Showing papers by "Neal L. Benowitz published in 1992"

Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N'-oxide.

Abstract: Liver microsomes from humans catalyze the NADPH-dependent oxidation of (S)-nicotine. The principal product is the 5'-carbon atom oxidation product, nicotine delta 1',5'-iminium ion, which is efficiently converted to the gamma-lactam derivative cotinine in the presence of aldehyde oxidase. Another major product is nicotine N'-oxide. In contrast to previous reports describing in vitro or in vivo studies, formation of only trans-nicotine N'-oxide was observed. Demethylation of nicotine was not observed. Studies on the biochemical mechanism of nicotine 5-carbon atom oxidation strongly implicate one major cytochrome P-450 isoenzyme (i.e., P-450 2A6) as largely responsible for delta 1',5'-iminium ion formation. Stereoselective formation of trans-nicotine N'-oxide may be catalyzed in large part by the flavin-containing monooxygenase (form II). These conclusions are based on the effects of alternate substrates for the flavin-containing monooxygenase, heat inactivation studies, immunoblot studies, and selective substrates for cytochromes P-450. The results suggest that (S)-nicotine trans N'-oxygenation and delta 1',5'-iminium ion formation may be selective probes of human liver flavin-containing monooxygenase form II and cytochrome P-450 2A6 activities, respectively, useful for in vivo phenotyping of humans.

Misclassification of Smoking Status by Self-reported Cigarette Consumption

Abstract: To evaluate possible misclassification of smokers and nonsmokers, we compared self-reported cigarette consumption and serum cotinine levels in a sample of 743 Mexican American participants in the Hispanic Health and Nutrition Examination Survey (HHANES). The study sample was stratified by sex and self-reported cigarettes consumed per day (0, 1 to 9, 10 to 19, and ⩾ 20) and selected from those with available serum. We defined biochemical smokers as persons with serum cotinine levels ⩾ 0.084 (µM/L (14 ng/ml). Misclassification was defined as a discrepancy between self-reported smoking and the serum cotinine level used to define a biochemical smoker. Of 189 self-reported nonsmokers, 12 (6.3%) were defined as biochemical smokers and possibly misclassified by self-report. Among 124 never smokers only 5 (4%) were biochemical smokers compared with 7 of 65 (10.8%) self-reported former smokers. Only 1 of the 12 misclassified nonsmokers reported living with a current smoker. In 9 of the 12 misclassif ied nonsmokers...

Smokeless tobacco, cardiovascular risk factors, and nicotine and cotinine levels in professional baseball players.

Abstract: BACKGROUND. The use of smokeless tobacco (ST), which has increased in popularity over the past 2 decades, results in considerable systemic exposure to nicotine. Nicotine might contribute to atherosclerosis by an effect on cardiovascular risk factors. METHODS. The effects of ST use on cardiovascular risk factors and cotinine and nicotine levels were studied in 1061 professional baseball players during spring training in 1988 and 1989. RESULTS. Of the study participants 477 (45%) were users. ST use was more common among Whites (55%) than among Blacks (29%) or Hispanics (21%), and users reported heavier consumption of alcohol (p less than .001) and had higher mean serum caffeine levels (p less than .001) than nonusers. ST users did not differ from nonusers in adjusted levels of systolic and diastolic blood pressure, pulse, and total or HDL-cholesterol. Among ST users, participants using snuff had higher mean serum cotinine levels than those who used chewing tobacco (p less than .001). There was no associatio...

Nicotine elimination and tolerance in non-dependent cigarette smokers

Abstract: Although most smokers are nicotine-dependent, recent studies suggest that some very light smokers (“chippers”, who smoke fewer than five cigarettes per day) may smoke for decades without developing dependence. It was considered that slowed nicotine elimination and/or reduced nicotine tolerance might underlie chippers' ability to maintain smoking at such low levels. To evaluate this hypothesis, we studied the elimination kinetics and pharmacodynamics of nicotine in chippers and matched regular smokers. Plasma nicotine levels and cardiovascular responses were observed for several hours after subjects were administered uniform doses of tobacco smoke. Chippers did show less chronic nicotine tolerance, but only on some response measures. Their rates of nicotine elimination equaled those of regular smokers. This finding, when coupled with other data about chippers' smoking patterns and nicotine absorption, establish that chippers cannot maintain substantial plasma nicotine levels between cigarettes, and thus suggest that attempts to maintain minimal trough levels of nicotine do not underlie chippers' smoking.

Intravenous nicotine retards transdermal absorption of nicotine: evidence of blood flow--limited percutaneous absorption.

Abstract: For most drugs delivered by the transdermal route, percutaneous absorption is limited by the rate of release of the drug from the device or by diffusion across the stratum corneum. However, systemic absorption also requires that the drug be taken up by dermal blood vessels. As part of a bioavailability study of a transdermal delivery system, we observed that a concomitant intravenous infusion of nicotine had a marked effect on the absorption kinetics of transdermal nicotine. Plasma concentrations of nicotine rose less rapidly, reached a lower peak, and peaked at a later time, indicating delayed absorption of transdermal nicotine after intravenous nicotine versus after transdermal nicotine administered alone. Nicotine is known to produce cutaneous vasoconstriction. The likely explanation for our observation is that intravenous nicotine constricts dermal blood vessels, thereby limiting percutaneous absorption. Other vasoconstrictor drugs would be expected to retard the absorption of transdermal nicotine and perhaps other transdermal drugs as well.

