Sodium intake from smokeless tobacco.
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Blood Pressure↗
Biomedical subjects
N L Benowitz
Publications and source records attributed to N L Benowitz.
Disposition kinetics of nicotine and cotinine enantiomers in rabbits and beagle dogs.
The disposition kinetics of nicotine and cotinine enantiomers was determined in rabbits. The clearance of (R)-nicotine was similar to that of (S)-nicotine, but clearance of (R)-cotinine was twice that of (S)-cotinine. Fractional conversions of both enantiomers of nicotine to cotinine were approximately 50%. These results suggest that in rabbits the biotransformation pathways of cotinine, but not nicotine, are influenced by stereochemistry. The disposition kinetics of nicotine enantiomers in beagle dogs was also studied. In dogs, the clearance of (R)-nicotine was slightly greater than the clearance of (S)-nicotine. Methods for the synthesis of (R)-nicotine and (R)-cotinine of high enantiomeric purity and a gas chromatographic method for determination of nicotine enantiomeric purity are described.
Animals↗
Nicotine gum: chew rate, subjective effects and plasma nicotine.
Two studies were conducted to assess the effects of varying the rate at which single pieces of nicotine gum (4 mg) were chewed. In each study, six cigarette-deprived volunteers were tested during four sessions. In each session, they were required to chew the gum for 10 min at varying rates; a variety of self-report and physiologic responses were recorded before and after chewing. All chewed gum was analyzed for amount of nicotine extracted, and blood samples were collected for nicotine analysis. Additionally, in Experiment 2, a measure of masticatory pressure was employed to assess the intensity of chewing and to empirically verify the number of chews. In both studies, we found a weak, but direct, relation between chew rate and the amount of extracted nicotine. Experiment 2 revealed a probable cause of the weaker than expected "dose-effect" function: subjects showed compensatory changes in behavior by chewing slower than instructed in the high rate conditions, and by chewing faster than instructed in the low rate conditions. Thus, despite instructions to vary chew rates across an 8-fold range, actual chew rate varied by only 2.2-fold. Intensity of chewing remained constant across conditions. Taken together, the findings suggest that rate of chewing nicotine gum can make a difference in the amount of nicotine extracted from the gum; however, compensatory changes in chew rate may attenuate attempts to systematically vary nicotine dose in this manner.
Adult↗
Recent studies of nicotine metabolism in humans.
Recent studies of quantitative and qualitative aspects of nicotine metabolism, and the use of metabolic data for estimating nicotine intake in humans are discussed. Previously reported methodology for determining nicotine bioavailability has been improved by using stable isotope-labeled nicotine administered intravenously. Combined gas chromatography-mass spectrometry with selected ion monitoring has been used to simultaneously determine concentrations of isotopically-labeled nicotine and tobacco-derived nicotine in blood. Nicotine intake from cigarette smoking was estimated from clearance of labeled nicotine and blood concentrations of tobacco-derived nicotine. Progress in elucidating the metabolic profile of nicotine in humans, and the use of nicotine metabolites as markers of tobacco smoke consumption is summarized.
Adult↗
Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum.
Because of recent resurgence in its consumption, the effects and health consequences of smokeless tobacco are of considerable public health interest. We studied the extent and time course of absorption of nicotine and cardiovascular effects of smokeless tobacco (oral snuff and chewing tobacco) and compared it with smoking cigarettes and chewing nicotine gum in 10 healthy volunteers. Maximum levels of nicotine were similar but, because of prolonged absorption, overall nicotine exposure was twice as large after single exposures to smokeless tobacco compared with cigarette smoking. All tobacco use increased heart rate and blood pressure, with a tendency toward a greater overall cardiovascular effect despite evidence of development of some tolerance to effects of nicotine with use of smokeless tobacco. Relatively low levels of nicotine and lesser cardiovascular responses were observed with use of nicotine gum. Adverse health consequences of smoking that are nicotine related would be expected to present a similar hazard with the use of smokeless tobacco.
Adult↗
Changes in rate and pattern of caffeine metabolism after cigarette abstinence.
Caffeine metabolism is known to be accelerated in cigarette smokers, but the effects of smoking on the kinetics and pattern of metabolism in a daily consumption pattern have not been described. We investigated the effects of tobacco abstinence on the rate and pattern of caffeine metabolism in nine habitual smokers who consumed six cups of coffee per day, each cup containing 2 mg/kg caffeine. Abstinence from smoking for 4 days resulted in a 46% increase in the 24-hour AUC. Thus, significant, although probably not complete, normalization of the enzyme-inducing effects of cigarette smoking can be seen after 4 days abstinence. During abstinence, 24-hour urine ratios of dimethylxanthines to caffeine and mono-dimethylxanthines to dimethylxanthines were reduced, suggesting that cigarette smoking accelerates both demethylation steps. Other metabolic pathways were unaffected.
