with customer-owners (patients), providers and administrators (n = 36) and a 10-participant beta-test will be used to refine a strategy to implement NMR testing in the health system. Phase two will involve a single-arm pilot trial (n = 50) and qualitative interviews throughout data collection (n = 48) to evaluate the implementation strategy and explore the real-world acceptability and feasibility of NMR testing to guide tobacco cessation with AN/AI populations., Discussion: This study utilizes a community-based participatory approach to refine and implement a nicotine metabolism-informed smoking cessation program in a Tribal healthcare setting. The process and findings from this study will reflect the importance of customer-owner choice and honor the lived experience involved in quitting commercial tobacco. Pilot study data will inform the effect and sample sizes required for a future pragmatic trial of NMR-guided smoking cessation., Trial Registration: This study will be registered with clinicaltrials.gov after the beta test is complete and the final IRB protocol is approved., (© 2024. The Author(s).)
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- 2024
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35. Human CYP2D6 varies across the estrous cycle in brains of transgenic mice altering drug response.
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Miksys S, McDonald C, Baghai Wadji F, Gonzalez FJ, and Tyndale RF
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- Animals, Female, Humans, Mice, Harmine pharmacology, Propranolol pharmacology, Male, Liver metabolism, Liver drug effects, Cytochrome P-450 CYP2D6 Inhibitors pharmacology, Hypothermia chemically induced, Hypothermia metabolism, Mice, Transgenic, Cytochrome P-450 CYP2D6 metabolism, Cytochrome P-450 CYP2D6 genetics, Brain metabolism, Brain drug effects, Estrous Cycle drug effects
- Abstract
Cytochrome P450 (CYP) 2Ds are drug metabolizing enzymes found in brain and liver which metabolize numerous centrally acting drugs. Inhibition and induction of CYP2D-mediated metabolism in rodent brain alters brain drug and metabolite concentrations and resulting drug response. In female rats, brain CYP2D metabolism varies across the estrous cycle and with exogenous estrogen, changing brain drug concentrations and response. In this study harmine-induced hypothermia was lower in humanized CYP2D6 transgenic female mice during estrus compared to diestrus. Pretreatment into the cerebral ventricles with propranolol, a selective irreversible inhibitor of human CYP2D6 in brain, increased hypothermia in estrus but not in diestrus. In vivo enzyme activity was higher in brains of transgenic mice in estrus compared to diestrus and was lower after pretreatment with inhibitor in estrus, but not in diestrus. Hepatic activity and plasma harmine concentrations were unaffected by either estrous phase or inhibition of brain CYP2D6. In wild-type female mice, harmine-induced hypothermia was unaffected by either estrous phase or inhibitor pretreatment. Male mice were used as positive controls, where pretreatment with inhibitor increased harmine-induced hypothermia in transgenic but not wild-type, mice. This study provides evidence for female hormone cycle-based regulation of drug metabolism by human CYP2D6 in brain and resulting drug response. This suggests that brain CYP2D6 metabolism may vary, for example, during the menstrual cycle, pregnancy, or menopause, or while taking oral contraceptives or hormone therapy. This variation could contribute to individual differences in response to centrally acting CYP2D6-substrate drugs by altering local brain drug and/or metabolite concentrations., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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36. Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline.
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Chenoweth MJ, Kim YJ, Nollen NL, Hawk LW Jr, Mahoney MC, Lerman C, Knight J, and Tyndale RF
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- Adult, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Dreams drug effects, Genome-Wide Association Study, Smoking Cessation methods, Smoking Cessation Agents adverse effects, Smoking Cessation Agents therapeutic use, Varenicline adverse effects
- Abstract
Varenicline, the most efficacious smoking cessation monotherapy, produces abnormal dreams. Although genetic contributions to varenicline-associated nausea and cessation have been identified, the role of genetics in abnormal dreams is unknown. We conducted a genomewide association study (GWAS) of abnormal dreams in 188 European ancestry smokers treated with varenicline (NCT01314001). Additive genetic models examined the likelihood of experiencing abnormal dreams 2 weeks following varenicline initiation. For the top locus, we tested for selectivity to varenicline, effects on cessation, replication, and generalizability to African ancestry (AA) individuals. The top GWAS variant associated with abnormal dreams was rs901886, mapping to intron 2 of ICAM5 on chromosome 19. The prevalence of abnormal dreams in those with rs901886 CC, CT, and TT genotypes was 15%, 36%, and 62%, respectively (odds ratio = 2.94 for T vs. C, 95% confidence interval = 1.92-4.55, P = 2.03e
-7 ; T allele frequency = 52%). This rs901886 association was selective to varenicline (P values > 0.05 on nicotine patch and placebo). There were also positive associations for rs901886 T (vs. C allele, P = 0.03) and for abnormal dreams (P = 0.06) with varenicline-aided cessation. Neither rs901886 (P = 0.40) nor abnormal dreams (P = 0.24) were associated with adherence. A similar direction of effect of rs901886 on abnormal dreams was observed in a second varenicline trial (NCT01836276). In AA individuals (n = 137), rs901886 was not associated with abnormal dreams (P = 0.41), but there was an association for a variant located ~ 74.4 kb 5' of ICAM5 (P = 2.56e-3 ). Variation in ICAM5 may influence abnormal dreams and cessation on varenicline. These findings provide additional support for genetically optimized smoking cessation approaches., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2024
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37. Executive functions and behavioral economic demand for cannabis among young adults: Indirect associations with cannabis consumption and cannabis use disorder.
