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Biomedical subjects

Neal L Benowitz

Publications and source records attributed to Neal L Benowitz.

At least 55 records · Page 3Linked to original sources
PubMed2004

Determination of ephedra alkaloid and caffeine concentrations in dietary supplements and biological fluids.

Dietary supplements containing botanical forms of caffeine and ephedra alkaloids have been widely promoted and used in the U.S. for weight loss and athletic enhancement despite a lack of adequate research on the pharmacology of these botanical stimulants. In order to analyze dietary supplements and perform human pharmacokinetic studies, an analytical approach with good precision and accuracy was needed with sufficient sensitivity to detect very low levels of ephedra alkaloids. A liquid chromatography-atmospheric pressure chemical ionization (APCI) tandem mass spectrometry (LC-MS-MS) method was developed for quantitating the various ephedrine-group alkaloids found in dietary supplements that contain Ephedra species, and in plasma and urine of persons consuming these supplements. Using this method, low nanogram-per-milliliter concentrations of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, methylpseudoephedrine, and caffeine can be quantitated in a 12-min LC-MS-MS run.

Alkaloids↗
PubMed2004

Pharmacogenetics of nicotine metabolism in twins: methods and procedures.

This article describes a pharmacogenetic investigation of nicotine metabolism in twins. One hundred and thirty-nine twin pairs (110 monozygotic and 29 dizygotic) were recruited and assessed for smoking status, zygosity, and health conditions known or suspected to affect drug metabolism. Participants underwent a 30-minute infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, followed by an 8-hour 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 phenotypes. DNA was genotyped to confirm zygosity and for variation in the primary gene involved in nicotine metabolism, CYP2A6. Univariate and multivariate biometric analyses planned for the future will determine genetic and environmental influences on each pharmacokinetic measure individually and in combination with each other, and in the presence and absence of covariates, including measured genotype. When the analyses are completed, this study will result in a more complete characterization of the impact of genetic and environmental influences on nicotine and cotinine metabolic pathways than has heretofore been reported. The approach taken, with its use of a quantitative model of nicotine metabolism, highly refined metabolic phenotypes, measured genotype, and advanced tools for biometric genetic analysis, provides a model for the use of twins in next-generation studies of complex drug-metabolism phenotypes.

Adult↗
PubMed2003

Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial.

BACKGROUND: Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoid-protease inhibitor interactions (because both share cytochrome P-450 metabolic pathways). OBJECTIVE: To determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients. DESIGN: Randomized, placebo-controlled, 21-day intervention trial. SETTING: The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California. PARTICIPANTS: 67 patients with HIV-1 infection. INTERVENTION: Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals. MEASUREMENTS: HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors. RESULTS: 62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 x 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was -0.07 (95% CI, -0.30 to 0.13) for marijuana and -0.04 (CI, -0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids. CONCLUSIONS: Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.

Administration, Oral↗
PubMed2003

Influence of menthol on caffeine disposition and pharmacodynamics in healthy female volunteers.

OBJECTIVES: The present study was undertaken to determine whether a single oral dose of menthol affects the metabolism of caffeine, a cytochrome P(450) 1A2 (CYP1A2) substrate, and pharmacological responses to caffeine in people. METHODS: Eleven healthy female subjects participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of caffeine (200 mg) in coffee taken together with a single oral dose of menthol (100 mg) or placebo capsules. Serum caffeine concentrations and cardiovascular and subjective parameters were measured throughout the study. RESULTS: Co-administration of menthol resulted in an increase of caffeine t(max) values from 43.6+/-20.6 min (mean+/-SD) to 76.4+/-28.0 min ( P<0.05). The C(max) values of caffeine were lower in the menthol phase than in the placebo phase, but this effect was not statistically significant ( P=0.06). (AUC)(0-24), (AUC)(0- infinity ), terminal half-life and oral clearance were not affected by menthol. Only nine subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. After caffeine, heart rate decreased in both treatment phases. The maximum decrease in heart rate was less in the menthol phase (-8.9+/-3.9 beats/min) than in the placebo phase (-13.1+/-2.1 beats/min) ( P=0.024). There were no statistically significant differences in systolic and diastolic blood pressures between the two treatments. CONCLUSIONS: We conclude that a single oral dose of pure menthol (100 mg) delays caffeine absorption and blunts the heart-rate slowing effect of caffeine, but does not affect caffeine metabolism. The possibility that menthol slows the absorption of other drugs should be considered.

