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Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 91 records · Page 5Linked to original sources
PubMed1995

Is serum cotinine a better measure of cigarette smoking than self-report?

OBJECTIVES: To address the question of whether serum cotinine is a better measure of cigarette smoking than self-reported behavior by examining the relation of biochemical, physical examination, and depression assessments to self-reported cigarette consumption and serum cotinine in a population-based sample. METHODS: Serum from 743 Mexican American participants in the Hispanic Health and Nutrition Examination Survey (HHANES) categorized by sex and number of cigarettes smoked per day (0, 1 to 9, 10 to 19, > or = 20) was analyzed for cotinine. HHANES results from hematocrit, hemoglobin, red blood cells (RBCs), white blood cells (WBCs), mean corpuscular volume (MCV), iron, transferrin, lead, erythrocyte protoporphyrin (EPP), vitamin E, vitamin A, cholesterol, body mass index (BMI), pulse rate, systolic and diastolic blood pressure (DBP), Center for Epidemiological Depression Scale (CES-D), and Diagnostic Interview Schedule (DIS) depression diagnosis were compared by category of cigarettes smoked per day and serum cotinine. RESULTS: Among women significant correlations were found between cigarettes per day and cotinine, respectively, and hematocrit (r = 0.148, r = 0.338), hemoglobin (r = 0.152, r = 0.342), WBCs (r = 0.160, r = 0.272), and BMI (r = -0.124, r = -0.164). Among men significant correlations were found between cigarettes per day and cotinine, respectively, and WBCs (r = 0.176, r = 0.296), MCV (r = 0.310, r = 0.264), lead (r = 0.105, r = 0.177), and BMI (r = -0.110, r = -0.192). Cotinine, but not cigarettes per day, was significantly correlated with hemoglobin (r = 0.179) and DBP (r = -0.146) in men and EPP (r = -0.135) and cholesterol (r = 0.105) in women. Mean CES-D score was correlated with cigarettes per day for both men (r = 0.106) and women (r = 0.158) but not with cotinine. CES-D caseness (score > or = 16) and a positive diagnosis of depression by DIS was not related to smoking behavior measures among men. Women smokers compared to nonsmokers had higher levels of depression. Multivariate regression models controlling for sex, age, and education indicated that serum cotinine was a significant predictor of hematocrit, hemoglobin, RBCs, WBCs, lead, and DBP; self-reported cigarettes was significant only for MCV. CONCLUSIONS: Serum cotinine may be a better method of quantifying risks from cigarette use in epidemiological studies.

Adult↗
PubMed1995

Sympathomimetic effects of paraxanthine and caffeine in humans.

Caffeine is metabolized extensively (on average 80%) to paraxanthine. With regular caffeine consumption, average serum levels of paraxanthine are two thirds those of caffeine. Both caffeine and paraxanthine competitively and nonselectively inhibit adenosine receptors in vitro. To examine the contribution of paraxanthine to the pharmacologic activity of caffeine, we administered to 12 subjects in a crossover design oral caffeine (2 or 4 mg/kg) versus placebo or oral paraxanthine (same dose as caffeine) versus placebo, each after 3 days of methylxanthine abstinence. Both caffeine and paraxanthine significantly increased diastolic blood pressure, plasma epinephrine levels, and free fatty acids. Caffeine and paraxanthine produced a similar magnitude of response at 4 mg/kg; however, caffeine appeared to produce greater responses than paraxanthine at 2 mg/kg. Caffeine and paraxanthine have similar sympathomimetic actions. The activity of paraxanthine needs to be considered in understanding the clinical pharmacology of caffeine, particularly with chronic, repetitive caffeine consumption.

Adult↗
PubMed1995

Deficient C-oxidation of nicotine.