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Coelho SG, Hendershot CS, Aston ER, Ruocco AC, Quilty LC, Tyndale RF, and Wardell JD
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- Humans, Female, Male, Young Adult, Adult, Marijuana Use psychology, Marijuana Use epidemiology, Cannabis, Economics, Behavioral, Adolescent, Inhibition, Psychological, Executive Function physiology, Marijuana Abuse psychology, Memory, Short-Term physiology
- Abstract
Behavioral economic demand for cannabis is robustly associated with cannabis consumption and cannabis use disorder (CUD). However, few studies have examined the processes underlying individual differences in the relative valuation of cannabis (i.e., demand). This study examined associations between executive functions and cannabis demand among young adults who use cannabis. We also examined indirect associations of executive functions with cannabis consumption and CUD symptoms through cannabis demand. Young adults ( N = 113; 58.4% female; mean age 22 years) completed a Marijuana Purchase Task. Participants also completed cognitive tasks assessing executive functions (set shifting, inhibitory control, working memory) and semistructured interviews assessing past 90-day cannabis consumption (number of grams used) and number of CUD symptoms. Poorer inhibitory control was significantly associated with greater O
max (peak expenditure on cannabis) and greater intensity (cannabis consumption at zero cost). Poorer working memory was significantly associated with lower elasticity (sensitivity of consumption to escalating cost). Lower inhibitory control was indirectly associated with greater cannabis consumption and CUD symptoms through greater Omax and intensity, and poorer working memory was indirectly associated with greater cannabis consumption and CUD symptoms through reduced elasticity. This study provides novel evidence that executive functions are associated with individual differences in cannabis demand. Moreover, these results suggest that cannabis demand could be a mechanism linking poorer executive functioning with heavier cannabis use and CUD, which should be confirmed in future longitudinal studies. (PsycInfo Database Record (c) 2024 APA, all rights reserved).- Published
- 2024
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38. Behavioral and Pharmacokinetic Assessment of Nicotine e-Cigarette Inhalation in Female Rats.
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Roeder NM, Mihalkovic A, Richardson BJ, Penman SL, Novalen M, Hammond N, Eiden R, Khokhar JY, Tyndale RF, and Thanos PK
- Subjects
- Animals, Female, Rats, Administration, Inhalation, Cotinine blood, Cotinine pharmacokinetics, Locomotion drug effects, Dose-Response Relationship, Drug, Nicotine pharmacokinetics, Nicotine blood, Nicotine administration & dosage, Electronic Nicotine Delivery Systems, Behavior, Animal drug effects, Rats, Sprague-Dawley
- Abstract
Introduction: Nicotine and tobacco use remain high both globally and in the United States, contributing to large health care expenditures. With a rise in e-cigarette use, it is important to have clinically relevant models of inhaled nicotine exposure., Aims and Methods: This study aims to extend prior preclinical nicotine inhalation animal data to females and provide both behavior and serum pharmacokinetics. We tested two inhalation doses of nicotine (24 mg/mL and 59 mg/ mL) and compared these to injected doses (0.4 mg/kg and 1 mg/kg). In addition, we assessed locomotor behavior after the same doses. Blood was collected at 10- and 120-minutes post-administration. We assessed nicotine and cotinine serum concentrations by LC-MS/MS., Results: Showed that while nicotine serum concentrations for the respective high and low-dose administrations were similar between both routes of administration, the route had differential effects on locomotor behavior. Inhaled nicotine showed a dose-dependent decrease in locomotor activity while injected doses showed the opposite trend., Conclusions: Our results indicate that the route of administration is an important factor when establishing preclinical models of nicotine exposures. Given that the overall use of e-cigarettes in vulnerable populations is on the rise, our study provides important behavioral and pharmacokinetic information to advance our currently limited understanding of the effects of nicotine vapor exposure., Implications: This study highlights behavioral differences between different routes of administration of similar doses of nicotine. Using a low and high dose of nicotine, we found that nicotine serum concentrations were similar between the different routes of administration. Our results indicate that different routes of administration have opposing effects on locomotor activity. These findings provide important implications for future behavioral models., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2024
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39. Relationships Between the Nicotine Metabolite Ratio and Laboratory Assessments of Smoking Reinforcement and Craving Among Adults in a Smoking Cessation Trial.
