Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses

Rationale Recent results suggest that treatment with the atypical antipsychotics clozapine and olanzapine is associated with increased insulin and lipid levels.Objective The aim of the present study was to investigate potential relationships between insulin or other hormones related to glucose–insulin homeostasis or lipids and steady-state serum concentrations of clozapine or olanzapine in patients on therapeutic doses.Methods Thirty-four patients, diagnosed with schizophrenia or related psychoses according to the DSM-IV criteria and treated with clozapine (n=18) or olanzapine (n=16), were studied. Median treatment time with the antipsychotics was 5.3 years (range 0.5–16.3 years). Fasting blood samples for insulin, C-peptide, insulin-like growth factor I, insulin-like growth factor binding protein-1, leptin, glucose and lipids were analyzed and investigated in relation to the patients' drug serum concentrations.Results Hyperinsulinemia was found in 30–60% of the patients, hyperglycemia in 10–30%, hyperlipidemia in 40–60% and hyperleptinemia in 10–20%. Moreover, levels of insulin, C-peptide and triglycerides correlated positively to the clozapine serum concentration and to the ratio of olanzapine to N-desmethylolanzapine concentrations. In contrast, levels of C-peptide, leptin and blood glucose were inversely correlated to the serum concentration of the metabolite N-desmethylolanzapine.Conclusions Metabolic abnormalities (i.e. hyperinsulinemia, hyperlipidemia and hyperleptinemia) and insulin resistance were associated with both clozapine and olanzapine treatments. Levels of insulin and triglycerides increased by increasing clozapine serum concentration and by increasing ratio of olanzapine to N-desmethylolanzapine; the last due to the metabolite N-desmethylolanzapine probably having an inverse effect to the main compound olanzapine. Thus, the metabolic abnormalities induced by these two drugs are clozapine-concentration dependent in clozapine-treated patients, and ratio of olanzapine to N-desmethylolanzapine-concentration dependent in olanzapine-treated patients.     

Lack of genotoxic effect in workers exposed to very low doses of 1,3-butadiene

1,3-butadiene (BD), a probable carcinogen to humans, has been shown to have an ill-defined genotoxicity in occupationally exposed workers. In the present study, the influence of exposure to very low doses of BD and to cigarette smoking was investigated on some cytogenetic endpoints, namely, sister chromatid exchanges (SCE), chromosomal aberrations (CA) and cells with a high frequency of SCE (HFC), in peripheral blood lymphocytes. Twenty-seven male workers employed in a petrochemical plant and 26 matched controls were included in the study. As regards the airborne BD values, there was a significant difference between exposed (median BD value 1.5, min–max 0.2–69.0 μg/m³) and non-exposed workers (median BD value 0.4, min–max <0.1–3.8 μg/m³). Genotoxic biomarkers were not able to distinguish between the two groups. The frequency of SCE was higher in smokers than in non-smokers (p=0.001), with a positive correlation between the number of cigarettes smoked per day and both SCE (r=0.4; p=0.004) and HFC frequency (r=0.3; p=0.04). Multiple regression analysis confirmed the influence of cigarette smoking on the level of SCE and HFC, while these parameters were not affected by personal exposure to BD. Overall, the biomarkers of genotoxic effect investigated in our study were not able to discriminate between workers with a very low exposure to BD and controls, while it was possible to distinguish between smokers and non-smokers on the basis of SCE.Piero Lovreglio and Nenad Bukvic have contributed equally to this study     

Hormonal, cardiovascular, and subjective responses to acute stress in smokers

Rationale  There are complex relationships between stress and smoking; smoking may reduce the emotional discomfort of stress, yet nicotine activates stress systems and may alter responses to acute stress. It is important to understand how smoking affects physiological and psychological outcomes after stress and how these may interact to motivate smoking. Objectives  This study aimed to examine the magnitude and time course of hormonal, cardiovascular, and psychological responses to acute psychosocial stress in smokers and non-smokers to investigate whether responses to acute stress are altered in smokers. Materials and methods  Healthy male non-smokers (n = 20) and smokers (n = 15) participated in two experimental sessions involving a standardized public speaking stress procedure and a control non-stressful task. The outcome measures included self-reported mood, cardiovascular measures (heart rate and blood pressure), and plasma hormone levels (noradrenaline, cortisol, progesterone, and allopregnanolone). Results  Smokers exhibited blunted increases in cortisol after the Trier Social Stress Test, and they reported greater and more prolonged subjective agitation than non-smokers. Stress-induced changes in progesterone were similar between smokers and non-smokers, although responses overall were smaller among smokers. Stress did not significantly alter levels of allopregnanolone, but smokers exhibited lower plasma concentrations of this neurosteroid. Conclusions  These findings suggest that smoking dampens hormonal responses to stress and prolongs subjective discomfort. Dysregulated stress responses may represent a breakdown in the body’s ability to cope efficiently and effectively with stress and may contribute to smokers’ susceptibility to acute stress, especially during abstinence.     

