Cytisinicline for Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.

Can Treatment Support Mitigate Nicotine Metabolism-Based Disparities in Smoking Abstinence? Secondary Analysis of the Helping HAND 4 Trial.

INTRODUCTION: The nicotine metabolite ratio (NMR), a biomarker of CYP2A6-mediated nicotine metabolism, predicts the efficacy of nicotine replacement therapy (NRT), with fast metabolizers benefiting less than slow metabolizers. Whether treatment support to optimize NRT use (henceforth "treatment support") modifies this pharmacogenetic relationship is unknown. METHODS: Hospitalized adult daily smokers were assigned to one of two post-discharge smoking cessation interventions offering NRT and counseling: (1) Transitional Tobacco Care Management, which delivered enhanced treatment support via free combination NRT at discharge and automated counseling, and (2) a quitline-based approach representing usual care (UC). The primary outcome was biochemically verified 7-day point prevalence abstinence 6 months after discharge. Secondary outcomes were the use of NRT and counseling during the 3-month intervention period. Logistic regression models tested for interactions between NMR and intervention, controlling for sex, race, alcohol use, and BMI. RESULTS: Participants (N = 321) were classified as slow (n = 80) or fast (n = 241) metabolizers relative to the first quartile of NMR (0.012-0.219 vs. 0.221-3.455, respectively). Under UC, fast (vs. slow) metabolizers had lower odds of abstinence at 6 months (aOR 0.35, 95% CI 0.13-0.95) and similar odds of NRT and counseling use. Compared to UC, enhanced treatment support increased abstinence (aOR 2.13, 95% CI 0.98-4.64) and use of combination NRT (aOR 4.62, 95% CI 2.57-8.31) in fast metabolizers, while reducing abstinence in slow metabolizers (aOR 0.21, 95% CI 0.05-0.87; NMR-by-intervention interaction p = .004). CONCLUSIONS: Treatment support increased abstinence and optimal use of NRT among fast nicotine metabolizers, thereby mitigating the gap in abstinence between fast and slow metabolizers. IMPLICATIONS: In this secondary analysis of two smoking cessation interventions for recently hospitalized smokers, fast nicotine metabolizers quit at lower rates than slow metabolizers, but providing fast metabolizers with enhanced treatment support doubled the odds of quitting in this group and mitigated the disparity in abstinence between fast and slow metabolizers. If validated, these findings could lead to personalized approaches to smoking cessation treatment that improve outcomes by targeting treatment support to those who need it most.

Varenicline serves as the training stimulus in the drug-discriminated goal-tracking task with rats: initial evaluation of potential neuropharmacological processes.

Varenicline (Chantix) is an FDA-approved smoking cessation aid that is pharmacologically similar to nicotine, the primary addictive component found within tobacco. In support of this similarity, previous drug discrimination research in rats has reported that the internal or interoceptive stimulus effects of nicotine and varenicline share stimulus elements. Those shared elements appear to be mediated, in part, by overlapping action at alpha4beta2-containing nicotinic acetylcholine receptors (nAChRs). The research supporting this conclusion, however, has only used nicotine, and not varenicline, as the training drug. Accordingly, we used the discriminated goal tracking (DGT) task in which 1 mg/kg varenicline signaled intermittent access to sucrose. On separate intermixed saline days, sucrose was not available. Rats acquired the discrimination as measured by a differential increase in dipper entries (goal tracking) evoked by varenicline. These rats then received a series of tests with several doses of varenicline, nicotine, nornicotine (a metabolite of nicotine and tobacco alkaloid), sazetidine-A (a partial alpha4beta2 agonist), PHA-543613 (an alpha7 agonist), and bupropion (a norepinephrine and dopamine reuptake inhibitor). Control of goal tracking by varenicline was dose-dependent. Nicotine and nornicotine evoked responding comparable to the varenicline training dose indicating full substitution. Sazetidine-A partially substituted for the varenicline stimulus, whereas bupropion and PHA-543613 evoked little to no varenicline-like responding. These findings indicate that varenicline can serve as the training stimulus in the DGT task. Further, stimulus control of varenicline in the DGT task is driven by its partial agonist activity at alpha4beta2-containing nAChRs. The use of this approach could lead to a better understanding of the pharmacological action of varenicline and help guide treatment geared towards tobacco cessation through a more targeted development of novel synthetically designed, subunit-specific pharmacological interventions.

