We examined whether a pretreatment phenotypic marker of nicotine metabolism rate (NMR) predicts successful smoking cessation with bupropion. Smokers (N = 414) were tested for pretreatment NMR, based on the ratio of 3′-hydroxycotinine/ cotinine derived during smoking, before entering a placebocontrolled randomized trial of bupropion plus counseling. At the end of the 10-week treatment phase, slow metabolizers (1st NMR quartile) had equivalent quit rates with placebo or bupropion (32%). Fast metabolizers (4th NMR quartile) had low quit rates with placebo (10%), and these were enhanced significantly by bupropion (34%). Smokers in the 2nd quartile (placebo: 25%, bupropion: 30%) and the 3rd quartile (placebo: 20%, bupropion: 30%) did not benefit significantly from bupropion. At the 6-month follow-up, the relationship between the NMR and quitting remained similar, but was no longer statistically significant. A pretreatment assessment of NMR may identify smokers who are most and least likely to benefit from treatment with bupropion for smoking cessation.Personalized medicine, in which therapies are delivered to individual patients on the basis of pretreatment biological markers, is emerging as a new model of healthcare delivery. 1,2 In the area of tobacco dependence treatment, genetic variants in nicotinemetabolizing enzymes are plausible candidates for prediction of therapeutic response. 3,4 Nicotine is metabolized to cotinine (COT), predominantly by the liver enzyme cytochrome P450 (CYP) 2A6; 5,6 COT is further metabolized to trans-3ʹ-hydroxycotinine (3HC) by the same enzyme. 5 Consistent with the premise that faster inactivation and elimination of nicotine lead to higher rates of smoking so as to maintain nicotine levels in the system, reproducible associations of CYP2A6 genotype with smoking behavior have been reported. 3,[7][8][9] The ratio of the levels of 3HC/COT arising from cigarette smoking, as measured in plasma, saliva, or urine, is associated with the CYP2A6 genotype. 3,10,11 This phenotype measure is highly reproducible and independent of time elapsed since the last cigarette. 12-14 Further, the ratio is strongly correlated with plasma nicotine levels and nicotine clearance. 10,14-16 Consistent with these genetic and pharmacokinetic data, we have reported that the nicotine metabolite ratio predicts successful quitting of smoking with the use of transdermal nicotine. 16 In this earlier investigation, the odds of achieving smoking cessation with transdermal nicotine therapy were reduced by 30% with each increasing quartile of the nicotine metabolite ratio. Faster metabolizers of nicotine were less successful in quitting than slower metabolizers and also had lower plasma levels of nicotine during treatment and stronger cravings to smoke.In order to extend this line of research on the role of NMR in achieving success in smoking cessation, we examined the predictive clinical validity of the 3HC/COT ratio within a double-blind placebo-controlled pharmacogenetic clinical trial of bupropion efficacy. [17][18][19] ...

OBJECTIVE:To investigate the independent influence of alterations in fat mass, body fat distribution and hormone release on pubertal increases in fasting serum insulin concentrations and on insulin resistance assessed by the homeostasis model (HOMA). DESIGN AND SUBJECTS: Cross-sectional investigation of pre-(n ¼ 11, n ¼ 8), mid-(n ¼ 10, n ¼ 11), and late-pubertal (n ¼ 10, n ¼ 11) boys and girls with normal body weight and growth velocity. MEASUREMENTS: Body composition (by a four-compartment model), abdominal fat distribution and mid-thigh interfascicular plus intermuscle (extramyocellular) fat (by magnetic resonance imaging), total body subcutaneous fat (by skinfolds), mean nocturnal growth hormone (GH) release and 06:00 h samples of serum insulin, sex steroids, leptin and insulin-like growth factor-I (IGF-I). RESULTS: Pubertal insulin resistance was suggested by greater (P < 0.001) fasting serum insulin concentrations in the latepubertal than pre-and mid-pubertal groups while serum glucose concentrations were unchanged and greater (P < 0.001) HOMA values in late-pubertal than pre-and mid-pubertal youth. From univariate correlation fat mass was most related to HOMA (r ¼ 0.59, P < 0.001). Two hierarchical regression models were developed to predict HOMA. In one approach, subject differences in sex, pubertal maturation, height and weight were held constant by adding these variables as a block in the first step of the model (r 2 ¼ 0.36). Sequential addition of fat mass (FM) increased r 2 (r 2 (inc)remental ¼ 0.08, r 2 ¼ 0.44, P < 0.05) as did the subsequent addition of a block of fat distribution variables (extramyocellular fat, abdominal visceral fat, and sum of skinfolds; r 2 inc ¼ 0.11, r 2 ¼ 0.55, P < 0.05). Sequential addition of a block of hormone variables (serum IGF-I and log (10) leptin concentrations; r 2 inc ¼ 0.04, P > 0.05) did not reliably improve r 2 beyond the physical characteristic and adiposity variables. In a second model, differences in sex and pubertal maturation were again held constant (r 2 ¼ 0.25), but body size differences were accounted for using percentage fat data. Sequential addition of percentage body fat (r 2 (inc)remental ¼ 0.11, r 2 ¼ 0.36, P < 0.05), then a block of fat distribution variables (percentage extramyocellular fat, percentage abdominal visceral fat, and percentage abdominal subcutaneous fat; r 2 inc ¼ 0.08, r 2 ¼ 0.44, P ¼ 0.058), and then a block of serum IGF-I and log (10) leptin concentrations (r 2 inc ¼ 0.07, r 2 ¼ 0.51, P < 0.05) increased r 2 . Mean nocturnal GH release was not related to HOMA (r ¼ 7 0.04, P ¼ 0.75) and therefore was not included in the hierarchical regression models. CONCLUSION: Increases in insulin resistance at puberty were most related to FM. Accumulation of fat in the abdominal visceral, subcutaneous and muscular compartments may increase insulin resistance at puberty beyond that due to total body fat. Serum concentrations of leptin and IGF-I may further modulate HOMA beyond the effects of adiposity and fat distribution. However, the results...

Two methods were used to assess nicotine-induced antinociception: tail withdrawal from a hot water bath and hind paw withdrawal from a hotplate. Nicotine doses which produced 75-80% maximum response were 0.75 mg/kg (free base) for tail withdrawal and 0.35 mg/kg for paw withdrawal. The peripheral blocker chlorisondamine (0.1 mg/kg, SC) and the central antagonist, mecamylamine (1 mg/kg, SC) were each effective in blocking nicotine-induced increases in tail withdrawal latencies, suggesting that this effect of nicotine depends on either the action of nicotine at peripheral receptors or the functional integrity of those receptors. In contrast, nicotine-induced increases in paw withdrawal latencies were blocked by mecamylamine but not by chlorisondamine, even at other agonist/antagonist dose combinations. The results indicate that these two effects of nicotine involve at least partially separate pathways and may reflect a different mix of the antinociceptive and motor depressing effects of nicotine.

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This laboratory study examined whether making sedentary activities contingent upon being physically active would increase obese children's physical activity. Fourteen obese children aged 8±12 y participated in a baseline session in which they had free choice among a variety of sedentary activities and riding a stationary bicycle. Children were then randomized to either a contingent group in which watching video cassette recorder (VCR) movies and playing video games were contingent upon riding the bicycle or a control group in which all physical and sedentary activities remained freely available. Contingent group children increased physical activity and decreased television activities in comparison to the control, even though other sedentary activities remained freely available. Findings suggest that highly valued sedentary activities can reinforce physical activities and that sedentary activities do not completely substitute amongst themselves. The automated system used to make television activities contingent upon physical activity has potential for modifying activity in the treatment of obesity.