Anabasine toxicity from a topical folk remedy.
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Anabasine↗
Biomedical subjects
Neal L Benowitz
Publications and source records attributed to Neal L Benowitz.
Increased nicotine and cotinine levels in smokers with schizophrenia and schizoaffective disorder is not a metabolic effect.
It has been hypothesized that smokers with schizophrenia take in more nicotine per cigarette than smokers without this disorder. This study examines this phenomenon by comparing the serum nicotine and cotinine levels in smokers with either schizophrenia or schizoaffective disorder compared to control smokers without mental illness. Serum cotinine and nicotine levels of smokers with schizophrenia or schizoaffective disorder were 1.3 times higher than control smokers (cotinine 291 versus 227 ng/mL; p = 0.0115; nicotine 28 versus 21 ng/mL; p < 0.001) despite smoking a similar number of cigarettes per day. Similar serum 3'-hydroxycotinine (3HC) to cotinine ratios in both groups indicate that this difference was not due to differences in the rate of metabolism of nicotine or cotinine. By examining serum nicotine and 3HC/cotinine ratios in addition to cotinine, this study expands upon previous research that relied on cotinine as an indirect indicator for nicotine intake. Our data support the hypothesis that the increased serum nicotine and cotinine levels observed are attributable to an increased nicotine intake per cigarette in smokers with schizophrenia as compared to those without mental illness.
Adult↗
Hemodynamic effects of ephedra-free weight-loss supplements in humans.
PURPOSE: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C. aurantium dietary supplements. SUBJECTS AND METHODS: Ten healthy adult nonsmokers participated in a randomized, double-blind, placebo-controlled, three-arm crossover study. Single doses of C. aurantium (Advantra Z) containing 46.9 mg synephrine, Xenadrine EFX, a multi-component formulation containing 5.5 mg synephrine, and placebo were administered with a one-week washout. RESULTS: Compared with placebo, Xenadrine EFX but not Advantra Z increased systolic and diastolic blood pressure with peak changes from baseline at 2 hours of 9.6 +/- 6.2 mm Hg systolic (P = 0.047), and 9.1 +/- 7.8 mm Hg diastolic (P = 0.002). Heart rate was increased from baseline at 6 hours compared with placebo (16.7 beats per minute with Xenadrine EFX, P = 0.011; 11.4 beats per minute with Advantra Z, P = 0.031). Dose-adjusted synephrine pharmacokinetics were similar between treatments with t(max) = 90 min, t(1/2) = 3.0 hours, V/F = 16347 L, and CL/F = 88.9 L/min for Xenadrine EFX. CONCLUSION: Ephedra-free weight loss supplements have significant cardiovascular stimulant actions, similar to ephedra. These effects are not likely caused by C. aurantium alone, because an eightfold higher dose of synephrine (Advantra Z) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the multi-component formulation.
Administration, Oral↗
Influence of menstrual cycle on cytochrome P450 2A6 activity and cardiovascular effects of nicotine.
BACKGROUND AND OBJECTIVES: The phase of the menstrual cycle has been reported to affect frequency of smoking, withdrawal symptoms, and the likelihood of smoking cessation in women. Cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Our objective was to evaluate the effect of the phase of the menstrual cycle on the activity of CYP2A6 and the cardiovascular effects of nicotine. METHOD: Eleven healthy, nonsmoking women received a 30-minute combined infusion of deuterium-labeled nicotine and cotinine (0.5 microg . kg(-1) . min(-1) of each compound) during the midfollicular and midluteal phases of the menstrual cycle. Nicotine and cotinine pharmacokinetic parameters and plasma adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine responses were measured over time. RESULTS: There were no biologically or statistically significant differences in the comparison of menstrual cycle phases with regard to the pharmacokinetics of nicotine and cotinine. Nicotine clearance was 1000 +/- 315 mL/min and 1047 +/- 271 mL/min in the follicular and luteal phases, respectively (geometric mean ratio, 1.06; 90% confidence interval, 0.87-1.29). Cotinine clearance was 44 +/- 20 mL/min and 55 +/- 42 mL/min in the follicular and luteal phases, respectively (geometric mean ratio, 1.13; 90% confidence interval, 0.90-1.41). Nicotine infusion increased blood pressure, heart rate, and epinephrine concentrations. There were no differences in catecholamine, ACTH, or hemodynamic responses to nicotine infusion between menstrual cycle phases, although norepinephrine concentrations were constantly higher in the luteal phase compared with the follicular phase. CONCLUSIONS: CYP2A6 activity is not affected by menstrual cycle phase, and it is unlikely that menstrual cycle-related smoking habits of women are determined by changes in nicotine pharmacokinetics. The effects of nicotine on plasma ACTH and catecholamine levels and hemodynamic parameters are not altered by menstrual cycle phase in healthy, nonsmoking women.