In most people, nicotine is extensively (70% to 80%) metabolized to cotinine by C-oxidation. In a clinical trial, a 57-year-old woman was found to have the expected plasma levels of nicotine but unusually low plasma levels of cotinine both when smoking cigarettes and while receiving transdermal nicotine. To characterize her metabolism, simultaneous infusions of deuterium-labeled nicotine (d2) and cotinine (d4) were administered, with comparison to 20 other control smokers. The clearance of nicotine was unusually low (6.5 ml/min/kg versus 17.2 ml/min/kg), and the half-life of nicotine significantly longer (348 minutes versus 138 minutes) in the index case subject compared with the control subjects. The clearance of cotinine was normal. The index case subject converted only 9% of nicotine to cotinine, compared with 72% for the control subjects. As far as we know, this is the first person with deficient C-oxidation of nicotine to be characterized. Deficient C-oxidation of nicotine is associated with a long half-life of nicotine and deficient generation of cotinine, both of which could influence the risks and addictiveness of tobacco use in affected individuals.

Adult↗
PubMed1995

Effects of caffeine ingestion on NE kinetics, fat oxidation, and energy expenditure in younger and older men.

Age-related differences in energy expenditure, fat oxidation, and norepinephrine (NE) kinetics after caffeine ingestion were examined using a placebo-controlled double-blind study in 10 older (O, 65-80 yr) and 10 younger (Y, 19-26 yr) men who were moderate consumers of caffeine. Caffeine ingestion resulted in similar increases in Y and O men for plasma caffeine levels (Y = 89 +/- 100 to 6,340 +/- 1,938 ng/ml, P < 0.05; O = 124 +/- 38 to 7,066 +/- 2,366 ng/ml, P < 0.05) and energy expenditure (Y = 11%, 1.38 +/- 0.15 to 1.52 +/- 0.22 kcal/min, P < 0.05; O = 9.5%, 1.15 +/- 0.13 to 1.26 +/- 0.20 kcal/min, P < 0.05). However, caffeine ingestion increased fatty acid concentrations (362 +/- 159 to 803 +/- 253 mumol/l, P < 0.05) and tended to increase rate of appearance of fatty acids (624 +/- 376 to 1,394 +/- 1,331 mumol/l, P = 0.07) in younger but not older men. Rates of fat oxidation and NE appearance and clearance did not significantly differ from baseline values in either group. In conclusion, older and younger men show a similar thermogenic response to caffeine ingestion, whereas older men show a smaller increase in fatty acid availability after a caffeine challenge. These metabolic differences are not related to alterations in NE kinetics or fat oxidation.

Administration, Oral↗
PubMed1995

Cigarette smoking sensitizes and desensitizes impedance-measured ADP-induced platelet aggregation in whole blood.

The effect of smoking on platelet aggregation appears to produce conflicting results, with some studies indicating an enhancement and others a decrease of aggregation. This epidemiological study of 120 male smokers, a subset of the Caerphilly Heart Disease Study, examined the relationship of two dimensions of smoking (time proximity of last cigarette before venepuncture and serum nicotine concentration) with threshold dose of adenosine diphosphate (ADP) necessary to induce platelet aggregation in whole blood. Means (range) of ADP threshold dose and nicotine concentration were 1.66 (0.5-2.5, censored) microM and 12.2 (0-35.2) ng/ml. Men smoking within 30 min of venepuncture demonstrated lower ADP threshold doses (-0.48 microM lower [95% C.I.: -0.95, -0.02])--reflecting increased sensitivity. Men with higher nicotine concentration had higher ADP threshold doses (Regression Coefficient: +0.032 microM per ng/ml [95% C.I.: 0.003, 0.062])--reflecting decreased sensitivity. Men smoking 30 min or more before venepuncture who also had high nicotine concentration (25-30 ng/ml) demonstrated the highest ADP threshold doses compared to never smokers and to men smoking the previous day (approximately 2.20 vs 1.86 and 1.81 microM). Relations involving nicotine concentration do not necessarily reflect a pharmacological effect although the potential for a short term nicotine mediated tolerance effect cannot be dismissed. These observations support an hypothesis suggesting a temporal sequence of platelet sensitization and desensitization during smoking.

