Air quality, mortality, and economic benefits of a smoke - free workplace law for non-smoking Ontario bar workers.

We estimated the impact of a smoke-free workplace bylaw on non-smoking bar workers' health in Ontario, Canada. We measured bar workers' urine cotinine before (n = 99) and after (n = 91) a 2004 smoke-free workplace bylaw. Using pharmacokinetic and epidemiological models, we estimated workers' fine-particle (PM2.5 ) air pollution exposure and mortality risks from workplace secondhand smoke (SHS). workers' pre-law geometric mean cotinine was 10.3 ng/ml; post-law dose declined 70% to 3.10 ng/ml and reported work hours of exposure by 90%. Pre-law, 97% of workers' doses exceeded the 90th percentile for Canadians of working age. Pre-law-estimated 8-h average workplace PM2.5 exposure from SHS was 419 µg/m(3) or 'Very Poor' air quality, while outdoor PM2.5 levels averaged 7 µg/m(3) , 'Very Good' air quality by Canadian Air Quality Standards. We estimated that the bar workers' annual mortality rate from workplace SHS exposure was 102 deaths per 100000 persons. This was 2.4 times the occupational disease fatality rate for all Ontario workers. We estimated that half to two-thirds of the 10620 Ontario bar workers were non-smokers. Accordingly, Ontario's smoke-free law saved an estimated 5-7 non-smoking bar workers' lives annually, valued at CA $50 million to $68 million (US $49 million to $66 million).

Gender-stratified gene and gene-treatment interactions in smoking cessation.

We conducted gender-stratified analyses on a systems-based candidate gene study of 53 regions involved in nicotinic response and the brain-reward pathway in two randomized clinical trials of smoking cessation treatments (placebo, bupropion, transdermal and nasal spray nicotine replacement therapy). We adjusted P-values for multiple correlated tests, and used a Bonferroni-corrected α-level of 5 × 10(-4) to determine system-wide significance. Four single-nucleotide polymorphisms (rs12021667, rs12027267, rs6702335, rs12039988; r2 > 0.98) in erythrocyte membrane protein band 4.1 (EPB41) had a significant male-specific marginal association with smoking abstinence (odds ratio (OR) = 0.5; 95% confidence interval (CI): 0.3-0.6) at end of treatment (adjusted P < 6 × 10(-5)). rs806365 in cannabinoid receptor 1 (CNR1) had a significant male-specific gene-treatment interaction at 6-month follow-up (adjusted P = 3.9 × 10(-5)); within males using nasal spray, rs806365 was associated with a decrease in odds of abstinence (OR = 0.04; 95% CI: 0.01-0.2). While the role of CNR1 in substance abuse has been well studied, we report EPB41 for the first time in the nicotine literature.

Phytohemagglutinin-induced lymphocyte transformation in humans receiving delta9-tetrahydrocannabinol.

Eight otherwise healthy male chronic marijuana smokers were hospitalized for a period of 30 days. Initially they received placebo, then a sustained dose of 210 milligrams of delta9-tetrahydrocannabinol (delta9-THC) per day for 18 days, followed by placebo. Lymphocyte responses to phytohemagglutinin were examined during each of these periods. Neither the daily ingestion of marijuana extract containing 210 milligrams of delta9-THC for 18 days nor the history of chronic marijuana smoking had a depressive effect on the lymphocyte responses of these subjects to phytohemagglutinin.

The pharmacogenetics research network: from SNP discovery to clinical drug response.

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

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.

Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers.

The relationship between thermogenic and potentially atherogenic effects of cigarette smoking (CS) and its cessation was investigated. Heavy smokers (n = 7, serum cotinine > 200 ng/ml, > 20 cigarettes/d) were maintained on isoenergetic, constant diets for 2 wk, 1 wk with and 1 wk without CS. Stable isotope infusions with indirect calorimetry were performed on day 7 of each phase, after an overnight fast. CS after overnight abstention increased resting energy expenditure by 5% (not significant vs. non-CS phase; P = 0.18). CS increased the flux of FFA by 77%, flux of glycerol by 82%, and serum FFA concentrations by 73% (P < 0.02 for each), but did not significantly affect fat oxidation. Hepatic reesterification of FFA increased more than threefold (P < 0.03) and adipocyte recycling increased nonsignificantly (P = 0.10). CS-induced lipid substrate cycles represented only 15% (estimated 11 kcal/d) of observed changes in energy expenditure. De novo hepatic lipogenesis was low (< 1-2 g/d) and unaffected by either acute CS or its chronic cessation. Hepatic glucose production was not affected by CS, despite increased serum glycerol and FFA fluxes. Cessation of CS caused no rebound effects on basal metabolic fluxes. In conclusion, a metabolic mechanism for the atherogenic effects of CS on serum lipids (increased hepatic reesterification of FFA) has been documented. Increased entry of FFA accounts for CS-induced increases in serum FFA concentrations. The thermogenic effect of CS is small or absent in heavy smokers while the potentially atherogenic effect is maintained, and cessation of CS does not induce a rebound lipogenic milieu that specifically favors accrual of body fat in the absence of increased food intake.

Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy.

This review discusses the known cardiovascular effects of smoking and the effects of nicotine without tobacco smoke and interprets the available data on cardiovascular risk during nicotine replacement therapy (NRT). Nicotine gum and patches are now approved for over the counter sale in the United States. Smokers with cardiovascular disease are advised to seek physician counseling before using nicotine products, but information regarding the safety of these products in such patients is not readily available to most physicians. Nicotine may contribute to cardiovascular disease, presumably by hemodynamic consequences of sympathetic neural stimulation and systemic catecholamine release. However, there are many potential cardiovascular toxins in cigarette smoke other than nicotine. The doses of nicotine obtained by regular cigarette smoking generally exceed those delivered by NRTs, and the cardiovascular effects of nicotine are, in general, more intense when delivered rapidly by cigarette smoking than the slower delivery by transdermal nicotine or nicotine gum. Because the dose-cardiovascular response relation for nicotine is flat, the effects of cigarette smoking in conjunction with NRT are similar to those of cigarette smoking alone. Cigarette smoking increases blood coagulability, a major risk factor for acute cardiovascular events, whereas transdermal nicotine does not appear to do so. Clinical trials of NRT in patients with underlying, stable coronary disease suggest that nicotine does not increase cardiovascular risk. At worst, the risks of NRT are no more than those of cigarette smoking. The risks of NRT for smokers, even for those with underlying cardiovascular disease, are small and are substantially outweighed by the potential benefits of smoking cessation.

Cardiovascular effects of carbon monoxide and cigarette smoking.

OBJECTIVES: This study was designed to compare the effects of inhaled carbon monoxide (CO), administered to achieve concentrations similar to those found in cigarette smoking, with the effects of cigarette smoking and air inhalation on heart rate and blood pressure, catecholamine release, platelet activation and C-reactive protein (CRP), a marker of inflammation. BACKGROUND: Carbon monoxide may contribute to smoking-induced cardiovascular disease. Exposure to environmental CO has been associated with increased cardiovascular morbidity and mortality. Animal and in vitro studies suggest that CO may contribute to atherosclerosis and endothelial injury. There is conflicting evidence about the hemodynamic consequences of exposure to CO and its role in platelet activation. METHODS: In a single-blind, crossover design, 12 healthy smokers inhaled CO at 1,200 ppm to 1,500 ppm to simulate CO intake from cigarette smoking, inhaled air on a similar schedule and smoked 20 cigarettes per day, each for seven days. Mean carboxyhemoglobin was 5 +/- 1% on CO treatment, 6 +/- 1% while smoking and 0.4 +/- 0.2% on air inhalations. RESULTS: There was no difference in blood pressure between the treatments. Mean heart rate was higher during cigarette smoking compared with CO and air inhalations (75 beats/min vs. 66 beats/min; p < 0.05). Plasma levels of platelet factor 4 and CRP and urine epinephrine and norepinephrine were higher while smoking, with no effect of CO compared with air. CONCLUSIONS: Carbon monoxide administered under conditions similar to those of cigarette smoking had no significant effect on blood pressure, heart rate, plasma catecholamines, platelet aggregation or CRP. The short-term chronotropic effect, adrenergic-activating, platelet-activating and CRP-increasing effects of smoking in healthy smokers are probably due to components of cigarette smoke other than CO.

Nicotine effects on eicosanoid formation and hemostatic function: comparison of transdermal nicotine and cigarette smoking.

OBJECTIVES: The purpose of this study was to examine the possible role of nicotine in enhancing coagulation and to assess the potential cardiovascular toxicity of transdermal nicotine therapy for smoking cessation. BACKGROUND: Cigarette smoking increases the risks of acute coronary events. A likely contributing mechanism is activation of coagulation. The role of nicotine in enhancing coagulability has not been resolved. METHODS: We compared in a crossover study the effects of cigarette smoking, transdermal nicotine and placebo transdermal nicotine, each for 5 days, in 12 healthy smokers. RESULTS: Cigarette smoking increased the urinary excretion of 11-dehydro-thromboxane B2 (reflecting thromboxane A2 generation) and increased plasma concentration of the platelet alpha-granule constituents, platelet factor 4 and beta-thromboglobulin, compared with placebo treatment, indicating in vivo platelet activation. Cigarette smoking was also associated with higher levels of fibrinogen in plasma. Transdermal nicotine produced plasma levels of nicotine in the same range as those during smoking but had no effect on thromboxane A2 metabolite excretion, platelet alpha-granule release or plasma fibrinogen, compared with placebo. Excretion of 2,3-dinor-6-keto-PGF1 alpha (reflecting prostacyclin generation) was not significantly influenced by any treatment. These results suggest that nicotine as such is not responsible for the platelet activation or elevation of plasma fibrinogen seen in smokers. However, we cannot exclude the possibility that intermittent bolus-like dosing of nicotine from cigarettes could have different effects from those produced by continually released transdermal nicotine. Other findings were that cigarette smoking and transdermal nicotine treatment were both associated with a higher white blood cell count compared with the placebo patch condition, suggesting a direct effect of nicotine to increase circulating white cells. Factor VII coagulant activity (VIIc) was significantly lower during cigarette smoking, than during either nicotine or placebo patch conditions. CONCLUSIONS: Transdermal nicotine has less effect on platelet activation and catecholamine release than does cigarette smoking, and its use in smoking cessation treatment of patients with coronary heart disease is likely to be safer than cigarette smoking.

Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia.

OBJECTIVES: We sought to determine the effects of nicotine patch therapy, when used to promote smoking cessation, on myocardial ischemia in patients with coronary artery disease. BACKGROUND: Nicotine patches substantially increase quit rates among cigarette smokers, but their safety in patients with myocardial ischemia who are attempting to quit smoking is unknown. METHODS: This is a prospective study using exercise thallium-201 single-photon emission computed tomography (SPECT) to assess serial changes in the total and ischemic myocardial perfusion defect size at baseline while patients were smoking and during treatment with 14- and 21-mg nicotine patches. Entry criteria required that patients 1) smoked > or = 1 pack of cigarettes per day; 2) had known coronary artery disease; and 3) had myocardial ischemia (i.e., > or = 5% reversible perfusion defect) on SPECT. All patients performed symptom-limited treadmill exercise, and the baseline SPECT study served as its own control. We interpreted and computer quantified the SPECT images with no knowledge of the testing sequence. RESULTS: Thirty-six of the 40 enrolled patients had exercise SPECT at baseline and during treatment with at least 14-mg nicotine patches. These patients had an initial perfusion defect size of 17.5 +/- 10.6% while smoking an average of 31 +/- 11 cigarettes per day for 40 +/- 12 years. A significant reduction in the total perfusion defect size (p < 0.001) was observed from baseline (17.5 +/- 10.6%) to treatment with 14-mg (12.6 +/- 10.1%) and 21-mg (11.8 +/- 9.9%) nicotine patches. This reduction occurred despite an increase in treadmill exercise duration (p < 0.05) and higher serum nicotine levels (p < 0.001). There was a significant correlation between the reduction in defect size and exhaled carbon monoxide levels (p < 0.001) because patients reduced their smoking by approximately 74% during the trial. CONCLUSIONS: Nicotine patches, when used to promote smoking cessation, significantly reduce the extent of exercise-induced myocardial ischemia as assessed by exercise thallium-201 SPECT.

Nicotine exposure among nondependent smokers.

Most theories of dependence imply that repeated exposure to an addictive drug leads inexorably to dependence. We examined nicotine exposure in "tobacco chippers," who smoke regularly without developing dependence. Blood samples were obtained before and after 10 chippers (smoking up to 5 cigarettes per day) and 12 dependent smokers (20 to 40 cigarettes per day) smoked a cigarette. Chippers' blood nicotine levels increased significantly, in amounts equaling those of dependent smokers. Assays of cotinine (a long-lasting nicotine metabolite) also suggested that chippers' per-cigarette nicotine absorption equaled that of dependent smokers. Chippers' cotinine levels were also compared with those of heavy smokers (38 cigarettes per day) whose consumption was reduced to 5 cigarettes per day in a previously published study. The heavy smokers compensated by tripling their per-cigarette nicotine intake. Chippers did not seem to be compensating; their cotinine values equaled those expected when regular smokers were not compensating for reduced cigarette availability.

Trazodone-oral cocaine interactions.

Depression and dysphoria can follow the long-term use of cocaine. Little is known about the interaction of antidepressant drugs with cocaine and similar stimulants in humans. The physiologic and subjective effects of an oral 2-mg/kg dose of cocaine hydrochloride were measured in eight healthy cocaine-using men after pretreatment with a single, 100-mg oral dose of the triazolopyridine antidepressant trazodone hydrochloride or placebo in a double-blind study. The cocaine-induced effects of increased BP, increased pupil size, and decreased skin temperature were diminished by trazodone pretreatment. Trazodone alone did not alter plasma epinephrine or norepinephrine levels. An increase in plasma epinephrine levels after cocaine administration was not altered by trazodone pretreatment, but the increase in the norepinephrine level was larger. Trazodone alone produced mild sleepiness. Cocaine-induced euphoria was not altered by trazodone pretreatment, although feelings of tension and shakiness after cocaine administration were diminished.

Toward a comprehensive long term nicotine policy.

Global tobacco deaths are high and rising. Tobacco use is primarily driven by nicotine addiction. Overall tobacco control policy is relatively well agreed upon but a long term nicotine policy has been less well considered and requires further debate. Reaching consensus is important because a nicotine policy is integral to the target of reducing tobacco caused disease, and the contentious issues need to be resolved before the necessary political changes can be sought. A long term and comprehensive nicotine policy is proposed here. It envisages both reducing the attractiveness and addictiveness of existing tobacco based nicotine delivery systems as well as providing alternative sources of acceptable clean nicotine as competition for tobacco. Clean nicotine is defined as nicotine free enough of tobacco toxicants to pass regulatory approval. A three phase policy is proposed. The initial phase requires regulatory capture of cigarette and smoke constituents liberalising the market for clean nicotine; regulating all nicotine sources from the same agency; and research into nicotine absorption and the role of tobacco additives in this process. The second phase anticipates clean nicotine overtaking tobacco as the primary source of the drug (facilitated by use of regulatory and taxation measures); simplification of tobacco products by limitation of additives which make tobacco attractive and easier to smoke (but tobacco would still be able to provide a satisfying dose of nicotine). The third phase includes a progressive reduction in the nicotine content of cigarettes, with clean nicotine freely available to take the place of tobacco as society's main nicotine source.

Orthostatic hypotension in ciguatera fish poisoning.

PURPOSE: The purpose of this study was to investigate the pathophysiology of persistent orthostatic hypotension in a patient with ciguatera fish poisoning. METHODS: A patient who became ill and who developed prolonged and symptomatic orthostatic hypotension with ciguatera fish poisoning after eating barracuda is described. Studies of autonomic function included measurements of plasma catecholamine levels in the supine and standing positions, and pressor responses to infusions of norepinephrine, atropine, and propranolol. RESULTS: Volume depletion was excluded as a cause for hypotension. Our patient showed low plasma catecholamine levels and marked pressor hypersensitivity to norepinephrine infusion. Hypotension and bradycardia were reversed by atropine infusion. The heart rate freed from autonomic influences, ie, after atropine plus propranolol infusion, was normal. CONCLUSIONS: In ciguatera fish poisoning, orthostatic hypotension appears to be a result of both parasympathetic excess and sympathetic failure.

Nicotine and coronary heart disease.

Nicotine may contribute to accelerated atherogenesis by inducing hyperlipidemia, injuring endothelial cells, and/or promoting thrombosis, although the evidence is not conclusive. Nicotine is likely to contribute to acute ischemic events in people who already have coronary heart disease via adverse effects on systemic hemodynamics, by promoting thrombosis, constricting coronary arteries, and/or facilitating arrhythmogenesis. Pharmacodynamic studies suggest that nicotine inhaled in cigarette smoke may have different cardiovascular effects than that absorbed more slowly, as from nicotine gum or transdermally. The safety of chronic nicotine exposure, such as with medicinal use of nicotine, cannot be predicted and requires empiric evaluation.

Depression of growth hormone and cortisol response to insulin-induced hypoglycemia after prolonged oral delta-9-tetrahydrocannabinol administration in man.

Six hospitalized volunteer male subjects were given insulin, 0.15 U/kg, before and after 14 days of administration of delta-9-tetrahydrocannabinol (THC) at a dose of 210 mg/day. A diminished maximal serum human growth hormone (GH) increase followed the prolonged THC ingestion. The mean maximal GH response was: 52.6 ng/ml +/- 8.7 (+/-SE) before THC and 18.8 ng/ml +/- 6.7 (+/-SE) during THC, P less than 0.01; corresponding cortisol responses were 20.1 mug/dl +/- 3.0 before THC and 10.0 mug/dl +/- 1.1 during THC, P less than 0.05. The data suggest suppression of the hypothalamic-pituitary axis after prolonged high dose THC use. This is consistent with other reported endocrine effects of marijuana in man.

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.

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.

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.

Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers.

Published research suggests that smokers metabolize nicotine and its major metabolite cotinine more rapidly than nonsmokers. To evaluate this possibility, we studied the disposition pharmacokinetics of intravenous deuterium-labeled nicotine in 11 smokers (administered 2.0 and 0.5 micrograms/kg/min x 30 minutes) and in 11 nonsmokers (0.5 micrograms/kg/min). Smokers did not metabolize nicotine more rapidly; the clearance of nicotine normalized for body weight was significantly slower in smokers than in nonsmokers. Cotinine elimination rates were similar in the two groups. The disposition pharmacokinetics of nicotine was similar for the low and high doses in the smokers, indicating that metabolism is dose-independent. Our findings argue against "metabolic tolerance" as a mechanism for the dose escalation observed in smokers after initiation of smoking. Our findings suggest that nicotine and cotinine kinetic parameters for smokers may be extrapolated to nonsmokers for estimating exposures to environmental tobacco smoke in nonsmokers.