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Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 19 recordsLinked to original sources
PubMed1992

Determination of the nicotine metabolite trans-3'-hydroxycotinine in urine of smokers using gas chromatography with nitrogen-selective detection or selected ion monitoring.

A gas chromatographic method for the determination of the nicotine metabolite trans-3'-hydroxycotinine is described. The method involves conversion of the metabolite to the tert.-butyldimethylsilyl derivative, chromatography on a fused-silica capillary column, and determination using nitrogen-phosphorus detection or electron ionization mass spectrometry with selected ion monitoring. A structural analogue, trans-3-hydroxy-1-methyl-5-(2-pyridyl)pyrrolidin-2-one (trans-3'-hydroxy-ortho-cotinine), was used as an internal standard. Using selected ion monitoring, good precision and accuracy were obtained for determination of trans-3'-hydroxycotinine in urine over the concentration range 10-10,000 ng/ml. There was a good correlation between concentrations determined by selected ion monitoring and by nitrogen-phosphorus detection in urine of smokers, although low concentrations determined using nitrogen-phosphorus detection tended to be somewhat higher, suggesting some interference from urinary constituents. Concentrations and 24-h excretion of trans-3'-hydroxycotinine in the urine of 22 cigarette smokers are reported and compared to concentrations and excretion of nicotine, cotinine, nicotine 1'-N-oxide, nornicotine, and cotinine N-oxide.

Chromatography, Gas↗
PubMed1992

How toxic is cocaine?

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.

Cocaine↗
PubMed1992

Nicotine elimination and tolerance in non-dependent cigarette smokers.

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.

Adult↗
PubMed1992

Chronically administered nicotine attenuates bradykinin-induced plasma extravasation and aggravates arthritis-induced joint injury in the rat.

We recently showed that acute administration of nicotine in the rat decreases bradykinin-induced plasma extravasation and that adrenal medullary-derived epinephrine, acting at a beta 2-adrenergic receptor, mediates the nicotine effect. Since agents which decrease bradykinin-induced plasma extravasation have been associated with increased joint injury in a rat model of chronic inflammation (experimental arthritis induced by subcutaneous injection of Mycobacterium butyricum) we examined the effect of chronic nicotine on both plasma extravasation and the severity of joint injury. In normal rats, bradykinin-induced plasma extravasation was decreased after nicotine administered both by repeated injection (10(-2) mg/kg, s.c., once per h for 4 h) and by continuous long-term infusion (subcutaneous mini-osmotic pump; 1.5 x 10(-3) mg/kg per h for 30 days). Nicotine-induced inhibition of bradykinin-induced plasma extravasation did not show tachyphylaxis. In rats with arthritis, chronic administration of nicotine also produced a decrease in bradykinin-induced plasma extravasation. This effect of chronic nicotine in the arthritic rats was antagonized by co-administration of hexamethonium (a nicotinic receptor antagonist), by surgical removal of the adrenal medulla, or by co-administration of ICI-118,551 (a beta 2-adrenoceptor antagonist). Chronic administration of nicotine decreased the latency to the onset of arthritis and, in a dose-dependent manner, led to an increase in the radiographic joint injury score.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗
PubMed1992

Cigarette smoking and nicotine addiction.

Smokers smoke in large part because of the addictive effects of nicotine. Nicotine affects mood and performance and has been clearly implicated as the source of addiction to tobacco. People smoke to deliver desired doses of nicotine to their bodies, with certain rates of delivery and intervals between doses; these behaviors tend to be consistent for a person from day to day. Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. New formulations of nicotine substitutes will provide more options to the physician for tailoring treatment to the needs of individual smokers. Other pharmacotherapies, particularly antidepressant drugs, hold promise for certain smokers.

Animals↗
PubMed1992

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

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.

Administration, Cutaneous↗
PubMed1992

Misclassification of smoking status by self-reported cigarette consumption.

