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Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 145 records · Page 8Linked to original sources
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↗
PubMed1991

Pharmacodynamics of nicotine: implications for rational treatment of nicotine addiction.

Rational treatment of the pharmacologic aspects of tobacco addiction includes nicotine substitution therapy. Understanding the pharmacodynamics of nicotine and its role in the addiction process provides a basis for rational therapeutic intervention. Pharmacodynamic considerations are discussed in relation to the elements of smoking cessation therapy: setting objectives, selecting appropriate medication and dosing form, selecting the optimal doses and dosage regimens, assessing therapeutic outcome, and adjusting therapy to optimize benefits and minimize risks.

Administration, Cutaneous↗
PubMed1991

Elevated nicotine levels in cervical lavages from passive smokers.

One hundred forty-five nonsmokers found to have normal cytologic diagnoses on routine Pap smears were interviewed regarding environmental exposure to tobacco smoke, and a 3 ml saline lavage of the cervix was collected for measurement of cervical nicotine levels by gas chromatography-mass spectroscopy. Nicotine levels tended to be highest among women exposed to tobacco smoke in the home, intermediate in women exposed only outside the home, and lowest in women recalling no exposure (p = 0.001).

Adolescent↗
PubMed1991

Basic and clinical psychopharmacology of nicotine.

Nicotine acts on nearly every physiological system of the human body. While the actions of nicotine on the autonomic nervous system may be of interest in understanding possible deleterious long-term effects of smoking on the cardiovascular system, the actions of nicotine on the central nervous system are of the most interest in understanding why people smoke. Many studies of the effects of nicotine on human cognitive function have been performed. Improvement in attention, learning, reaction time, and problem solving have been reported. However, most of the results are inconclusive owing to methodologic problems. Whether the enhanced performance observed after smoking is attributable to relief of symptoms of abstinence or to a primary effect of nicotine on the brain is not clear. The pharmacodynamic effects of nicotine must be considered in the design of studies of the effects of nicotine on human performance. It is not known if the effects of nicotine on performance are subject to tolerance. The facilitation of performance, perceived as a reinforcement, may tend to lessen throughout the day, as do other effects of nicotine. Studies of chronic tolerance to the behavioral effects of nicotine are needed; comparisons between regular smokers and occasional smokers may be helpful. At present, the facilitatory actions of nicotine on human performance have been explained in terms of arousal. However, nicotine actions cannot be explained in terms of this single concept. Different processes, including attention, stimulus evaluation, and response selection, appear to be involved in the effect of nicotine on human information processing. Finally, one must consider that the predominant effects of nicotine may differ among individuals, as different people smoke for different reasons, and the motives for (rewards of) smoking may vary in different situations.

Alzheimer Disease↗
PubMed1990

Diagnosis and management of pheochromocytoma.

The diverse manifestations of this tumor reflect variations in the hormones it releases and their patterns of release and in the individual-to-individual differences in catecholamine sensitivities. There is relatively little correlation between circulating levels of the catecholamines and the extent or even existence of hypertension in these patients. An unusual case starts the discussion.

Adrenal Gland Neoplasms↗
PubMed1990

Determination of nornicotine in smokers' urine by gas chromatography following reductive alkylation to N'-propylnornicotine.

A sensitive gas chromatographic assay has been developed to measure concentrations of nornicotine in human urine. A structural analogue, 5-methylnornicotine, is used as an internal standard. Both nornicotine and the internal standard were converted to the corresponding N'-propyl derivatives using a novel reductive alkylation procedure. The N'-propyl derivatives have good chromatographic properties, which allows quantitative measurement in the low nanograms per milliliter range. Concentrations of nornicotine in smokers' urine were quantitated and compared with the concentrations of nicotine and its metabolites, cotinine, nicotine-N-oxide and cotinine-N-oxide.

Alkylation↗
PubMed1990

Nicotine exposure among nondependent smokers.