Occupancy of dopamine D2 receptors by antipsychotic drugs is related to nicotine addiction in young patients with schizophrenia

Rationale Occupancy of dopamine D₂ receptors by antipsychotic drugs depends on the individual availability of D₂ receptors and on the dose and type of antipsychotic medication. It has been suggested that a low availability of these receptors may increase the risk for addictive behavior. Objective This study aims to show that patients with relatively high occupancy of D₂ receptors by antipsychotic drugs are more prone to nicotine consumption. Methods Striatal D₂ receptor occupancy by equivalent doses of olanzapine or risperidone was assessed with [¹²³I]iodobenzamide single-photon emission computed tomography (SPECT) in 36 patients with schizophrenia. Smoking status at the time of SPECT imaging was assessed. The number of cigarettes used in the following three consecutive years was estimated with the Life Chart Schedule (LCS). Results There was a positive and significant relation between D₂ receptor occupancy following treatment with olanzapine (n=19) or risperidone (n=12) and the number of cigarettes smoked in three consecutive years (r=0.60, p<0.001) in patients who smoked. There was a significant difference in the percentage of D₂ occupancy for smokers (mean 74.3%, SD 12.8, n=31) and nonsmokers (mean 49.8%, SD 9.1, n=5). Conclusion Frequency of cigarette smoking in schizophrenic patients treated with antipsychotic medication is significantly and negatively related to the availability of striatal D₂ receptors.     

Effects of acute tyrosine/phenylalanine depletion on the selective processing of smoking-related cues and the relative value of cigarettes in smokers

Rationale Acute tyrosine/phenylalanine depletion (ATPD) is a validated neurobiological challenge that results in reduced dopaminergic neurotransmission, allowing examination of the effects of a hypodopaminergic state on craving-related processes. Objectives We studied 16 nonabstaining smokers (>10 cigarettes/day; 9 males; age 20–33 years) to whom was administered a tyrosine/phenylalanine-free mixture (TYR/PHE-free) and a balanced amino acid mixture (BAL) in a double-blind, counterbalanced, crossover design. Methods Subjective cigarette craving, attentional bias to smoking-related word cues, relative value of cigarettes, negative mood, and expired carbon monoxide (CO) levels were measured at various timepoints through 300 min. Participants smoked at hourly intervals to prevent acute nicotine withdrawal during testing. Results The TYR/PHE-free mixture, as compared to the BAL mixture, was associated with a greater increase in CO levels from baseline (p = 0.01). Adjusting for the potential confounding influence of between-condition differences in CO levels across time, TYR/PHE-free mixture was associated with increased demand for cigarettes (p = 0.01) and decreased attentional bias toward smoking-related words (p = 0.003). There were no significant differences between conditions in either subjective craving or depressed or anxious mood (p values > 0.05). Conclusion Among nonabstaining daily smokers, acute dopaminergic depletion via ATPD may influence smoking behavior and indices of smoking-related motivation, such as attentional bias to smoking cues and relative cigarette value, which are not readily captured by subjective craving.     

Cigarette smoking by women: interactions with alcohol use

Cigarette smoking increased during alcohol self-administration in comparison to an alcohol-free baseline in 24 women given access to alcohol for 21 days. Heavy smokers (25 or more cigarettes per day) increased smoking significantly during drinking (P<0.05). Analysis of tobacco smoking by level of alcohol consumption showed that both heavy and moderate alcohol users increased smoking significantly during alcohol availability (P<0.05, 0.01). The heavy and moderate smokers smoked significantly more between noon and midnight (P<0.001) than at other times when alcohol was available. The rate of cigarette smoking (defined by inter-cigarette intervals) was faster during alcohol self-administration than during the alcohol-free baseline. Heavy smokers smoked most cigarettes at intervals of 11–20 min during heavy or moderate drinking. During the pre-alcohol baseline, these women smoked most cigarettes at intervals of 21–30 or 31–40 min. Most women (70–74%) also increased tobacco smoking at the premenstruum. Both heavy and occasional smokers increased smoking at the premenstruum significantly more than the moderate smokers (P<0.05). All women reported increased psychological discomfort at the premenstruum on the Premenstrual Assessment Form (PAF) but reports of physical discomfort were more marked in women who smoked less at the premenstruum. These data extend previous findings in men that alcohol consumption is associated with increased cigarette smoking to female social drinkers.     