Adrenocorticotropic Hormone↗
Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.
OBJECTIVE: Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi-ingredient formulations contribute to the adverse effects of these supplements. METHODS: In this study, 16 healthy adults (8 women) took 2 doses each of ephedra-guarana alone, Xenadrine RFA, a multicomponent dietary supplement containing 25 mg ephedra alkaloids and 200 mg caffeine, or placebo 5 hours apart in a randomized, double-blind, 3-arm crossover study. RESULTS: Peak plasma ephedrine levels averaged 130 to 140 ng/mL. Compared with placebo, Xenadrine and ephedra-guarana significantly increased heart rate (maximum increase, 9.4 +/- 8.6 beats/min; P = .002), blood pressure (maximum increase in systolic and diastolic pressure, 11.5 +/- 10.7 mm Hg and 7.3 +/- 7.4 mm Hg, respectively; P = .015), postprandial glucose concentration (maximum change, 41.0 +/- 18.8 mg/dL; P < .0001), and insulin concentration (maximum change, 41.2 +/- 47.8 microIU/mL; P = .005). Serum potassium concentrations were significantly decreased by both treatments. Hemodynamic and metabolic changes were observed after both the first and second doses. However, plasma free fatty acid concentrations increased after the first dose only. Xenadrine RFA produced higher increases in glucose concentration than ephedra-guarana, but no other pharmacodynamic differences between the treatments were found. CONCLUSIONS: Consumption of 2 doses of ephedra and guarana supplements, per supplement label recommendations, results in persistent increases in heart rate and blood pressure and unfavorable actions on glucose and potassium homeostasis. Such effects could be detrimental in persons with hypertension, atherosclerosis, or glucose intolerance, conditions that are strongly associated with obesity.
Adolescent↗
Support for previously identified alcoholism susceptibility Loci in a cohort selected for smoking behavior.
BACKGROUND: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior. METHODS: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality. RESULTS: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies. CONCLUSIONS: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition.
Alcohol Drinking↗
Nicotine metabolism: the impact of CYP2A6 on estimates of additive genetic influence.
To conduct a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty nine twin pairs [110 monozygotic (MZ) and 29 dizygotic (DZ)] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite, cotinine, followed by an 8-h in-hospital stay. Blood and urine samples were taken at regular intervals for analysis of nicotine, cotinine and metabolites by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry and subsequent characterization of pharmacokinetic and metabolism phenotypes. DNA was genotyped to confirm zygosity and for variation in the gene for the primary enzyme involved in nicotine metabolism, CYP2A6 (alleles tested: *1, *1x2, *2, *4, *7, *9 and *12). Univariate biometric analyses quantified genetic and environmental influences on each pharmacokinetic measure in the presence and absence of covariates, including measured CYP2A6 genotype. The best-fitting model identified a substantial amount of variation in the weight-adjusted rate of total clearance of nicotine attributable to additive genetic influences [59.4%, 95% confidence interval (CI)=44.7-70.7]. The majority of variation in the clearance of nicotine via the cotinine pathway was similarly genetically influenced (60.8%, 95% CI=46.9-71.5). Heritability estimates were reduced to 54.2% and 51.8%, respectively, but remained substantial after taking into account the effect of variation in CYP2A6 genotype. These results suggest the involvement of additional genetic factors (e.g. uncharacterized or novel CYP2A6 alleles as well as other genes in the metabolic pathway) that remain to be identified.
Adolescent↗
Effect of pregnancy on a measure of FMO3 activity.
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Antioxidants↗
Metabolism and disposition kinetics of nicotine.