- Author
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Cooper RK Jr, Mahoney MC, Tiffany ST, Colder CR, Tyndale RF, and Hawk LW Jr
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- Humans, Female, Male, Adult, Middle Aged, Cues, Saliva chemistry, Saliva metabolism, Cigarette Smoking psychology, Young Adult, Craving, Smoking Cessation psychology, Smoking Cessation methods, Reinforcement, Psychology, Nicotine
- Abstract
Introduction: People who metabolize nicotine more quickly are generally less successful at quitting smoking. However, the mechanisms that link individual differences in the nicotine metabolite ratio (NMR), a phenotypic biomarker of the rate of nicotine clearance, to smoking outcomes are unclear. We tested the hypotheses that higher NMR is associated with greater smoking reinforcement, general craving, and cue-induced cigarette craving in a treatment-seeking sample., Methods: Participants were 252 adults who smoke cigarettes enrolled in a randomized controlled smoking cessation trial (NCT03262662) conducted in Buffalo, New York, USA. Participants completed the Choice Behavior Under Cued Conditions (CBUCC) paradigm, a laboratory choice procedure, ~1 week before the first cessation treatment visit, at which time a saliva sample was collected for NMR assessment. On each CBUCC trial, participants reported cigarette craving during cue presentation (cigarette, water) and spent $0.01-$0.25 for a chance (5%-95%) to sample the cue (one puff, sip), providing measures of smoking reinforcement (spending for cigarettes vs. water), general cigarette craving (averaged across cigarette and water cues), and cue-specific craving (cigarette craving during cigarette vs. water cues)., Results: As observed in prior work, the NMR was significantly higher among White and female participants. As expected, both spending and cigarette craving were significantly greater on cigarette compared to water trials. However, contrary to our hypotheses, higher NMR was not associated with greater smoking reinforcement, general craving, or cue-specific craving., Conclusions: The present data do not support that smoking reinforcement or craving is related to nicotine metabolism among individuals seeking to quit smoking., Implications: Though greater smoking reinforcement, general craving, and cue-specific craving are hypothesized to be linked to faster nicotine metabolism, there was no evidence of such relationships in the present sample of adults seeking to quit smoking. Further research, including replication and consideration of alternate hypotheses, is warranted to elucidate the mechanisms by which the NMR is related to smoking cessation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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40. Factors influencing JUUL e-cigarette nicotine vapour-induced reward, withdrawal, pharmacokinetics and brain connectivity in rats: sex matters.
- Author
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Frie JA, McCunn P, Eed A, Hassan A, Luciani KR, Chen C, Tyndale RF, and Khokhar JY
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- Rats, Male, Female, Animals, Smoking, Brain metabolism, Reward, Nicotine pharmacology, Electronic Nicotine Delivery Systems
- Abstract
Though vaping likely represents a safer alternative to smoking, it is not without risks, many of which are not well understood, especially for vulnerable populations. Here we evaluate the sex- and age-dependent effects of JUUL nicotine vapour in rats. Following passive nicotine vapour exposures (from 59 mg/ml JUUL nicotine pods), rats were evaluated for reward-like behaviour, locomotion, and precipitated withdrawal. Pharmacokinetics of nicotine and its metabolites in brain and plasma and the long-term impact of nicotine vapour exposure on functional magnetic resonance imaging-based brain connectivity were assessed. Adult female rats acquired conditioned place preference (CPP) at a high dose (600 s of exposure) of nicotine vapour while female adolescents, as well as male adults and adolescents did not. Adult and adolescent male rats displayed nicotine vapour-induced precipitated withdrawal and hyperlocomotion, while both adult and adolescent female rats did not. Adult females showed higher venous and arterial plasma and brain nicotine and nicotine metabolite concentrations compared to adult males and adolescent females. Adolescent females showed higher brain nicotine concentration compared to adolescent males. Both network-based statistics and between-component group connectivity analyses uncovered reduced connectivity in nicotine-exposed rats, with a significant group by sex interaction observed in both analyses. The short- and long-term effects of nicotine vapour are affected by sex and age, with distinct behavioural, pharmacokinetic, and altered network connectivity outcomes dependent on these variables., (© 2023. The Author(s).)
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- 2024
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41. Feasibility of precision smoking treatment in a low-income community setting: results of a pilot randomized controlled trial in The Southern Community Cohort Study.