Adenosine Diphosphate↗
PubMed1994

A low dose of subcutaneous nicotine improves information processing in non-smokers.

Many studies have found that cigarette smoking or nicotine improves mental functioning in abstinent smokers. An unresolved issue is whether this improvement is due primarily to a direct facilitation of performance or to relief of the impairment caused by nicotine withdrawal. We evaluated the performance of 12 non-smokers before and twice (15 and 45 min) after a subcutaneous injection of 0.8 mg nicotine, 0.8 ml saline, and a control no treatment, on a choice reaction time (RT) task. Each treatment was given on a separate day; the control day was given on the first session. The order of nicotine and saline was balanced between subjects, and injections were given double-blind. The RT task manipulated stimulus and response processing. These manipulations consisted of two levels of stimulus complexity and two levels of response complexity, resulting in four task conditions. These manipulations along with latency measures of the event-related potential were used to identify the components of processing that mediated nicotine's effects on performance. During each active drug session blood nicotine levels, cardiovascular, and subjective responses were measured before and after each of the three tests (pre-drug, 15 min and 45 min post-drug). For the information processing measures only the comparisons of the pre- and 15-min post-test showed significant drug effects. Nicotine compared to saline significantly increased the number of responses at the fast end of the RT distribution. However, there were no changes in accuracy. Nicotine also speeded mean RT compared with saline or the control day, but the effects were only significant for the control-nicotine comparison.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Seizures associated with poisoning and drug overdose.

A retrospective review of cases consulted by the San Francisco Bay Area Regional Poison Control Center during a 2-year period was performed to determine the causes and consequences of seizures associated with poisoning and drug intoxication. Of 233 charts coded as involving seizures, 191 occurred in humans and were available for analysis. The leading causes of seizures reported to the Poison Control Center were cyclic antidepressants (55 cases, 29%); cocaine and other stimulants (55 cases, 29%); diphenhydramine and other antihistamines (14 cases, 7%); theophylline (10 cases, 5%); and isoniazid (10 cases, 5%). Stimulants and diphenhydramine were more likely than other drugs to produce brief, self-limited seizures. In contrast, poisoning by cyclic antidepressants, cardiodepressant antiarrhythmic agents, or theophylline was more likely to be associated with death. Seizures in elderly patients were more likely to result in complications and death. The frequency of seizure-related cases by substance type was also compared with the results of an earlier survey performed in 1981, and found a striking increase in the proportion of seizures caused by cocaine and (23% in 1988 to 1989 compared with 4% in 1981). Poison Control Center data can provide valuable information about the causes and consequences of drug-related medical complications, as well as highlight changing trends in drug-related injury.

Adolescent↗
PubMed1994

Divergent tolerance to metabolic and cardiovascular effects of nicotine in smokers with low and high levels of cigarette consumption.

Cigarette smokers on average weigh less than nonsmokers. However, among smokers, those who smoke the most weigh the most. To better understand the effects of nicotine on body weight, we investigated the pharmacodynamics of intravenous nicotine and cigarette smoking in low-level smokers (10 or fewer cigarettes per day) and high-level smokers (15 to 30 cigarettes per day). Cigarette smoking and intravenous nicotine increased heart rate and energy expenditure in most smokers. The effects of intravenous nicotine and smoking were of similar magnitude, confirming that the effects of smoking are mediated by nicotine. Nicotine produced a slightly greater increase in heart rate in low-level versus high-level smokers, but energy expenditure increased to a much greater extent in low-level versus high-level smokers. The plots of plasma nicotine concentration versus responses suggest development of acute tolerance to both heart rate acceleration and increased energy expenditure in low-level smokers; high-level smokers show a similar pattern of tolerance for heart rate but show only a brief increase in energy expenditure and a hysteresis curve consistent with either rapid development of tolerance or no effect. Thus there is evidence of differential development or rate of loss of tolerance to cardiovascular versus metabolic effects of nicotine in low-level versus high-level smokers. Pharmacodynamic differences between low-level and high-level smokers may explain, at least in part, the unusual relationship between cigarette consumption and body weight.