Effect of Varenicline Added to Counseling on Smoking Cessation Among African American Daily Smokers: The Kick It at Swope IV Randomized Clinical Trial.

Importance: African American smokers have among the highest rates of tobacco-attributable morbidity and mortality in the US, and effective treatment is needed for all smoking levels. Objectives: To evaluate the efficacy of varenicline vs placebo among African American adults who are light, moderate, and heavy daily smokers. Design, Setting, and Participants: The Kick It at Swope IV (KIS-IV) trial was a randomized, double-blind, placebo-controlled clinical trial conducted at a federally qualified health center in Kansas City. A total of 500 African American adults who were daily smokers of all smoking levels were enrolled from June 2015 to December 2017; final follow-up was completed in June 2018. Interventions: Participants were provided 6 sessions of culturally relevant individualized counseling and were randomized (in a 3:2 ratio) to receive varenicline (1 mg twice daily; n = 300) or placebo (n = 200) for 12 weeks. Randomization was stratified by sex and smoking level (1-10 cigarettes/d [light smokers] or >10 cigarettes/d [moderate to heavy smokers]). Main Outcomes and Measures: The primary outcome was salivary cotinine-verified 7-day point prevalence smoking abstinence at week 26. The secondary outcome was 7-day point prevalence smoking abstinence at week 12, with subgroup analyses for light smokers (1-10 cigarettes/d) and moderate to heavy smokers (>10 cigarettes/d). Results: Among 500 participants who were randomized and completed the baseline visit (mean age, 52 years; 262 [52%] women; 260 [52%] light smokers; 429 [86%] menthol users), 441 (88%) completed the trial. Treating those lost to follow-up as smokers, participants receiving varenicline were significantly more likely than those receiving placebo to be abstinent at week 26 (15.7% vs 6.5%; difference, 9.2% [95% CI, 3.8%-14.5%]; odds ratio [OR], 2.7 [95% CI, 1.4-5.1]; P = .002). The varenicline group also demonstrated greater abstinence than the placebo group at the end of treatment week 12 (18.7% vs 7.0%; difference, 11.7% [95% CI, 6.0%-17.7%]; OR, 3.0 [95% CI, 1.7-5.6]; P < .001). Smoking abstinence at week 12 was significantly greater for individuals receiving varenicline compared with placebo among light smokers (22.1% vs 8.5%; difference, 13.6% [95% CI, 5.2%-22.0%]; OR, 3.0 [95% CI, 1.4-6.7]; P = .004) and among moderate to heavy smokers (15.1% vs 5.3%; difference, 9.8% [95% CI, 2.4%-17.2%]; OR, 3.1 [95% CI, 1.1-8.6]; P = .02), with no significant smoking level × treatment interaction (P = .96). Medication adverse events were generally comparable between treatment groups, with nausea reported more frequently in the varenicline group (163 of 293 [55.6%]) than the placebo group (90 of 196 [45.9%]). Conclusions and Relevance: Among African American adults who are daily smokers, varenicline added to counseling resulted in a statistically significant improvement in the rates of 7-day point prevalence smoking abstinence at week 26 compared with counseling and placebo. The findings support the use of varenicline in addition to counseling for tobacco use treatment among African American adults who are daily smokers. Trial Registration: ClinicalTrials.gov Identifier: NCT02360631.

Pharmaceutical interventions: A solution to stop smoking

Background: Smoking has become a worldwide problem and the more problematic is when the youth of any country is highly involved in consuming tobacco that is dangerous for the human being. The Indian youth is involved in smoking-like activities that are dangerous for them. Objectives: To analyze the role of new treatment ways including nicotine gum, nicotine patch, and nicotine replacement therapy backed by pharmaceutical interventions to eliminate smoking from Indian society. Method: The hypotheses of this study are formed on the basis of previous studies and the identification of gap in practices. This study is based on the cross-sectional data that was collected with the help of a questionnaire based on a five-point Likert scale from the Indian pharma industry people. The sample size for this study was 340 with a response rate of 50%. Results: In this study, 179 valid questionnaires were collected back from the respondents, and according to the results, nicotine gum, nicotine patch, and nicotine replacement therapies have a significant (p<0.05) effect on smoker attitudes. Conclusion: This study concludes that pharmaceutical interventions are critical to stopping the smoking habit in Indian society, and this contribution is providing a solution to stop smoking by affecting the smoker’s attitude and smoking behavior. (AU)

Online biological sample preparation with restricted access hybrid carbon nanotubes for determination of anti-smoking drugs.

