Efficacy and Safety of Varenicline for Smoking Cessation

Nicotine Dependence Center, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
The American journal of medicine (Impact Factor: 5). 05/2008; 121(4 Suppl 1):S32-42. DOI: 10.1016/j.amjmed.2008.01.017
Source: PubMed


Effective treatment of nicotine addiction is essential for reducing the substantial current and predicted morbidity and mortality associated with tobacco smoking. Despite the availability of effective treatments for smoking cessation, such as nicotine replacement therapy and bupropion sustained-release (SR), abstinence rates remain less than optimal. Varenicline is the first in a new class of agents for smoking cessation, the alpha(4)beta(2) nicotinic acetylcholine receptor (nAChR) partial agonists. Nicotine addiction is mediated by stimulation of central alpha(4)beta(2) nAChRs by nicotine, which causes the release of dopamine, ultimately leading to the pleasurable effects of smoking. As a nAChR partial agonist, varenicline attenuates the craving and withdrawal symptoms that occur with abstinence from nicotine and also reduces the rewarding effects of nicotine obtained from smoking in patients who lapse. Thus, varenicline offers a new therapeutic option for the treatment of nicotine addiction. Clinical trials have demonstrated superior efficacy of this agent over placebo and bupropion-SR for achieving abstinence from smoking, and varenicline has also been shown to significantly delay smoking relapse. As the newest agent approved for smoking cessation, the mechanism of action, efficacy, and safety of varenicline.

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Available from: J. Taylor Hays, Oct 02, 2015
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    • "Given that nicotine and cocaine alone each increase dopamine levels (DiChiara, 2000; DiChiara and Imperato, 1988a; Pettit and Justice, 1991), although through different mechanisms (Koob and LeMoal, 2006; Kuhar et al, 1991), identifying medications that may reduce abuse of nicotine þ cocaine in combination is an intriguing chal- lenge. Varenicline (Chantix/Champix) was approved for the treatment of nicotine dependence by the FDA in 2006 and has been effective in facilitating smoking cessation (Cinciripini et al, 2013; Hawk et al, 2012; Hays et al, 2008; Jorenby et al, 2006; Niaura et al, 2006; Tonstad, 2006). Varenicline was designed as a partial agonist at a4b2* nicotinic acetylcholine receptors (nAChRs) (Faessel et al, 2010; Rollema et al, 2007a) and a full agonist at a7 nicotinic receptors (Coe et al, 2005; Mihalak et al, 2006). "
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    ABSTRACT: Nicotine dependence and cocaine abuse are major public health problems and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies, and reduced nicotine self-administration and substituted for the nicotine discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004 to 0.04 mg/kg/hr) was administered intravenously every 20 min for 23 h each day for 7-10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.Neuropsychopharmacology accepted article preview online, 22 November 2013. doi:10.1038/npp.2013.325.
    Preview · Article · Nov 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Surprisingly, bupropion increases tobacco use in non-treatment seeking smokers (Cousins et al., 2001) and decreases seizure threshold, which is a limiting side-effect (Kuate et al, 2004). Varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic receptors (Coe et al., 2005; Mihalak et al, 2006), reduces nicotine reinforcement and craving (Gonzales et al., 2006; Oncken et al, 2006; West et al, 2008), but with sideeffects including agitation, depression and suicidal ideation (Hays et al., 2008). Clearly, there is a need for more efficacious smoking cessation therapeutics. "
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    ABSTRACT: Although several therapeutic agents are available to aid in tobacco smoking cessation, relapse rates continue to be high, warranting the development of alternative pharmacotherapies. Nicotine-evoked dopamine release from its presynaptic terminals in the central nervous system leads to reward which maintains continued tobacco use. The ability of indolizidine (-)-235B' and a sub-library of structurally related analogs to inhibit nicotine-evoked [(3)H]dopamine release from rat striatal slices was determined in the current study. Indolizidine (-)-235B' inhibited nicotine-evoked [(3)H]dopamine release in a concentration-dependent manner (IC(50)=42 nM, I(max)=55%). Compound (-)-237D, the double bond-reduced analog, afforded the greatest inhibitory potency (IC(50)=0.18 nM, I(max)=76%), and was 233-fold more potent than indolizidine (-)-235B'. The des-8-methyl aza-analog of indolizidine (-)-235B', ZZ-272, also inhibited nicotine-evoked [(3)H]dopamine release (IC(50)=413 nM, I(max)=59%). Concomitant exposure to maximally effective concentrations of indolizidine (-)-235B', ZZ-272 or (-)-237D with a maximally effective concentration of α-conotoxin MII, a selective antagonist for α6β2-containing nicotinic receptors, resulted in inhibition of nicotine-evoked [(3)H]dopamine release no greater than that produced by each compound alone. The latter results suggest that indolizidine (-)-235B', (-)-237D, ZZ-272 and α-conotoxin MII inhibit the same α-conotoxin MII-sensitive nicotinic receptor subtypes. Thus, indolizidine (-)-235B' and its analogs act as antagonists of α6β2-nicotinic receptors and constitute a novel structural scaffold for the discovery of pharmacotherapies for smoking cessation.
    Full-text · Article · Feb 2011 · European journal of pharmacology
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    • "They mediate acetylcholine (Ach) neurotransmission and adjust the activities of neurotransmitters such as dopamine, serotonin, glutamate, and GABA (Girod et al, 2000; Kenny et al, 2000; Dehkordi et al, 2007; Grady et al, 2007). These receptors are associated with diseases such as epilepsy, cognition disorders, Alzheimer's diseases, Parkinson's diseases, and nicotine addiction (Dougherty et al, 2003; Vincler & McIntosh, 2007; Hays et al, 2008; Kuryatov et al, 2008; Owen et al, 2008; O'Leary et al, 2008; Pons et al, 2008). The nAChRs can be classified according to several subunits. "
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    ABSTRACT: Three dimensional quantitative structure activity relationship between diazabicyclo[4.2.0]octanes and nicotinic acetylcholine receptor (halpha4beta2 and halpha3beta4) agonists was studied using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). From 11 CoMFA and CoMSIA models, CoMSIA with steric and electrostatic fields gave the best predictive models (q(2)=0.926 and 0.945, r(2) (ncv)=0.983 and 0.988). This study can be used to develop potent halpha4beta2 receptor agonists with low activity on halpha3beta4 subtype.
    Preview · Article · Feb 2009 · Korean Journal of Physiology and Pharmacology
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