Adult↗
PubMed1994

Metabolism of nicotine to cotinine studied by a dual stable isotope method.

OBJECTIVES: (1) To determine the disposition kinetics of nicotine and cotinine, including the fractional conversion of nicotine to cotinine, (2) to compare the disposition kinetics of deuterium-labeled and unlabeled cotinine, and (3) to develop a pharmacokinetically based method for estimating daily intake of nicotine from cigarette smoking. STUDY DESIGN: Twenty cigarette smokers received a combined infusion of deuterium-labeled nicotine (d2) and cotinine (d4). Six nonsmokers received a combined infusion of unlabeled cotinine, cotinine-d2 and cotinine-d4. Daily intake of nicotine was estimated with use of the plasma cotinine concentration during ad libitum smoking, clearance of labeled cotinine, and fractional conversion of nicotine to cotinine. RESULTS: The kinetics of labeled versus unlabeled cotinine and of cotinine in smokers versus nonsmokers were similar. On average, 72% of nicotine was converted to cotinine, with a range from 55% to 92%. Subjects with lower clearances of nicotine had lower fractional conversion of nicotine to cotinine, indicating that this is the most rapid of the proximate metabolic pathways for nicotine. The equation for estimating daily intake of nicotine from smoking was: Dnic (mg/24 hr) = K x (Plasma Cot) (ng/ml), where K averaged 0.08, with a range from 0.047 to 0.102. Individual variability in the clearance of cotinine (coefficient of variation, 27.5%) accounts for more of the variability in K than does variability in the fractional conversion of nicotine to cotinine (coefficient of variation, 12.3%). CONCLUSIONS: Our study provides quantitative data on individual variability in the extent of C-oxidation of nicotine to cotinine and a quantitative perspective on the use of plasma cotinine as an indicator of daily intake of nicotine from tobacco.

Adult↗
PubMed1994

Metabolic interactions between surplus dietary energy intake and cigarette smoking or its cessation.

Cigarette smoking (CS) alters lipid metabolism and is associated clinically with an atherogenic lipid profile. We recently showed that, under controlled eucaloric dietary conditions, CS stimulates lipolysis without increasing oxidation of fat and that cessation of CS does not result in a rebound tendency to synthesize or store fat. We asked here whether the ad libitum intake of surplus dietary energy interacts with the metabolic effects of CS or its cessation. Eight male heavy smokers were allowed ad libitum food intake in a metabolic ward, 1 wk in CS phase and 1 wk in non-CS phase, followed by 4 wk of outpatient non-CS and a repeat 7-day study. De novo hepatic lipogenesis (DNL), lipolysis, substrate cycling of free fatty acids (FFA), hepatic glucose production, and energy expenditure were measured by using a multiple stable-isotope infusion protocol and indirect calorimetry. Surplus dietary energy intake (> 150% of predicted energy needs) occurred in five of eight subjects (2 subjs > 5,500 kcal/day, 3 subjs > 4,000 kcal/day) with weight gain of 1-4 kg/wk, but with no difference between CS and non-CS phases. Acute CS significantly increased (P < 0.05) serum FFA concentrations (58%), FFA flux (63%), and glycerol flux (36%); nonsignificantly increased extra-adipocyte (hepatic) esterification of FFA (125%, P = 0.10) and resting energy expenditure (4.1%, P = 0.22); and did not change adipocyte reesterification of FFA or whole body oxidation of fat. Basal metabolic parameters (after overnight abstention from CS) did not differ between phases. Fractional DNL correlated significantly with excess energy intake (r2 = 0.39) and with percentage of total energy needs provided by carbohydrate (r2 = 0.47). The absence or presence of CS did not affect the increase in fractional DNL in subjects with excess energy intake, however. We conclude that cessation of CS does not result in a rebound tendency to synthesis or storage of fat, even in the presence of positive short-term energy balance, contrary to previous suggestions. Moreover, stimulation of lipolysis by CS does not increase oxidation of fat and thereby protect against fat deposition under conditions of surplus energy intake. The prevention of weight gain after cessation of CS, whether or not nicotine is provided, should focus on energy balance (calorigenesis as well as intake) rather than specific alterations in lipid metabolism.