- Author
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Lee SS, Senft Everson N, Sanderson M, Selove R, Blot WJ, King S, Gilliam K, Kundu S, Steinwandel M, Sternlieb SJ, Cai Q, Warren Andersen S, Friedman DL, Connors Kelly E, Fadden MK, Freiberg MS, Wells QS, Canedo J, Tyndale RF, Young RP, Hopkins RJ, and Tindle HA
- Subjects
- Aged, Humans, Cohort Studies, Feasibility Studies, Pilot Projects, Male, Female, Smoking epidemiology, Smoking therapy, Tobacco Smoking
- Abstract
Background: The feasibility of precision smoking treatment in socioeconomically disadvantaged communities has not been studied., Methods: Participants in the Southern Community Cohort Study who smoked daily were invited to join a pilot randomized controlled trial of three smoking cessation interventions: guideline-based care (GBC), GBC plus nicotine metabolism-informed care (MIC), and GBC plus counseling guided by a polygenic risk score (PRS) for lung cancer. Feasibility was assessed by rates of study enrollment, engagement, and retention, targeting > 70% for each. Using logistic regression, we also assessed whether feasibility varied by age, sex, race, income, education, and attitudes toward precision smoking treatment., Results: Of 92 eligible individuals (79.3% Black; 68.2% with household income < $15,000), 67 (72.8%; 95% CI 63.0-80.9%) enrolled and were randomized. Of these, 58 (86.6%; 95% CI 76.4-92.8%) engaged with the intervention, and of these engaged participants, 43 (74.1%; 95% CI 61.6-83.7%) were retained at 6-month follow-up. Conditional on enrollment, older age was associated with lower engagement (OR 0.83, 95% CI 0.73-0.95, p = 0.008). Conditional on engagement, retention was significantly lower in the PRS arm than in the GBC arm (OR 0.18, 95% CI 0.03-1.00, p = 0.050). No other selection effects were observed., Conclusions: Genetically informed precision smoking cessation interventions are feasible in socioeconomically disadvantaged communities, exhibiting high enrollment, engagement, and retention irrespective of race, sex, income, education, or attitudes toward precision smoking treatment. Future smoking cessation interventions in this population should take steps to engage older people and to sustain participation in interventions that include genetic risk counseling., Trial Registration: ClinicalTrials.gov No. NCT03521141, Registered 27 April 2018, https://www., Clinicaltrials: gov/study/NCT03521141., (© 2024. The Author(s).)
- Published
- 2024
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42. Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension.
- Author
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Langlois AWR, Pouget JG, Knight J, Chenoweth MJ, and Tyndale RF
- Subjects
- Humans, Female, Biological Specimen Banks, UK Biobank, Nicotine, Genotype, Cytochrome P-450 CYP2A6 genetics, Lung Neoplasms epidemiology, Lung Neoplasms genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
- Abstract
CYP2A6 is a polymorphic enzyme that inactivates nicotine; structural variants (SVs) include gene deletions and hybrids with the neighboring pseudogene CYP2A7. Two studies found that CYP2A7 deletions were associated with ovarian cancer risk. Using their methodology, we aimed to characterize CYP2A6 SVs (which may be misidentified by prediction software as CYP2A7 SVs), then assess CYP2A6 SV-associated risk for ovarian cancer, and extend analyses to lung cancer. An updated reference panel was created to impute CYP2A6 SVs from UK Biobank array data. Logistic regression models analyzed the association between CYP2A6 SVs and cancer risk, adjusting for covariates. Software-predicted CYP2A7 deletions were concordant with known CYP2A6 SVs. Deleterious CYP2A6 SVs were not associated with ovarian cancer (OR = 1.06; 95% CI: 0.80-1.37; p = 0.7) but did reduce the risk of lung cancer (OR = 0.44; 95% CI: 0.29-0.64; p < 0.0001), and a lung cancer subtype. Replication of known lung cancer associations indicates the validity of array-based SV analyses., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2024
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43. Pharmacogenetics of Biochemically Verified Abstinence in an Opioid Agonist Therapy Randomized Clinical Trial of Methadone and Buprenorphine/Naloxone.