Nicotine is of importance as the addictive chemical in tobacco, pharmacotherapy for smoking cessation, a potential medication for several diseases, and a useful probe drug for phenotyping cytochrome P450 2A6 (CYP2A6). We review current knowledge about the metabolism and disposition kinetics of nicotine, some other naturally occurring tobacco alkaloids, and nicotine analogs that are under development as potential therapeutic agents. The focus is on studies in humans, but animal data are mentioned when relevant to the interpretation of human data. The pathways of nicotine metabolism are described in detail. Absorption, distribution, metabolism, and excretion of nicotine and related compounds are reviewed. Enzymes involved in nicotine metabolism including cytochrome P450 enzymes, aldehyde oxidase, flavin-containing monooxygenase 3, amine N-methyltransferase, and UDP-glucuronosyltransferases are represented, as well as factors affecting metabolism, such as genetic variations in metabolic enzymes, effects of diet, age, gender, pregnancy, liver and kidney diseases, and racial and ethnic differences. Also effects of smoking and various inhibitors and inducers, including oral contraceptives, on nicotine metabolism are discussed. Due to the significance of the CYP2A6 enzyme in nicotine clearance, special emphasis is given to the effects and population distributions of CYP2A6 alleles and the regulation of CYP2A6 enzyme.
Absorption↗
Carcinogen exposure during short-term switching from regular to "light" cigarettes.
OBJECTIVES: "Light" cigarettes are extremely popular and are perceived by many smokers as less hazardous than higher-yield cigarettes. The objectives of this study were (a) to assess a battery of biomarkers of tobacco smoke exposure that includes tobacco smoke carcinogens, (b) to examine the behavioral nature of compensation, and (c) to examine the consistency of an individual's tobacco smoke exposure when smoking the same cigarette at different times. METHODS: The study was a 3-week crossover study in which smokers smoked their usual cigarettes during weeks 1 and 3, and a light cigarette, with a machine-determined nicotine yield of about 50% of the usual cigarette, during week 2. Blood and urine biomarkers of exposure and subjective questionnaires were collected weekly. RESULTS: Based on cotinine and carboxyhemoglobin levels, compensation averaged 78% and 83%, respectively. Urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-butanol, a metabolite of the tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-butanone, and a number of polycyclic aromatic hydrocarbon metabolites was similar in all conditions. Compensation was accomplished both by smoking cigarettes more intensively and by smoking more cigarettes per day. Exposures to various tobacco smoke constituents while smoking the usual brand of cigarette in weeks 1 and 3 were highly correlated. CONCLUSION: Our findings support the idea that smokers compensate to a high degree when switched from their usual brand to a light cigarette. Short-term switching resulted in no significant reduction in carcinogen exposure. Our assessment, based on measures of biochemical exposures, supports the idea that switching to light cigarettes is unlikely to reduce the health risks of cigarette smoking.
Adult↗
Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects.
OBJECTIVES: The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people. METHODS: Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2nd, 5th and 7th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry. RESULTS: Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC0-24, Cmax, t(max), dehydrofelodipine/felodipine AUC0-24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments. CONCLUSIONS: We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.
Adult↗
Cigarette smoking and infection.
BACKGROUND: Infectious diseases may rival cancer, heart disease, and chronic lung disease as sources of morbidity and mortality from smoking. We reviewed mechanisms by which smoking increases the risk of infection and the epidemiology of smoking-related infection, and delineated implications of this increased risk of infection among cigarette smokers. METHODS: The MEDLINE database was searched for articles on the mechanisms and epidemiology of smoking-related infectious diseases. English-language articles and selected cross-references were included. RESULTS: Mechanisms by which smoking increases the risk of infections include structural changes in the respiratory tract and a decrease in immune response. Cigarette smoking is a substantial risk factor for important bacterial and viral infections. For example, smokers incur a 2- to 4-fold increased risk of invasive pneumococcal disease. Influenza risk is severalfold higher and is much more severe in smokers than nonsmokers. Perhaps the greatest public health impact of smoking on infection is the increased risk of tuberculosis, a particular problem in underdeveloped countries where smoking rates are increasing rapidly. CONCLUSIONS: The clinical implications of our findings include emphasizing the importance of smoking cessation as part of the therapeutic plan for people with serious infectious diseases or periodontitis, and individuals who have positive results of tuberculin skin tests. Controlling exposure to secondhand cigarette smoke in children is important to reduce the risks of meningococcal disease and otitis media, and in adults to reduce the risk of influenza and meningococcal disease. Other recommendations include pneumococcal and influenza vaccine in all smokers and acyclovir treatment for varicella in smokers.