Administration, Oral↗
PubMed2003

Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism.

OBJECTIVES: Our objectives were to examine the effects of cigarette smoking on the disposition kinetics of chlorzoxazone and caffeine as probes of cytochrome p450 (CYP) 2E1, CYP1A2, xanthine oxidase, and N-acetyltransferase-2 activity and to test the hypothesis that carbon monoxide inhibits drug metabolism via these pathways. METHODS: Twelve cigarette smokers were studied in 3 treatment conditions, each lasting 7 days, during which they smoked cigarettes, breathed carbon monoxide to achieve carboxyhemoglobin levels similar to those associated with cigarette smoking, or breathed air. In each treatment condition, subjects received oral chlorzoxazone (250 mg) and caffeine (250 mg) with measurement of disposition kinetics and urine metabolite profiles. RESULTS: Compared with the air condition, cigarette smoking significantly induced the metabolism of chlorzoxazone (oral clearance, 5.9 +/- 1.5 mL x min(-1) x kg(-1) versus 4.8 +/- 1.0 mL x min(-1) x kg(-1), P <.005) and caffeine (2.0 +/- 0.8 mL x min(-1) x kg(-1) versus 1.5 +/- 0.7 mL x min(-1) x kg(-1), P <.001) but had no effect on caffeine urine metabolite ratios that reflect xanthine oxidase and N-acetyltransferase-2 activity. Considerable individual variability was noted in the extent of induction of metabolism by cigarette smoking, particularly as it affects chlorzoxazone (change in oral clearance ranged from -10% to +71%). Carbon monoxide had no effect on chlorzoxazone or caffeine metabolism or caffeine metabolic profile. CONCLUSIONS: This study provides novel evidence that cigarette smoking accelerates chlorzoxazone metabolism, most likely reflecting induction of CYP2E1 activity, in humans. Induction of CYP2E1 activity by cigarette smoking could contribute to tobacco-induced cancer, alcohol-induced liver disease, and the risk of acetaminophen hepatotoxicity.

Adult↗
PubMed2003

Determinants of salivary cotinine concentrations in Chinese male smokers.

BACKGROUND: Identifying factors that affect cotinine levels in smokers may be useful for smoking cessation programs. Our aims were to characterize the distribution of salivary cotinine levels in Chinese smokers and to investigate factors that influence cotinine concentrations. METHODS: In a cross-sectional study, 600 Chinese adult smokers answered a questionnaire on smoking habits and provided a saliva sample for cotinine analysis. Modification of the relation between number of cigarettes smoked and cotinine concentration by individual characteristics, smoking behavior, and type of tobacco was evaluated. RESULTS: Quadratic model provided the best fit for the relation between number of cigarettes smoked in the previous 24 hours and salivary cotinine concentration. Among those smoking up to 20 cigarettes, the median cotinine concentration was higher among younger subjects, those smoking cigarettes without filter and regular rather than light cigarettes, and those inhaling frequently and deeply. Such trends were not observed among heavier smokers. The increase in cotinine per cigarette tended to be larger in those with lower median cotinine level. CONCLUSIONS: Our findings show that smoking behavior-related factors modify the relation between number of cigarettes smoked and salivary cotinine concentration. This suggests that smokers may regulate their smoking behavior to achieve a certain optimum nicotine level.

Adolescent↗
PubMed2003

Tobacco use and dependence.

