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N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 73 records · Page 4Linked to original sources
PubMed1997

Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking.

AIMS: Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. METHODS: Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and continine. Plasma levels of nicotine, cotinine, and 3'-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and continine levels. RESULTS: There was considerable individual variation in plasma nicotine and cotinine levels and in the daily of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Continine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to continine. CONCLUSIONS: Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.

Administration, Cutaneous↗
PubMed1997

Systemic absorption and effects of nicotine from smokeless tobacco.

Nicotine is absorbed in substantial quantities from smokeless tobacco and could contribute to the adverse consequences of smokeless tobacco use. Chronic systemic exposure to nicotine could contribute to accelerated coronary artery disease, acute cardiac ischemic events, and hypertension. Systemic absorption of sodium and mutagenic chemicals from smokeless tobacco could aggravate hypertension or cardiac failure, or contribute to cancer, respectively. Information concerning the potential hazards of nicotine and other systemically absorbed toxins may be incorporated into educational programs to discourage the use of smokeless tobacco.

Biological Availability↗
PubMed1997

Pharmacodynamics of acute tolerance to multiple nicotinic effects in humans.

Tolerance is an important determinant of addiction as well as therapeutic and/or toxic effects of drugs. The development of acute tolerance to various effects of nicotine was studied in nine healthy smokers who were abstaining from tobacco. Nicotine was infused rapidly to reach a concentration of about 25 ng/ml, followed by a computer-controlled infusion to maintain that concentration. A novel semiparametric model of nicotine effects and tolerance was developed. Tolerance to various effects of nicotine (increases in heart rate, blood pressure, plasma epinephrine and energy expenditure) occurred within the range of nicotine levels found in smokers. However, the rate of tolerance development varied considerably. The half-lives of tolerance ranged from 3.5 min for the increase in energy expenditure to 70 min for systolic blood pressure. There was no apparent tolerance to the effects on free fatty acid concentrations, which reflects lipolysis. Differences in the pharmacodynamics of tolerance may reflect differences in rate of desensitization of various subtypes of nicotinic receptors and/or differences in mechanisms of tolerance for various nicotinic effects.

Adult↗
PubMed1997

Society for Research on Nicotine and Tobacco.

The proceedings of the second annual scientific conference of the Society for Research on Nicotine and Tobacco are summarized. The goal of the annual conference was to disseminate information about ongoing nicotine research from biological, behavioral and social perspectives. Data were presented describing our current understanding of the structure and function of neuronal nicotinic acetylcholine receptors, by which nicotine exerts most, if not all, of its effects in the brain. The conformational complexity of receptor subunits expressed in different brain areas contributes significantly to the complexity of responses observed to nicotinic agonists. Nicotine is being developed as a medication that might be used to maintain smoking cessation and to treat various medical diseases. The potential toxicity of nicotine, apart from cigarette smoking, is an important variable in assessing the benefits and risks of such therapeutic applications. The risks of nicotine-containing medications appear to be far less than those associated with tobacco use. Recent data indicate that cigarette smoking is increasing among young in the United States. Adolescent smokers are interested in quitting and make frequent quit attempts, but are usually not successful. Effective methods are needed to manage adolescent smokers before they become heavily addicted. Nicotine replacement as a pharmacological treatment for smoking cessation has made a significant contribution in improving quit rates. New medications have been developed that target specific populations of smokers.

Adolescent↗
PubMed1997

Saliva cotinine levels as a function of collection method.

Saliva cotinine is commonly used to estimate nicotine intake but laboratories use different methods of collection. In three small trials, comparisons were made between (1) sugar vs. unstimulated saliva production (n = 29), (2) wax chewing vs. unstimulated production (n = 15) and (3) between two consecutive unstimulated saliva samples (n = 10). Sugar-stimulated saliva cotinine scores were 26% below unstimulated levels (p < 0.001); correlation between measures was high (r = 0.90; p < 0.001). Wax stimulated saliva yielded levels 6% below unstimulated (p < 0.05; correlation: r = 0.98; p < 0.001). No differences were observed between two unstimulated samples taken within a approximately 20-minute period (correlation: r = 0.99; p < 0.001). It is postulated that changes in salivary flow can account for the findings.

