| Titre : |
Smoking cessation with varenicline, a selective alpha-4-beta-2 nicotinic receptor partial agonist : results from a 7-week, randomized, placebo and Bupropion controlled trial with 1 year follow-up |
| Type de document : |
texte imprimé |
| Auteurs : |
Mitchell Nides, Auteur ; Cheryl Oncken, Auteur ; David H. Gonzales, Auteur |
| Editeur : |
American Medical Association (AMA) |
| Année de publication : |
2006 |
| Collection : |
Archives of internal medicine, ISSN 0003-9926 num. Vol 14, n.28 |
| Importance : |
p. 1561-1568 |
| Présentation : |
ill., tab., graph. |
| Langues : |
Anglais (eng) |
| Catégories : |
[TABAC] étude
[TABAC] sevrage tabagique:méthode de sevrage:méthode individuelle:approche pharmacologique:varénicline
|
| Index. décimale : |
TA 6.2.3.1.4 Autres substituts nicotiniques |
| Résumé : |
Background Currently available smoking cessation therapies have limited success rates. Varenicline tartrate is a novel, selective nicotinic receptor partial agonist developed specifically for smoking cessation. This study evaluated the efficacy, tolerability, and safety of 3 varenicline doses for smoking cessation. Bupropion hydrochloride was included as an active control.
Methods A phase 2, multicenter, randomized, double-blind, placebo-controlled study of healthy smokers (18-65 years old). Subjects were randomized to varenicline tartrate, 0.3 mg once daily (n = 128), 1.0 mg once daily (n = 128), or 1.0 mg twice daily (n = 127), for 6 weeks plus placebo for 1 week; to 150-mg sustained-release bupropion hydrochloride twice daily (n = 128) for 7 weeks; or to placebo (n = 127) for 7 weeks.
Results During the treatment phase, the continuous quit rates for any 4 weeks were significantly higher for varenicline tartrate, 1.0 mg twice daily (48.0%; P<.001) and 1.0 mg once daily (37.3%; P<.001), than for placebo (17.1%). The bupropion rate was 33.3% (P = .002 vs placebo). The carbon monoxide–confirmed continuous quit rates from week 4 to week 52 were significantly higher in the varenicline tartrate, 1.0 mg twice daily, group compared with the placebo group (14.4% vs 4.9%; P = .002). The bupropion rate was 6.3% (P = .60 vs placebo). Discontinuation owing to treatment-emergent adverse events was 15.9% for bupropion, 11.2% to 14.3% for varenicline, and 9.8% for placebo. No dose-related increases occurred in adverse events for varenicline.
Conclusions Varenicline tartrate demonstrated both short-term (1 mg twice daily and 1 mg once daily) and long-term efficacy (1 mg twice daily) vs placebo. Varenicline was well tolerated and may provide a novel therapy to aid smoking cessation.
Cigarette smoking remains the world's leading cause of preventable death,1 contributing to 5 million premature deaths in 2000,2 which is estimated to increase to 10 million by 2020.1 Surveys show that most smokers want to quit,3 but most attempts are unaided, with success rates of only 3% to 5% at 1 year.3 Current pharmacotherapies, such as nicotine replacement therapy (NRT), bupropion hydrochloride, and nortriptyline hydrochloride, have shown moderate success, typically doubling short-term quit rates vs placebo,4- 7 with success at 1 year averaging approximately 7% to 30%, depending on the level of adjunctive behavioral counseling.8,9 Consequently, additional, more efficacious smoking cessation medications are needed.
Varenicline tartrate is a novel, nonnicotine agent developed expressly for smoking cessation. It is a selective nicotinic acetylcholine receptor partial agonist that binds specifically at the α4β2 nicotinic receptor subtype.10 The α4β2 receptor is thought to mediate the rewarding properties of nicotine by modulating the release of dopamine in the nucleus accumbens.11- 13 Cytisine, a plant-derived α4β2 partial agonist used for many years as a smoking cessation aid in eastern Europe,14 provided a structural starting point for the development of the higher-affinity varenicline. The agonist effect of oral varenicline on dopamine release is 35% to 60% of that observed with nicotine,10 theoretically sufficient to attenuate craving and withdrawal without producing its own dependence syndrome. The slower release of dopamine with varenicline compared with smoking would also reduce any potential for abuse.10 Varenicline also has a competitive antagonist effect on nicotine due to a substantially higher affinity for the α4β2 receptor.10 Starting therapy 1 week before the target quit day could potentially lead to at least partial extinction of smoking behavior by blocking the rewarding effects of smoked nicotine.15,16 In addition, the blockade of reward could reduce the chance that a “slip” while still undergoing treatment would lead to a full-blown relapse.
The current study was part of a phase 2 program conducted to select the optimal dose for larger-scale, phase 3 studies. The primary objectives were to assess the efficacy, tolerability, and safety of 3 doses of varenicline administered for 6 weeks. A bupropion arm was included as an active control. |
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