Adult↗
Cardiovascular effects of smoking in patients with ischemic heart disease.
The cardiovascular effects of smoking, including the occurrence of ventricular arrhythmias, were examined in 52 patients with ischemic heart disease. The study was a randomized, crossover comparison between smoking six cigarettes and nonsmoking with observer-blinded primary outcome measurements. Continuous Holter ECG recording for four hours showed no significant differences in the proportion of patients experiencing ventricular ectopy or the total number and complexity of ventricular premature beats during smoking vs nonsmoking. Aside from the first cigarette, smoking did not significantly alter blood pressure or heart rate. Mean (+/- SEM) plasma epinephrine (pg/ml) increased (p = 0.02) from baseline (52 +/- 4) to a maximum of 64 +/- 6 at 240 minutes with younger subjects exhibiting a more marked rise (p = 0.02) than subjects over 55 years of age. Plasma norepinephrine was unchanged by smoking. A power calculation confirmed the conclusion that the resumption of smoking after overnight abstention does not acutely increase the occurrence of ventricular ectopic activity in patients with ischemic heart disease.
Adult↗
Elimination of cotinine from body fluids: implications for noninvasive measurement of tobacco smoke exposure.
Cotinine elimination from plasma, saliva, and urine was studied over 11 days in five subjects (three nonsmokers and two occasional smokers). Half-lives for cotinine averaged 16-19 hours in the different body fluids (range 10 to 27 hours between subjects). There was no tendency for the half-life in saliva to be longer than in plasma or urine. We conclude that choice of body fluid for cotinine assay in smoking studies should depend on practical rather than pharmacokinetic considerations.
Adult↗
Cotinine in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers.
Cotinine was measured in the serum, saliva, and urine of nonsmokers, passive smokers, and active smokers. Serum and saliva could not discriminate between nonsmokers and passive smokers. Mean urine cotinine was higher in passive smokers than nonsmokers but there was a great deal of intersubject overlap. Cotinine in all body fluids could separate active smokers from the other two groups. Among smokers, light smokers had lower levels than heavier smokers.
Adult↗
Pheochromocytoma--recent advances in diagnosis and treatment.
These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs Homer A. Boushey, Professor of Medicine, and David G. Warnock, Associate Professor of Medicine, under the direction of Dr Lloyd H. Smith, Jr, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143.
Adrenal Gland Neoplasms↗
Effects of the stereoisomers of nicotine and nornicotine on schedule-controlled responding and physiological parameters of dogs.
The behavioral and physiological effects of five tobacco alkaloids were assessed in two different test paradigms. One group of beagle dogs (N = 5) responded under a multiple fixed-interval (FI) 300 sec, fixed-ratio (FR) 30 response schedule of food presentation. With both l-nicotine (0.1-3.0 mumol/kg i.m.) and l-nornicotine (0.1-10.0 mumol/kg i.m.), FI response rates, when averaged across the entire session, were increased at low doses and decreased at high doses; FR response rates were only decreased. d-Nicotine (0.1-30.0 mumol/kg i.m.), and d- and dl-nornicotine (0.1-10.0 mumol/kg i.m.) produced a transient increase in FI response rates at low doses. The effects of the same five compounds on pupillary diameter, rectal temperature and heart rate were measured in a second group of beagle dogs (N = 6). Both pupillary diameter and rectal temperature were decreased initially by l-nicotine (0.6 mumol/kg i.v.), d-nicotine (6.0 mumol/kg i.v.) and d-, l- and dl-nornicotine (3.0 mumol/kg i.v.); base-line levels were recovered within 60 min. Aside from differences in potency, the time courses of action were similar for all five compounds. Increases in heart rate also were produced by all five compounds, but there were marked differences in the duration of action. l-Nicotine and d- and dl-nornicotine produced appreciable, sustained increases in heart rate, whereas d-nicotine and l-nornicotine produced moderate, brief increases. The combined results of the present experiments indicate the stereoisomers of nicotine and nornicotine are behaviorally and physiologically active, and may contribute in varying amounts to the pharmacologic actions of tobacco.
Animals↗
Toxicity of nicotine: implications with regard to nicotine replacement therapy.
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Cardiovascular Diseases↗
Pharmacodynamic model of tolerance: application to nicotine.
