AIM: The primary aim of this study was to determine the safety and efficacy of the monoamine oxidase-B (MAO-B) inhibitor selegiline hydrochloride (SEL, l-Deprenyl; Eldepryl((R))) as an aid for smoking cessation in cigarette smokers. METHODS: One hundred and one nicotine-dependent adult cigarette smokers without current psychiatric or substance use disorders participated in this 8-week randomized, double-blind, placebo-controlled trial. Participants received either SEL (5mg bid, n=51) or placebo (PLO, n=50), in combination with brief (<10min) manualized smoking cessation counseling. The main smoking outcome measures were 7-day point prevalence abstinence at end of trial (EOT), 4-week continuous smoking abstinence at end of trial (CA), and 7-day point prevalence abstinence at 6-month follow-up (6MFU). Abstinence was determined by an absence of self-reported cigarette smoking and biochemically verified by expired breath carbon monoxide and plasma cotinine levels. RESULTS: Rates of smoking abstinence did not differ by medication group (EOT: SEL=16%, PLO=20%, p=0.57; CA: SEL=14%, PLO=18%, p=0.56; 6MFU: SEL=12%, PLO=16%, p=0.54). Adverse events were modest and comparable between medication groups. Participants receiving SEL were more likely than those receiving PLO to report dry mouth (25.5% versus 8.2%, p<0.05). CONCLUSIONS: Our results suggest that SEL was safe and well-tolerated by adult cigarette smokers, but did not improve smoking abstinence rates compared to PLO.

Contingency management (CM) is a powerful behavioral intervention shown to reduce the use of a variety of substances including tobacco. Use of CM techniques for smoking cessation has been restricted by the use of multiple daily measurements of breath CO as the objective indicator to reinforce abstinence. Cotinine, with its longer half-life, may be a better marker. We evaluated the use of urinary cotinine (determined using once-daily semiquantitative immunoassay test strips and verified using quantitative GC/HPLC techniques) as an abstinence indicator in treatment-seeking adult and adolescent smokers participating in a CM-based intervention program. Both techniques of determining urinary cotinine were highly sensitive and moderately specific at detecting abstinence, and they were highly concordant. However, specificity was somewhat lower during the first few days of a quit attempt and improved over time. The results were similar in adults and adolescent smokers, and suggest that during the first few days of a quit attempt it would be advisable to continue to use daily multiple CO measurements to verify abstinence. However, once abstinence is achieved, once-daily immunoassay test strips could be used for continued monitoring of urinary cotinine levels. Immunoassay testing can identify individuals who relapse to smoking, though this study cannot evaluate whether the strips can identify resumption of abstinence. These results suggest that the use of cotinine as an abstinence indicator, by reducing the number of daily appointments, could significantly enhance the feasibility and utility of CM-based interventions for smoking cessation.

RATIONALE: Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H(3) receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine-induced hyperlocomotion. The present study examined the involvement of the histaminergic system in these effects of thioperamide in mice. MATERIALS AND METHODS: We investigated whether immepip, a selective H(3) agonist, could reverse the potentiating effects of thioperamide. Moreover, the non-imidazole H(3) inverse agonist A-331440 was tested on the locomotor effects of cocaine. Using high-performance liquid chromatography with ultraviolet detection, cocaine plasma concentrations were measured to study potential drug-drug interactions between thioperamide and cocaine. Finally, thioperamide was tested on the locomotor effects of cocaine in histamine-deficient knockout mice in order to determine the contribution of histamine to the modulating effects of thioperamide. RESULTS: Thioperamide potentiated cocaine-induced hyperlocomotion in normal mice, and to a higher extent, in histamine-deficient knockout mice. A-331440 only slightly affected the locomotor effects of cocaine. Immepip did not alter cocaine-induced hyperactivity but significantly reduced the potentiating actions of thioperamide on cocaine's effects. Finally, plasma cocaine concentrations were more elevated in mice treated with thioperamide than in mice that received cocaine alone. CONCLUSIONS: The present results indicate that histamine released by thioperamide through the blockade of H(3) autoreceptors is not involved in the ability of this compound to potentiate cocaine induced-hyperactivity. Our data suggest that thioperamide, at least at 10 mg/kg, increases cocaine-induced locomotion through the combination of pharmacokinetic effects and the blockade of H(3) receptors located on non-histaminergic neurons.

The clinical pharmacology of biochemical measures of nicotine exposure has been thoroughly reviewed with regard to usefulness and limitations in detecting abstinence from cigarette smoking. While plasma nicotine concentration measures only acute nicotine exposure, plasma, salivary, and urine cotinine concentrations reflect exposure over an extended period of time. Although, expired carbon monoxide (CO) is frequently used to confirm self reports, it has a relatively short half life, calling into question whether this measure might provide misleading information by exaggerating smoking cessation success rates. To examine this question, we analyzed expired CO, plasma cotinine and self report data collected in a clinical trial in which subjects (N=207) were randomly assigned to gain- or loss-framed messages for smoking cessation in combination with open label sustained-release bupropion (300mg/day). In examining measurements collected at 6 weeks, 3 and 6 months, results showed that CO significantly overestimated abstinence rates as compared with cotinine, although the discrepancy was less at the later time points. These data suggest that while expired CO is a useful and well-established marker in certain contexts, when testing extended abstinence from smoking with non-nicotine medications, cotinine measurements should be preferred.