- Author
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Kazi I, Chenoweth MJ, Jutras-Aswad D, Ahamad K, Socias ME, Le Foll B, and Tyndale RF
- Subjects
- Humans, Methadone therapeutic use, Analgesics, Opioid adverse effects, Pharmacogenetics, Cytochrome P-450 CYP3A, Narcotic Antagonists adverse effects, Buprenorphine, Naloxone Drug Combination therapeutic use, Opiate Substitution Treatment, Buprenorphine therapeutic use, Opioid-Related Disorders drug therapy, Opioid-Related Disorders genetics
- Abstract
Methadone and buprenorphine/naloxone are opioid agonist therapies for opioid use disorder treatment. Genetic factors contribute to individual differences in opioid response; however, little is known regarding genetic associations with clinical outcomes in people receiving opioid agonist therapies. Participants diagnosed with opioid use disorder, principally consisting of prescription opioids (licit or illicit), were randomized to methadone or buprenorphine/naloxone for 24 weeks of daily treatment (NCT03033732). Urine was collected at 12 biweekly study visits and analyzed for non-treatment opioids. Variants in genes involved in methadone metabolism (CYP2B6, CYP2C19, and CYP3A4), buprenorphine metabolism (CYP3A4 and UGT2B7), and μ-opioid receptor function (OPRM1) were genotyped and analyzed for their association with the number of non-treatment opioid-free urine screens. Primary analyses focused on the last 12 weeks (6 study visits, post-titration) of treatment among those reporting White ethnicity. Additional sensitivity and exploratory analyses were performed. Among methadone-treated participants (n = 52), the OPRM1 rs1799971 AA genotype (vs. G-genotypes, i.e., having one or two G alleles) was associated with greater opioid-free urine screens (incidence rate ratio = 5.24, 95% confidence interval (CI) = 2.43-11.26, P = 0.000023); longitudinal analyses showed a significant genotype-by-time interaction over the full 24 weeks (12 study visits, β = -0.28, 95% CI = -0.45 to -0.11, P = 0.0015). Exploratory analyses suggest an OPRM1 rs1799971 genotype effect on retention. No evidence of association was found between other genetic variants, including in metabolic variants, and non-treatment opioid-free urine screens in the methadone or buprenorphine/naloxone arms. Those with the OPRM1 rs1799971 G-genotypes may have a poorer response to methadone maintenance treatment, an effect that persisted through 24 weeks of treatment., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2024
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44. CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study.
- Author
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Giratallah H, Chenoweth MJ, Pouget JG, El-Boraie A, Alsaafin A, Lerman C, Knight J, and Tyndale RF
- Subjects
- Humans, Nicotine genetics, Mendelian Randomization Analysis, Smoking adverse effects, Smoking genetics, Cytochrome P-450 CYP2A6 genetics, Cytochrome P-450 CYP2A6 metabolism, Lung Neoplasms genetics, Respiratory Tract Diseases complications
- Abstract
CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887). Causal effects of phenotypic CYP2A6 activity (measured as the nicotine metabolite ratio: 3'-hydroxycotinine/cotinine) on the phenome-wide significant (PWS) signals were then estimated in two-sample Mendelian Randomization using the wGRS as the instrument. Time-to-diagnosis age was compared between faster versus slower CYP2A6 metabolizers for the PWS signals in survival analyses. In the total sample, six PWS signals were identified: two lung cancers and four obstructive respiratory diseases PheCodes, where faster CYP2A6 activity was associated with greater disease risk (Ps < 1 × 10-6). A significant CYP2A6-by-smoking status interaction was found (Psinteraction < 0.05); in current smokers, the same six PWS signals were found as identified in the total group, whereas no PWS signals were found in former or never smokers. In the total sample and current smokers, CYP2A6 activity causal estimates on the six PWS signals were significant in Mendelian Randomization (Ps < 5 × 10-5). Additionally, faster CYP2A6 metabolizer status was associated with younger age of disease diagnosis for the six PWS signals (Ps < 5 × 10-4, in current smokers). These findings support a role for faster CYP2A6 activity as a causal risk factor for lung cancers and obstructive respiratory diseases among current smokers, and a younger onset of these diseases. This research utilized the UK Biobank Resource., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
- Full Text
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45. Identification of Sociodemographic, Clinical, and Genetic Factors to Aid Alaska Native and American Indian People to Successfully Quit Smoking.