The authors propose a model of pharmacodynamic response that, when integrated with a pharmacokinetic model, allows characterization of the development of functional tolerance. The model may be conceived of in several equivalent ways; one of these sees tolerance as a result of (noncompetitive) antagonism of agonist effect by a hypothetical substance (e.g., metabolite) produced by a first-order process, driven by agonist concentration. Tolerance thus lags behind, and is approximately proportional to, agonist concentrations. Two new parameters quantifying tolerance are introduced: kantO, which describes the elimination kinetics of the antagonist and determines the rate of development and disappearance of tolerance, and Cant50, which determines the magnitude of tolerance that can be achieved. The model was tested in eight volunteers on data produced after three sequences of paired i.v. administrations of nicotine separated by different intervals of time. Blood concentrations of nicotine and heart rate were measured. The proposed tolerance model was fitted to the nicotine data. The estimate of kantO suggests a half-life of development and regression of tolerance of 35 min, and the estimate of Cant50 suggests that tolerance, at its full development, causes an approximately 80% reduction of initial (nontolerant) effect. This model provides a quantitative pharmacokinetic-pharmacodynamic description of the development of acute tolerance that also carries physiologic meaning. The quantitative information provided by this model may improve understanding of the temporal patterns of drug abuse and complications thereof.
Adult↗
Identification and quantitative analysis of cotinine-N-oxide in human urine.
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Chromatography, High Pressure Liquid↗
Electrophysiologic effects of cigarette smoking in patients with and without chronic beta-blocker therapy.
After refraining from smoking for at least 8 hours, 22 adult male habitual smokers underwent baseline electrophysiologic study including atrial and ventricular burst pacing and programmed premature stimulation with single extrastimuli. After smoking 2 of their usual brand of cigarettes in rapid succession, the electrophysiologic protocol was repeated. Nicotine, catecholamine and carbon monoxide concentrations all increased significantly. Smoking increased heart rate and improved atrioventricular conduction in the 13 patients receiving chronic beta-blocker therapy (mostly for angina pectoris); increases in heart rate and improvement in atrioventricular conduction were not different statistically from those seen in patients not receiving beta-blocker therapy, suggesting the possibility of a direct effect of nicotine or other components of tobacco smoke. Ventricular refractoriness was not altered and atrial and ventricular arrhythmias were not increased by smoking. Persistent sympathomimetic actions of cigarette smoking may explain in part the failure of beta-blocking drugs to reduce cardiac mortality risk in smokers after myocardial infarction.
Adrenergic beta-Antagonists↗
Determination of benzoylecgonine and cocaine in biologic fluids by automated gas chromatography.
A method is described for extraction of the cocaine metabolite benzoylecgonine, conversion to the butyl ester derivative and gas chromatographic analysis using packed or capillary columns. Using a capillary column, cocaine and benzoylecgonine may be determined simultaneously. The extraction scheme has been designed to facilitate processing of large numbers of samples generated in pharmacokinetic studies. Structural analogues, m-toluylecgonine and m-toluylecgonine methyl ester, are used as internal standards. Concentrations as low as 10 ng/ml in 1-ml samples of plasma or urine are readily determined. Between-run coefficients of variation were 1.01% for cocaine and 4.18% for benzoylecgonine for concentrations of 75 and 350 ng/ml, respectively.
Autoanalysis↗
The effect of cigarette smoking on penile erection.
Clinical observations suggest that cigarette smoking impairs erectile function in patients with moderate arterial insufficiency. To evaluate the effects of smoking on the physiology of erection, we studied six healthy adult mongrel dogs in which bipolar cuff electrodes were implanted around the cavernous nerves. After threshold stimulation parameters for penile erection were established, cigarette smoke collected in a 60-ml. syringe was released slowly near the dog's mouth, to be inhaled by natural breathing. Stimulation of the cavernous nerve was repeated and blood samples for nicotine, cotinine and blood gases were obtained before and after each cigarette. The systolic and intracorporeal pressure, flow through the internal pudendal artery, and venous flow from the corpora cavernosa were recorded at baseline and with each electrostimulation after smoke inhalation. Five of the six dogs were unable to achieve full erection after inhalation of smoke from two to three cigarettes. Some decrease of flow through the internal pudendal artery occurred and the venous restriction ability was almost completely abolished by smoking. Further, when nicotine was injected intravenously into two additional dogs, the same phenomenon was observed. These findings support the idea that cigarette smoking may contribute to impotence in some patients.
Animals↗
Prolonged absorption with development of tolerance to toxic effects after cutaneous exposure to nicotine.
This report describes a patient who developed nicotine poisoning after cutaneous application of nicotine sulfate. Measurement of nicotine and metabolite levels in the blood demonstrated prolonged absorption of nicotine despite vigorous skin decontamination. This suggests that the skin may be a reservoir for slow release of nicotine into the circulation. Despite extraordinarily high levels of nicotine, the patient had full resolution of signs and symptoms of intoxication, indicating rapid and profound development of tolerance.
Administration, Topical↗