Search PubMed⌕ Search

Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 19 recordsLinked to original sources
PubMed1996

Validation of urine caffeine metabolite ratios with use of stable isotope-labeled caffeine clearance.

OBJECTIVE: A number of caffeine metabolite ratios have been proposed to measure CYP1A2 activity in vivo. The data to validate these ratios are scanty. The objective of this study was to validate urine caffeine metabolite ratios versus stable isotope-labeled caffeine clearance under different caffeine dosing conditions. STUDY DESIGN: Two experiments, one with nine nonsmoking subjects and the other with 12 cigarette smokers, were performed. We explored the relationship between caffeine clearance, measured by means of intravenous infusions of stable isotope-labeled caffeine, and a number of caffeine metabolite ratios during administration of different single or multiple doses of caffeine to smokers and nonsmokers on three different occasions over a 2-week period, using different durations of urine collections, including spot urines. The stable isotope technique allowed simultaneous oral dosing of caffeine and measurement of caffeine metabolite ratios and caffeine clearance, the latter reflecting CYP1A2 activity. RESULTS: The caffeine metabolite ratio of AAMU + 1U +1X/17U (5-acetylamino-6-amino-3-methyluracil + 1-methyluric acid + 1 methylxanthine/1,7-dimethyluric acid) maintained a significant correlation with caffeine clearance for all the above conditions (gamma2 range, 0.4 to 0.9) except for dose. With high doses of caffeine (12 mg/kg), a significant relationship was not observed. AAMU + 1U + 1X/17U also correlated with the formation clearance of paraxanthine (gamma2 = 0.6, p = 0.002). Other reported caffeine metabolite ratios did not display the same robust correlation with caffeine clearance under all these different conditions. CONCLUSIONS: We conclude that AAMU+1U+1X/17U measured from a single spot urine collection is a valid measure of CYP1A2 activity except at very high levels of caffeine dosing. The validity of the other proposed caffeine metabolite ratios is questionable.

Adult↗
PubMed1996

The effect of liver disease on urine caffeine metabolite ratios.

OBJECTIVES: A number of caffeine metabolite ratios (CMRs) have been proposed to measure CYP1A2 activity in vivo. The effect of liver disease on these ratios is not clear. The objective of this study was to determine the influence of liver disease on caffeine metabolite ratios. STUDY DESIGN: Two studies were performed. First, in healthy control subjects and in subjects with cirrhosis, caffeine clearance was measured by intravenous infusion of stable isotope-labeled caffeine while subjects consumed oral caffeine. Second, spot urine samples were collected from control subjects and from subjects with either chronic hepatitis or cirrhosis while they consumed caffeine. RESULTS: In study 1, caffeine clearance was decreased in subjects with cirrhosis (control mean, 0.14 L/hr/kg; cirrhosis mean, 0.04 L/hr/kg; p = 0.003). CMRs were affected by liver disease (e.g., ratio characterizing paraxanthine demethylation [AAMU + 1X + 1U/17U], control median, 8.3; cirrhosis median, 6.2; p = 0.005). AAMU + 1X + 1U/17U correlated significantly with caffeine clearance in the control group (r2 = 0.68; p = 0.0001) and in subjects with cirrhosis (r2 = 0.41; p = 0.05). In study 2, there was a significant difference between control subjects and subjects with cirrhosis for AAMU + 1X + 1U/17U (median for control subjects, 6.2; median for subjects with cirrhosis, 4.3; p = 0.001) but not between control subjects and patients with chronic hepatitis. CONCLUSIONS: We conclude that AAMU + 1X + 1U/17U is affected by liver disease and reflects the decrease in CYP1A2 activity in subjects with cirrhosis. AAMU + 1X + 1U/17U measured from a spot urine sample reflects caffeine clearance in subjects with cirrhosis and may be useful as a hepatic function test. Despite the large interindividual variation observed, the test can be repeated easily in the same patient and an individual patient's decline in CYP1A2 activity, such as in patients with progressively deteriorating liver function, can be monitored.

Adult↗
PubMed1996

Orthostatic hypertension due to vascular adrenergic hypersensitivity.

Autoregulatory mechanisms ensure relatively small fluctuations of blood pressure with postural changes in healthy people. Although orthostatic hypotension is well recognized and commonly encountered, there are only a few reports of orthostatic hypertension. Most of the reported cases of orthostatic hypertension were related to excessive venous pooling, with an initial drop in cardiac output followed by overcompensation with an excessive release of catecholamines, or to nephroptosis with orthostatic activation of the renin-angiotensin system. We describe a 44-year-old woman with normal supine blood pressure and severe orthostatic hypertension who did not demonstrate an initial decrease in cardiac output and had normal plasma and urinary catecholamines and renin release. Pharmacological tests of autonomic nervous system function showed an increased pressor sensitivity to norepinephrine (11 to 14 times normal), normal sensitivity to isoproterenol, diminished baroreceptor reflex sensitivity, and exquisite sensitivity to alpha-adrenergic blockers. This unusual case of orthostatic hypertension appears to be secondary to vascular adrenergic hypersensitivity.

Adrenergic alpha-Antagonists↗
PubMed1996

Marijuana and hyperthermia.

BACKGROUND: Animal and human laboratory studies suggest marijuana may cause hyperthermia. However, there are no clinical case reports of life-threatening hyperthermia associated with use of marijuana alone. CASE REPORT: We report a patient who developed severe hyperthermia after smoking a marijuana cigarette and jogging on a warm day. He presented with delirium; hot, red, dry skin; and a rectal temperature of 41.7 degrees C. Historical and laboratory data indicated he had used cannabinoids and no other drugs. This is the first report of life-threatening hyperthermia temporally associated with use of marijuana alone.

Adult↗
PubMed1995

Nicotine patches.

Explore the source record for details and available documents.

Administration, Cutaneous↗
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↗