Comprehensive metabolic study of nicotine in equine plasma and urine using liquid chromatography/high-resolution mass spectrometry for the identification of unique biomarkers for doping control.

Nicotine is classified as a stimulant, and its use is banned in horse racing and equestrian sports by the International Federation of Horseracing Authorities and the Fédération Équestre Internationale, respectively. Because nicotine is a major alkaloid of tobacco leaves, there is a potential risk that doping control samples may be contaminated by tobacco cigarettes or smoke during sample collection. In order to differentiate the genuine doping and sample contamination with tobacco leaves, it is necessary to monitor unique metabolites as biomarkers for nicotine administration and intake. However, little is known about the metabolic fate of nicotine in horses. This is the first report of comprehensive metabolism study of nicotine in horses. Using liquid chromatography/electrospray ionization high-resolution mass spectrometry, we identified a total of 17 metabolites, including one novel horse-specific metabolite (i.e., 4-hydroxy-4-(3-pyridyl)-N-methylbutanamide), in post-administration urine samples after nasoesophageal administration of nicotine to three thoroughbred mares; eight of these compounds were confirmed based on reference standards. Among these metabolites, N-hydroxymethylnorcotinine was the major urinary metabolite in equine, but it could only be tentatively identified by mass spectral interpretation due to the lack of reference material. In addition, we developed simultaneous quantification methods for the eight target analytes in plasma and urine, and applied them to post-administration samples to establish elimination profiles of nicotine and its metabolites. The quantification results revealed that trans-3'-hydroxycotinine could be quantified for the longest period in both plasma (72 h post-administration) and urine (96 h post-administration). Therefore, this metabolite is the most appropriate monitoring target for nicotine exposure for the purpose of doping control due to its long detection times and the availability of its reference material. Further, we identified trans-3'-hydroxycotinine as a unique biomarker allowing differentiation between nicotine administration and sample contamination with tobacco leaves.

Intravenous and oral suicidal e-liquid poisonings with confirmed nicotine and cotinine concentrations.

The increasing availability of e-cigarettes is a potential toxicological concern. E-cigarettes appeared on the Polish market in 2006, and since 2009 they have been widely available with a new source of nicotine, the so-called e-liquid. In this paper two cases of suicidal oral and intravenous poisonings with the e-liquid are described. The clinical courses of these poisonings are presented. Nicotine and cotinine concentrations in the patient's blood were determined using high performance liquid chromatography with diode array detection. In the course of intoxication patient No. 1, classic symptoms of acute nicotine poisoning without convulsions were observed. Nicotine and cotinine concentrations measured in serum were 0.096 and 4.4mg/L, respectively. The case of patient No. 2, admission with no typical symptoms of nicotine poisoning was identified, except unconsciousness and slow respiration. Nicotine and cotinine concentrations in the serum at the time of No. 2 admissions were determined to be 0.8 and 1.3mg/L, respectively. With the increasing number of e-liquid poisonings cases, it should be aware that these products can be a readily available source of poison.

Chronic administration of nicotine enhances NMDA-activated currents in the prefrontal cortex and core part of the nucleus accumbens of rats.

Nicotine is an addictive substance of tobacco. It has been suggested that nicotine acts on glutamatergic (N-methyl-d-aspartate, NMDA) neurotransmission affecting dopamine release in the mesocorticolimbic system. This effect is reflected in neuroadaptative changes that can modulate neurotransmission in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) core (cNAcc) and shell (sNAcc) regions. We evaluated the effect of chronic administration of nicotine (4.23 mg/kg/day for 14 days) on NMDA activated currents in dissociated neurons from the PFC, and NAcc (from core and shell regions). We assessed nicotine blood levels by mass spectrophotometry and we confirmed that nicotine increases locomotor activity. An electrophysiological study showed an increase in NMDA currents in neurons from the PFC and core part of the NAcc in animals treated with nicotine compared to those of control rats. No change was observed in neurons from the shell part of the NAcc. The enhanced glutamatergic activity observed in the neurons of rats with chronic administration of nicotine may explain the increased locomotive activity also observed in such rats. To assess one of the possible causes of increased NMDA currents, we used magnesium, to block NMDA receptor that contains the NR2B subunit. If there is a change in percent block of NMDA currents, it means that there is a possible change in expression of NMDA receptor subunits. Our results showed that there is no difference in the blocking effect of magnesium on the NMDA currents. The magnesium lacks of effect after nicotinic treatment suggests that there is no change in expression of NR2B subunit of NMDA receptors, then, the effect of nicotine treatment on amplitude of NMDA currents may be due to an increase in the quantity of receptors or to a change in the unitary conductance, rather than a change in the expression of the subunits that constitute it.

Nicotine intake and smoking topography in smokers with bipolar disorder.

OBJECTIVES: Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized. METHODS: We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included. RESULTS: There were no differences between the BPD and CON groups in baseline smoking characteristics or serum nicotine or cotinine levels. Fifty-one smokers with BPD (68.9%) were taking one of the following mood stabilizers: valproic acid, lamotrigine, carbamazepine, oxcarbazepine, lithium, or topiramate. The 3-hydroxycotinine-to-cotinine ratio, a marker of cytochrome P450 2A6 (CYP2A6) metabolic activity, was significantly higher in BPD versus CON and versus SCZ (0.68 versus 0.49 versus 0.54; p =0.002). The difference between groups, however, was no longer significant when the analysis was repeated with those taking hepatic enzyme-inducing drugs (carbamazepine, oxcarbazepine, and topiramate) included as a covariate. The time between puffs, or interpuff interval (IPI), was shorter in BPD versus CON by an average of 3.0sec (p<0.05), although this was no longer significant when we removed smokers from the analysis of those taking hepatic enzyme inducers. CONCLUSIONS: Smokers with BPD are not different from CON on most measures of nicotine intake and smoking topography. We found an increased rate of nicotine metabolism in smokers taking mood stabilizers that are hepatic enzyme inducers, including carbamazepine, oxcarbazepine, and topiramate. Smokers with rapid nicotine metabolism might be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood and brain, and may have more difficulty in quitting smoking, although this requires further study.

Nicotine and food deprivation decrease the ability to resist smoking.

RATIONALE: Attempts to simultaneously control food intake and smoking may lead to smoking cessation failure. We sought to model this relationship using a human laboratory paradigm of smoking lapse behavior. OBJECTIVES: We examined the combined effect of food and nicotine deprivation, compared to nicotine deprivation alone, on the ability to resist smoking and on subsequent ad libitum smoking. METHODS: In a between-subjects design, daily smokers (N = 30) were all deprived of nicotine for 18 h and were either food-deprived (12 h) or not during a laboratory session. Following exposure to individualized food cues, participants had the option of initiating tobacco self-administration or delaying up to 50 min in exchange for monetary reinforcement. Subsequently, the tobacco self-administration period consisted of 1 h in which participants could choose to smoke or receive monetary reinforcement for cigarettes not smoked. RESULTS: Smokers who had been deprived of food and nicotine smoked their first cigarette sooner and were more likely to smoke at some point during the laboratory session, compared to those who were only nicotine-deprived. Those who were food- and nicotine-deprived smoked slightly more cigarettes than those who were nicotine-deprived only, although this difference was not statistically significant. There were no sex differences in outcomes. Hunger and food craving ratings while trying to resist smoking were greater in the food + nicotine-deprived group. Tobacco craving was predictive of outcome in both conditions. CONCLUSIONS: These findings support the hypothesis that food deprivation can undermine a smoker's ability to resist smoking.

Multidrug poisoning involving nicotine and tramadol.

A fatal case of multidrug poisoning by tramadol and nicotine is reported. Tramadol is a centrally acting analgesic used in the treatment of moderate to severe acute or chronic pain. Nicotine, a lipid-soluble alkaloid, is one of the most readily available drugs in modern society. A 46-year-old man was found dead in his bed, and a suicide note was discovered near the body. He had 25 transdermal nicotine patches attached to his thorax and abdomen. Two half emptied bottles were found on the bedside table; the toxicological examination revealed that they contained tobacco and nicotine as well as other drugs such as diphenhydramine. At autopsy, areas of fresh and old myocardial infarction as well as diffuse pulmonary congestion and edema were present. The tramadol concentration was 6.6 microg/mL in femoral venous blood, while levels of nicotine and its primary metabolite cotinine were determined to be 0.6 and 2.0 microg/mL in femoral venous blood. Based on these results, we determined the cause of death to be cardiorespiratory failure induced by the additive effects of tramadol and nicotine shortly after consumption.

Pilot study of compliance with healthcare facility smoking laws in Georgia.

In 2003 Georgian Parliament restricted smoking in all healthcare facilities to designated smoking areas. Observed compliance has been low. This quantitative study of airborne nicotine and particulate concentrations in nine healthcare facilities in Tbilisi and Region Kakheti in February, 2007 was a pilot to assess the degree of noncompliance with the law and to identify potential strategies for increasing compliance. Passive sampling of nicotine and active sampling of PM(2.5) in selected healthcare facilities. None of the facilities we monitored had designated smoking areas that met the legal requirements. Fifty of the 51 samplers registered concentrations of nicotine above the level of detection. Of these, 52% showed concentrations below 1 microg/m(3) nicotine, 27% showed concentrations between 1 and 5 microg/m(3) and 20% were above 5 microg/m(3). The highest nicotine levels were found in medical staff offices, and in undesignated "informal smoking areas". These data support qualitative observations that the law restricting smoking in Georgian healthcare facilities to designated areas is poorly enforced and does not protect patients and employees from secondhand smoke. These findings suggest that Georgian law should be changed to make all healthcare institutions smoke free environments and that there is a need for tobacco control programs targeted at medical professionals in Georgia.

Relationship of human toenail nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol to levels of these biomarkers in plasma and urine.

Recently, we developed sensitive and quantitative methods for analysis of the biomarkers of tobacco smoke exposure nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human toenails. In this study, we further evaluated the newly developed toenail biomarkers by investigating their relationship to demographic factors, reported exposure, plasma nicotine, cotinine, and trans-3'-hydroxycotinine, and urinary NNAL. Toenails of 105 smokers, mean age 38.9 years (range, 19-68), were analyzed. Fifty-five (53.4%) were male, with approximately equal numbers of Whites and African-Americans. The average number of cigarettes smoked per day was 18 (range, 5-50). There was no effect of age or gender on the toenail biomarkers. Toenail NNAL was higher in White than in African-American participants (P = 0.019). Toenail nicotine and toenail cotinine correlated significantly with cigarettes smoked per day (r = 0.24; P = 0.015 and r = 0.26; P = 0.009, respectively). Toenail nicotine correlated with plasma nicotine (r = 0.39; P < 0.001); toenail cotinine correlated with plasma cotinine (r = 0.45; P < 0.001) and plasma trans-3'-hydroxycotinine (r = 0.30; P = 0.008); and toenail NNAL correlated with urine NNAL (r = 0.53; P = 0.005). The results of this study provide essential validation data for the use of toenail biomarkers in investigations of the role of chronic tobacco smoke exposure in human cancer.

Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations.