Effect of tryptophan depletion on the attentional salience of smoking cues

Rationale There is increasing evidence linking cigarette craving and smoking behavior to serotonergic neurotransmission. Objectives The purpose of the current study was to examine the effects of a serotonergic challenge on the attentional salience of various cues associated with cigarettes. We hypothesized that cigarette-related word cues would be more distracting after acute tryptophan depletion than after a placebo challenge. We also hypothesized that smokers vulnerable to recurrent depression would show greater attentional bias towards these cues than smokers without a history of depression. Methods Thirty-four smokers diagnosed as having (n = 15) or lacking (n = 19) a history of DSM-IV major depressive disorder (MDD) underwent acute tryptophan depletion (ATD) and placebo challenges in double-blind and counterbalanced order 1 week apart. Five hours after consumption of each mixture, subjects completed a modified Stroop task to measure attentional bias to smoking-related, positive affect, and negative affect word cues. Stroop interference was calculated as a difference score between latencies for the motivationally salient and the neutral (furniture) word lists. Results Controlling for change in dysphoric mood from baseline to 5 h, repeated measures MANOVAs showed that ATD, as compared to placebo challenge, produced greater interference for smoking word cues [F(1,29)=4.15, p = 0.05], but not for negative [F(1,29)=2.78, p = 0.11] or positive [F(1,29)=1.60, p = 0.22] affect word cues. Conclusions Acutely compromising central serotonergic neurotransmission via ATD heightens the attentional salience of cigarette-related cues, perhaps by triggering reward and motivational deficits underlying nicotine dependence.     

Effects of instructions on responses to the nicotine patch: a laboratory study

Rationale Smokers have weak positive expectancies for nicotine replacement therapies relative to smoking (Juliano and Brandon, Nicotine Tob Res, 6:569–574, 2004). Objectives This study investigated if a manipulation designed to alter expectancies for the nicotine patch was effective in increasing positive expectancies for the patch and influencing smoking cessation outcomes during a 2-day abstinence period. Materials and methods Smokers (n = 72) were randomly assigned to receive information that emphasized either patch benefits (n = 25) or standard patch information including side effects (n = 25). Participants wore placebo patches but were told that the patches contained nicotine. A control condition (n = 22) was informed that they received placebo patches while given standard patch information to independently test the effect of the nicotine-dose instructional set on abstinence outcomes. Results Benefits information significantly increased positive expectancies for the patch and promoted positive mood during the abstinence period relative to the side effects information. Nicotine-dose instructions resulted in fewer lapsed cigarettes and higher ratings of patch helpfulness than placebo instructions. In particular, women’s smoking behavior appeared to be more influenced by nicotine instructions than that of men. Conclusions The results of this preliminary study suggest that information provided to smokers about patch effects and nicotine content may influence behavioral and subjective outcomes of patch use.     

Neuroactive steroids, negative affect, and nicotine dependence severity in male smokers

Rationale Nicotine administration alters neuroactive steroids in rodent models, and serum levels of the neuroactive steroid DHEAS (dehydroepiandrosterone sulfate) appear to be higher in smokers. These molecules may be relevant to tobacco addiction and affective symptoms.Objectives This study aims to investigate DHEAS, allopregnanolone, pregnenolone, and other steroids in male smokers to determine potential associations with nicotine dependence severity and negative affect.Materials and methods Allopregnanolone and pregnenolone serum levels were determined by gas chromatography/mass spectrometry, while DHEAS and other steroid levels were determined by radioimmunoassay in 28 male smokers. Correlational analyses were performed to determine potential associations with rating measures, including the Fagerstrom Test for Nicotine Dependence (FTND), the addiction subscale of the Ikard Smoking Motivation Questionnaire (ISMQ), the craving item on the Reasons to Smoke (RTS) Questionnaire, and the negative affect and craving subscales of the Shiffman–Jarvik Withdrawal Questionnaire.Results DHEAS levels were inversely correlated with the negative affect subscale of the Shiffman–Jarvik Withdrawal Questionnaire (r=−0.60, p=0.002) and the RTS craving item (r=−0.43, p=0.03), and tended to be inversely correlated with the FTND scores (r=−0.38, p=0.067) and the ISMQ addiction subscale (r=−0.38, p=0.059), adjusting for age. Allopregnanolone levels were positively correlated with cotinine levels (r=0.57, p=0.006); pregnenolone levels tended to be positively correlated with cotinine levels (r=0.40, p=0.066).Conclusions DHEAS levels were inversely correlated with negative affect and craving measures, and may predict nicotine dependence severity. Allopregnanolone levels were positively correlated with cotinine levels, suggesting that this neuroactive steroid may be upregulated in smokers. Neuroactive steroids may represent novel smoking cessation agents.     