Adult↗
PubMed1994

Role of vagal afferents and spinal pathways modulating inhibition of bradykinin-induced plasma extravasation by intrathecal nicotine.

1. Nicotine, a major active component of tobacco smoke, has been shown to modulate the inflammatory response via both peripheral and central nervous system pathways. Recently we found that spinal intrathecal administration of nicotine dose-dependently inhibits bradykinin-induced plasma extravasation (BK-induced PE) in the knee joint of the rat and that the dose-response curve for the inhibition of BK-induced PE by intrathecal nicotine is shifted to the left, by six orders of magnitude, after surgical interventions in the abdominal cavity, which might have interrupted visceral afferents to the neuraxis. Therefore we focused, in this study, on the contribution of the vagal afferents to depression of BK-induced PE by intrathecal nicotine. Furthermore, the effect of acute spinalization at the level C6-C8 was investigated. The hypothesis was that impulse activity in vagal afferents has a pronounced inhibitory effect on the modulation of BK-induced PE by intrathecal nicotine and that spinal pathways are important in mediating this effect. 2. Chronic subdiaphragmatic vagotomy and elimination of vagal afferents, by neonatal capsaicin treatment or by application of kainic acid to the nodose ganglia, enhanced the potency of intrathecal nicotine depression of BK-induced PE, by six to seven orders of magnitude when compared with the control. 3. Acute subdiaphragmatic vagotomy enhanced the potency of intrathecal nicotine-induced depression of BK-induced PE (without changing its maximum effect), by about three to four orders of magnitude when compared with the sham-operated (control) animals (with intact vagus nerves).(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1994

Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers.

The relationship between thermogenic and potentially atherogenic effects of cigarette smoking (CS) and its cessation was investigated. Heavy smokers (n = 7, serum cotinine > 200 ng/ml, > 20 cigarettes/d) were maintained on isoenergetic, constant diets for 2 wk, 1 wk with and 1 wk without CS. Stable isotope infusions with indirect calorimetry were performed on day 7 of each phase, after an overnight fast. CS after overnight abstention increased resting energy expenditure by 5% (not significant vs. non-CS phase; P = 0.18). CS increased the flux of FFA by 77%, flux of glycerol by 82%, and serum FFA concentrations by 73% (P < 0.02 for each), but did not significantly affect fat oxidation. Hepatic reesterification of FFA increased more than threefold (P < 0.03) and adipocyte recycling increased nonsignificantly (P = 0.10). CS-induced lipid substrate cycles represented only 15% (estimated 11 kcal/d) of observed changes in energy expenditure. De novo hepatic lipogenesis was low (< 1-2 g/d) and unaffected by either acute CS or its chronic cessation. Hepatic glucose production was not affected by CS, despite increased serum glycerol and FFA fluxes. Cessation of CS caused no rebound effects on basal metabolic fluxes. In conclusion, a metabolic mechanism for the atherogenic effects of CS on serum lipids (increased hepatic reesterification of FFA) has been documented. Increased entry of FFA accounts for CS-induced increases in serum FFA concentrations. The thermogenic effect of CS is small or absent in heavy smokers while the potentially atherogenic effect is maintained, and cessation of CS does not induce a rebound lipogenic milieu that specifically favors accrual of body fat in the absence of increased food intake.

Adipocytes↗