Untreated samples were injected directly into a column switching system, an online SPE technique, using an extraction column packed with restricted access hybrid carbon nanotubes (RAHCNTs), a novel type of restricted access material, in an ultra-high performance liquid chromatography, coupled to a mass spectrometer (UHPLC-MS/MS). The synthesis of used restricted access material was relatively simple, quick, and reproducible, and had a high material yield. Compared to its predecessor, which is covered with bovine serum albumin (Restricted Access Carbon Nanotubes-RACNTs), RAHCNTs have improved performance when used for the analysis of organic compounds. These molecules have a greater adsorption capacity due to the insertion of hydrophilic monomers (tetraethyl orthosilicate (TEOS), 3-(trimethoxysilyl)propyl methacrylate (MPS), glycerol dimethacrylate (GDMA), and hydroxyethyl methacrylate (HEMA)) in the external layer. In addition, the formation of the hybrid material provides greater chemical and thermal stability, supporting wide pH and temperature ranges, and high concentrations of acidic and basic solutions. It also supports high proportions of organic solvents in the medium. Another significant advantage of the material is its longer lifetime, as it can be reused for approximately 500 analytical cycles without any loss of efficiency, versus 300 for RACNTs. In the method developed to determine anti-smoking drugs (varenicline and bupropion) simultaneously, as well as nicotine and some of their metabolites in human blood serum, the RAHCNTs were capable of retaining the analytes efficiently, whereas the macromolecules were excluded (almost 100%). The method was linear for all the determined analytes (coefficients of determination higher than 0.99), with limits of detection and quantification ranging from 0.6 to 2.5 µg L-1 and from 1.0 to 5.0 µg L-1, respectively. High extraction recovery values were obtained (higher than 88%), as well as inter and intra-assay accuracy and precision results that are in accordance with values recommended by the FDA. The method is promising for therapeutic monitoring and new personalized strategies for patients under antismoking treatment, using a small sample volume (100 µL). In addition, RAHCNTs are capable of simultaneously extracting analytes with very different physical-chemical characteristics.

Treatment of Tobacco Smoking: A Review.

IMPORTANCE: More deaths in the US are attributed to cigarette smoking each year than to any other preventable cause. Approximately 34 million people and an estimated 14% of adults in the US smoke cigarettes. If they stopped smoking, they could reduce their risk of tobacco-related morbidity and mortality and potentially gain up to 10 years of life. OBSERVATIONS: Tobacco smoking is a chronic disorder maintained by physical nicotine dependence and learned behaviors. Approximately 70% of people who smoke cigarettes want to quit smoking. However, individuals who attempt to quit smoking make an average of approximately 6 quit attempts before achieving long-term abstinence. Both behavioral counseling and pharmacotherapy while using nicotine replacement therapy (NRT) products, varenicline, or bupropion are effective treatments when used individually, but they are most effective when combined. In a meta-analysis including 19 488 people who smoked cigarettes, the combination of medication and behavioral counseling was associated with a quit rate of 15.2% over 6 months compared with a quit rate of 8.6% with brief advice or usual care. The EAGLES trial, a randomized double-blind clinical trial of 8144 people who smoked, directly compared the efficacy and safety of varenicline, bupropion, nicotine patch, and placebo and found a significantly higher 6-month quit rate for varenicline (21.8%) than for bupropion (16.2%) and the nicotine patch (15.7%). Each therapy was more effective than placebo (9.4%). Combining a nicotine patch with other NRT products is more effective than use of a single NRT product. Combining drugs with different mechanisms of action, such as varenicline and NRT, has increased quit rates in some studies compared with use of a single product. Brief or intensive behavioral support can be delivered effectively in person or by telephone, text messages, or the internet. The combination of a clinician's brief advice to quit and assistance to obtain tobacco cessation treatment is effective when routinely administered to tobacco users in virtually all health care settings. CONCLUSIONS AND RELEVANCE: Approximately 34 million people in the US smoke cigarettes and could potentially gain up to a decade of life expectancy by stopping smoking. First-line therapy should include both pharmacotherapy and behavioral support, with varenicline or combination NRT as preferred initial interventions.