Orthostatic Hypotension in Ciguatera Fish Poisoning

Abstract: Purpose— The purpose of this study was to investigate the pathophysiology of persistent orthostatic hypotension in a patient with ciguatera fish poisoning Methods— A patient who became ill and who developed prolonged and symptomatic orthostatic hypotension with ciguatera fish poisoning after eating barracuda is described Studies of autonomic function included measurements of plasma catecholamine levels in the supine and standing positions, and pressor responses to infusions of norepinephrine, atropine, and propranolol Results— Volume depletion was excluded as a cause for hypotension Our patient showed low plasma catecholamine levels and marked pressor hypersensitivity to norepinephrine infusion Hypotension and bradycardia were reversed by atropine infusion The heart rate freed from autonomic influences, ie, after atropine plus propranolol infusion, was normal Conclusions— In ciguatera fish poisoning, orthostatic hypotension appears to be a result of both parasympathetic excess and sympathetic failure ( Arch Intern Med 1992;152:2131-2133)

How toxic is cocaine

Abstract: The toxicities of cocaine are far-ranging. They include sudden death, acute medical and psychiatric illness, infectious complications, reproductive disturbances, trauma, criminal activities and societal disruption, including child neglect and abuse and lost job productivity. This chapter focuses on the medical complications. Medical complications in general reflect the intense sympathomimetic activities of cocaine ('sympathetic neural storm'). Psychiatric complications include acute anxiety or panic and paranoid psychosis. Cardiovascular complications include arrhythmias and sudden death, acute myocardial infarction, myocarditis, dissecting aneurysm and bowel infarction. Neurological complications include seizure, intracerebral haemorrhage and brain injury due to hyperthermia and/or seizures, and headache. The incidence of medical complications has been estimated using two databases collected prospectively in the United States. In 1989 and 1990 cocaine ranked first in total encounters, major medical complications and drug-related deaths. An attempt was made to assess the intrinsic toxicity of cocaine by computing the incidence of adverse health outcomes per population of drug abusers. Rates of emergency department visits and deaths were 15.1 and 0.5 respectively, per 1000 persons using drugs in the past year. The magnitude of the cocaine problem, while considerable, is relatively small compared with that of cigarette smoking or alcohol abuse.

Workshop on problem-based learning as a method for teaching clinical pharmacology and therapeutics in medical school.

Abstract: On March 5 through 6, 1989, the Council for Medical Student Education in Clinical Pharmacology,’ which was at that time composed of representatives from the American College of Clinical Pharmacology, the American Society for Clinical Pharmacology and Therapeutics, the American Society for Pharmacology and Experimental Therapeutics, and the Association for Medical School Pharmacology, sponsored a workshop entitled “Strategies for Implementing Clinical Pharmacology and Therapeutics Teaching in Medical Schools” held in Nashville, Tennessee. This workshop brought together more than 40 faculty members from various institutions to discuss obstacles encountered by efforts to change medical

Sympathoadrenal contribution to nicotinic and muscarinic modulation of bradykinin-induced plasma extravasation in the knee joint of the rat.

Abstract: Previous results from this laboratory demonstrated that plasma extravasation produced by intra-articular infusion of bradykinin in the rat is mediated by an action on the sympathetic terminals in the knee joint and that adrenal medullary epinephrine regulates the plasma extravasation provoked by bradykinin. Because the release of epinephrine is under cholinergic control, we have now evaluated the effect of nicotinic and muscarinic cholinergic agonists on bradykinin-induced plasma extravasation in the knee joint of the rat. We report that s.c. administration of nicotine and carbachol attenuated plasma extravasation induced by bradykinin; this attenuation was significantly antagonized by systemic injection of hexamethonium and atropine, respectively. The nicotine and carbachol effects were also significantly attenuated after removal of the adrenal medulla. These results indicate that both nicotine and carbachol can inhibit bradykinin-induced plasma extravasation and that this inhibition is mediated, at least in part, through activation of nicotinic and muscarinic receptors in the adrenal medulla. Finally, local perfusion of the knee joint with hexamethonium did not affect the inhibition of bradykinin-induced plasma extravasation produced by systemic nicotine. Intra-articular perfusion of atropine potentiated the inhibition of bradykinin-induced plasma extravasation by systemic carbachol, indicating that muscarinic receptors in the synovium also contribute to plasma extravasation. The inhibitory action of nicotine on plasma extravasation may contribute, in part, to the reported increased severity of arthritis in individuals who smoke.

The genetics of drug dependence: tobacco addiction.

Abstract: Most people experiment with cigarette smoking in childhood or adolescence Why do some but not others become regular smokers? Most smokers in the United States say they would like to quit smoking

Nicotine Replacement Therapy During Pregnancy-Reply

Abstract: In Reply. —Drs Seidman and Stevenson suggest that nicotine may be a teratogen and that providing a potentially toxic drug to pregnant women raises significant medical and ethical questions. There is no question that nicotine is a potentially toxic drug and even a teratogen. The critical issues in deciding to administer a potentially toxic drug to a patient include the likelihood of toxic effects in the doses and dosing regimens to be administered and the potential benefits vs risks of the therapy. Studies demonstrating direct toxic effects of nicotine in animals generally have used doses of nicotine higher than those consumed by tobacco users or delivered by nicotine replacement therapies. The relevance of animal toxicity studies to the understanding of the toxic effects of nicotine in humans is therefore still uncertain. On the other hand, we know without question that tobacco smoking during pregnancy may be highly injurious to the