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CPT: Pharmacometrics & Systems... Jul 2021Varenicline is an approved smoking cessation aid in adults. Population pharmacokinetics (popPK) and exposure-response (ER) (continuous abstinence rates [CAR] weeks 9-12...
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 (AUC ) was nonsignificant (p = 0.303). Nausea/vomiting incidence increased with AUC (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.
Topics: Adolescent; Area Under Curve; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase IV as Topic; Humans; Models, Biological; Racial Groups; Randomized Controlled Trials as Topic; Sex Factors; Smokers; Smoking Cessation Agents; Tissue Distribution; Varenicline; Young Adult
PubMed: 34062053
DOI: 10.1002/psp4.12645 -
Pharmacotherapy Feb 2018Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also... (Review)
Review
Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventable cause of death in developed countries. Since the development of nicotine replacement therapy (NRT) in 1978, treatment options have continued to evolve and expand. Despite this, currently available treatments remain insufficient, with less than 25% of smokers remaining abstinent 1 year after treatment. In this article, we review existing and emerging smoking cessation pharmacotherapies, with a special emphasis on the most promising agents that are currently being investigated. A search of the Cochrane Database of Systematic Reviews and the PubMed, Ovid, and ClinicalTrials.gov databases (August 2 to September 1, 2017) was undertaken for articles on smoking cessation pharmacotherapies, applying no language restrictions. More than 40 pharmacotherapies were reviewed including conventional pharmacotherapies-NRT, bupropion, and varenicline (all approved by the U.S. Food and Drug Administration as first-line treatment of smoking cessation)-and novel therapies: cytisine, N-acetylcysteine, cycloserine, memantine, baclofen, topiramate, galantamine, and bromocriptine. Studies of combination NRT and varenicline showed the greatest smoking cessation rates. Clonidine and nortriptyline are second-line treatments used when first-line treatments fail or are contraindicated, or by patient preference. Some novel therapies, especially acetylcholinesterase inhibitors, cytisine, and N-acetylcysteine, display promising results. Because the results of randomized clinical trials were reported using varied end points and outcome measures, direct comparisons between different pharmacotherapies cannot easily be evaluated. Additional high-quality randomized double-blind placebo-controlled trials with long-term follow-up, using validated sustained abstinence measures, are needed to find more effective smoking cessation aids.
Topics: Antidepressive Agents; Humans; Smoking Cessation; Tobacco Smoking; Tobacco Use Cessation Devices; Varenicline
PubMed: 29250815
DOI: 10.1002/phar.2073 -
Behavioural Brain Research Jan 2021Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and...
Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on motivation for a food reinforcer. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that (a) nicotine decreased economic demand for sucrose, (b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and (c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that had not been exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards.
Topics: Animals; Behavior, Animal; Drug Interactions; Economics, Behavioral; Feeding Behavior; Male; Motivation; Nicotine; Nicotinic Agonists; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Reinforcement, Psychology; Smoking Cessation Agents; Sucrose; Varenicline
PubMed: 32931838
DOI: 10.1016/j.bbr.2020.112887 -
Journal of the American College of... Dec 2018Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among... (Review)
Review
Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among youth and smoking cessation among established smokers are key for reducing smoking prevalence and the associated negative health consequences. Proven tobacco cessation treatment includes pharmacotherapy and behavioral support, which are most effective when provided together. First-line medications (varenicline, bupropion, and nicotine replacement) are effective and safe for patients with CVD. Clinicians who care for patients with CVD should give as high a priority to treating tobacco use as to managing other CVD risk factors. Broader tobacco control efforts to raise tobacco taxes, adopt smoke-free laws, conduct mass media campaigns, and restrict tobacco marketing enhance clinicians' actions working with individual smokers.
Topics: Bupropion; Cigarette Smoking; Health Promotion; Humans; Smoking Cessation; Tobacco Use; Tobacco Use Cessation; Tobacco Use Cessation Devices; Treatment Outcome; Varenicline
PubMed: 30522631
DOI: 10.1016/j.jacc.2018.10.020 -
Drug and Alcohol Dependence Aug 2021There is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances....
BACKGROUND
There is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances. While varenicline and naltrexone each have FDA-approval for nicotine and alcohol use disorder, respectively, there is evidence that their clinical benefit may extend across the two disorders. Critically, the effect of combined varenicline and naltrexone on neural reactivity to alcohol cues among heavy drinking smokers has not yet been studied. Probing the effect of the combination therapy on alcohol cue-reactivity may give insight to the mechanisms underlying its efficacy.
