Anti-nicotine abuse vaccines in the pipeline: an update

Three different companies have completed Phase II clinical studies of their anti-nicotine vaccines and are rushing to obtain regulatory approval and to bring their vaccine candidates to the market. The vaccines are composed of the nicotine molecule linked to a carrier protein and an adjuvant. The results in all three clinical studies are encouraging. Preliminary results seem to indicate that subjects with high anti-nicotine antibody levels demonstrate high quit rates and that the vaccines appear to be compatible with and complementary to approved forms of smoking cessation therapies. The data available do not yet allow us to give definitive results for long-term quit rates. We expect the vaccines to appear on the market during a time window between 2009 and 2011.     

A review of smoking cessation interventions for smokers aged 50 and older

Objectives

Cigarette smoking poses substantial health risks at any age, but is particularly dangerous for older smokers, who are already at heightened risk for various health conditions. Studies suggest that older smokers are motivated to quit and succeed, but few of these have been randomized controlled trials. There is a need to systematically evaluate the research on effective interventions in older smokers.

Methods

We followed PRISMA guidelines in the development of this systematic review, which included randomized controlled trials of cessation interventions with smokers aged 50 or older.

Results

We found 740 unique titles matching specified search criteria; 13 met final eligibility criteria. Nearly all the cessation treatments combined counseling with other strategies. Eight studies provided smoking cessation medications. None of the studies used newer forms of technology such as web- or text-based interventions. Nine of the 13 studies reported a significant intervention effect at one or more time points, with three studies reporting sustained treatment effects at 12 mos or longer. In general, more intensive interventions and those with combined approaches including medications and follow-up counseling achieved the best outcomes.

Conclusion

The quit rates from these studies and the relative effectiveness of different intervention approaches are consistent with the general smoking cessation literature. However, in most studies, treatment effects were of short duration, and absolute quit rates were low, leaving the vast majority of older smokers at high risk for smoking-related health conditions. This systematic review suggests a need for additional research to design and test future interventions specifically tailored for older smokers.     

QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch-clamp technique was used to assess the I(Kr) -, I(Ks) -, and I(Na) -blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea-pig hearts was used to evaluate the MAPD(90) -, MAP amplitude-, phase 0 dV/dt-, and ECG-modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an I(Kr) blocker. IC(50) was estimated at 34 μm. In contrast, bupropion had hardly any effect on I(Ks) and I(Na) . Bupropion had no significant MAPD(90) -modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS-widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its I(Kr) -blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS-widening, MAP amplitude- and phase 0 dV/dt -reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti-arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling.     

Effects of bupropion on the reinstatement of nicotine-induced conditioned place preference by drug priming in rats

Nicotine is one of the most widely consumed psychoactive drugs, and its consumption is currently associated with other drugs of abuse, such as opioids. The aim of the present study was to evaluate the efficacy of the atypical antidepressant drug bupropion (5, 10 and 20 mg/kg, ip) in blocking the reinstatement of nicotine-induced conditioned place preference (CPP) provoked by nicotine and morphine. It was shown that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, ip, free base, three drug sessions). Once established, nicotine-induced CPP was extinguished by repeated testing. Following this extinction phase, the reinstatement of CPP was investigated. Nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, ip) or morphine (10 mg/kg, ip). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Our results demonstrated that bupropion (10 and 20 mg/kg) attenuated the nicotine-induced reinstatement of nicotine-conditioned response. Moreover, bupropion (5 and 10 mg/kg) diminished the morphine-induced reinstatement of nicotine-conditioned response. The results of our studies suggest that bupropion may offer an interesting approach to the relapse-prevention pharmacotherapy of addiction, including nicotinism and polydrug abuse.     

Evaluating drug effects on children''s cognitive functioning

1. In our studies of drug therapy in child psychiatry disorders, we have been using a battery of tests to monitor any effects of medication on the various components of cognitive processing. Our intention was to measure skills required by the children for successful classroom performance.

2. We have used used this test battery approach in open clinical trials of bupropion (Wellbutrin) and of alprazolam (Xanax) with child psychiatry patients.

3. On no single test was the effect of bupropion vs placebo significant; however, there was no indication of any cognitive deterioration with bupropion. Group performance with alprazolam was more variable, and again no individual test showed significant changes with medication.

4. These initial applications of the cognitive battery indicate that bupropion, a new anti- depressant and alprazolam, an anxiolytic have no adverse effects on cognition at therapeutically effective doses.     

Safety and tolerability of new-generation anti-obesity medications: a narrative review

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk–benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk–benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk–benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk–benefit.     

Effect of sustained-release (SR) bupropion on craving and withdrawal in smokers deprived of cigarettes for 72 h

Rationale Sustained-release (SR) bupropion enhances quit rates of smokers, generally decreases tobacco withdrawal, and in some studies, reduces craving.Objective Investigate the effects of SR bupropion on craving and withdrawal during cigarette abstinence.Methods Twenty three smokers participated in three 17-day periods composed of 14 out-patient days followed by 3 (72 h) in-patient days. During the out-patient days, subjects received SR bupropion, placebo, or no drug. During the in-patient days, subjects were abstinent from cigarettes on two occasions while receiving either SR bupropion or placebo and smoked freely during the other occasion. SR bupropion was titrated over the first three out-patient days followed by a fixed dose (300 mg/day) for 14 days (including the three in-patient abstinence days). Cigarette craving, withdrawal, and selected physiological measures were assessed repeatedly over the 72-h periods.Results During the 72-h periods, craving intensity was significantly lower with free smoke and SR bupropion than with placebo, and significantly lower during free smoke than during SR bupropion. Overall withdrawal symptoms were significantly lower with free smoke than with either placebo or SR bupropion. Among individual withdrawal symptoms (excluding craving), appetite increase was significantly reduced during SR bupropion compared to placebo. During placebo and SR bupropion, craving intensity displayed a circadian pattern that was different from that observed during free smoke.Conclusions SR bupropion reduced craving and appetite increase during smoking abstinence. These findings support the hypothesis that craving and withdrawal symptoms may be controlled by distinct central nervous system pathways.