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Biomedical subjects

N L Benowitz

Publications and source records attributed to N L Benowitz.

At least 199 records · Page 11Linked to original sources
PubMed1987

Determinants of nicotine intake while chewing nicotine polacrilex gum.

Nicotine polacrilex gum is widely used as substitution therapy during cigarette smoking cessation. We studied circadian blood nicotine concentrations, daily intake of nicotine, and extraction of nicotine from gum in smokers switched experimentally to 2 or 4 mg nicotine gum, 12 pieces per day. Nicotine levels and intake were much lower while chewing gum than during ad libitum smoking. Extraction of nicotine from gum by the chewer was incomplete, averaging 53% and 72% for 2 and 4 mg gum, and variable (more than twofold) among individuals. The systemic dose of nicotine was less than expected based on analysis of nicotine in the chewed gum. Disproportionately higher metabolite-to-nicotine ratios while chewing gum compared with smoking suggested that some nicotine was swallowed and underwent first-pass metabolism. Nicotine and metabolite data were used to estimate buccal vs. gastrointestinal absorption. Relative buccal absorption vs. swallowing of nicotine appears to be an important determinant of systemic nicotine intake.

Adult↗
PubMed1987

Influence of tobacco abstinence on the disposition kinetics and effects of nicotine.

Habitual tobacco smoking accelerates the metabolism of many drugs. With tobacco abstinence, it was expected that nicotine metabolism would be slower than when smoking. To test this hypothesis, the disposition kinetics of intravenous nicotine were studied in 20 healthy smokers while smoking, after abstaining from smoking for 1 week, and (in six subjects) when smoking again. Cardiovascular responses to nicotine were also measured. Unexpectedly, total and nonrenal clearance of nicotine increased by 36% and 39%, respectively, during abstinence. The increase in clearance after brief abstinence suggests that nicotine or its metabolites or another component of cigarette smoke inhibits nicotine metabolism in smokers. Cardiovascular responses to nicotine were greater after 1 week compared with overnight abstinence, consistent with loss of tolerance.

Adult↗
PubMed1987

Brain phenobarbital uptake during prolonged status epilepticus.

The brain uptake of phenobarbital during prolonged status epilepticus (3 h) was studied in paralyzed, ventilated sheep. The first 30 min of status epilepticus was characterized by systemic hypertension, increased CBF, increased peripheral vascular resistance, a fall in brain pH, and an elevation in brain lactate concentrations. Subsequently, hemodynamic factors normalized and brain acidosis persisted. Phenobarbital administered during the early phase of status epilepticus produced higher levels of brain phenobarbital concentration, which was greatest at the earliest sample time (5 min following infusion), compared to nonseizure controls. This elevation persisted for the first 3 h following the infusion. Phenobarbital administration during the established phase of status epilepticus, when systemic blood pressure, peripheral vascular resistance, and CBF had returned to preseizure values, resulted in attenuated brain phenobarbital uptake not different from controls for the first 30 min. These results are explained by disruption of the blood-brain barrier to phenobarbital during the early (hypertensive) phase of status epilepticus.

Animals↗
PubMed1987

Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics.

Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for a given nicotine concentration during the rising phase of nicotine concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict "brain" concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.

Adult↗
PubMed1987

Spontaneous cigarette brand switching: consequences for nicotine and carbon monoxide exposure.

A group of smokers who had participated in smoking-related studies three to six years earlier were re-studied to assess changes in their smoking practices. Individuals who smoked the same brands of cigarettes showed no change in plasma cotinine (reflecting exposure to nicotine) or expired carbon monoxide (CO) concentration. Those who switched to cigarettes of lower nicotine yield (average decrease 38 per cent) showed reduced plasma cotinine concentrations, due primarily to smoking fewer cigarettes per day. The intake of nicotine per cigarette was not different. Subjects who smoked cigarettes of higher yield (102 per cent increase) had higher cotinine and CO levels, due to greater intake per cigarette.

Adult↗
PubMed1987

Cigarette abstinence, nicotine gum, and theophylline disposition.

When cigarette smokers with chronic lung disease become acutely ill or require surgery, they are often forced to stop smoking and may use nicotine gum. Smoking is known to accelerate the metabolism of theophylline, but the effects of short-term abstinence or nicotine gum on theophylline metabolism have not been reported. We studied the effects of brief tobacco abstinence and nicotine gum on theophylline elimination in healthy volunteers. Abstinence from smoking for 1 week resulted in a 37.6% decrease in clearance and a 35.8% increase in half-life. Nicotine gum had no effect on theophylline clearance. Our data indicate that at least partial normalization of the enzyme-inducing effects of smoking can be seen after brief cigarette abstinence. For smokers who are taking theophylline chronically, their dose of theophylline will need to be reduced by one fourth to one third after brief tobacco abstinence. Plasma concentration monitoring may be necessary for optimal dosing of theophylline in such patients.

Adult↗
PubMed1986

Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide.

In the hope of reducing the adverse health consequences of smoking, physicians frequently advise their patients who cannot quit to smoke fewer cigarettes. Habitual smokers may compensate for the reduced number of cigarettes, however, by taking in more smoke per cigarette. We measured the intake of tar (estimated as mutagenic activity of the urine), nicotine, and carbon monoxide during short-term cigarette restriction. With a reduction from an average of 37 cigarettes to an average of 5 cigarettes per day, the intake of tobacco toxins per cigarette increased roughly threefold and daily exposure to tar and carbon monoxide declined only 50 percent. We conclude that smoking fewer cigarettes may reduce exposure to toxins and related adverse health consequences. However, consistent with a tendency to maintain intake of nicotine, the magnitude of the benefit is much less than expected. Whether "oversmoking" persists during long-term restriction of cigarettes requires further investigation.

Adult↗
PubMed1986

Reduced tar, nicotine, and carbon monoxide exposure while smoking ultralow- but not low-yield cigarettes.

An unresolved public health issue is whether some modern cigarettes are less hazardous than others and whether patients who cannot stop smoking should be advised to switch to lower-yield cigarettes. We studied "tar" (estimated by urine mutagenicity), nicotine, and carbon monoxide exposure in habitual smokers switched from their usual brand to high- (15 mg of tar), low- (5 mg of tar), or ultralow-yield (1 mg of tar) cigarettes. There were no differences in exposure comparing high- or low-yield cigarettes, but tar and nicotine exposures were reduced by 49% and 56%, respectively, and carbon monoxide exposure by 36% while smoking ultralow-yield cigarettes. Similarly, in 248 subjects smoking their self-selected brand, nicotine intake, estimated by blood concentrations of its metabolite cotinine, was 40% lower in those who smoked ultralow but no different in those smoking higher yields of cigarettes. Our data indicate that ultralow-yield cigarettes do deliver substantial doses of tar, nicotine, and carbon monoxide, but that exposures are considerably less than for other cigarettes.

Adult↗
PubMed1986

Status epilepticus: divergence of sympathetic activity and cardiovascular response.

To study changes in plasma catecholamine concentrations and their relationship to changes in systemic and pulmonary vascular pressures, we induced status epilepticus by intravenous administration of bicuculline in 5 anesthetized, paralyzed, ventilated adult sheep. Status epilepticus was accompanied by marked elevations in plasma epinephrine and norepinephrine levels (390-fold and 163-fold, respectively) and by marked elevations in systemic and pulmonary vascular pressures. Vascular pressure returned to normal in 60 minutes, despite plasma catecholamine levels that remained elevated for the 3-hour duration of the study. Mild metabolic acidosis and hyperkalemia were also noted. We discuss the implications of these findings with regard to the management of hypotension during status epilepticus.

Alkalosis↗
PubMed1986

Mouth versus deep airways absorption of nicotine in cigarette smokers.

Nicotine from the alkaline smoke of cigars is absorbed through the buccal mucosa, but such absorption from the more acidic smoke of American cigarettes has not been reported. Forty-one male and 52 female smokers were studied under normal ventilation and smoking conditions, and under high ventilation and controlled smoking conditions that restricted intake to the mouth only, with no inhalation. The major finding is that there is virtually no intake of nicotine through the buccal mucosa while smoking American cigarettes. Confirming prior reports, plasma nicotine and expired CO levels showed no correlation with the analytical yields of nicotine and CO of the cigarettes smoked. Fifteen nonsmokers (7 male, 8 female) participated in this study as controls. Data from these subjects provided additional information regarding absorption of nicotine and carbon monoxide during passive smoking. Within the highly ventilated environment, there was no significant change of CO and nicotine levels of nonsmokers. However, within the normally ventilated environment, there was minimal increase in both substances, statistically significant only for nicotine. These results suggest that nicotine may be a better indicator of exposure to second-hand smoke than carbon monoxide.

Absorption↗
PubMed1986

Additive cardiovascular effects of nicotine and ethanol.

Ethanol and tobacco consumption are commonly associated. Both are risk factors for adverse cardiovascular events. To better understand the interactions, the influence of oral ethanol pretreatment (0.5 or 1.0 gm/kg over 60 minutes) on cardiovascular responses to and disposition kinetics of intravenous nicotine was studied in healthy volunteers. Ethanol increased heart rate, systolic blood pressure, and pressure-rate product in a dose-related manner. Nicotine had additive effects on heart rate and pressure-rate product. It also decreased skin temperature, reflecting cutaneous vasoconstriction, but this effect was antagonized by ethanol. Ethanol did not affect metabolic clearance but increased CLR of nicotine by 25%. Additive cardiovascular effects of ethanol and nicotine could contribute to arrhythmias and sudden death in patients with coronary heart disease. It is unlikely that an effect of ethanol on nicotine metabolism is responsible for increased cigarette smoking while drinking ethanol.

Administration, Oral↗
PubMed1986

Clinical pharmacology of nicotine.

Nicotine is the primary reason why people consume tobacco products and it may contribute to causation of tobacco-related diseases. This chapter reviews the human pharmacology of nicotine, the evidence for a role of nicotine in human disease, and the use of nicotine (gum) as a therapeutic agent in smoking cessation therapy.

Animals↗
PubMed1985

Theophylline overdose: acute single ingestion versus chronic repeated overmedication.

Currently available guidelines for managing theophylline intoxication do not distinguish between acute single ingestion and chronic repeated overmedication and do not reliably predict which patients should undergo hemoperfusion. Although hemoperfusion is widely recommended when serum concentrations exceed 40-60 mg/l, many patients with acute overdose tolerate much higher levels without serious toxicity. Because manifestations of toxicity might be dependent on the chronicity of the overdose, the authors retrospectively compared the clinical features of 15 patients with chronic repeated overmedication with those of 27 patients suffering acute single overdose. Patients suffering chronic repeated overmedication developed seizures (7/15) and serious arrhythmias (4/15) with serum levels of 28-70 mg/l. By contrast, only one of 19 patients suffering acute single overdose with peak levels less than 100 mg/l had seizures, and only two of 19 with levels less than 100 mg/l had serious arrhythmias. However, of the eight single-overdose patients with levels over 100 mg/l, seven had seizures and three had serious arrhythmias. Single-overdose patients were easily recognized by the presence of hypotension, hypokalemia, and low serum bicarbonate, features not present in chronic-type patients. Thus, while patients with theophylline overdose caused by chronic repeated overmedication frequently develop seizures and arrhythmias with serum levels of 40-70 mg/l, those with acute single ingestion are highly unlikely to suffer serious complications unless serum levels exceed 100 mg/l. Management of the intoxication, especially selection of patients for hemoperfusion, should be based on whether the overdose is caused by an acute single ingestion or chronic repeated overmedication.

Acute Disease↗
PubMed1985

Propranolol antagonism of phenylpropanolamine-induced hypertension.

Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine.

Administration, Oral↗
PubMed1985

Altered methadone pharmacokinetics in methadone-maintained pregnant women.

We studied the influence of human pregnancy on the maternal disposition and effects of methadone. Nine healthy pregnant women who had been on p.o. methadone maintenance for at least 2 months were studied between 20 and 34 weeks of gestation (phase I), 35 and 40 weeks (phase II), 1 to 4 weeks post partum (phase III) and 8 to 9 weeks post partum (phase IV). Two subjects who breast-fed their infants had plasma and breast milk samples collected simultaneously. With or without normalization for dose and body weight, trough plasma concentrations of methadone were significantly lower and total or unbound methadone clearances greater during pregnancy than after delivery. Plasma protein binding of methadone was lower during pregnancy but the difference was only statistically significant between phases I and IV. The greater ratios of urinary excretion of the major metabolites to total and unbound methadone areas under the curve during pregnancy suggests that methadone metabolism was enhanced. The ratios of concentrations of methadone in milk to plasma were constant in two subjects, 0.32 +/- 0.06 and 0.61 +/- 0.07, respectively. Some of the women reported symptoms of methadone withdrawal during pregnancy, even when the daily methadone dose did not change. Because of the lower plasma methadone concentrations, increased methadone doses may be required during pregnancy to achieve methadone maintenance.

Adult↗