Biomedical subjects
Publications and source records attributed to N L Benowitz.
There has been a dramatic rise in the number of adverse medical effects related to cocaine abuse since the widespread introduction of crystallized freebase cocaine or "crack" in the mid-1980s. In particular, cardiovascular and central nervous system toxicity is becoming more widely recognized and requires aggressive medical management to prevent potentially high morbidity and mortality.
Insofar as smokers regulate body levels of nicotine, nicotine replacement is expected to suppress the desire to smoke a cigarette. Our study was designed to test the hypothesis that i.v. replacement of nicotine will suppress daily intake of nicotine from ad libitum cigarette smoking and to compare the physiological effects of prolonged exposure to nicotine infused i.v. to the effect of smoking cigarettes throughout the day. Eight subjects received a 14-hr infusion of deuterium-labeled nicotine dosed to achieve levels of nicotine similar to those while smoking cigarettes for each individual (average, 33.1 mg; range, 17.7-49.9 mg) or saline (placebo). Cigarette smoking was permitted as desired. Nicotine infusion did not significantly affect the number of cigarettes smoked or the amount of tobacco burned, but nicotine intake from cigarette smoking was suppressed in all but one subject by an average of 24.6% (range, 4.0-51.2%). Down-regulation of levels of nicotine while smoking in response to infusion of nicotine was imprecise, which may be a result of psychosocial factors influencing smoking behavior along with the development of tolerance to toxic effects of nicotine as a consequence of prolonged exposure to nicotine. Intravenous nicotine and cigarette smoking increased average heart rate and blood pressure throughout the day and 24-hr urinary epinephrine excretion to a similar extent. Despite higher levels of nicotine when subjects smoked during infusion of nicotine, there were no additional nicotine-related effects. No adverse effects were noted; most subjects could not distinguish nicotine from saline.(ABSTRACT TRUNCATED AT 250 WORDS)
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An automated gas chromatographic method for determination of theophylline in plasma is described. A novel feature of this assay is the use of triethylsulfonium hydroxide as an on-column alkylating agent. A simple extraction procedure together with automated sample injection and data processing has facilitated processing of large numbers of samples generated in pharmacokinetic studies. The between-run coefficient of variation was 2.2% at 5 micrograms/ml (n = 5) and 3.9% at 15 micrograms/ml (n = 6). Within-run coefficient of variation was 2.4% at 5 micrograms/ml (n = 9) and 3.3% at 15 micrograms/ml (n = 6). Accuracy was 105% at a concentration of 5 micrograms/ml and 102% at 15 micrograms/ml.
STUDY OBJECTIVE: To compare exposure to nicotine and related cardiovascular effects as well as urinary mutagenicity (a potential marker of systemic absorption of carcinogenic compounds) during use of oral snuff, chewing tobacco, and cigarettes, as desired. DESIGN: Crossover sequential treatments, balanced-order experimental study. SETTING: Clinical research center. PARTICIPANTS: Eight healthy men who regularly smoked cigarettes and had previous experience with the use of both oral snuff and chewing tobacco. INTERVENTIONS: Four 3- or 4-day blocks during which participants used oral snuff, chewing tobacco, and cigarettes as desired, or abstained from all tobacco. Concentrations of nicotine and cotinine (the primary metabolite of nicotine), cardiovascular effects, and urine sodium, catecholamine and mutagenicity were measured over 24 hours at the end of each treatment block. MEASUREMENTS AND MAIN RESULTS: Circadian exposure to nicotine and cardiovascular effects, including urinary catecholamine excretion, were similar for all forms of tobacco use. Urine sodium excretion was greater while using smokeless tobacco than while smoking, probably due to absorption of sodium from the smokeless tobacco. Urine mutagenicity was markedly increased while smoking cigarettes and tended to be increased (P less than 0.10) while chewing tobacco but not while using oral snuff. CONCLUSIONS: Systemic absorption of nicotine, sodium, and carcinogenic chemicals from smokeless tobacco may cause or aggravate human illness in addition to the known adverse effects on the oral cavity.
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STUDY OBJECTIVE: To examine the interaction between dapsone and trimethoprim in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Measurement of drug levels as part of an open study of dapsone alone and randomized, double-blind comparison of trimethoprim-dapsone with trimethoprim-sulfamethoxazole in treating Pneumocystis carinii pneumonia in patients with AIDS. SETTING: County hospital and AIDS clinic. PATIENTS: Eighteen patients treated with dapsone alone, 30 with trimethoprim-dapsone, and 30 with trimethoprim-sulfamethoxazole. INTERVENTION: Dapsone, 100 mg/d; trimethoprim, 20 mg/kg body weight per day, and sulfamethoxazole, 100 mg/kg.d; administered for 21 days. MEASUREMENTS AND MAIN RESULTS: Concentrations of dapsone were 40% higher in patients treated with trimethoprim-dapsone than in those treated with dapsone alone (2.1 compared with 1.5 micrograms/mL; P less than 0.05). Trimethoprimdapsone-treated patients had fewer treatment failures but more side effects and treatment terminations due to toxicity than those treated with dapsone alone. The concentration of trimethoprim was 48.4% higher in patients treated with trimethoprim-dapsone than in those treated with trimethoprim-sulfamethoxazole, (18.4 compared with 12.4 micrograms/mL; P less than 0.05). Discontinuation of therapy due to toxicity was commoner in the trimethoprim-sulfamethoxazole group (57% compared with 30%). CONCLUSIONS: A bidirectional drug interaction exists between dapsone and trimethoprim, resulting in higher concentrations of each in the presence of the other.