METHODS
Forty-seven heavy drinking smokers enrolled in two medication studies were randomized to receive varenicline alone (n = 11), varenicline plus naltrexone (n = 11), or placebo (n = 25). Participants completed an fMRI alcohol cue-reactivity task and rated their in-scanner alcohol craving. Whole-brain analyses examined the effect of medication on alcohol cue-elicited neural response.
RESULTS
Varenicline plus naltrexone attenuated alcohol cue-elicited activation in mesolimbic regions relative to varenicline alone and to placebo (Z > 2.3, p < 0.05). The combination varenicline and naltrexone group also endorsed lower in-scanner alcohol craving relative to varenicline alone group (p = 0.04).
CONCLUSIONS
These findings provide evidence for the benefit of combined therapy of varenicline and naltrexone over varenicline alone for the attenuation of alcohol cue-elicited neural activation. This study provides a preliminary proof-of-mechanism for this combination pharmacotherapy and suggests that naltrexone may be driving the reductions in cue-elicited alcohol craving in the brain. Further clinical studies using the combined therapy to treat heavy drinking smokers are warranted.
Topics: Alcohol Drinking; Alcoholism; Cues; Double-Blind Method; Humans; Naltrexone; Smokers; Varenicline
PubMed: 34175784
DOI: 10.1016/j.drugalcdep.2021.108825 -
BMJ Open Jan 2016To establish which non-psychotropic medications have been assessed in relation to risk of suicide or attempted suicide in observational studies, document reported... (Review)
Review
OBJECTIVES
To establish which non-psychotropic medications have been assessed in relation to risk of suicide or attempted suicide in observational studies, document reported associations and consider study strengths and limitations.
DESIGN
Systematic review.
METHODS
Four databases (Embase, Medline, PsycINFO and International Pharmaceutical Abstracts) were searched from 1990 to June 2014, and reference lists of included articles were hand-searched. Case-control, cohort and case only studies which reported suicide or attempted suicide in association with any non-psychotropic medication were included.
OUTCOME MEASURES
The outcomes eligible for inclusion were suicide and attempted suicide, as defined by the authors of the included study.
RESULTS
Of 11,792 retrieved articles, 19 were eligible for inclusion. Five studies considered cardiovascular medication and antiepileptics; two considered leukotriene receptor antagonists, isotretinoin and corticosteroids; one assessed antibiotics and another assessed varenicline. An additional study compared multiple medications prescribed to suicide cases versus controls. There was marked heterogeneity in study design, outcome and exposure classification, and control for confounding factors; particularly comorbid mental and physical illness. No increased risk was associated with cardiovascular medications, but associations with other medications remained inconclusive and meta-analysis was inappropriate due to study heterogeneity.
CONCLUSIONS
Whether non-psychotropic medications are associated with increased risk of suicide or attempted suicide remains largely unknown. Robust identification of suicide outcomes and control of comorbidities could improve quantification of risk associated with non-psychotropic medication, beyond that conferred by underlying physical and mental illnesses.
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anticonvulsants; Cardiovascular Agents; Humans; Isotretinoin; Leukotriene Antagonists; Observational Studies as Topic; Prescription Drugs; Risk; Risk Factors; Suicide; Suicide, Attempted; Varenicline
PubMed: 26769782
DOI: 10.1136/bmjopen-2015-009074 -
The Cochrane Database of Systematic... Aug 2016Smoking cessation is the most important treatment for smokers with chronic obstructive pulmonary disease (COPD), but little is known about the effectiveness of different... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Smoking cessation is the most important treatment for smokers with chronic obstructive pulmonary disease (COPD), but little is known about the effectiveness of different smoking cessation interventions for this particular group of smokers.
OBJECTIVES
To evaluate the effectiveness of behavioural or pharmacological smoking cessation interventions, or both, in smokers with COPD.
SEARCH METHODS
We searched all records in the Cochrane Airways Group Specialised Register of Trials. In addition to this electronic search, we searched clinical trial registries for planned, ongoing, and unpublished trials. We searched all databases from their inception. We checked the reference lists of all included studies and of other systematic reviews in relevant topic areas. We searched for errata or retractions from eligible trials on PubMed. We conducted our most recent search in March 2016.