Tobacco Use Disorder.

Tobacco use disorder is highly prevalent; more than a billion individuals use tobacco worldwide. Popular views on the addictive potential of tobacco often underestimate the complex neural adaptations that underpin continued use. Although sometimes trivialized as a minor substance, effects of nicotine on behavior lead to profound morbidity over a lifetime of exposure. Innovations in processing have led to potent forms of tobacco and delivery devices. Proactive treatment strategies focus on pharmacotherapeutic interventions. Innovations on the horizon hold promise to help clinicians address this problem in a phenotypically tailored manner. Efforts are needed to prevent tobacco use for future generations.

Trends in Incident Varenicline Prescribing Among Veterans Following the US Food and Drug Administration Drug Safety Warnings.

Objective: To evaluate national trends in incident varenicline and nicotine replacement therapy (NRT) prescribing among Department of Veterans Affairs (VA) beneficiaries before and after US Food and Drug Administration (FDA) warnings regarding neuropsychiatric side effects with varenicline use.Methods: All adult VA patients identified as smokers from 2007 to 2019 (N = 3,600,947) were determined and monthly counts of new varenicline and NRT users were calculated. An interrupted time-series analysis estimated the effect of the FDA warnings on varenicline and NRT prescribing overall and among Veterans with and without mental health disorders.Results: The incident use rate of varenicline decreased from a peak of 6.2 per 1,000 veteran smokers in October 2007 to 1.0 by July 2009 following the first FDA warning (pre-warning monthly slope = -0.27; P = .03). New NRT use increased from 10.7 per 1,000 veteran smokers in October 2007 to a peak of 12.6 per 1,000 in July 2009 (slope change = 0.71; P = .01), suggesting potential substitution. Following removal of the FDA boxed warning in December 2016, varenicline prescribing increased but did not return to pre-warning levels by December 2019. Among veterans with and without mental health disorders, varenicline use decreased 90% and 88%, respectively, following the first FDA warning, and both groups had comparable rates of new NRT use.Conclusions: Following the first FDA warning, incident use of varenicline declined significantly among veterans both with and without mental health disorders. Despite removal of the FDA boxed warning in December 2016, new use of varenicline had not returned to pre-warning levels 3 years following the removal.

Comparison of Cardiovascular Safety for Smoking Cessation Pharmacotherapies in a Population-Based Cohort in Australia.