Three male smokers were exposed to a free-operant avoidance schedule in which a lever press postponed a point subtraction on a counter for twenty seconds. Subtractions were scheduled to occur every 5 seconds in the absence of lever presses. Prior to each experimental session the subject was administered varying amounts of nicotine via either chewing nicotine gum or smoking low or high nicotine yield cigarettes. Smoking cigarettes resulted in increased avoidance responding relative to baseline nonsmoking rates. Chewing nicotine gum did not produce changes in avoidance responding, however, nicotine blood levels produced by chewing nicotine gum were similar to levels produced by smoking cigarettes. The differential responding determined by route of nicotine administration is discussed and the implications for use of nicotine gum as an adjunct for smoking cessation is addressed.
To examine the plausibility of the hypothesis that smoking a cigarette after a meal is motivated by accelerated metabolism of nicotine, we studied the influence of a high-protein meal on the disposition of nicotine in seven healthy smokers. Indocyanine green clearance, an estimate of hepatic blood flow, increased 31%, 50 minutes after the test meal. Consuming the meal during a steady state infusion of nicotine resulted in a small (18%) but consistent decrease in blood levels of nicotine. Our data demonstrate that food accelerates the metabolism of nicotine, but the time course and magnitude of the decline in levels of nicotine suggest that altered disposition of nicotine is not the primary motivation for smoking after meals.
Coffee drinking and cigarette smoking are strongly correlated behaviors which have been suggested to act synergistically to produce adverse health consequences, particularly coronary heart disease (CHD). We studied in smokers the influence of four days of multiple daily doses of coffee containing different doses or no caffeine on cigarette smoking behavior, nicotine intake from smoking, heart rate and blood pressure, circadian serum glucose, and urinary catecholamine excretion. We observed a tendency toward greater cigarette consumption during caffeine consumption, and a tendency toward higher plasma nicotine levels during low-dose caffeine compared with the no-caffeine condition; however, these effects were small. No caffeine effects on any other of the above parameters were observed. Previously published research has usually studied effects of single doses of caffeine, which does not account for development of tolerance to effects of caffeine. If caffeine does contribute to CHD risk, it is not likely to be related to caffeine effects on smoking behavior, nicotine intake, blood pressure, heart rate, glucose tolerance, or catecholamine release. Adverse effects of long-term caffeine consumption on lipids cannot be excluded.
When cigarette smokers with chronic lung disease stop smoking, they may do so with the aid of chewing nicotine gum. Smoking is known to accelerate the metabolism of theophylline, but the effects of nicotine gum on theophylline metabolism have not been determined. We studied the effects of nicotine and placebo gum on theophylline metabolism in healthy volunteers. Clearance of theophylline decreased by 32% after cessation of smoking in comparison to while chewing placebo gum. Clearance while chewing nicotine gum was similar to that measured while chewing placebo gum. Nicotine gum appears to have no effect on theophylline metabolism. For smokers who are chronically taking theophylline, the dose of theophylline will need to be reduced by one-fourth to one-third after smoking cessation and initiation of nicotine gum use.
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Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.
Blood pressure is, on average, lower in cigarette smokers than in nonsmokers. In a cross-sectional study of 288 normotensive bus drivers, we found a significant inverse correlation between serum cotinine (the major metabolite of nicotine) and systolic and diastolic blood pressure that could not be accounted for by age, body weight, or alcohol consumption. Over the observed range of cotinine values, the average decrease in blood pressure was 10.7 and 7.0 mm Hg for systolic and diastolic blood pressures, respectively. We suggest that cotinine be measured to assess the influence of cigarette smoking in epidemiologic studies of blood pressure.
A variety of drugs and toxins can produce severe abdominal pain and, in some cases, a surgical abdomen. Toxins can be classified according to mechanisms of injury: 1. Corrosives often produce severe gastroenteritis and may result in gastric or esophageal perforations. Examples of corrosive substances include aspirin, iron, mercury, acids and alkali. 2. Drugs may cause intestinal ileus or obstruction by pharmacologic actions (i.e., anticholinergic drugs and narcotics) or by mechanical obstruction (charcoal and drug bezoars). 3. Abdominal pain simulating an acute abdomen may result from systemic effects of black widow spider envenomation or intoxication with heavy metals such as lead and arsenic. 4. Ischemic bowel disease may occur from use of vasoconstrictor drugs, such as ergotamines, amphetamines and cocaine, or may follow treatment with catecholamines or digitalis in critically ill patients. Small bowel ischemia is life-threatening and may require bowel resection. 5. Many drugs cause abdominal pain by directly injuring abdominal organs, such as the liver and pancreas. Antibiotic-associated colitis may present with abdominal pain and inflammatory diarrhea. Consideration of drugs and toxins plays an important role in the differential diagnosis of the acute abdomen.
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