- Author
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Avey JP, Schaefer KR, Noonan CJ, Trinidad SB, Muller CJ, Claw KG, Dillard DA, Todd MR, Beans JA, Tyndale RF, Robinson RF, and Thummel KE
- Subjects
- Adult, Humans, American Indian or Alaska Native genetics, Nicotine therapeutic use, Nicotinic Agonists therapeutic use, Retrospective Studies, Smoking drug therapy, Tobacco Use Cessation Devices, Smoking Cessation methods, Sociodemographic Factors
- Abstract
Introduction: Alaska Native and American Indian (ANAI) people have a smoking prevalence of 23%. Nicotine metabolite ratio (NMR) and genetic testing may enable tailored selection of tobacco cessation medication., Aims and Methods: The purpose of this study was to evaluate the relative contributions of NMR, cessation medication, demographics, and tobacco use history to cessation. Participants were recruited into an observational cohort study consisting of a baseline visit prior to their quit date and 6-week follow-up. Demographic and tobacco use surveys and blood, urine, and breath samples were collected at each visit. Electronic health records were queried for cessation medications. NMR was categorized into slow or normal nicotine metabolism phenotypes (<0.31 and ≥ 0.31, respectively). The main outcome was cessation at 6 weeks. Analyses consisted of descriptive statistics, medication and phenotype concordance, and estimates of relative risk (RR) of quitting., Results: We enrolled 151 ANAI adults who smoked cigarettes daily. Two-thirds had normal nicotine metabolism phenotype. Retrospective medication and phenotype concordance was 39%. The overall quit rate was 25%. No demographic factors or tobacco use history were associated with quit success. Varenicline and bupropion increased the likelihood of quitting (RR = 2.93 [1.42, 6.03] and RR = 2.52 [1.12, 5.64], respectively) compared to nicotine replacement therapy. Non-optimal medication and phenotype concordance decreased likelihood of quit success (RR = 0.44 [0.22, 0.91]) compared to optimal concordance., Conclusions: This exploratory study found associations between quit success and tobacco cessation medication as well as medication and phenotype concordance. Additional research is needed to assess use of NMR for treatment selection among ANAI people., Implications: These results broadly support additional community-engaged research to improve medication and phenotype concordance in tribal health settings. Such future research on implementing meditcation and phenotype concordance holds promise to improve expectations, quit success, and health outcomes amongst individuals attempting to quit smoking., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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46. Nicotine Metabolite Ratio Decreases After Switching Off Efavirenz-Based Therapy in People With HIV Who Smoke.
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Medaglio D, Bilker WB, Han X, Merlin JS, Plankey M, Martin J, Crane HM, Hojat LS, Bamford L, Schnoll R, Tyndale RF, Ashare RL, and Gross R
- Subjects
- Humans, Nicotine metabolism, Cotinine, Cigarette Smoking, HIV Infections drug therapy
- Abstract
Rates of cigarette smoking in people with HIV (PWH) are two to three times higher than in people without HIV. Nicotine is metabolized by CYP2A6 and the nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is a measure of nicotine clearance. Higher NMR has been observed in PWH and is associated with lower quit rates. Efavirenz, a mainstay antiretroviral therapy (ART) globally, partially upregulates its own metabolism through CYP2A6. We hypothesized that efavirenz also upregulates nicotine metabolism by CYP2A6, resulting in a higher NMR, and switching to non-efavirenz ART would decrease the NMR, potentially leading to improved quit rates. We compared the NMR during and after efavirenz use among PWH in a longitudinal, multisite cohort. Eligibility criteria included: (i) active cigarette smoking, (ii) ART switched from efavirenz-based to non-efavirenz-based regimen, (iii) plasma available at pre- and post-ART switch, and (iv) viral suppression during study period. Plasma cotinine and 3-hydroxycotinine were measured by liquid chromatography-tandem mass spectrometry. T-tests compared the NMR on and off efavirenz. Samples were collected between 2010 and 2019 in 72 PWH. The mean NMR difference after switching to a non-efavirenz-based regimen was -0.24 (SD: 0.37, P < 0.001); 44 PWH had at least a 0.1 decrease in NMR. Effect modification by race was present; Black PWH had a larger mean decrease. Our findings suggest that previously observed higher NMR among PWH may be due to direct pharmacologic effects of ART. Assessing the effect of ART on the NMR suggests that avoiding nicotine metabolism inducers could potentially increase quit rates., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)
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- 2024
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47. Smoking, tobacco dependence, and neurometabolites in the dorsal anterior cingulate cortex.
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O'Neill J, Diaz MP, Alger JR, Pochon JB, Ghahremani D, Dean AC, Tyndale RF, Petersen N, Marohnic S, Karaiskaki A, and London ED
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- Adult, Humans, Gyrus Cinguli metabolism, Creatine metabolism, Neuroinflammatory Diseases, Glutamic Acid metabolism, Choline, Smoking, Tobacco Use Disorder
- Abstract
Cigarette smoking has a major impact on global health and morbidity, and positron emission tomographic research has provided evidence for reduced inflammation in the human brain associated with cigarette smoking. Given the consequences of inflammatory dysfunction for health, the question of whether cigarette smoking affects neuroinflammation warrants further investigation. The goal of this project therefore was to validate and extend evidence of hypoinflammation related to smoking, and to examine the potential contribution of inflammation to clinical features of smoking. Using magnetic resonance spectroscopy, we measured levels of neurometabolites that are putative neuroinflammatory markers. N-acetyl compounds (N-acetylaspartate + N-acetylaspartylglutamate), glutamate, creatine, choline-compounds (phosphocholine + glycerophosphocholine), and myo-inositol, have all been linked to neuroinflammation, but they have not been examined as such with respect to smoking. We tested whether people who smoke cigarettes have brain levels of these metabolites consistent with decreased neuroinflammation, and whether clinical features of smoking are associated with levels of these metabolites. The dorsal anterior cingulate cortex was chosen as the region-of-interest because of previous evidence linking it to smoking and related states. Fifty-four adults who smoked daily maintained overnight smoking abstinence before testing and were compared with 37 nonsmoking participants. Among the smoking participants, we tested for associations of metabolite levels with tobacco dependence, smoking history, craving, and withdrawal. Levels of N-acetyl compounds and glutamate were higher, whereas levels of creatine and choline compounds were lower in the smoking group as compared with the nonsmoking group. In the smoking group, glutamate and creatine levels correlated negatively with tobacco dependence, and creatine correlated negatively with lifetime smoking, but none of the metabolite levels correlated with craving or withdrawal. The findings indicate a link between smoking and a hypoinflammatory state in the brain, specifically in the dorsal anterior cingulate cortex. Smoking may thereby increase vulnerability to infection and brain injury., (© 2023. The Author(s).)