OBJECTIVES: To review tobacco use and dependence including nicotine pharmacology and addiction, and pharmacologic treatment. DATA SOURCES: Professional journals, books, government publications. CONCLUSION: Smoking is addictive and a major health problem. Habitual nicotine use is central to sustaining smoking dependence. This article provides the necessary basis for understanding nicotine addiction and pharmacologic therapies. IMPLICATIONS FOR NURSING PRACTICE: Nurses' knowledge about nicotine addiction is important in helping patients to quit smoking.

Health Education↗
PubMed2003

Nicotine metabolite ratio as a predictor of cigarette consumption.

The rate of nicotine metabolism is hypothesized to be a determinant of how much a person smokes. That is, rapid metabolizers would be expected to need more nicotine and, therefore, smoke more than slow metabolizers. Nicotine is metabolized extensively by the liver enzyme CYP2A6, primarily to cotinine. Cotinine is itself metabolized by CYP2A6 to 3'-hydroxycotinine (3-HC). The ratio of metabolite to parent (i.e., 3-HC:cotinine) would be expected to reflect CYP2A6 activity. We measured the ratio of 3-HC:cotinine in the urine of 72 smokers. This ratio was significantly correlated with the number of cigarettes smoked per day (r=.33, p=.005), though not with the Fagerström Test for Nicotine Dependence. This finding supports the hypothesis that the rate of nicotine metabolism is a determinant of the level of cigarette consumption and supports the use of the 3-HC:cotinine ratio as a noninvasive marker of nicotine metabolism.

Adult↗
PubMed2003

Vitamin C supplementation decreases oxidative stress biomarker f2-isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke.

Exposure to environmental tobacco smoke (ETS) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers. Current research suggests that some of these diseases are associated with elevated oxidative stress. We investigated the effect of antioxidant (AO) intervention on the lipid peroxidation biomarker F2-isoprostanes (F2-IsoPs), an index of oxidative stress, in plasma of nonsmokers exposed to ETS (passive smokers). We measured free F2-IsoP concentrations in plasma of 67 passive smokers at baseline and after 2 mo of daily intervention with AOs or placebo. The study subjects (47 females, 20 males; mean age 46 +/-15) were randomized into one of three treatment groups: vitamin C, "mixture" (vitamin C, vitamin E, and a-lipoic-acid), and placebo. Investigated confounders included plasma baseline AO levels, lipid and total cholesterol profiles, transferrin saturation, and C-reactive protein. Plasma F2IsoP concentrations of subjects in the vitamin C and mixture groups decreased significantly by 17.2 pmol/l (P = 0.0105) and 19.2 pmol/l (P = 0.0083) when compared with the placebo group (11.4% and 12.7%, respectively). Daily AO supplementation (especially with vitamin C) decreases this oxidative stress biomarker in passive smokers. This finding might be of importance for the prevention of ETS-associated adverse health effects in nonsmokers.

Adult↗
PubMed2002

Acute aortic dissection related to crack cocaine.

BACKGROUND: Although single case reports have described acute aortic dissection in relation to cocaine use, this condition is not widely recognized, and the features of cocaine-related aortic dissection have not been defined. METHODS AND RESULTS: We reviewed all available hospital charts from 1981 to 2001 with the ICD-9 diagnosis of aortic dissection. Among the 38 cases of acute aortic dissection, 14 (37%) were related to cocaine use. Crack cocaine was smoked in 13 cases and powder cocaine was snorted in 1 case. The mean interval between cocaine use and the onset of symptoms was 12 hours (range, 0 to 24). Patients with cocaine-related dissection were much younger and more likely to undergo surgery compared with patients with aortic dissection without cocaine use. Most in the cocaine group were black, with a history of untreated hypertension. However, the two groups did not differ in other respects, including dissection type. CONCLUSIONS: In an inner city population, acute aortic dissection in the setting of crack cocaine use is common, presumably as a consequence of abrupt, transient, severe hypertension and catecholamine release. This diagnosis should be considered in cocaine users with severe chest pain.

Acute Disease↗
PubMed2002

The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir.