Most theories of dependence imply that repeated exposure to an addictive drug leads inexorably to dependence. We examined nicotine exposure in "tobacco chippers," who smoke regularly without developing dependence. Blood samples were obtained before and after 10 chippers (smoking up to 5 cigarettes per day) and 12 dependent smokers (20 to 40 cigarettes per day) smoked a cigarette. Chippers' blood nicotine levels increased significantly, in amounts equaling those of dependent smokers. Assays of cotinine (a long-lasting nicotine metabolite) also suggested that chippers' per-cigarette nicotine absorption equaled that of dependent smokers. Chippers' cotinine levels were also compared with those of heavy smokers (38 cigarettes per day) whose consumption was reduced to 5 cigarettes per day in a previously published study. The heavy smokers compensated by tripling their per-cigarette nicotine intake. Chippers did not seem to be compensating; their cotinine values equaled those expected when regular smokers were not compensating for reduced cigarette availability.

Cotinine↗
PubMed1990

Pharmacokinetic considerations in understanding nicotine dependence.

The pharmacokinetic and pharmacodynamic characteristics of a drug are important determinants of whether users become dependent on it and of the temporal patterns of drug use. Characteristics of cigarette smoking, which produces a high degree of dependence, and the use of nicotine gum, which has a relatively low risk of dependence, are compared. Nicotine from tobacco smoke is rapidly absorbed and transferred into the brain. This results in high brain concentrations and intensive psychological effects, with relatively little development of tolerance. The smoker may titrate the level of drug and associated psychological effects of nicotine. Thus, smoking provides a nearly optimal situation for behavioural reinforcement. Chewing nicotine gum results in slow absorption of nicotine, leading to lower levels of nicotine in the brain and substantial time for development of tolerance. Thus, the intensity of effect is less and the onset of effect is delayed from the onset of dosing, providing less opportunity for behavioural reinforcement. Pharmacokinetic and pharmacodynamic modelling techniques have been applied to these processes and used to assess the implications for understanding the daily smoking cycle.

Animals↗
PubMed1990

Effect of chronic caffeine administration on monoamine and monoamine metabolite concentrations in rat brain.

Caffeine was chronically administered in four doses (0, 10, 25, and 50 mg/kg/day) to rats via twice-daily intraperitoneal injections for 30 days. Concentrations of brain tissue monoamines, dopamine (DA), norepinephrine (NE), and serotonin (5HT), and monoamine metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5HIAA), were determined. At the 10 mg/kg/day dose, no significant changes were found compared with controls. At 25 mg/kg/day and 50 mg/kg/day significant changes were observed within each monoamine system. In striatum, DA and 5HT were increased, while DOPAC was decreased. In frontal cortex, NE was increased. In cerebellum, 5HT and MHPG were increased.

Animals↗
PubMed1990

Synthesis of (3'R,5'S)-trans-3'-hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3'-hydroxycotinine in humans is highly stereoselective.

A method for the synthesis of (3'R,5'S-trans-3'-hydroxycotinine, a major metabolite of nicotine in humans, is described. The method involves deprotonation of (S)-cotinine with lithium diisopropylamide (LDA) followed by oxidation with the transition metal peroxide oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH) to give an 80:20 mixture of trans-/cis-3'-hydroxycotinine. The pure (greater than 98%) trans isomer is obtained by conversion to the solid hexanoate ester, recrystallization, and cleavage of the ester by heating with n-butylamine. GC-MS analysis of urine extracts from several smokers indicated that in humans metabolic 3'-hydroxycotinine is 95-98% trans.

Biotransformation↗
PubMed1990

Dose-dependency of caffeine metabolism with repeated dosing.

Some recent epidemiologic studies have reported a nonlinear dose-response in the relationship between coffee consumption and health risks, such that the risks increase disproportionately to the increase in dose. Assuming caffeine contributes to the adverse health effects of coffee, a possible explanation for the nonlinear dose-response relationship is dose-dependent metabolism of caffeine. We examined the hypothesis that under chronic dosing conditions the metabolism of caffeine is dose-dependent. Nine healthy subjects were given, in randomized 5-day treatment blocks, placebo, 4.2 (low) and 12 (high) mg/kg/day caffeine in decaffeinated coffee, in six divided doses spaced throughout the day. On the third day of each dosing period, 25 mg of stable-isotope labeled caffeine (2-13C, 1,3-15N2) was given intravenously. Clearance of labeled caffeine fell from 0.118 (placebo treatment) to 0.069 (low dose; p less than 0.005) and to 0.54 (high dose; p less than 0.001) L/hr/kg. The formation and metabolite clearances of paraxanthine, the major primary metabolite of caffeine, also decreased comparing the low and high doses (p less than 0.05). We conclude that caffeine metabolism is dose-dependent, resulting in nonlinear accumulation of methylxanthines in the body. Dose-dependent metabolism of caffeine may explain in part why people who drink large amounts of coffee are at greater risk for cardiovascular disease.