Importance: Although concerns exist regarding a potential increased risk of cardiovascular events for smoking cessation pharmacotherapies, there is general consensus that any increased risk associated with their use would be outweighed by the benefits of smoking cessation; thus, clinical guidelines recommend that such pharmacotherapies be offered to everyone who wants to quit smoking. In the interest of minimizing risk to patients, prescribers need evidence indicating how these pharmacotherapies compare with one another in terms of cardiovascular safety. Objective: To compare the risk of major adverse cardiovascular events (MACE) among individuals initiating varenicline, nicotine replacement therapy (NRT) patches, or bupropion. Design, Setting, and Participants: This retrospective, population-based cohort study using linked pharmaceutical dispensing, hospital admissions, and death data was conducted in New South Wales, Australia. Participants included adults who were dispensed a prescription smoking cessation pharmacotherapy between 2008 and 2015 or between 2011 and 2015, depending on the availability of the pharmacotherapies being compared. Pairwise comparisons were conducted for risk of MACE among 122 932 varenicline vs 92 148 NRT initiators; 342 064 varenicline vs 10 457 bupropion initiators; and 102 817 NRT vs 6056 bupropion initiators. Exposure: First course of the smoking cessation pharmacotherapy of interest. Main Outcomes and Measures: The primary outcome was MACE, defined as a composite of acute coronary syndrome, stroke, and cardiovascular death. Secondary outcomes were the individual components of MACE. Inverse probability of treatment weighting with high-dimensional propensity scores was used to account for potential confounding. Cox proportional hazards regression models with robust variance were used to estimate hazard ratios (HRs) and 95% CIs. Data were analyzed January 24, 2019, to September 1, 2021. Results: The mean (SD) age of included individuals ranged from 41.9 (14.2) to 49.8 (14.9) years, and the proportion of women ranged from 42.8% (52 702 of 123 128) to 52.2% (53 693 of 102 913). The comparison of 122 932 varenicline initiators and 92 148 NRT patch initiators showed no difference in the risk of MACE (HR, 0.87; 95% CI, 0.72-1.07) nor in the risk of the secondary outcomes of acute coronary syndrome (HR, 0.96; 95% CI, 0.76-1.21) and stroke (HR, 0.72; 95% CI, 0.45-1.14). However, decreased risk of cardiovascular death was found among varenicline initiators (HR, 0.49; 95% CI, 0.30-0.79). The results of comparisons involving bupropion were inconclusive owing to wide confidence intervals (eg, risk of MACE: 342 064 varenicline vs 10 457 bupropion initiators, HR, 0.87 [95% CI, 0.53-1.41]; 102 817 NRT patch vs 6056 bupropion initiators, HR, 0.79 [95% CI, 0.39-1.62]). Conclusions and Relevance: The finding of this cohort study that varenicline and NRT patch use have similar risk of MACE suggests that varenicline, the most efficacious smoking cessation pharmacotherapy, may be prescribed instead of NRT patches without increasing risk of major cardiovascular events. Further large-scale studies of the cardiovascular safety of varenicline and NRT relative to bupropion are needed.

Transcranial Magnetic Stimulation Treatment for Smoking Cessation: An Introduction for Primary Care Clinicians.

Tobacco use remains the number one preventable cause of death in the United States, resulting in significant public health and economic costs. Despite progress in reducing tobacco use through pharmacotherapy and psychotherapy smoking cessation interventions, additional treatment options are still needed to improve treatment effectiveness. As an adjunctive treatment, the US Food and Drug Administration recently cleared transcranial magnetic stimulation (TMS), a noninvasive brain stimulation technique, as an aid for smoking cessation in adults. Given that most smoking cessation interventions occur in the primary care setting, this article aims to introduce TMS, to provide an overview of the evidence of TMS for smoking cessation, and to outline the procedures for implementing TMS in the primary care setting when referral to an interventional psychiatrist is not possible. With growing scientific evidence and increasing regulatory approval of TMS for smoking cessation, this novel treatment option is now available for patients who want to quit smoking but have been unsuccessful with pharmacologic approaches.

Effect of Cytisine vs Varenicline on Smoking Cessation: A Randomized Clinical Trial.

Importance: Cytisine is more effective than placebo and nicotine replacement therapy for smoking cessation. However, cytisine has not been tested against the most effective smoking cessation medication, varenicline, which is associated with adverse events known to lead to discontinuation of therapy. Objective: To examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation. Design, Setting, and Participants: This noninferiority, open-label randomized clinical trial with allocation concealment and blinded outcome assessment was undertaken in Australia from November 2017 through May 2019; follow-up was completed in January 2020. A total of 1452 Australian adult daily smokers willing to make a quit attempt were included. Data collection was conducted primarily by computer-assisted telephone interview, but there was an in-person visit to validate the primary outcome. Interventions: Treatments were provided in accordance with the manufacturers' recommended dosage: cytisine (n = 725), 1.5-mg capsules taken 6 times daily initially then gradually reduced over the 25-day course; varenicline (n = 727), 0.5-mg tablets titrated to 1 mg twice daily for 84 days (12 weeks). All participants were offered referral to standard telephone behavioral support. Main Outcomes and Measures: The primary outcome was 6-month continuous abstinence verified using a carbon monoxide breath test at 7-month follow-up. The noninferiority margin was set at 5% and the 1-sided significance threshold was set at .025. Results: Among 1452 participants who were randomized (mean [SD] age, 42.9 [12.7] years; 742 [51.1%] women), 1108 (76.3%) completed the trial. Verified 6-month continuous abstinence rates were 11.7% for the cytisine group and 13.3% for the varenicline group (risk difference, -1.62% [1-sided 97.5% CI, -5.02% to ∞]; P = .03 for noninferiority). Self-reported adverse events occurred less frequently in the cytisine group (997 events among 482 participants) compared with the varenicline group (1206 events among 510 participants) and the incident rate ratio was 0.88 (95% CI, 0.81 to 0.95; P = .002). Conclusions and Relevance: Among daily smokers willing to quit, cytisine treatment for 25 days, compared with varenicline treatment for 84 days, failed to demonstrate noninferiority regarding smoking cessation. Trial Registration: anzctr.org.au Identifier: ACTRN12616001654448.