BACKGROUND AND OBJECTIVES: The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV). METHODS: Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline. RESULTS: At day 14, the 8-h area under the curve (AUC(8)) changed by -10.2% (P = 0.15), maximum concentration (C(max)) by -17.4% (P = 0.46), and minimum concentration (C(min)) by -12.2% (P = 0.28) for patients in the NFV marijuana arm (n = 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n = 9): AUC8 had changed by -14.5% (P = 0.074), C(max) by -14.1% (P = 0.039), and C(min) by -33.7% (P = 0.65). CONCLUSION: Despite a statistically significant decrease in C(max) of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.

Adult↗
PubMed2002

Slower metabolism and reduced intake of nicotine from cigarette smoking in Chinese-Americans.

BACKGROUND: Lung cancer rates are lower in Asians and Latinos than in whites. Ethnic differences in nicotine metabolism might explain, in part, ethnic differences in cigarette consumption and/or nicotine intake per cigarette and resultant tobacco-related cancer risk. We compared the rate of nicotine metabolism and the intake of nicotine per cigarette smoked among smokers of different ethnicities. METHODS: Healthy volunteer smokers, including 37 Chinese-Americans, 40 Latinos, and 54 whites, received simultaneous infusions of deuterium-labeled nicotine and cotinine, a metabolite of nicotine. From blood and urine measurements, the disposition kinetics and daily intake of nicotine from smoking were determined. All statistical tests were two-sided. RESULTS: Total and nonrenal clearance of nicotine and cotinine and metabolic clearance of nicotine via the cotinine pathway were similar in Latinos and whites and statistically significantly lower in Chinese-Americans. Intake of nicotine per cigarette by Chinese-Americans (0.73 mg; 95% confidence interval [CI] = 0.53 to 0.94 mg) was statistically significantly lower than that by Latinos (1.05 mg; 95% CI = 0.85 to 1.25 mg) or whites (1.10 mg; 95% CI = 0.91 to 1.30 mg; P =.039). Among all of the participants, there was a statistically significant positive correlation between nicotine clearance and daily intake of nicotine from cigarette smoking and between nicotine clearance and nicotine intake per cigarette (r =.41 and r =.39, respectively) (P<.001 for both). CONCLUSIONS: The lower nicotine (and, therefore, tobacco smoke) intake per cigarette and the fewer cigarettes smoked per day, which may result, in part, from slower clearance of nicotine, may explain lower lung cancer rates in Chinese-Americans. Lower lung cancer rates among Latinos compared with whites, given their similar nicotine intake per cigarette, are probably due to smoking fewer cigarettes. The results with Chinese-Americans may have implications for dosing with nicotine medications to aid smoking cessation in Chinese- American smokers and perhaps in other Asian smokers.

Adult↗
PubMed2002

Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster.

Topical lidocaine has been recently marketed as a new treatment for post-herpetic neuralgia. The aim of our study was to characterize the absorption profile of and systemic exposure to lidocaine from patch and gel formulations in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. The bioavailability of lidocaine from the patch formulation averaged 3%, and was similar after single and repeated doses. Systemic exposure to lidocaine and monoethylglycinexylidide (MEGX), the primary active metabolite of lidocaine, after application of lidocaine gel or patches was minimal in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. Considering the benefit versus risk of topical lidocaine, systemic absorption and toxicity of lidocaine seems not to be a significant risk.

Acute Disease↗
PubMed2002

Influence of arterial vs. venous sampling site on nicotine tolerance model selection and parameter estimation.