The effects of maternal smoking on pregnancy outcome and placental histopathology lesions

ObjectiveTo study the effects of maternal smoking on pregnancy outcome and placental histopathology findings.Materials & methodsMaternal and labor characteristics and pathological reports were compared between term placentas of complicated and uncomplicated pregnancies of: heavy smokers (>10 cigarettes per day, H-smokers), moderate smokers (<10 cigarettes per day, M-smokers) and non-smokers (controls, N-smokers).ResultsBirth-weights were lower in the H-smokers and M-smokers as compared to the N-smokers (p < 0.001), with a higher rate of small for gestational age (SGA): 18.2%, 19.2% and 11.4%, respectively (p = 0.01). Deliveries among smokers were characterized by higher rates of abnormal fetal heart rate tracings during labor as compared to non-smokers (p = 0.01). Rates of placental maternal and fetal stromal-vascular supply lesions was similar between the groups.ConclusionsMaternal smoking is associated with higher rates of SGA. Tobacco’s potential influence is probably through the disruption of normal placental epigenetic patterns, not expressed in placental histopathology lesions.     

The relationship between level of cigarette consumption and latency to the onset of retrospectively reported withdrawal symptoms

Rationale Subthreshold smokers (who smoke ≤5 cigarettes/day) experience withdrawal symptoms, yet they smoke less than is required to maintain serum nicotine levels.Objectives For study 1, our aim was to determine (1) if adult subthreshold smokers report withdrawal symptoms; (2) how they rate symptom severity; (3) the length of their latency to withdrawal symptoms; (4) and the relationship between level of cigarette consumption and latency to withdrawal. The aim of study 2 was to attempt to replicate the results of study 1 in a nationally representative sample and to compare subthreshold and threshold (≥6 cigarettes/day) smokers.Methods Study 1 was conducted through telephone interviews. Study 2 was conducted through secondary analysis of data from the National Youth Tobacco Survey (self-administered in schools).Results In study 1, all subjects experienced withdrawal symptoms. The mean number of symptoms was 4.3; mean intensity of each symptom was >6 (1–10 scale). A quarter of the subjects could go for ≥2 days before experiencing withdrawal. More frequent smokers had a shorter latency to withdrawal (r=−0.43, p<0.001, n=36). In study 2, 63% of subthreshold smokers reported feeling at least one withdrawal symptom. Median latency to withdrawal was 168 h for subthreshold and 2 h for threshold smokers. A negative correlation between level of cigarette consumption and latency to withdrawal was observed for both groups.Conclusions Although subthreshold smokers experience significant withdrawal symptoms, they can smoke infrequently because symptoms may not appear for one to several days. Consistent with the sensitization–homeostasis theory, low doses of nicotine can suppress withdrawal symptoms over long periods.     

Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals

We investigated the degree of striatal dopamine-2 (D₂) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10–25 mg/day in comparison to patients treated with clozapine 300–600 mg/day (n = 6) or haloperidol 5–20 mg/day (n = 10). ¹²³I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D₂ receptors. For the quantification of striatal D₂ receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D₂ receptor occupancy rate of 75% (range 63–85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67–94). During clozapine treatment, the mean D₂ receptor occupancy of 33% (range < 20–49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D₂ receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D₂ receptor occupancy and clinical improvement. Received: 18 March 1998/Final version: 10 June 1998     

Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking

Rationale It has been suggested that a susceptibility locus near the gene encoding the brain-derived neurotrophic factor (BDNF) contributes to individual differences in human addiction vulnerability. BDNF modulates several behaviors that are associated with addictive drugs, and upregulation of BDNF was found to be associated with several drugs of abuse such as amphetamine, cocaine, and nicotine. In this study, we addressed the question if a common BDNF missense variation (Val66Met) influences the risk for smoking behavior in otherwise healthy human volunteers. Materials and methods In total, 320 healthy unrelated volunteers (155 male, 165 female, mean age: 38.4 ± 14.1 years) consisting of 43.3% never smokers, 20.9% former smokers, and 35.6% current smokers were investigated. Results The frequency of both Met/Met genotype and Met allele was significantly increased in current and in former smokers when compared to never smokers (χ ² = 10.856, df = 2, p = 0.004 and χ ² = 4.350, df = 1, p = 0.045, respectively). Conclusions Our results suggest that humans who carry the Met allele of the BDNF missense polymorphism might be more vulnerable to initiate and also maintain smoking.     