BACKGROUND: Individuals with schizophrenia smoke at higher rates (58%-88%) than the general population ( approximately 22%), and have difficulty quitting. We determined whether the combination of sustained-release (SR) bupropion (BUP) with the transdermal nicotine patch (TNP) was well-tolerated and superior to placebo (PLO)+TNP for smoking cessation in schizophrenia. METHODS: A 10-week, double-blind, placebo-controlled trial of BUP (300 mg/day) in combination with TNP (21 mg/24h) for 58 outpatient smokers with schizophrenia was conducted. Primary outcome measures were continuous smoking abstinence in the last 4 weeks of the trial (Days 43-70) and 7-day point prevalence abstinence at 6 months post-target quit date (TQD)(week 26). RESULTS: Smokers assigned to the BUP+TNP group (n = 29) were more likely to achieve continuous smoking abstinence (8/29, 27.6%) than the PLO+TNP group (n = 29, 1/29, 3.4%)[Fisher's Exact Test, p <.05]; at 6-months post-TQD, 4/29 (13.8%) versus 0/29 (0.0%) achieved 7-day point prevalence smoking abstinence (p =.11). Neither bupropion SR nor smoking abstinence significantly altered the positive or negative symptoms of schizophrenia. The combination was well-tolerated in smokers with schizophrenia. CONCLUSIONS: Combination therapy with bupropion SR+TNP versus placebo+TNP is well-tolerated and significantly improved short-term smoking abstinence in smokers with schizophrenia.

Prospect theory suggests that because smoking cessation is a prevention behavior with a fairly certain outcome, gain-framed messages will be more persuasive than loss-framed messages when attempting to encourage smoking cessation. To test this hypothesis, the authors randomly assigned participants (N=258) in a clinical trial to either a gain- or loss-framed condition, in which they received factually equivalent video and printed messages encouraging smoking cessation that emphasized either the benefits of quitting (gains) or the costs of continuing to smoke (losses), respectively. All participants received open label sustained-release bupropion (300 mg/day) for 7 weeks. In the intent-to-treat analysis, the difference between the experimental groups by either point prevalence or continuous abstinence was not statistically significant. Among 170 treatment completers, however, a significantly higher proportion of participants were continuously abstinent in the gain-framed condition as compared with the loss-framed condition. These data suggest that gain-framed messages may be more persuasive than loss-framed messages in promoting early success in smoking cessation for participants who are engaged in treatment.(PsycINFO Database Record (c) 2007 APA, all rights reserved).

We report results of a randomized, double-blind, placebo-controlled, within-subject study (n = 8) to determine the ability of cocaethylene to modulate acute responses to cocaine and identify significant pharmacokinetic interactions between cocaine and cocaethylene. Stable plasma cocaethylene concentrations (0, 50, or 200 ng/ml) were maintained for 840 minutes. Cocaine (0, 0.25, or 0.5 mg/kg) was injected over 1 minute after 240 minutes of cocaethylene. Blood samples, subjective, and physiological measures were collected. No differences over baseline responses were observed following 240 minutes of a steady state cocaethylene infusion for cardiovascular or subjective responses."Rush" duration following a cocaine challenge (0.5 mg/kg) declined when administered during the course of a 200 ng/mL cocaethylene infusion.(p = 0.01). No pharmacokinetic interaction occurred when cocaine was administered in conjunction with cocaethylene. Findings indicate that continuous 8-hour exposure to cocaethylene is safe, produces acute tolerance to itself, and reduces some behavioral effects of coadministered cocaine. Agonist substitution therapy may have potential as an alternative treatment for cocaine dependence.

The Medication Adherence Questionnaire (MAQ) is a scale used to evaluate adherence to medications. The present study assessed the factor structure and validity of the MAQ with cigarette smokers. A principal components analysis was conducted on MAQ scores from a sample of smokers presenting for treatment in a clinical trial of naltrexone and nicotine patch for smoking cessation (N = 385). Indices of convergent and predictive validity were tested using electronic medication caps for naltrexone, nicotine patch counts, plasma drug levels of naltrexone, and treatment outcomes. The principal components analysis revealed two factors. Factor 1, labeled "unintentional nonadherence," measured the extent to which individuals were nonadherent because they were careless or forgot to take their medications. Factor 2, labeled "purposeful nonadherence," assessed nonadherence related to purposefully stopping medication use after feeling better or worse. Only the second factor was shown to have good convergent and predictive validity. Specifically, this factor was related to pill-taking behavior measured with electronic medication caps and drug plasma levels and nicotine patch use based on nicotine patch count data, and it was associated with smoking cessation outcome. Thus the purposeful nonadherence factor of the MAQ may be used as a brief screening tool for medication adherence with cigarette smokers seeking treatment. Information obtained with this questionnaire could be used to counsel patients regarding the importance of medication adherence.

BACKGROUND: Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. We compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting. METHODS: Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/dayx3 days) in a randomized, counterbalanced manner. RESULTS: Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement. CONCLUSIONS: 1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS.

We examined drug interactions between buprenorphine, an opioid partial agonist available by prescription for treatment of opioid dependence, and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per PI) participated in 24-h pharmacokinetic studies, before and after administration of each PI. Symptoms of opiate withdrawal and excess were determined before and after PI administration. PI pharmacokinetics were determined and compared between opiate-dependent participants and healthy control participants (n=15 per PI). Administration of RTV, but not of NFV or LPV/R, resulted in a significant increase in the buprenorphine area under the concentration-time curve (AUC). Symptoms of opiate excess, however, were not observed. Buprenorphine had no significant effects on PI AUC. Adjustments of doses of either buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease.