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Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 37 records · Page 2Linked to original sources
PubMed2000

Nicotine blood levels and subjective craving for cigarettes.

This study examined cigarette craving and blood nicotine levels in 11 male heavy smokers who were observed during 16 h of tobacco abstinence. Subjects rated their urge to smoke on a new brief 10-item questionnaire, Urge to Smoke (UTS), Schuh and Stitzer's four-item Visual Analog Scale (SSI), and a Strength of Urge to Smoke (SUTS) item. Testing occurred: 1) after 16 h (1700 h the night before to 0900 h the next morning) of abstinence from smoking; 2) after an ad lib smoking period following the 16 h abstinence; 3) every hour during 6 hours of abstinence; 4) and finally, after the 6 h abstinence, another ad lib smoking period. Thus, subjects smoked twice in each session. Blood plasma nicotine levels were measured before, after, and every 2 h during the 6-h abstinence period for a total of six measures. Blood pressure and heart rate were measured prior to each blood draw. There was a significant negative correlation between blood nicotine levels and craving for cigarettes on all craving questionnaires (rs = -0.55 to -0.78; ps < 0.002). Carbon monoxide was shown to correlate highly with nicotine blood levels (rs = 0.83 to 0.98 across subjects; ps < 0.001). Results are consistent with the hypothesis that "urge to smoke" reflects nicotine seeking in continuing smokers.

Adult↗
PubMed2000

Simultaneous determination of mecamylamine, nicotine, and cotinine in plasma by gas chromatography-mass spectrometry.

The nicotine receptor antagonist mecamylamine has been shown to increase the efficacy of transdermal nicotine as a pharmacotherapy for tobacco addiction. A product for simultaneous transdermal administration of nicotine and mecamylamine is undergoing clinical trials. In order to carry out pharmacokinetic studies, quantitation of low nanogram per milliliter levels of mecamylamine and nicotine was required. This paper describes a method for simultaneous determination of mecamylamine, nicotine, and the nicotine metabolite, cotinine, in human plasma using gas chromatography-mass spectrometry (GC-MS). Limits of quantitation for mecamylamine, nicotine and cotinine are 2, 1 and 2 ng/ml, respectively.

Cotinine↗
PubMed2000

Nicotine impairs endothelium-dependent dilatation in human veins in vivo.

BACKGROUND: Cigarette smoking is associated with impaired endothelium-dependent dilatation in human veins and arteries. An in vivo study in animals suggests that nicotine may contribute to this abnormality. We tested the hypothesis that local administration of nicotine at a dose reproducing the plasma concentration observed during smoking would impair endothelium-dependent vasodilatation in human veins in vivo. METHODS: We studied 11 healthy nonsmokers with the dorsal hand vein compliance technique. After 70% to 80% preconstriction with phenylephrine, endothelium-dependent venous relaxation was assessed by infusion of bradykinin (1 to 278 ng/min), a potent vasodilator acting primarily in this model through endothelial release of nitric oxide and prostanoids. Sodium nitroprusside (0.0001 to 3166 ng/min) was used to test endothelium-independent relaxation. Dose-response curves were constructed before and during nicotine coinfusion at a rate of 40 ng/min, reproducing a plasma concentration of 15 ng/mL. RESULTS: After a 10-minute preinfusion, nicotine administration was associated with a loss in sensitivity to bradykinin (P < .001). After 30 and 60 minutes of preinfusion with nicotine, the venorelaxant effect of bradykinin was further reduced (P < .001). A similar inhibition of the response to bradykinin by nicotine persisted in the presence of indomethacin (INN, indomethacin). Coinfusion of nicotine did not attenuate sodium nitroprusside-induced venodiiation. CONCLUSION: The results show that acute local exposure to nicotine in vivo is associated with an impaired response to endothelium-derived nitric oxide in human veins. This finding may provide further insight into the pathophysiology of smoking-induced endothelial dysfunction.

Adult↗
PubMed2000

Nicotine metabolism and elimination kinetics in newborns.