Adult↗
Mentholated cigarette smoking inhibits nicotine metabolism.
Smoking mentholated cigarettes has been suggested to convey a greater cancer risk compared with smoking nonmentholated cigarettes. Two of the possible mechanisms by which mentholated cigarette smoking could increase risk are by increasing systemic exposure to tobacco smoke toxins and by affecting the metabolism of nicotine or tobacco smoke carcinogens. To examine these possibilities, we performed a crossover study in 14 healthy smokers, one-half of whom were African-Americans and one-half whites. Subjects were randomly assigned to smoke mentholated or nonmentholated cigarettes for 1 week, then to cross over to the other type of cigarettes for another week. Subjects were confined to a Clinical Research Center for 3 days of each week, during which time blood levels of nicotine and carbon monoxide were measured throughout the day and an intravenous infusion of deuterium-labeled nicotine and cotinine was administered to determine the rate and pathways of nicotine metabolism. The systemic intake of nicotine and carbon monoxide was, on average, not affected by mentholation of cigarettes. Mentholated cigarette smoking did significantly inhibit the metabolism of nicotine (clearance: 1289 versus 1431 ml/min, two sided, p = 0.02). Inhibition of nicotine metabolism occurred both by slower oxidative metabolism to cotinine and by slower glucuronide conjugation. Our data do not support the hypothesis that mentholated cigarette smoking results in a greater absorption of tobacco smoke toxins. Our finding of impaired metabolism of nicotine while mentholated cigarette smoking suggests that mentholated cigarette smoking enhances systemic nicotine exposure.
Adult↗
Smoking less as a treatment goal for those who cannot stop smoking.
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Bupropion↗
Enhanced stimulant and metabolic effects of combined ephedrine and caffeine.
OBJECTIVE: Herbal weight loss and athletic performance-enhancing supplements that contain ephedrine and caffeine have been associated with serious adverse health events. We sought to determine whether ephedrine and caffeine have clinically significant pharmacologic interactions that explain these toxicities. METHODS: Sixteen healthy adults ingested 25 mg ephedrine, 200 mg caffeine, or both drugs in a randomized, double-blind, placebo-controlled crossover study. Plasma and urine samples were collected over a 24-hour period and analyzed by liquid chromatography-tandem mass spectrometry for ephedrine and caffeine concentrations. Heart rate, blood pressure, and subjective responses were recorded. Serum hormonal and metabolic markers were serially measured during a 3-hour fasting period. RESULTS: Ephedrine plus caffeine increased systolic blood pressure (peak difference, 11.7 +/- 9.4 mm Hg; compared with placebo, P =.0005) and heart rate (peak difference, 5.9 +/- 8.8 beats/min; compared with placebo, P =.001) and raised fasting glucose, insulin, free fatty acid, and lactate concentrations. Ephedrine alone increased heart rate and glucose and insulin concentrations but did not affect systolic blood pressure. Caffeine increased systolic blood pressure and plasma free fatty acid and urinary epinephrine concentrations but did not increase heart rate. Compared with ephedrine, caffeine produced more subjective stimulant effects. Clinically significant pharmacokinetic interactions between ephedrine and caffeine were not observed. Women taking oral contraceptives had prolonged caffeine elimination (mean elimination half-life, 9.7 hours versus 5.0 hours in men; P =.05), but sex differences in pharmacodynamic responses were not seen. CONCLUSIONS: The individual effects of ephedrine and caffeine were modest, but the drugs in combination produced significant cardiovascular, metabolic, and hormonal responses. These enhanced effects appear to be a result of pharmacodynamic rather than pharmacokinetic interactions.
Adolescent↗
Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity.
