Dataset Information

CC4, a dimer of cytisine, is a selective partial agonist at ?4?2/?6?2 nAChR with improved selectivity for tobacco smoking cessation.

ABSTRACT:

Background and purpose

Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4).

Experimental approach

The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours.

Key results

When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal ?4?2, ?3?4, ?7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through ?4?2 and ?6?2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the ?3?4 and ?7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions.

Conclusion and implications

Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for ?2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.

SUBMITTER: Sala M

PROVIDER: S-EPMC3631374 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CC4, a dimer of cytisine, is a selective partial agonist at α4β2/α6β2 nAChR with improved selectivity for tobacco smoking cessation.

Sala Mariaelvina M Braida Daniela D Pucci Luca L Manfredi Irene I Marks Michael J MJ Wageman Charles R CR Grady Sharon R SR Loi Barbara B Fucile Sergio S Fasoli Francesca F Zoli Michele M Tasso Bruno B Sparatore Fabio F Clementi Francesco F Gotti Cecilia C

British journal of pharmacology 20130201 4

<h4>Background and purpose</h4>Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4).<h4>Ex ...[more]

PMID: 22957729

Similar Datasets

Project description:ImportanceCytisine 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.ObjectiveTo examine whether standard cytisine treatment (25 days) was at least as effective as standard varenicline treatment (84 days) for smoking cessation.Design, setting, and participantsThis 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.InterventionsTreatments 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 measuresThe 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.ResultsAmong 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 relevanceAmong 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 registrationanzctr.org.au Identifier: ACTRN12616001654448.

Project description:ImportanceNo new tobacco cessation medication has been licensed in the US since 2006. Cytisine, a plant-based partial agonist of nicotinic acetylcholine receptors, has demonstrated safety and efficacy in several randomized clinical trials and is currently available in many countries. However, the drug is not commercially available in the US. A New Drug Application to license cytisine as a smoking cessation medication in the US is being prepared for review by the US Food and Drug Administration, whose request for additional safety data will delay submission of the application by approximately 1 year.ObjectiveTo project the potential public health impact of cytisine, and delays in its availability, as a smoking cessation aid in the US.Design, setting, and participantsThis mathematical model estimated life expectancy gains from smoking cessation for people aged 18 to 99 years in the US, reflecting the civilian, noninstitutionalized population. The model also accounted for cytisine uptake and effectiveness, as well as potential relapse among people who stop smoking.ExposureCytisine availability as a tobacco cessation treatment immediately or after 1 year.Main outcomes and measuresThe main outcomes were the number of adults able to stop smoking and sustain long-term abstinence and aggregate life-years gained.ResultsThe base case includes an estimated 29.4 million US civilian noninstitutionalized adults who smoke cigarettes (age distribution, 18-24 years: 5.5%; 25-44 years: 37.3%; 45-64 years: 41.8%; ≥65 years: 15.5%). With a conservative assumption that 3.8% of these individuals would use cytisine in the first year of availability, immediate cytisine availability could lead 71 000 more people to quit smoking over 1 year and maintain long-term abstinence. This would produce more than 500 000 additional life-years compared to the status quo in which cytisine is unavailable and fewer people stop smoking. Each additional year of delay in the availability of cytisine might reduce population-level life expectancy by 10 000 years. The model results were most sensitive to changes in cytisine uptake and effectiveness.Conclusions and relevanceSmoking cessation generates large gains in life expectancy. This mathematical model demonstrated that immediate cytisine availability, even if used successfully by only a small fraction of people who smoke, could produce major public health benefits. Given the need for new tobacco cessation pharmacotherapy options, the magnitude of cytisine's potential public health benefits, and the morbidity and mortality associated with delay in its availability, a timely review of cytisine for approval in the US is warranted.

Project description:BackgroundAbout 85% of patients receiving opioid agonist therapy (OAT) for opioid dependence are smoking tobacco. Although smoke-related pulmonary diseases are significant contributors to morbidity and mortality, few smoking cessation interventions are evaluated within this group, and few OAT patients are offered smoking cessation as an integrated part of their addiction treatment. This study protocol describes an integrated smoking cessation intervention aimed at patients receiving OAT and smoking tobacco.MethodsThis is a multicentre, randomised controlled clinical trial that will recruit 266 daily tobacco smoking patients receiving OAT in OAT outpatient clinics in Bergen and Stavanger, Norway. The patients randomised for the intervention arm will be offered smoking cessation therapy consisting of weekly brief behavioural interventions and prescription-free nicotine replacement products. In the control arm, patients will receive standard care without any added interventions related to smoking cessation. The smoking cessation intervention includes psychoeducational techniques with components from motivational interviewing, and nicotine replacement products such as nicotine lozenges, patches, and chewing gum. The duration of the intervention is 16 weeks, with the option of extending it by a further 8 weeks. The main outcomes are measured at 16 weeks after initiation of the intervention, and sustained effects are evaluated 1 year after intervention initiation. The primary outcome is smoking cessation verified by carbon monoxide (CO) levels or at least a 50% reduction in the number of cigarettes smoked. Secondary outcomes are changes in psychological well-being, biochemical inflammation markers, changes in physical health, quality of life, and fatigue.DiscussionIntegration of other treatments to standard OAT care improves adherence and completion rates providing another rationale for integrated smoking cessation treatment. Thus, if integrated smoking cessation treatment is superior to standard care, this trial provides important information on further scale-up.Trial registrationClinicalTrials.gov NCT05290025. Registered on 22 March 2022.

Project description:IntroductionHealth professionals' own beliefs and practices, especially their smoking status, has been described to strongly influence their willingness to provide brief tobacco interventions (5 A's) to their patients. This study examines the association between the smoking status of faculty members in US dental programmes and (1) practice pattern; (2) perceived confidence; and (3) perceived educational preparedness of new graduates in providing the 5 A's to their patients.MethodsThis study presents data from the National Tobacco Survey of Personnel in Dental and Allied Academic Programs (TSPDAP) conducted in 2018. Faculty members in US dental/allied dental schools were invited to participate in this survey. Data were stratified based on the smoking status of the respondents as "never" and "ever" smokers (smoked <100 and ≥100 cigarettes during their lifetime, respectively). Multiple logistic regression models were used to calculate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs).ResultsData of 1896 participants were analysed, of whom 1032 (54.4%) were categorised as "ever" smokers. In the final regression model, low perceived barrier score was significantly associated with high practice pattern (aOR, 0.94; 95% CI, 0.92-0.97), high perceived confidence (aOR, 0.92; 95% CI, 0.90-0.95), and high perceived educational preparedness (aOR, 0.97; 95% CI, 0.94-0.98) in delivering the 5 A's to patients. Similarly, high perceived effectiveness was significantly associated with high practice pattern (aOR, 1.08; 95% CI, 1.05-1.11), high perceived confidence (aOR, 1.10; 95% CI, 1.06-1.13), and high perceived educational preparedness (aOR, 1.06; 95% CI, 1.03-1.09) in delivering the 5 A's to their patients. The smoking status of the dental personnel did not show any significant association with practice pattern, perceived confidence, or perceived educational preparedness in delivering the 5 A's to their patients.ConclusionsThe smoking status of oral health care personnel was not significantly associated with their participation in tobacco cessation interventions.