Patterns of intermittent smoking: An analysis using Ecological Momentary Assessment

Non-daily smokers comprise a substantial proportion of US smokers, but there has been little study of their patterns of smoking, which are often assumed to reflect “social smoking.” We used Ecological Momentary Assessment methods to study smoking patterns in 27 non-daily smoking adults who recorded each cigarette smoked over three weeks by leaving a voice mail message indicating their circumstances at the time of smoking. All told, 689 cigarettes were recorded over 589 person-days of observation. On average, participants smoked on 67% of days, averaging 2.1 (SD = 0.91) cigarettes per day on days they smoked; 22% of all cigarettes were smoked in bouts (within an hour of another cigarette). Altogether, 19% of cigarettes were smoked when drinking alcohol and 29% when participants were socializing. Smoking patterns varied widely across participants. A pair of hierarchical cluster analyses distinguished three groups: Those who smoked primarily (81% of cigarettes) in the daytime (Early smokers; n = 15, 58% of total sample), those who smoked primarily (75% of cigarettes) at night (Late smokers; n = 7, 27%), and a distinct, classic “Social smoking” group (n = 4, 15% of total sample), who smoked mostly at night but also primarily when socializing or drinking (86% of their cigarettes), in the evening (71% of their cigarettes), on weekends (65% of their cigarettes), and in bouts (71% of their cigarettes). Overall, results suggest that non-daily smoking patterns are quite heterogeneous, and that many non-daily smokers may not be primarily social smokers.     

Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin

Objective The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe.Methods A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition.Results The S-warfarin between smokers and non-smokers did not differ by >25% after inhibition. There was no difference in S-warfarin during baseline (p=0.45) or inhibition (p=0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42±29% and 26±18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (C_{at 1 h}) or (−) 3S,5R-fluvastatin AUC_{0–12 h} and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between C_{at 1 h} and extent of warfarin inhibition.Conclusions Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.     

Effect of impulsivity on craving and behavioral reactivity to smoking cues

Introduction Nearly 25% of American adults remain regular smokers. Current smokers may be especially likely to possess characteristics that impair their ability to quit, such as impulsivity. Impulsive individuals may be overly prone to smoke because they are particularly drawn to rewarding stimuli and related cues. The aim of this study was to test the hypothesis that more impulsive smokers are more responsive to cigarette cues than other smokers. Materials and methods In a repeated measures design, 60 euthymic, adult smokers (50% female) were exposed to a smoking cue and a neutral cue in two experimental sessions. Cue reactivity was operationalized as changes in cigarette craving and preference for immediate vs delayed smoking after cue exposure. Results Impulsivity predicted a heightened craving response to both cues but particularly the smoking cue (t [161] = 3.21, p = 0.002). Smokers with high levels of impulsivity exhibited a greater preference for immediate rewards over larger, delayed rewards in terms of both hypothetical (t [58] = 5.99, p = 0.001) and actual (z = 3.02, p = 0.003) rewards. Conclusion These data suggest that increased reactivity to environmental smoking cues contributes to the link between impulsivity and smoking.     

Hydroxyethylvaline adduct formation in haemoglobin as a biological monitor of cigarette smoke intake

The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the HOEtVal thiohydantoin product, derivatization of this by trimethylsilylation and quantitation by capillary gas chromatography with selective ion monitoring mass spectrometry using a tetradeuterated internal standard. The method was applied to globin samples from 26 habitual cigarette smokers and 24 non-smokers. There was a significant correlation between cigarette smoke intake as measured by the average number of cigarettes smoked per day and HOEtVal levels (r=0.537, p<0.01). Background levels were found in non-smokers (mean 49.9 pmol/g Hb, range 22–106 pmol/g Hb). Smoking increased these levels by 71 pmol/g Hb/ 10 cigarettes per day.Cotinine levels in plasma of the smokers were determined by GC-NPD using 2-methyl-4-nitroaniline as internal standard. For non-smokers cotinine was determined by GC-MS selective ion monitoring using d₃-methylcotinine as internal standard. There was no correlation between number of cigarettes smoked per day and cotinine levels (r=0.297, p>0.05) although cotinine was correlated with HOEtVal (r=0.43, p<0.01).The HOEtVal adduct levels thus appear to be a suitable biomonitor for exposure to hydroxyethylating agents in cigarette smoke, reflecting an integrated dose over the erythrocyte lifetime. This is in contrast to plasma cotinine determinations which reflect only the previous day's exposure to nicotine in smoke.     

