Showing papers by "Neal L. Benowitz published in 2000"

Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids

Abstract: Background Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in the United States as a means of losing weight and increasing energy. In the light of recently reported adverse events related to use of these products, the Food and Drug Administration (FDA) has proposed limits on the dose and duration of use of such supplements. The FDA requested an independent review of reports of adverse events related to the use of supplements that contained ephedra alkaloids to assess causation and to estimate the level of risk the use of these supplements poses to consumers. Methods We reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999. A standardized rating system for assessing causation was applied to each adverse event. Results Thirty-one percent of cases were considered to be definitely or probably related to the use of supplement...

Nicotine blood levels and subjective craving for cigarettes.

Abstract: 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.

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

Abstract: 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, indometacin). Coinfusion of nicotine did not attenuate sodium nitroprusside–induced venodilation. 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. (Clin Pharmacol Ther 2000;67:391-7.) Clinical Pharmacology & Therapeutics (2000) 67, 391–397; doi: 10.1067/mcp.2000.105153

Nicotine metabolism and elimination kinetics in newborns.

Abstract: 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. Clinical Pharmacology & Therapeutics (2000) 67, 458–465; doi: 10.1067/mcp.2000.106129

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

Abstract: 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. Clinical Pharmacology & Therapeutics (2000) 67, 653–659; doi: 10.1067/mcp.2000.107086

The use of pharmacotherapies for smoking cessation during pregnancy

Abstract: A workshop entitled “The use of pharmacotherapies for smoking cessation during pregnancy”, sponsored by the National Institute of Child Health and Human Development (NICHD) and the Robert Wood Johnson Foundation (RWJF), was held in Rockville, Maryland, on 19 May 1999. The goals of the workshop were: (1) to determine the current state of knowledge related to the use of pharmacotherapies for smoking cessation during pregnancy; and (2) to outline a research agenda to determine the effectiveness and safety of these pharmacotherapies. Attending the workshop were many of the academic experts working in this area in the USA and representatives from NICHD, RWJF, the National Cancer Institute (NCI), the National Institute of Drug Abuse (NIDA), the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), the American College of Obstetrics and Gynecology (ACOG), the Society for Research on Nicotine and Tobacco (SRNT), and several pharmaceutical companies. In the USA, of the four million women who deliver babies each year, approximately 0.8–1 million smoke during their pregnancies. Smoking has a substantial adverse impact on pregnancy outcomes including growth retardation, preterm birth, perinatal mortality, sudden infant death syndrome (SIDS), and childhood behavioural problems. In developed countries, more than a third of all cases of growth retardation is caused by maternal smoking, and the more a woman smokes, the larger the effect on fetal growth. Stopping smoking is one of the major preventive measures likely to have a substantial impact on improving pregnancy outcome. Smoking most likely achieves its negative impact on pregnancy outcome through a number of mechanisms. These include the following: (1) nicotine is a toxin at the cellular level and also may act through its vasoconstrictive properties; (2) carbon monoxide—a major byproduct of cigarette smoking—binds to haemoglobin, resulting in a functional maternal anaemia; (3) carbon monoxide also …

Non-Nicotine Pharmacotherapy for Smoking Cessation

Abstract: Nicotine replacement therapy (NRT) has been the mainstay of smoking cessation therapy for >15 years. However, 70 to 90% of smokers fail to quit despite NRT. Non-nicotine medications have been investigated as alternative therapies to achieve smoking cessation. NRT is believed to work by relieving withdrawal symptoms, and perhaps by desensitising nicotinic cholinergic receptors. Non-nicotine medications may work in a variety of ways, including nicotinic cholinergic receptor agonism (lobeline), nicotine-like effects on neurotransmitter systems (antidepressants, clonidine), nicotinic cholinergic receptor antagonism (mecamylamine) and sensory stimulation/aversion (citric or ascorbic acid inhalants or spray, silver acetate). The only non-nicotine drug approved for smoking cessation in the US is the antidepressant amfebutamone (bupropion). Two large clinical trials have demonstrated the benefit of the drug, with cessation ratios more than twice that of placebo. Amfebutamone is effective in increasing smoking cessation regardless of a history of or current depression, and is generally well tolerated, although it occasionally produces agitation and in excessive doses can cause seizures. Clinical trials suggest the benefit of a number of other non-nicotine medications: the tricyclic antidepressant nortriptyline, the antihypertensive clonidine, and silver acetate. A mecamylamine-nicotine combination may be effective, and sensory stimulants, such as citric or ascorbic acid inhalers or sprays, might enhance the effects of nicotine or other pharmacotherapies. The availability of non-nicotine medications expands the options for smoking cessation therapy. A stepped care approach for the selection of pharmacotherapies is presented in this review. With this approach, initial therapy would involve an attempt to quit using over-the-counter nicotine products. If this fails, therapy with other forms of NRT, such as nicotine nasal spray, or non-nicotine medication such as amfebutamone or other antidepressants, and/or intensive behavioural therapy, should be tried. Failure to quit at the second step should lead to combinations of nicotine and non-nicotine therapies, as well as clonidine and other newer treatments. Future prospects for the pharmacotherapy of smoking cessation include the use of nicotine receptor subtype-specific agonists and antagonists, targeted to deal with specific reinforcement and/or specific withdrawal symptoms. Also of future interest is the development of nicotine antibodies that might neutralise the effects of nicotine. It is hoped that ultimately medications can be matched with the individual characteristics of a smoker, and that smoking cessation could be facilitated in most smokers.

Nasal mucosal versus gastrointestinal absorption of nasally administered cocaine.

Abstract: Objective: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance of local absorption through the nasal mucosa. Methods: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were determined using nonparametric, subject-specific population deconvolution. Results: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated to be 19% (95% CI: 11–26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23–37%) of total systemic cocaine exposure. Conclusions: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective effects rather than higher bioavailability.