Efficacy of Combining Varenicline and Naltrexone for Smoking Cessation and Drinking Reduction: A Randomized Clinical Trial.

OBJECTIVE: Pharmacological treatments that can concomitantly address cigarette smoking and heavy drinking stand to improve health care delivery for these highly prevalent co-occurring conditions. This superiority trial compared the combination of varenicline and naltrexone against varenicline alone for smoking cessation and drinking reduction among heavy-drinking smokers. METHODS: This was a phase 2 randomized double-blind clinical trial. Participants (N=165) who were daily smokers and drank heavily received either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus matched placebo pills for 12 weeks. Primary outcomes were 7-day point prevalence of nicotine abstinence (bioverified by a breath CO reading ≤5 ppm) at the 26-week follow-up and number of drinks per drinking day during the 12-week treatment phase. RESULTS: Smoking abstinence at week 26 was significantly higher in the varenicline plus placebo condition than in the varenicline plus naltrexone condition (N=37 [45.1%] compared with N=22 [26.5%]). For drinks per drinking day, there was a medication effect favoring the combination of varenicline and naltrexone over varenicline alone across the 12-week treatment phase, although it did not meet the significance threshold. CONCLUSIONS: These findings suggest that smoking cessation and drinking reduction can be concomitantly targeted with pharmacotherapy and that while varenicline alone may be sufficient as a smoking cessation aid in heavy-drinking smokers, the combination of varenicline and naltrexone may confer benefits with regard to drinking outcomes, particularly during the 12-week period of active medication treatment.

Cytisine and cytisine derivatives. More than smoking cessation aids.

Cytisine, a natural bioactive compound that is mainly isolated from plants of the Leguminosae family (especially the seeds of Laburnum anagyroides), has been marketed in central and eastern Europe as an aid in the clinical management of smoking cessation for more than 50 years. Its main targets are neuronal nicotinic acetylcholine receptors (nAChRs), and pre-clinical studies have shown that its interactions with various nAChR subtypes located in different areas of the central and peripheral nervous systems are neuroprotective, have a wide range of biological effects on nicotine and alcohol addiction, regulate mood, food intake and motor activity, and influence the autonomic and cardiovascular systems. Its relatively rigid conformation makes it an attractive template for research of new derivatives. Recent studies of structurally modified cytisine have led to the development of new compounds and for some of them the biological activities are mediated by still unidentified targets other than nAChRs, whose mechanisms of action are still being investigated. The aim of this review is to describe and discuss: 1) the most recent pre-clinical results obtained with cytisine in the fields of neurological and non-neurological diseases; 2) the effects and possible mechanisms of action of the most recent cytisine derivatives; and 3) the main areas warranting further research.

Population pharmacokinetics and exposure-response analyses of varenicline in adolescent smokers.

Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12 and nausea/vomiting incidence) for varenicline in adolescent smokers were characterized using data from two phase 1 and one phase 4 studies. A one-compartment popPK model with first-order absorption and elimination adequately fitted the observed data. The effect of female sex on apparent clearance was significant. Apparent volume of distribution increased with body weight and decreased by 24%, 15%, and 14% for black race, "other" race, and female sex, respectively. The observed range of exposure in the phase 4 study was consistent with that expected for each dose and body-weight group from the results obtained in adolescent PK studies, supporting that varenicline dose and administration were appropriate in the study. The relationship between CAR9-12 and varenicline area under the concentration-time curve (AUC) from 0 to 24 hours (AUC24 ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC24 (p < 0.001) and was higher in females. Varenicline PK and ER for tolerability in adolescent smokers were comparable with adults, while ER for efficacy confirmed the negative results reported in the phase 4 study.