Biomarkers↗
PubMed1997

Individual differences in nicotine kinetics and metabolism in humans.

Individual differences in susceptibility to nicotine addiction, the likelihood of successful smoking cessation, and the development of adverse health effects of smoking are well recognized. The basis for these individual differences is as yet unknown. This chapter examines individual differences in the metabolism and kinetics of nicotine as a possible factor. Rare individuals appear to be deficient metabolizers of nicotine. Individual differences are described both in the pattern and rates of nicotine metabolism. Ethnic differences in cotinine metabolism have also been observed. However, the enzymes responsible for nicotine metabolism and their genetic regulation have not been fully characterized. Understanding the basis for individual differences in nicotine kinetics and metabolism, and linking these differences to pharmacodynamic studies, may provide important clues for the prevention and treatment of nicotine and possibly other drug addictions.

Cotinine↗
PubMed1996

Absorption rate of methylxanthines following capsules, cola and chocolate.

OBJECTIVE: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. METHODS: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. RESULTS: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 micrograms.ml-1); and 2 (Cmax: 2.05 micrograms.ml-1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5-2.0 h after treatment (For cola, Cmax: 1.57 micrograms.ml-1); and for chocolate, Cmax: 1.50 micrograms.ml-1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 micrograms.ml-1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 micrograms.ml-1). CONCLUSIONS: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Absorption↗
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

CYP2D6 phenotype and the metabolism of nicotine and cotinine.

That CYP2D6 activity is an important determinant of nicotine metabolism and that people who have abnormal CYP2D6 genes are poor metabolizers of nicotine has been reported in the medical literature. The aim of this study was to assess the role of CYP2D6 in nicotine metabolism. Specifically, we compared the clearance of stable isotope-labelled nicotine and cotinine in 11 poor and 33 extensive metabolizers of dextromethorphan, a probe for CYP2D6 activity. The groups were matched by gender, age and ethnicity. Nicotine and cotinine kinetics were quite similar for cases and controls. These data suggest that CYP2D6 is not a major isozyme for the metabolism of nicotine or cotinine.

Adult↗
PubMed1996

Pharmacology of nicotine: addiction and therapeutics.

Nicotine maintains tobacco addiction and has therapeutic utility to aid smoking cessation and possibly to treat other medical diseases. Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution within the nervous system, presumably mediating the complex actions of nicotine described in tobacco users. The effects of nicotine in people are influenced by the rate and route of dosing and by the development of tolerance. The metabolism of nicotine is now well characterized in humans. A few individuals with deficient C-oxidation of nicotine, unusually slow metabolism of nicotine, and little generation of cotinine have been described. Nicotine affects most organ systems in the body, although its contribution to smoking-related disease is still unclear. Nicotine as a medication is currently available as a gum, a transdermal delivery device, and a nasal spray, all of which are used for smoking cessation. Nicotine is also being investigated for therapy of ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, sleep apnea, and attention deficit disorder.

Administration, Cutaneous↗
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

The benefits of stopping smoking and the role of nicotine replacement therapy in older patients.

Considerable benefits accrue from stopping smoking in older patients. Reversal of the short term cardiovascular adverse effects of smoking is rapid. Long term risk reduction appears to occur as a result of decreased life-time exposure to tobacco smoke. The pharmacology of nicotine has not been studied in older patients but is unlikely to change in clinically important ways with advancing age. Nicotine replacement doubles long term success rates, compared with placebo, among younger smokers of > or = cigarettes per day. There is no reason to believe its efficacy should be less among older smokers. Transdermal nicotine is the replacement therapy of choice in older patients because of once-daily administration and good tolerability. Approximately half of the users of transdermal nicotine smoke concurrently with treatment. It is unlikely that concurrent smoking or high doses of nicotine replacement therapy will adversely effect healthy patients. While it is generally believed that patients with unstable coronary heart disease may be at risk from concurrent smoking during nicotine replacement therapy, it is unclear whether this risk is greater than the risk of smoking alone. Nicotine replacement therapy is a logical approach for motivated, older smokers who are unable to stop smoking by simpler means. Results can be augmented by including other interventions, such as counselling and follow-up support.

Administration, Cutaneous↗
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.

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Administration, Cutaneous↗