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 greater than or equal to 20) and selected from those with available serum. We defined biochemical smokers as persons with serum cotinine levels greater than or equal to 0.084 microM/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 misclassified nonsmokers, serum cotinine levels were consistent with light smoking. Among the 547 self-reported smokers, 66 (12.1%) were found to have serum cotinine levels less than or equal to 0.084 microM/L (14 ng/ml) and possibly misclassified by self-report. Of these, one person reported 20 or more cigarettes per day. We conclude that self-reported cigarette consumption may be an insufficient measure of the risks associated with tobacco use and measurement of serum cotinine may be important to assess the magnitude of misclassification of smoking status in epidemiologic studies.

Adult↗
PubMed1992

Orthostatic hypotension in ciguatera fish poisoning.

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.

Animals↗
PubMed1992

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

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.

Adrenal Medulla↗
PubMed1991

Selected ion monitoring method for determination of nicotine, cotinine and deuterium-labeled analogs: absence of an isotope effect in the clearance of (S)-nicotine-3',3'-d2 in humans.

A method for simultaneous determination of nicotine, its metabolite cotinine, and the stable isotope-labeled analogs nicotine-3',3'-d2 and cotinine-4',4'-d2 in human plasma has been developed. The method utilizes capillary column gas chromatography with detection by electron impact mass spectrometry and selected ion monitoring. Sensitivity is adequate for determination of nicotine and nicotine-d2 at concentrations as low as 1 ng ml-1, and cotinine and cotinine-d2 at concentrations as low as 10 ng ml-1 with good precision and accuracy. The method has been used to compare the elimination kinetics of (S)-nicotine-3',3'-d2 with natural nicotine in human subjects. Total clearance of nicotine-3',3'-d2 was virtually identical to the total clearance of natural nicotine, which validates the use of the deuterium-labeled analog in quantitative studies of nicotine metabolic disposition.

Adult↗
PubMed1991

Effects of caffeine with repeated dosing.

We have recently demonstrated dose-dependency of caffeine metabolism under multiple dosing conditions. Whether there are persistent pharmacodynamic actions of caffeine under such circumstances is the focus of this report. Nine healthy subjects were given, in randomized 5 day blocks, placebo, 4.2 (low) and 12 (high) mg.kg-1.day-1 of caffeine in 6 divided doses. After 5 days, complete tolerance developed to the effects of caffeine on blood pressure, heart rate and plasma glucose concentrations. The 24-h area under the curve (AUC) for plasma norepinephrine and the AUC for the total sum of free fatty acids (FFA) both demonstrated a trend to increase with the high dose caffeine treatment. When the AUC for norepinephrine was split into 12 h time periods, a significant difference between the placebo and the high dose treatment block was seen. We conclude that regular consumption of 12 mg.kg-1 of caffeine per day (equivalent to approximately 6 to 11 cups of coffee per day) may produce pharmacodynamic effects not completely compensated for by the development of tolerance. Mechanisms of tolerance may be overwhelmed by the nonlinear accumulation of caffeine and other methylxanthines in the body when caffeine metabolism becomes saturable.

Adult↗
PubMed1991

Stable isotope method for studying transdermal drug absorption: the nicotine patch.

A stable isotope-labeled drug method was used to determine the absolute bioavailability and absorption kinetics of a transdermal nicotine-delivery system (TTS). TTSs are being developed as an adjunct to smoking-cessation therapy. Deuterium-labeled nicotine was infused for 24 hours simultaneously to TTS application in cigarette-abstinent smokers. In 11 subjects with good patch adhesion, an average systemic dose of 19 mg nicotine was delivered, with average absolute bioavailability of 82%. The rate of nicotine absorption was maximal between 6 and 12 hours after TTS application and declined thereafter, plateauing between 16 and 24 hours at 62% of the maximal rate. Ten percent of nicotine was absorbed after the TTS was removed, demonstrating a reservoir for nicotine in the skin. Our study demonstrates the applicability of stable isotope methods in understanding the clinical pharmacology of transdermal drugs.

Administration, Cutaneous↗
PubMed1991

Stable isotope studies of nicotine kinetics and bioavailability.

The stable isotope-labeled compound 3',3'-dideuteronicotine was used to investigate the disposition kinetics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavailability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30-minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half-life averaging 203 minutes. This half-life was longer than that previously reported, indicating the presence of a shallow elimination phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smoke-monitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nicotine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nicotine and suggests that there may be significant extrahepatic metabolism of nicotine.

Administration, Inhalation↗