SELECTION CRITERIA
We included randomised controlled trials assessing the effectiveness of any behavioural or pharmacological treatment, or both, in smokers with COPD reporting at least six months of follow-up abstinence rates.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted the data and performed the methodological quality assessment for each study. We resolved any disagreements by consensus.
MAIN RESULTS
We included 16 studies (involving 13,123 participants) in this systematic review, two of which were of high quality. These two studies showed that nicotine sublingual tablet and varenicline increased the quit rate over placebo (risk ratio (RR) 2.60 (95% confidence interval (CI) 1.29 to 5.24) and RR 3.34 (95% CI 1.88 to 5.92)). Pooled results of two studies also showed a positive effect of bupropion compared with placebo (RR 2.03 (95% CI 1.26 to 3.28)). When pooling these four studies, we found high-quality evidence for the effectiveness of pharmacotherapy plus high-intensity behavioural treatment compared with placebo plus high-intensity behavioural treatment (RR 2.53 (95% CI 1.83 to 3.50)). Furthermore, we found some evidence that high-intensity behavioural treatment increased abstinence rates when compared with usual care (RR 25.38 (95% CI 8.03 to 80.22)) or low-intensity behavioural treatment (RR 2.18 (95% CI 1.05 to 4.49)). Finally, the results showed effectiveness of various combinations of psychosocial and pharmacological interventions.
AUTHORS' CONCLUSIONS
We found high-quality evidence in a meta-analysis including four (1,540 participants) of the 16 included studies that a combination of behavioural treatment and pharmacotherapy is effective in helping smokers with COPD to quit smoking. Furthermore, we conclude that there is no convincing evidence for preferring any particular form of behavioural or pharmacological treatment.
Topics: Adult; Behavior Therapy; Bupropion; Combined Modality Therapy; Female; Humans; Male; Nicotine; Nicotinic Agonists; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Smoking Cessation; Varenicline
PubMed: 27545342
DOI: 10.1002/14651858.CD010744.pub2 -
American Family Physician Sep 2017
Review
Topics: Adult; Drug Labeling; Humans; Smoking Cessation; Smoking Cessation Agents; Varenicline
PubMed: 28925657
DOI: No ID Found -
The Journal of Pharmacology and... Mar 2021Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs).... (Comparative Study)
Comparative Study
Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for 42* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse. SIGNIFICANCE STATEMENT: Nicotine addiction is a serious public health problem. Cotinine is the major metabolite of nicotine, but its involvement in nicotine reinforcement remains elusive. Our findings indicate that cotinine, at doses producing clinically relevant blood cotinine levels, supported intravenous self-administration in rats. Cotinine self-administration was less robust than nicotine. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results suggest cotinine may play a role in the development of nicotine use and misuse.
Topics: Animals; Cotinine; Dose-Response Relationship, Drug; Drug Interactions; Female; Male; Mecamylamine; Nicotine; Rats; Rats, Wistar; Receptors, Nicotinic; Self Administration; Varenicline
PubMed: 33361363
DOI: 10.1124/jpet.120.000367 -
Expert Review of Clinical Pharmacology Mar 2019Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting,... (Review)
Review
Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting, headache, and abdominal cramps. Prevalence has shifted from the United States and Europe to China, India, and Brazil. Worldwide 8 million individuals are afflicted, including women and children. Areas covered: Mecamylamine (Inversine®, Vecamyl®), a nicotinic acetylcholine receptor (nAChR) antagonist, should be tested as a remedy for green tobacco sickness. Mecamylamine is approved as an oral tablet for the treatment of hypertension, is safe, and is off-patent. Mecamylamine attenuates many of the effects of nicotine and tobacco including seizures, thereby supporting its use as an effective pharmacotherapy for tobacco dependence. Varenicline (Chantix®) and cytisine (Tabex®) are low efficacy (i.e. intrinsic activity) nAChR agonists, are used as smoking cessation aids, and are viable options to test as remedies against green tobacco sickness. Nicotine immunization strategies may provide further options for future testing. Expert commentary: Efforts to demonstrate reversal and/or prevention of green tobacco sickness by mecamylamine will underscore the importance of nicotine in this illness and highlight a new medication for effective treatment of tobacco poisoning.
Topics: Agricultural Workers' Diseases; Humans; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Plant Leaves; Nicotiana; Vaccines; Varenicline
PubMed: 30650314
DOI: 10.1080/17512433.2019.1570844