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- 2023
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48. Circulating Endocannabinoids and N-Acylethanolamines in Individuals with Cannabis Use Disorder-Preliminary Findings.
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Boachie N, Gaudette E, Bazinet RP, Lin L, Tyndale RF, Mansouri E, Huestis MA, Tong J, Le Foll B, Kish SJ, George TP, and Boileau I
- Abstract
Background: Endocannabinoids and related N-acylethanolamines (NAEs) are bioactive lipids with important physiological functions and putative roles in mental health and addictions. Although chronic cannabis use is associated with endocannabinoid system changes, the status of circulating endocannabinoids and related NAEs in people with cannabis use disorder (CUD) is uncertain., Methods: Eleven individuals with CUD and 54 healthy non-cannabis using control participants (HC) provided plasma for measurement by high-performance liquid chromatography-mass spectrometry of endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and related NAE fatty acids (N-docosahexaenoylethanolamine (DHEA) and N-oleoylethanolamine (OEA)). Participants were genotyped for the functional gene variant of FAAH (rs324420, C385A) which may affect concentrations of AEA as well as other NAEs (OEA, DHEA)., Results: In overnight abstinent CUD, AEA, OEA and DHEA concentrations were significantly higher (31-40%; p < 0.05) and concentrations of the endocannabinoid 2-AG were marginally elevated (55%, p = 0.13) relative to HC. There were no significant correlations between endocannabinoids/NAE concentrations and cannabis analytes, self-reported cannabis use frequency or withdrawal symptoms. DHEA concentration was inversely related with marijuana craving ( r = -0.86; p = 0.001). Genotype had no significant effect on plasma endocannabinoids/NAE concentrations., Conclusions: Our preliminary findings, requiring replication, might suggest that activity of the endocannabinoid system is elevated in chronic cannabis users. It is unclear whether this elevation is a compensatory response or a predating state. Studies examining endocannabinoids and NAEs during prolonged abstinence as well as the potential role of DHEA in craving are warranted.
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- 2023
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49. Efficacy of insula deep repetitive transcranial magnetic stimulation combined with varenicline for smoking cessation: A randomized, double-blind, sham controlled trial.
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Ibrahim C, Tang VM, Blumberger DM, Malik S, Tyndale RF, Trevizol AP, Barr MS, Daskalakis ZJ, Zangen A, and Le Foll B
- Subjects
- Humans, Varenicline therapeutic use, Transcranial Magnetic Stimulation, Insular Cortex, Double-Blind Method, Treatment Outcome, Smoking Cessation, Tobacco Use Disorder therapy
- Abstract
Background: Current smoking cessation treatments are limited in terms of efficacy, particularly with regards to long term abstinence. There is a large amount of evidence implicating the insula in nicotine addiction., Objective: To examine the efficacy of bilateral repetitive transcranial magnetic stimulation (rTMS) directed to the insular cortex with the H11 coil, relative to sham stimulation, on smoking abstinence and smoking outcomes in smokers who are receiving standard varenicline treatment., Methods: This randomized, double-blind, sham controlled trial recruited 42 participants who were randomized to receive either active (n = 24) or sham (n = 18) high frequency rTMS directed to the insula (4 weeks), while receiving varenicline treatment (12 weeks). The primary outcome was 7-day point prevalence abstinence at the end of 12 weeks., Results: Smokers in the active group had significantly higher abstinence rates than those in the sham group (82.4% vs. 30.7%, p = 0.013) at the end of treatment (Week 12). Secondary outcome measures of abstinence rate at the end of rTMS treatment (Week 4), abstinence rate at 6 months, and smoking outcomes (e.g., craving, withdrawal) showed no significant differences between groups. No differences were found in adverse events reported between the groups., Conclusion: This study provides evidence of the potential benefit of having a combined treatment for smoking cessation using insula rTMS with the H11 coil and varenicline. Maintenance rTMS sessions and continuation of varenicline for those in abstinence may induce longer-term effects and should be considered in future studies., Competing Interests: Declaration of competing interest BLF has obtained funding from Pfizer Inc. (GRAND Awards, including salary support) for investigator-initiated projects. BLF has obtained funding from Indivior for a clinical trial sponsored by Indivior. BLF has in-kind donations of cannabis products from Aurora Cannabis Enterprises Inc. and