Determinants of plasma concentrations of nicotine and cotinine during cigarette smoking and transdermal nicotine treatment

Objective: Interindividual variability in plasma concentrations of nicotine and its proximate metabolite, cotinine, is considerable during smoking and transdermal nicotine treatment, even among individuals taking in nominally similar doses of nicotine. This report explores the determinants of this variability and the utility of baseline (smoking) plasma concentrations to predict concentrations during transdermal nicotine treatment. Methods: Data were analysed from a smoking cessation study (n = 466), and from a pharmacokinetic study (n = 12). Multiple regression models examined the relationships of plasma concentrations to individual characteristics such as smoking pattern, absorbed dose of nicotine, and pharmacokinetic parameters. Results: Plasma concentrations of nicotine and cotinine were highly variable in both studies. Indirect estimates of plasma clearance (baseline plasma concentration divided by cigarettes per day) together with other factors could account for 18 to 33% of the variability during transdermal nicotine treatment in the smoking cessation study. In contrast, 75 to 99% was accounted for by direct measurements of plasma clearances and systemic dose of nicotine in the pharmacokinetic study. Conclusion: Plasma concentrations of nicotine and cotinine during transdermal nicotine treatment are poorly predicted by clinical history or baseline plasma concentrations. This is a result of inadequate characterisation of highly variable individual pharmacokinetic parameters and absorbed dose of nicotine. Considering the interindividual variability of plasma nicotine and cotinine concentrations together with the lack of clinical end-points for transdermal nicotine dosing, it seems logical to investigate the utility of a therapeutic drug monitoring approach for transdermal nicotine treatment – particularly for high dose regimens (> 22 mg per 24 hours). Received: 7 May 1996 / Accepted in revised form: 21 August 1996     

Clozapine Serum Concentrations are Lower in Smoking than in Non-Smoking Schizophrenic Patients

Abstract Serum concentrations of clozapine and its main metabolite demethylclozapine were measured in 44 schizophrenic inpatients, of whom ten were non-smokers and 34 smokers. When comparing their clozapine dose and body weight-related serum drug levels, we found that clozapine and demethylclozapine concentrations were about 40% lower in the smoking than in the non-smoking group, probably due to an inducing effect of smoking on the cytochrome P450 (CYP) 1A2, which is involved in the metabolism of clozapine. We conclude that dosage adjustment may be necessary in clozapine-treated smokers.     

Sensitivity and tolerance to nicotine in smokers and nonsmokers

We studied the responses of smokers and life-long non-smokers to transdermal nicotine patches over 24 h in three groups of subjects: non-smokers on a 15 mg patch (n=8), non-smokers on a 30 mg patch (n=8) and smokers on a 30 mg patch (n=8). Unexpectedly, the non-smokers appeared to absorb nicotine more rapidly. The increase in blood nicotine concentrations of non-smokers over the first 2 h of patch use was double that of the smokers, with mean increases of 4.5 (SD=3.7), 10.9 (SD=4.2) and 4.1 (SD=2.7) ng/ml in the three groups, respectively (P<0.005). The smokers had no pleasant or unpleasant effects from the 30 mg patch ( C_max 13.9 ng/ml, SD=4.9; T_max 8.75 h) but all eight non-smokers experienced mild nausea and lightheadedness (P<0.01) within the first hour, and seven dropped out (P<0.01) at 3–8 h due mainly to severe nausea, vomiting or headache ( C_max 18.4 ng/ml, SD=4.9; T_max 5.25 h). Only one non-smoker dropped out on the 15 mg patch, but five had transient nausea in the first hour ( C_max 7.9 ng/ml, SD=3.0; T_max 8.0). Our study provides evidence of chronic pharmacodynamic nicotine tolerance in smokers, but does not address whether this is acquired or innate. The higher rate of transdermal nicotine absorption in non-smokers is unexplained and requires replication.