OBJECTIVE: To characterize the presence of and elimination kinetics of nicotine and its metabolites in newborns. METHODS: Blood samples from 13 newborns were collected during the first day of life and analyzed for nicotine and cotinine. Single daily urine samples were collected from nine newborns for up to 7 days and analyzed by gas chromatography-mass spectrometry for nicotine, cotinine, 3'-hydroxycotinine, and their conjugates. NONMEM was used to determine population half-life values. RESULTS: Blood and urine data gave similar results for nicotine and cotinine elimination kinetics. The elimination half-life for nicotine was 11.2 hours (95% confidence interval [CI], 8.0 to 18.9) based on blood data and 9.0 hours (95% CI, 7.0 to 12.4) based on urine data. The elimination half-life for cotinine was 16.3 hours (95% CI, 12.4 to 23.9) based on blood data and was 22.8 hours (95% CI, 19.5 to 25.8) based on urine data. The elimination half-lives for the other metabolites were 13 hours for conjugated nicotine; 19.8 hours for conjugated cotinine; 18.8 hours for 3'-hydroxycotinine; and 19.4 hours for conjugated 3'-hydroxycotinine. The half-life of nicotine is three to four times longer in newborns than in adults, whereas the half-life of cotinine is similar in newborns and adults. CONCLUSIONS: In adults, CYP2A6 is the predominant enzyme responsible for the metabolism of both nicotine and cotinine. The prolonged elimination of nicotine but not of cotinine in the newborn compared with that in the adult may be a result of different newborn CYP2A6 enzymatic substrate specificity, low CYP2A6 activity with another enzyme that is primarily responsible for cotinine metabolism, or differences in tissue distribution.

Aryl Hydrocarbon Hydroxylases↗
PubMed2000

Effects of cigarette smoking and carbon monoxide on nicotine and cotinine metabolism.

OBJECTIVES: To examine the effects of cigarette smoking on the disposition kinetics of nicotine and cotinine, to determine the effects of cigarette smoking on pathways of nicotine and cotinine metabolism, and to test the hypothesis that carbon monoxide inhibits the metabolism of nicotine. STUDY DESIGN: Twelve cigarette smokers were studied in three treatment conditions, each lasting 7 days, during which they smoked cigarettes, breathed carbon monoxide to achieve carboxyhemoglobin levels similar to cigarette smoking, or breathed air. In each treatment condition, subjects received a combined infusion of deuterium-labeled nicotine (d2) and cotinine (d4), with measurement of disposition kinetics and urine metabolite profile. RESULTS: Cigarette smoking significantly inhibited the metabolism of nicotine but had no effect on cotinine metabolism. Cigarette smoking markedly induced the O-glucuronidation of trans-3'-hydroxycotinine but had no effect on the N-glucuronidation of nicotine or cotinine. Carbon monoxide had no effect on nicotine or cotinine kinetics or metabolic profile. CONCLUSIONS: This study confirms previous observations that cigarette smoking inhibits nicotine metabolism but disproves the hypothesis that this effect is due to carbon monoxide. Induction of glucuronidation must be considered in understanding the effects of cigarette smoking on drug metabolism.

Adult↗
PubMed2000

Nicotine-mecamylamine interactions.

OBJECTIVES: Mecamylamine blocks nicotinic cholinergic receptors and has been proposed, in combination with nicotine, as a novel therapy to aid smoking cessation. The objective of this study was to characterize the pharmacokinetic and pharmacodynamic interactions between transdermal mecamylamine and intravenous nicotine. STUDY DESIGN: Twelve cigarette smokers were studied while receiving transdermal mecamylamine 6 mg/24 h and placebo patches for 7 days each. On the fifth day of patch use, subjects received a combined infusion of deuterium-labeled nicotine and cotinine, with measurement of disposition kinetics of nicotine and cotinine, and cardiovascular and plasma catecholamine responses to nicotine. Half of the subjects were studied under alkaline urine conditions and the other half under acidic urine conditions. RESULTS: Steady-state plasma mecamylamine concentrations were twice as high (mean, 12.2 versus 6.3 ng/mL), consistent with lower renal clearance (2.1 versus 5.8 mL/min/kg) during alkaline compared with acidic urine conditions. Mecamylamine did not significantly affect the clearances of nicotine or cotinine. Mecamylamine significantly reduced the volume of distribution and inhibited the cardioacceleratory and epinephrine-releasing effects of nicotine. CONCLUSIONS: Mecamylamine has little effect on the clearance of nicotine and is not expected to affect steady-state levels during transdermal nicotine dosing. The reduction of the volume of distribution of nicotine by mecamylamine suggests that part of the antagonism of nicotinic central nervous system effects by mecamylamine may be due to a pharmacokinetic interaction-most likely decreased transport of nicotine into the brain or decreased binding to nicotine receptors. Mecamylamine may decrease the potential adverse cardiovascular effects of coadministered nicotine.

Administration, Cutaneous↗
PubMed2000

Safety of intra-amniotic digoxin administration before late second-trimester abortion by dilation and evacuation.

OBJECTIVE: The purpose of this study was to determine the safety of intra-amniotic digoxin injection before late second-trimester pregnancy termination by dilation and evacuation through an assessment of maternal systemic digoxin absorption, cardiac rhythm, and coagulation parameters. STUDY DESIGN: Pregnant women at between 19 and 23 weeks' gestation received 1.0 mg digoxin through intra-amniotic injection and then had serum digoxin levels determined for 48 hours and Holter cardiac monitoring performed for 24 hours. Clotting parameters were assessed before digoxin injection and 24 hours later, at the time of the dilation and evacuation procedure. RESULTS: Eight patients completed the study. The mean (+/-SD) serum digoxin peak concentration was 0.81 +/- 0.22 microg/L (range, 0.5-1.1 microg/L). The mean (+/-SD) time to peak digoxin concentration was 11.0 +/- 5.55 hours (range, 4-20 hours). Ambulatory cardiac monitoring showed no rhythm or conduction abnormalities associated with digoxin. Prothrombin time, partial thromboplastin time, and fibrinogen levels did not change significantly between determinations before and after the dilation and evacuation procedure (11.5 to 11.4 seconds, 24.1 to 24.4 seconds, and 441 to 475 mg/dL, respectively). CONCLUSION: The maximum digoxin concentration peak achieved after intra-amniotic injection was in the low therapeutic range. No rhythm or conduction abnormalities associated with digoxin were noted by Holter monitoring. Coagulation parameters did not change significantly. On the basis of the limited systemic absorption and the absence of clinically significant cardiac or clotting effects, intra-amniotically administered digoxin may be considered safe for use before late second-trimester pregnancy terminations.

Abortion, Induced↗
PubMed1999

Nicotine addiction.

Nicotine maintains tobacco addiction. Nicotine acts on nicotinic cholinergic receptors, which demonstrate diversity in subunit structure, function, and distribution in the nervous system, mediating the multiple actions of nicotine described in tobacco users. Nicotine addiction is more prevalent and more severe in people with a history of major depression, schizophrenia, or alcohol or other drug abuse problems. The cigarette is a highly efficient drug delivery system, delivering nicotine rapidly and in relatively high concentrations to the brain, a situation that optimizes the likelihood of self-administration. The severity of nicotine addiction can be as- sessed using the Fagerström Tolerance Questionnaire or the DSM-IV, but these instruments are imprecise predictors of the key behavior in addiction, which is the difficulty in stopping tobacco use when there are compelling reasons to do so.

Behavior, Addictive↗
PubMed1999

Disposition kinetics and effects of menthol.

BACKGROUND: Menthol is widely used in a variety of commercial products and foods, but its clinical pharmacology is not well studied. To determine the disposition kinetics and to examine subjective and cardiovascular effects of menthol, we conducted a crossover placebo-controlled study that compared pure menthol versus placebo, along with an uncontrolled exposure to menthol in food or beverage. A novel assay for the measurement of menthol in biological fluids was also developed. METHODS: Twelve subjects were studied; each received a 100 mg l-menthol capsule, a placebo capsule, and 10 mg menthol in mint candy or mint tea on three different occasions. Plasma and urine levels of menthol and conjugated menthol (glucuronide), cardiovascular measurements, and subjective effects were measured at frequent intervals. RESULTS: Menthol was rapidly metabolized, and only menthol glucuronide could be measured in plasma or urine. The plasma half-life of menthol glucuronide averaged 56.2 minutes (95% confidence interval [CI], 51.0 to 61.5) and 42.6 minutes (95% CI, 32.5 to 52.7) in menthol capsule and mint candy/mint tea conditions, respectively (P < .05). The plasma area under the plasma concentration-time curve ratios for menthol capsule to mint candy/mint tea treatment averaged 9.2 (95% CI, 8.2 to 10.1). Urinary recovery of menthol as the glucuronide averaged 45.6 and 56.6% for menthol capsule and mint candy/tea, respectively (difference not significant). After menthol capsule dosing, the decrease in heart rate was less than the decrease after placebo administration (P < .05). Menthol reduced subjective vigor value at 30 minutes. CONCLUSIONS: We conclude that pure menthol and menthol in food or beverages have a similar systemic bioavailability and that menthol has a small cardioaccelerating effect.

Adult↗
PubMed1999

Biomarkers of environmental tobacco smoke exposure.

Biomarkers are desirable for quantitating human exposure to environmental tobacco smoke (ETS) and for predicting potential health risks for exposed individuals. A number of biomarkers of ETS have been proposed. At present cotinine, measured in blood, saliva, or urine, appears to be the most specific and the most sensitive biomarker. In nonsmokers with significant exposure to ETS, cotinine levels in the body are derived primarily from tobacco smoke, can be measured with extremely high sensitivity, and reflect exposure to a variety of types of cigarettes independent of machine-determined yield. Under conditions of sustained exposure to ETS (i.e., over hours or days), cotinine levels reflect exposure to other components of ETS. Supporting the validity of cotinine as a biomarker, cotinine levels have been positively correlated to the risks of some ETS-related health complications in children who are not cigarette smokers.