BACKGROUND: Nicotine and a variety of other drugs and toxins are metabolized by cytochrome P450 (CYP) 2A6. Our objective was to evaluate the use of oral nicotine with measurement of the trans-3'-hydroxycotinine (3HC)/cotinine (COT) metabolite ratio as a noninvasive probe of CYP2A6 activity. METHODS: Sixty-two healthy volunteers received an oral solution of deuterium-labeled nicotine (2 mg) and its metabolite cotinine (10 mg). Plasma nicotine and plasma and saliva cotinine and 3HC concentrations were measured over time. RESULTS: The 3HC/COT ratio derived from deuterium-labeled cotinine, measured in either plasma (2-8 hours after administration) or saliva (at 6 hours), was strongly correlated with the oral clearance of nicotine (r = 0.76-0.83, depending on the time of measurement). The 6-hour 3HC/COT ratio from nicotine derived from tobacco in 14 smokers was highly correlated with the ratio derived from deuterium-labeled nicotine (r = 0.88) and was also highly correlated with the oral clearance of nicotine (r = 0.90). Two subjects homozygous for inactive CYP2A6 alleles produced no 3HC, confirming the specificity of the metabolite ratio. The 3HC/COT ratio was also highly correlated with the clearance and half-life of cotinine, consistent with the fact that cotinine is also primarily metabolized by CYP2A6. CONCLUSIONS: The 3HC/COT ratio derived from nicotine either administered as a probe drug or from tobacco use, measured in either plasma or saliva, is highly correlated with the oral clearance of nicotine. The ratio appears to be a useful noninvasive marker of the rate of nicotine metabolism (which is important in studying nicotine addiction and smoking behavior), as well as a general marker of CYP2A6 activity (which is important in studying drug and toxin metabolism).
Adult↗
Determinants of salivary cotinine levels among current smokers in Mexico.
The present study describes salivary cotinine levels and their relationship to cigarettes smoked per day in Mexican smokers. Using a sampling strategy based on the number of cigarettes per day, we recruited 1,222 smokers from Mexico City and the state of Morelos in Mexico during 1999. Smoking behaviors and other factors known to affect nicotine intake and cotinine level were identified in an interview using a standardized questionnaire. Salivary cotinine was measured by capillary gas chromatography with nitrogen-phosphorus detection. We used generalized additive models to describe the relationship between salivary cotinine levels and variables of interest. The mean age of the population was 39.7 years (SD=15.6 years), with a mean cotinine level of 194.7 ng/ml (SD=134.8; range=10.1-767). Participants smoked a mean of 15.5 cigarettes per day (SD=11.3). Salivary cotinine and cigarettes smoked per day were positively related, although the association was not linear, flattening above 20 cigarettes per day. After adjusting for cigarettes per day, we found that significant predictors of cotinine levels included age, body mass index, cigarette producer, and smoking behavior variables. These results may have implications for dosing with nicotine medications to aid smoking cessation in Mexican smokers and suggest that whether the cigarette is labeled light or regular has no relationship to nicotine dose from smoking cigarettes.
Adolescent↗
Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements.
Dietary supplements that contain Ma Huang (ephedra alkaloids) and guarana (caffeine) are widely marketed and used in the U.S. for weight loss and athletic performance enhancement, despite a lack of adequate research on the pharmacology of these botanical stimulants. We developed and applied a novel liquid chromatography-tandem mass spectrometry (LC-MS-MS) method to quantitate the various ephedra alkaloids found in dietary supplements that contain Ephedra species. The quantities of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedine, methylpseudoephedrine, and caffeine were determined for 35 commercial dietary supplements and compared with the amounts listed on the product labels. The total ephedra alkaloid content ranged from 5.97 mg to 29.3 mg per serving. Two supplement brands did not list the quantity of ephedra alkaloids on the label, and four did not list the amount of caffeine per serving. Of the products tested, 31% contained > 110% of the total ephedra alkaloids listed on the label, and 6% of the supplements contained < 90% of the listed amount. For caffeine, 86% of the product lots that listed the caffeine amount contained less than 90% of the labeled quantity. No products contained > 110% of the declared caffeine content. The total ephedra alkaloid content varied significantly from lot to lot in 5 of 9 products. Three product brands contained proportions of alkaloids that exceeded amounts reported for E. sinica, including one that was 98% ephedrine, one that had 10% norpseudoephedrine, and one that contained an average of 13% methylephedrine. We conclude that product inconsistency is common among some commercially available dietary supplements that contain ephedra alkaloids and caffeine.
Alkaloids↗