In this modeling study we utilize previously published nicotine pharmacokinetic (PK) and pharmacodynamic (PD, heart rate) data to investigate the influence of PK sampling site (venous vs. arterial) on the selection of a specific PD tolerance model and estimation of its parameters. We describe a general model for tolerance which includes as special cases feedback (TF), and kinetic based tolerance (TK) models. A TK model has arterial plasma drug concentrations (Ca) driving (hypothetical) effect (Ce) and antagonist (Cm) site concentrations, which drive a non-feedback effect (Enf): tolerance depends on the relative rate of equilibration of Ce and Cm with Ca. The TF model adds feedback which makes tolerance depend on Enf, not just on drug kinetics for nicotine. The arterial-sampling-analysis (PKPDa) has Ca driving Ce and Cm. The venous-sampling-analysis (PKPDv) does the same but estimates Ca from venous data by means of deconvolution. A TF model (with Cm = Ce) was always selected in the PKPDa. According to this model tolerance developed rapidly with a median half-life of 6.6 min, and median decrease of effect due to tolerance of 31%. Different variants of the TF or TK models were selected in the PKPDv. Parameter estimates for PKPDv show higher variability, and, for the TF model, lower rate and extent of tolerance development and threefold increase in EC50. The study shows that (i) TF models are more appropriate than TK models to describe nicotine effect data, (ii) venous sampling may lead to incorrect model selection and inaccurate and imprecise parameter estimation in respect to arterial sampling, and (iii) arterial sampling should be preferred for accurate (non-steady-state) PD modeling.

Arteries↗
PubMed2002

Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use.

OBJECTIVE: Serious cardiovascular toxicity has been reported in people taking dietary supplements that contain ma huang (Ephedra) and guarana (caffeine). We assessed the pharmacokinetics and pharmacodynamics of a dietary supplement that contains these herbal stimulants. METHODS: Eight healthy adults received a single oral dose of a thermogenic dietary supplement labeled to contain 20 mg ephedrine alkaloids and 200 mg caffeine after an overnight fast. Serial plasma and urine samples were analyzed by use of liquid chromatography-tandem mass spectrometry for ephedrine alkaloid and caffeine concentrations, and heart rate and blood pressure were monitored for 14 hours. RESULTS: Plasma clearance and elimination half-lives for ephedrine, pseudoephedrine, and caffeine were comparable to published values reported for drug formulations. A prolonged half-life of ephedrine and pseudoephedrine was observed in 1 subject with the highest urine pH. Mean systolic blood pressure increased significantly to a maximum of 14 mm Hg above baseline at 90 minutes after ingestion (P <.001). There was a lag in the mean heart rate response that reached a maximum change of 15 beats/min above baseline at 6 hours after ingestion (P <.001). Diastolic blood pressure changes were insignificant. Two subjects who were taking oral contraceptives had longer caffeine half-lives (15.5 +/- 0.3 hours versus 5.6 +/- 1.7 hours) and lower values for oral clearance (0.34 +/- 0.01 mL/min. kg versus 0.99 +/- 0.41 mL/min. kg) than subjects who were not taking oral contraceptives. CONCLUSIONS: Botanical stimulants have disposition characteristics similar to their pharmaceutical counterparts, and they can produce significant cardiovascular responses after a single dose.

Adult↗
PubMed2002

Reducing tobacco harm: research challenges and issues.

The emergence of potential reduced-exposure tobacco and cigarette-like products and the reduction of smoking as a treatment approach, have recently been forcing the debate and discussion about the science that is necessary to inform policies, regulation, and programs. To deal effectively with the issues evolving around tobacco harm reduction, a comprehensive and strategic research agenda must be forged, and a multi-disciplinary, collaborative approach must be taken. The goal of this article is to describe research challenges and issues related to tobacco exposure and harm reduction. Scientists from multiple disciplines and individuals from government agencies, nonprofit organizations, and tobacco control advocacy groups as well as the pharmaceutical and tobacco industries attended a two-day meeting that focused on addressing the current knowledge regarding tobacco harm reduction, identifying gaps in knowledge, and recommending research directions. Workgroups, comprising a subset of attendees, met after the conference to synthesize, discuss, and prioritize the important research frontiers. The resulting document provides guidance for scientists, grant funding agencies, industry and policy makers by identifying areas in which to invest research effort and funds to develop a science base to ensure the future health of this nation and world.

Communication↗