Adult↗
PubMed1990

Pharmacoepidemiology of the effect of caffeine on blood pressure.

In experimental studies, caffeine increases blood pressure in caffeine-naive or nontolerant individuals, but not in regular caffeine consumers. Using an epidemiologic approach, we examined the hypothesis that serum-caffeine concentration would be positively associated with blood pressure in infrequent (but not habitual) caffeine users in a group of bus drivers. Infrequent and habitual users of caffeine showed no differences in systolic or diastolic blood pressures when there is no measurable caffeine in the serum. However, at serum concentrations of caffeine typical of those achieved after one to two cups of coffee, infrequent users demonstrated greater systolic and diastolic pressures, averaging +5.3 mm Hg and +3.6 mm Hg, respectively, compared with habitual users. The magnitude of difference remained after adjustment for age, body mass index, race, sex, and tobacco and alcohol use. These elevations are large enough to exaggerate the prevalence of hypertension, if such assessments are based on cross-sectional surveys that fail to assess both proximate caffeine consumption and usual caffeine consumption habits.

Adult↗
PubMed1990

Influence of race, tobacco use, and caffeine use on the relation between blood pressure and blood lead concentration.

A number of studies have suggested a small to moderate positive relation between blood pressure and blood lead concentration in males (2-4 mmHg/In(microgram/dl]. However, this 1986 study of San Francisco bus drivers suggests larger relations in black males (n = 132) for both systolic pressure (7.5 mmHg/In(microgram/dl] and diastolic pressure (4.7 mmHg/In(microgram/dl] at very low blood lead concentrations (2-21 micrograms/dl). This increase appears to result from negative confounding, particularly after taking into account tobacco use. Relations are even larger in blacks who infrequently use caffeine (16.7 and 10.4 mmHg/In(microgram/dl) for systolic and diastolic pressure, respectively). In contrast, a negative relation between systolic pressure and blood lead concentration (-5.7 mmHg/In(microgram/dl] is suggested in nonblack males (n = 117). These findings indicate that race, lead accumulation, and physiologic effects related to caffeine use (e.g., catecholamine effects) may interact to produce marked differences in effect on blood pressure.

Black or African American↗
PubMed1990

Clinical pharmacology of caffeine.

Caffeine is the most widely consumed stimulant drug in the world. This chapter reviews the human pharmacology of caffeine; the evidence for its role in causing human disease, including addiction; and its potential usefulness as a therapeutic agent.

Abnormalities, Drug-Induced↗
PubMed1990

Apparent underreporting of cigarette consumption among Mexican American smokers.

To determine the accuracy of self-report of cigarette consumption among Mexican American smokers, we compared self-reported cigarette use and serum cotinine concentrations in a sample of 547 participants in the Hispanic Health and Nutrition Examination Survey (HHANES). We defined underreporting of cigarette use as a cotinine to cigarette-per-day ratio of greater than 0.142 microM/l which represented a substantial discrepancy between self-reported consumption and serum cotinine. Of the 98 men and 97 women who reported smoking one to nine cigarettes/day, 20.4 percent and 24.7 percent, respectively, underreported their cigarette consumption. Underreporting was less common among men and women smoking 10 to 19 cigarettes/day (8.3 percent and 10.8 percent, respectively) and 20 or more cigarettes/day (2.2 percent and 2.9 percent, respectively). Comparison of underreporters to other smokers by demographic characteristics within sex and cigarettes/day categories showed no differences. Differences in cotinine metabolism and extremely efficient smoking are alternative explanations that can not be ruled out with these data. We believe, however, that a proportion of Mexican American light smokers may underreport the quantity of cigarettes smoked per day, and may truly be moderate or heavy smokers.

Adult↗