Adult↗
PubMed1999

Minor tobacco alkaloids as biomarkers for tobacco use: comparison of users of cigarettes, smokeless tobacco, cigars, and pipes.

OBJECTIVES: This study (1) determined levels of various tobacco alkaloids in commercial tobacco products. (2) determined urinary concentrations, urinary excretion, and half-lives of the alkaloids in humans; and (3) examined the possibility that urine concentrations of nicotine-related alkaloids can be used as biomarkers of tobacco use. METHODS: Nicotine intake from various tobacco products was determined through pharmacokinetic techniques. Correlations of nicotine intake with urinary excretion and concentrations of anabasine, anatabine, nornicotine, nicotine, and cotinine were examined. By using urinary excretion data, elimination half-lives of the alkaloids were calculated. RESULTS: Alkaloid levels in commercial tobacco products, in milligrams per gram, were as follows: nicotine, 6.5 to 17.5; nornicotine, 0.14 to 0.66; anabasine, 0.008 to 0.030; and anatabine, 0.065 to 0.27. Measurable concentrations of all alkaloids were excreted in the urine of most subjects smoking cigarettes, cigars, and pipes and using smokeless tobacco. Correlations between nicotine intake and alkaloid concentrations were good to excellent. CONCLUSIONS: Anabasine and anatabine, which are present in tobacco but not in nicotine medications, can be used to assess tobacco use in persons undergoing nicotine replacement therapy.

Adult↗
PubMed1999

Drug interactions with tobacco smoking. An update.

Cigarette smoking remains highly prevalent in most countries. It can affect drug therapy by both pharmacokinetic and pharmacodynamic mechanisms. Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens. Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1, CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta. There are genetic polymorphisms in the inducibility of CYP1A1, with some evidence that high inducibility is more common in patients with lung cancer. CYP1A2 is a hepatic enzyme responsible for the metabolism of a number of drugs and activation of some procarcinogens. Caffeine demethylation, using blood clearance or urine metabolite data, has been used as an in vivo marker of CYP1A2 activity, clearly demonstrating an effect of cigarette smoking, CYP2E1 metabolises a number of drugs as well as activating some carcinogens. Our laboratory has found in an intraindividual study that cigarette smoking significantly enhances CYP2E1 activity as measured by the clearance of chlorzoxazone. In animal studies, nicotine induces the activity of several enzymes, including CYP2E1, CYP2A1/2A2 and CYP2B1/2B2, in the brain, but whether this effect is clinically significant is unknown. Similarly, although inhibitory effects of the smoke constituents carbon monoxide and cadmium on CYP enzymes have been observed in vitro and in animal studies, the relevance of this inhibition to humans has not yet been established. The mechanism involved in most interactions between cigarette smoking and drugs involves the induction of metabolism. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis with enhanced heparin binding to antithrombin III. Cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Pharmacodynamic interactions have also been described. Cigarette smoking is associated with a lesser magnitude of blood pressure and heart rate lowering during treatment with beta-blockers, less sedation from benzodiazepines and less analgesia from some opioids, most likely reflecting the effects of the stimulant actions of nicotine. The impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy. Cigarette smoking should be specifically studied in clinical trials of new drugs.

Animals↗
PubMed1999

Ethnic differences in N-glucuronidation of nicotine and cotinine.

We previously reported that the metabolism of cotinine, the proximate metabolite of nicotine, is significantly slower in black than in white cigarette smokers. To understand why the metabolism of nicotine and cotinine might differ between blacks and whites, we studied the pattern of nicotine metabolism in blacks and whites. One hundred eight healthy smokers (51 blacks and 57 whites), of similar age, gender distribution, and smoking history, received an i.v. infusion of deuterium-labeled nicotine and cotinine. The clearance of cotinine, the fractional conversion of nicotine to cotinine, and the metabolic clearance of nicotine to cotinine were significantly lower in blacks than in whites. Blacks excreted significantly less nicotine as nicotine-N-glucuronide and less cotinine as cotinine-N-glucuronide than whites, but there was no difference in the excretion of 3'-hydroxycotinine-O-glucuronide. Nicotine and cotinine glucuronidation appeared to be polymorphic, with evidence of slow and fast N-glucuronide formers among blacks but was unimodal with fast conjugators only among whites. Other findings of note included the demonstration of a significant correlation between the distribution volumes of nicotine and cotinine with lean body mass: there was a smaller distribution volume and a shorter half-life for cotinine in women than in men and a smaller volume of distribution of cotinine in blacks than in whites. We conclude that the metabolism of cotinine is slower in blacks than in whites because of both slower oxidative metabolism of nicotine to cotinine (presumably via cytochrome P-450 2A6) and slower N-glucuronidation. Ethnic differences in the metabolism of other drugs undergoing N-glucuronidation should be studied.

Adult↗