Human cytochrome P450 (CYP) 2A6 metabolizes nicotine to cotinine and is a possible modulator of nicotine addiction. Quantitative and qualitative differences in nicotine addiction have been observed between ethnic groups. However, there are few data on the ethnic influences of the CYP2A6-nicotine metabolism relationship, particularly with regard to black subjects. We determined the nicotine metabolism and CYP2A6 genotype in 176 white subjects and 160 black subjects, comparing them with our previous data from 209 Korean subjects and 92 Japanese subjects. Large interindividual differences were observed in the cotinine/nicotine ratios in plasma calculated as an index of nicotine metabolism in white subjects (range, 0.6-36.5) and in black subjects (range, 0.9-30.4). No ethnic difference in the metabolic ratio was observed among white subjects (mean, 7.2 +/- 5.0), black subjects (mean, 7.1 +/- 4.7), and Korean subjects (mean, 8.7 +/- 11.9), whereas Japanese subjects showed a significantly (P < .005) lower metabolic ratio (mean, 3.8 +/- 3.1) compared with the other populations. Women showed significantly (P < .05) higher metabolic ratios than men in the black population (8.0 +/- 5.3 versus 6.0 +/- 3.7). Obvious ethnic differences in the CYP2A6 alleles were observed among these 4 populations. The combined frequencies of the alleles lacking or showing reduced enzymatic activity (CYP2A6*2, CYP2A6*4, CYP2A6*5, CYP2A6*7, CYP2A6*9, CYP2A6*10, CYP2A6*11, CYP2A6*17, CYP2A6*19, and CYP2A6*20) were 9.1%, 21.9%, 42.9%, and 50.5% in white, black, Korean, and Japanese subjects, respectively. These CYP2A6 alleles were associated with reduced nicotine metabolism. Among the homozygotes of CYP2A6*1, interindividual and ethnic differences in the metabolic ratio were still observed. Thus some factors other than genetic ones might also contribute to the interindividual and ethnic differences. This comprehensive study of 4 populations extends our understanding of nicotine metabolism and the impact of genetic polymorphisms of the CYP2A6 gene.

The influence of caffeine on nicotine's discriminative stimulus, subjective, and reinforcing effects.

Caffeine may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining the association of coffee intake with smoking status. In this study, smokers were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo (0). Then, generalization of nicotine discrimination was tested, using both 2- and 3-choice ("novel" option) procedures, across a range of doses (0-20 microg/kg) following pretreatment with 0, 2.5, and 5.0 mg/kg caffeine p.o. Nicotine reinforcement was assessed after the end of generalization testing using a choice procedure. Caffeine pretreatment did not alter nicotine discrimination and self-administration. Caffeine and nicotine influenced some subjective and cardiovascular responses, but there were no interaction effects except for diastolic blood pressure. These results do not support the notion that caffeine acutely alters nicotine's discriminative stimulus, subjective, or reinforcing effects.

The effect of tobacco blend additives on the retention of nicotine and solanesol in the human respiratory tract and on subsequent plasma nicotine concentrations during cigarette smoking.

The influence of the tobacco additives diammonium hydrogen phosphate (DAP) and urea on the delivery and respiratory tract retention of nicotine and solanesol and on the uptake of nicotine into venous blood was investigated in 10 smokers under mouth-hold and 75 and 500 mL inhalation conditions. Three cigarettes with identical physical specifications were produced from a common lamina tobacco blend. The control cigarette contained nonammoniated reconstituted tobacco sheet (RTS), whereas DAP and other ammonia compounds were added to the RTS of the second cigarette. Urea was added to the tobacco of the third cigarette. The presence of DAP or urea in the test cigarettes did not significantly influence solanesol retention within the mouth during the mouth-hold condition. Nicotine retention within the mouth during the mouth-hold condition was, however, significantly higher for the DAP cigarette (64.3 +/- 10.5%) than for the urea (53.3 +/- 11.3%) or control cigarette (46.3 +/- 8.6%), but this did not result in an increase in nicotine uptake into venous blood. Solanesol retentions during the 75 and 500 mL inhalation volume conditions and nicotine retentions during the 75 mL inhalation volume condition were not significantly different for the three cigarette types. Although the nicotine retention approached 100% with each cigarette type during the 500 mL inhalation condition, the nicotine retention for the urea-treated cigarette (99.6 +/- 0.2%) was marginally, but statistically, significant, higher than for the control (99.1 +/- 0.5%) and DAP-treated cigarettes (98.8 +/- 0.6%). There were no statistically significant differences between the indices of nicotine uptake into venous blood for the three cigarette types in any of the inhalation conditions.

Effects of continuous nicotine infusion on nicotine self-administration in rats: relationship between continuously infused and self-administered nicotine doses and serum concentrations.

RATIONALE: The efficacy of nicotine replacement therapy (NRT) for smoking cessation is limited. One reason for this limited efficacy may be that typical serum nicotine concentrations provided by NRT do not match the peak arterial nicotine concentrations achieved from smoking. OBJECTIVE: The purpose of the present study was to determine whether continuous nicotine infusion at a rate producing serum nicotine concentrations that match the estimated peak arterial nicotine concentrations associated with nicotine self-administration (NSA) in rats produces greater suppression of NSA than lower infusion rates. METHODS: The effects of continuous nicotine infusion were studied by intravenously administering nicotine at various rates (1.0, 3.0, and 8.0 mg/kg per day) to rats concurrently self-administering nicotine (0.03 mg/kg per infusion) during 23-h sessions or cocaine (0.17 mg/kg per infusion) during 2-h sessions. RESULTS: Continuous nicotine infusion suppressed NSA in a rate-related fashion. NSA was suppressed by 17, 50, and 73% at infusion rates of 1.0, 3.0 and 8.0 mg/kg per day, respectively. The 8.0-mg/kg per day infusion rate, which provided venous serum nicotine concentrations equaling the peak arterial concentrations associated with NSA, suppressed NSA to a greater extent than lower infusion rates. The 8.0-mg/kg per day nicotine infusion rate had no effect on cocaine-maintained responding, demonstrating that its effects were specific for suppression of NSA. This infusion rate provided a mean percentage replacement of nicotine from NSA of more than 700%. Reacquisition of NSA after suppression by the two highest infusion rates was delayed compared with reacquisition after saline extinction. CONCLUSIONS: Continuous nicotine infusion produced an infusion rate-related suppression of NSA that was greatest when the infusion provided nicotine doses and venous serum concentrations substantially higher than those typically associated with NRT in humans.

Caffeine potentiates the discriminative-stimulus effects of nicotine in rats.

RATIONALE: Caffeine and nicotine are the main psychoactive ingredients of coffee and tobacco, respectively, with a high frequency of concurrent use in humans. OBJECTIVES: The aim of the present study was to examine the interaction of caffeine and nicotine in rats trained to discriminate nicotine from saline. METHODS: Two groups of male Sprague-Dawley rats ( n=8 per group) were trained to discriminate 0.4 mg/kg nicotine, SC, from saline under a fixed ratio schedule of food presentation. One group of rats was chronically exposed to caffeine (1.0 mg/ml) dissolved in their drinking water whereas the other group was exposed to tap water. Effects of IP injections of caffeine on nicotine-lever selection were subsequently examined. In separate groups of rats exposed to the same caffeine-drinking or water-drinking regimen, effects of caffeine pretreatment on nicotine plasma levels were evaluated. RESULTS: Although caffeine (1.0-30.0 mg/kg) did not generalize to nicotine when administered alone, it markedly potentiated discriminative-stimulus effects of the threshold dose of nicotine (0.05 mg/kg) in both water- and caffeine-drinking rats. Nicotine plasma levels were, however, not affected by acute or chronic caffeine exposure. CONCLUSIONS: Caffeine appears to enhance the discriminative-stimulus effects of the threshold dose of nicotine by a pharmacodynamic rather than a pharmacokinetic interaction. This suggests that caffeine consumption may be a contributing factor in the onset, maintenance of and relapse to tobacco dependence.

Oral nicotine administration decreases tumor necrosis factor-alpha expression in fat tissues in obese rats.

To investigate the effect of oral nicotine administration on insulin resistance and insulin secretion in an animal model of obesity, Zucker fatty rats were administered nicotine tartrate dihydrate orally through tap water (4.6 mg/kg/d, N group). Plasma nicotine concentrations in N group were 33.67 +/- 10.49 ng/mL. The control (C) group consisted of pair-fed control rats. After 8 weeks of nicotine administration, both groups of rats were administered glucose (2 g/kg) orally in an anesthetized state, and blood was collected for glucose and plasma insulin measurements. The pancreases were isolated and perfused in vitro under pentobarbital anesthesia 1 week after glucose administration. The fat tissues were excised. The levels of tumor necrosis factor (TNF)-alpha protein were assessed using enzyme-linked immunosorbent assay (ELISA) or Western blot analysis. Serum leptin levels were measured using radioimmunoassay (RIA). Blood glucose levels in N group were significantly lower than in C group before and 120 minutes after glucose administration. The insulin secretion from the isolated perfused pancreases of N group appeared to be decreased compared with C group, but there was no significant difference. Histologic examination showed that the mean size of the pancreatic islets in N group was significantly smaller than in C group. The composition ratios of alpha and beta cell mass of the pancreatic islets and fibroelastic tissues were not altered by nicotine administration. Portal TNF-alpha levels were comparable to peripheral levels in both groups. There were no significant differences in peripheral serum levels of TNF-alpha, free fatty acids (FFA), or leptin levels between N and C group. The TNF-alpha levels in visceral fat tissues in N group were significantly lower than those in C group. These results suggest that oral nicotine administration reduces insulin resistance in obese diabetic rats by decreasing production of TNF-alpha in the visceral fat tissues. Decreased islet size may be a secondary phenomenon induced by ameliorated insulin resistance, because the cellularity and fibroelastic tissues were not affected by the nicotine.

An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics.

AIMS: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal nicotine has therapeutic value in active disease; however side-effects are troublesome. The aim of this study was to develop an oral formulation of nicotine which would be slowly released in the colon over 6 h, and to examine its pharmacokinetic profile in 12 healthy volunteers, with measurements of serum nicotine and cotinine, its principal metabolite. METHODS: Nicotine was combined with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13 different vehicles and their release profiles examined in vitro. The polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic studies because it consistently produced a suitable release pattern which was linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire 50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine, contained in 2 and 5 capsules, respectively, were administered to 12 subjects, all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h, serum nicotine and cotinine concentrations were measured by gas liquid chromatography. RESULTS: There was considerable intersubject variability in the nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h after ingestion of the capsules, corresponding with the oro-caecal transit time. Cmax nicotine values were 2.2 and 5 ng ml-1, obtained 7 h after the ingestion of 6 and 15 mg, respectively, of the formulation. The corresponding Cmax values for cotinine were 37 and 94.4 ng ml-1, occurring after 9-10 h. The mean for elimination half-lives in the 24 studies, including the 6 and 15 mg doses, for nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine-carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg dose 11 out of the 12 reported adverse effects which were systemic or gastrointestinal in nature-their timing corresponded with peak serum concentrations of nicotine. CONCLUSIONS: An oral formulation of nicotine has been developed; in the ileum and colon, this becomes available for slow linear release over 6 h and delivers high concentrations of nicotine for topical effect on the colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and gastrointestinal side-effects. High concentrations of topical nicotine in the colon are achieved with relatively low systemic bioavailablity-reflected by the Cmax and AUC values for nicotine. This, or comparable formulations, may be of therapeutic value in ulcerative colitis.

Lung cancer and environmental tobacco smoke: occupational risk to nonsmokers.

The principal epidemiologic evidence that environmental tobacco smoke (ETS) increases the risk of lung cancer in (lifelong) nonsmokers is from studies of nonsmoking women married to smokers. This article estimates exposure-response curves for 14 studies (1, 249+ cases, 7 countries) with data on lung cancer categorized by the number of cigarettes/day smoked by the husband. The pooled results from the five U.S. studies alone are extrapolated to ETS levels in the workplace using measures of serum cotinine and nicotine samples from personal monitors as markers of exposure to ETS. It is predicted that the increase in lung cancer risk for nonsmoking women from average ETS exposure at work (among those exposed at work) is on the order of 25% (95% confidence interval (CI) = 8, 41) relative to background risk (i.e., with no ETS exposure from any source). This compares to an estimate of 39% (95% CI = 5, 65) for nonsmoking women whose husbands smoke at the adult male smoker's average of 25 cigarettes/day. At the 95th percentiles of exposure, the estimate from spousal smoking is 85% (95% CI = 32, 156), compared to 91% (95% CI = 34, 167) from workplace ETS exposure. Subject to the validity of the assumptions required in this approach, the outcome supports the conclusion that there is a significant excess risk from occupational exposure to ETS. The excess risk from ETS at work is typically lower than that from spousal smoking, but may be higher at the 95th percentiles of exposure.

Arterial/venous plasma nicotine concentrations following nicotine nasal spray.

BACKGROUND AND OBJECTIVES: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. SUBJECTS AND METHODS: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1-2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. RESULTS AND CONCLUSIONS: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r = 0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations.

Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers.

Positron emission tomography (PET) studies with [11C]L-deprenyl-D2 have shown that brain monoamine oxidase (MAO) B is 40% lower in smokers than in non-smokers. Here we investigated whether MAO B inhibition can be detected after smoking a single cigarette. Eight normal healthy non-smokers (35 +/- 11 years) received two PET studies 2 h apart with [11C]L-deprenyl-D2, one at baseline and the second 5-10 min after the subject had smoked a single cigarette. Plasma nicotine and expired carbon monoxide (CO) were measured prior to smoking and 10 min after smoking completion as an index of tobacco smoke exposure. A three-compartment model was used to calculate lambda k3, a model term which is proportional to MAO B activity and which is derived from the time course of carbon-11 in the brain and the time course of the radiotracer in the plasma and K1, the plasma-to-brain transfer constant (for [11C]L-deprenyl-D2) which is related to brain blood flow. Subjects experienced difficulty inhaling and became dizzy and/or nauseous after smoking. Plasma nicotine averaged 11.6 +/- 5.5 ng/ml and expired CO averaged 8 +/- 10 ppm after smoking. The average lambda k3 and K1 for 11 different brain regions did not differ significantly between baseline and smoking. These results indicate that the reduction in MAO B in smokers probably occurs gradually and requires chronic tobacco smoke exposure.

Dose-related cardiovascular and endocrine effects of transdermal nicotine.

BACKGROUND: Transdermal nicotine in doses up to 21 mg/24 hr is used to facilitate smoking cessation. However, this dose does not achieve the nicotine plasma levels seen among heavy smokers, and underdosing may be one of the reasons for the limited efficacy of transdermal nicotine. There are some concerns about the adverse cardiovascular effects of nicotine, especially with concomitant smoking. Treatment with higher doses of transdermal nicotine has been proposed for highly dependent smokers, but the effects of such treatment on the cardiovascular system have not been determined. The objective of this study was to determine the cardiovascular effects of high-dose transdermal nicotine with concomitant smoking. METHODS: Twelve healthy male smokers received three doses of transdermal nicotine (21, 42, and 63 mg/24 hr) and placebo, each for 5 days, in a balanced order. The subjects smoked during the first 4 days of each treatment and abstained from smoking during the fifth day. Ambulatory 24-hour daytime and nighttime heart rate and blood pressure values were determined for each treatment; plasma nicotine, cotinine, and carboxyhemoglobin levels and urinary catecholamines with aldosterone were measured on days 4 and 5. The data were compared by means of repeated-measures ANOVA. RESULTS: There was no difference in heart rate or blood pressure and no changes in the pattern of circadian variations with various transdermal nicotine doses compared with smoking alone, consistent with the development of tolerance. Urinary epinephrine level was significantly higher (p < 0.05) with transdermal nicotine compared with no nicotine but was not higher with transdermal nicotine and smoking compared with smoking alone. No change was found in fibrinogen and lipid profiles with different nicotine doses. CONCLUSIONS: High-dose nicotine treatment, even with concomitant smoking, caused no short-term adverse effects on the cardiovascular system.