study medication donations from Pfizer Inc. (varenicline for smoking cessation) and Bioprojet Pharma. He was also provided a coil for a Transcranial magnetic stimulation (TMS) study from Brainsway. BLF has obtained industry funding from Canopy Growth Corporation (through research grants handled by the Centre for Addiction and Mental Health and the University of Toronto), Bioprojet Pharma, Alcohol Countermeasure Systems (ACS), Alkermes and Universal Ibogaine. Lastly, BLF has received in kind donations of nabiximols from GW Pharmaceuticals for past studies funded by CIHR and NIH. He has participated in a session of a National Advisory Board Meeting (Emerging Trends BUP-XR) for Indivior Canada and is part of Steering Board for a clinical trial for Indivior. He has been consultant for Shinogi. He is supported by CAMH, Waypoint Centre for Mental Health Care, a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto and a Chair in Addiction Psychiatry from the department of Psychiatry of University of Toronto. MSB has received funding from the Brain and Behavior Research Foundation (Formerly NARSAD) and is a full-time employee at Otsuka Canada Pharmaceutical Inc. DMB receives research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health – US (NIH), Brain Canada Foundation and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he was the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen. He has participated in an advisory board for Welcony Inc. VMT receives research support through the Brain & Behavior Research Foundation, the Physician Services Incorporated Foundation, Research in Addiction Medicine Scholars (RAMS) Program (R25DA033211) from the National Institute on Drug Abuse, and the Labatt Family Network for Research on the Biology of Depression. ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc and industry-initiated trials through Magnus Inc. He also currently serves on the scientific advisory board for Brainsway Inc. His work has been supported by the National Institutes of Mental Health (NIMH), the Canadian Institutes of Health Research (CIHR), Brain Canada and the Temerty Family, Grant and Kreutzcamp Family Foundations. AZ is an inventor of Deep TMS coils and has financial interest in BrainsWay which produces and markets these coils. CI, SM, APT, RFT have no conflicts of interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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50. Association Between Fatty Acid Amide Hydrolase and Alcohol Response Phenotypes: A Positron Emission Tomography Imaging Study With [ 11 C]CURB in Heavy-Drinking Youth.
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Best LM, Hendershot CS, Buckman JF, Jagasar S, McPhee MD, Muzumdar N, Tyndale RF, Houle S, Logan R, Sanches M, Kish SJ, Le Foll B, and Boileau I
- Subjects
- Humans, Positron-Emission Tomography methods, Endocannabinoids metabolism, Ethanol, Amidohydrolases genetics, Amidohydrolases metabolism, Phenotype, Alcoholism diagnostic imaging
- Abstract
Background: Reductions in fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid anandamide, may play a role in drinking behavior and risk for alcohol use disorder. We tested the hypotheses that lower brain FAAH levels in heavy-drinking youth are related to increased alcohol intake, hazardous drinking, and differential response to alcohol., Methods: FAAH levels in the striatum, prefrontal cortex, and whole brain were determined using positron emission tomography imaging of [
11 C]CURB in heavy-drinking youth (N = 31; 19-25 years of age). C385A FAAH genotype (rs324420) was determined. Behavioral (n = 29) and cardiovascular (n = 22) responses to alcohol were measured during a controlled intravenous alcohol infusion., Results: Lower [11 C]CURB binding was not significantly related to frequency of use but was positively associated with hazardous drinking and reduced sensitivity to the negative effects of alcohol. During alcohol infusion, lower [11 C]CURB binding related to greater self-reported stimulation and urges and lower sedation (p < .05). Lower heart rate variability was related to both greater alcohol-induced stimulation and lower [11 C]CURB binding (p < .05). Family history of alcohol use disorder (n = 14) did not relate to [11 C]CURB binding., Conclusions: In line with preclinical studies, lower FAAH in the brain was related to a dampened response to the negative, impairing effects of alcohol, increased drinking urges, and alcohol-induced arousal. Lower FAAH might alter positive or negative effects of alcohol and increase urges to drink, thereby contributing to the addiction process. Determining whether FAAH influences motivation to drink through increased positive/arousing effects of alcohol or greater tolerance should be investigated., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
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