Naltrexone augments the effects of nicotine replacement therapy in female smokers

BACKGROUND: There is increased recognition that gender differences may influence outcomes and may modify vulnerability to tobacco addiction, severity of course and response to different treatments. We hypothesized that naltrexone, which has been used to successfully treat opioid and alcohol dependence, when combined with nicotine replacement therapy (NRT) and psychosocial therapy (PT) may enhance smoking cessation rates in women. METHODS: Forty-four adult female smokers meeting DSM-IV criteria for nicotine dependence with expired carbon monoxide content of > or = 15 ppm were randomly assigned in a double blind placebo controlled clinical trial of naltrexone 50 mg + NRT patch + psychosocial therapy (N + NRT + PT)(N = 12) or placebo + NRT patch + psychosocial therapy (P + N + PT)(N=12) for 12 weeks. RESULTS: Twelve weeks of treatment was completed by 54.5%. Smoking cessation among females who completed the 12 weeks for N + NRT + PT was 91.7% (11/12) and for P + NRT + PT was 50% (6/12). CONCLUSION: Naltrexone combined with NRT and psychosocial therapy appears to have a positive cessation effect on women and may be a new treatment option for recidivist female smokers.     

Effects of early postnatal exposure to low concentrations of carbon monoxide on cognitive functions in rats.

Male Wistar rats were exposed to 75 and 150 ppm of carbon monoxide (CO) from day 1 after birth until postnatal day 10 and their cognitive functions were evaluated at 3 and 18 months of age. The results show that early postnatal exposure to CO does not affect the acquisition and reacquisition of an active avoidance task in both adult and aged rats. Conversely, our previous findings indicate that prenatal exposure to CO (75 and 150 ppm), resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those found in human cigarette smokers, induces long-lasting learning and memory deficits. These findings suggest that neurofunctional sequelae of prenatal CO exposure are notably different from those occurring in response to early postnatal exposure and that the vulnerability of the developing brain to prolonged, relatively mild, decrease in oxygen availability induced by CO critically depends on the particular period of developmental exposure.     

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.     

In situ assessment of the rat heart during chronic carbon monoxide exposure using nuclear magnetic resonance imaging

Ventricular hypertrophy induced in male Sprague-Dawley rats by inhalation of 500 ppm carbon monoxide (40% carboxyhemoglobin level) for 0-62 days was assessed by contiguous 2-mm thick axial cardiac cross-sections, using 32 accumulated averages of ungated fast-scan gradient-recalled nuclear magnetic resonance (NMR) images. Following final imaging, the rats were sacrificed and the hematocrit and heart mass were determined. The mean outside diameter of the left ventricle plus interventricular septum (LV + S) showed a strong correlation (r = 0.73, P less than 0.01) with the duration of CO exposure, while the correlation coefficients for the LV + S lumen diameter and wall thickness were marginally significant. The mean pleural space diameter also increased significantly (r = 0.64, P less than 0.05) with the duration of CO exposure. The ratio of the LV + S wall thickness and the lumen radius was 0.53 in the rats exposed to CO for 0-8 days; this value did not change with longer CO exposure. The LV + S outside and lumen diameter showed significant correlations to the hematocrit (r = 0.72, p less than 0.05 and r = 0.66, P less than 0.05, respectively), and the LV + S outside diameter correlated with the increase in the LV + S mass (r = 0.72, P less than 0.05). The results achieved with NMR imaging are consistent with past morphometric studies of CO-induced ventricular hypertrophy, where heart dimensions were determined in relaxed frozen tissue, and corroborate the eccentric nature of CO-induced ventricular hypertrophy.     

A 12-week double-blind, placebo-controlled study of bupropion sr added to high-dose dual nicotine replacement therapy for smoking cessation or reduction in schizophrenia

The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy (NRT) and weekly group cognitive behavioral therapy (CBT) for smoking reduction or cessation in schizophrenia. Fifty-one adult smokers with schizophrenia were randomly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch, nicotine polacrilex gum, and CBT. The treatment goal was smoking cessation. The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50% to 100% smoking reduction at week 12. Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide (CO) and psychiatric symptoms. Subjects on bupropion + NRT had a greater rate of 50% to 100% smoking reduction at weeks 12 (60% vs. 31%; P = 0.036) and 24, a lower expired air CO in the treatment and follow-up periods, (F = 13.8; P < 0.001) and a greater continuous abstinence rate at week 8, before NRT taper, (52% vs. 19%; P = 0.014). However, relapse rates in subjects on bupropion + dual NRT were 31% during NRT taper (weeks 8-12) and 77% at the 12-month follow-up. Abstinence rates did not differ by treatment group at weeks 12 (36% vs. 19%), 24 (20% vs. 8%), or 52 (12% vs. 8%). Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment, study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention.     

重度一氧化碳中毒性肺水肿急诊集束治疗分析

目的 探讨重度一氧化碳中毒性肺水肿急诊处置方法。方法重度一氧化碳中毒性肺水肿患者12例,急诊处置采用集束治疗,要点：①保护性通气间断纯氧氧疗。②甲基强的松龙240mg／d,静脉点滴。③6％羟乙基淀粉钠500ml＋10％氯化钠60ml＋速尿100mg,200ml／h,恒速泵入。结果显效9例（75．0％）,有效3例（25．0％）。氧合指数（203．4±69．7）VS（434．6±973X）（P〈0．01）。X线胸片的变化显效8例（66．7％）,有效4例（33．3％）。本组12例患者经后续高压氧等综合治疗,均治愈出院,其中,发生迟发性脑病1例。结论集束治疗可能是重度一氧化碳中毒性肺水肿的有效方法。     

Prenatal exposure model simulating CO inhalation in human cigarette smokers: sphingomyelin alterations in the rat sciatic nerve

Prenatal exposure to low concentrations of carbon monoxide (CO, 150 ppm) causes long-term alterations in sphingomyelin (SM) homeostasis in peripheral nervous system, but not brain of male rat offspring. In particular, unlike sphinganine (intermediate of complex sphingolipid biosynthesis de novo), the concentrations of sphingosine (intermediate of complex sphingolipid turnover) were increased by 2.35-fold in the sciatic nerve of CO-exposed offspring with respect to controls (P<0.05, overall one-way ANOVA). These subtle alterations were not accompanied by changes in motor activity (F=0.25, df=1/10, n.s., overall one-way-ANOVA). The results suggest that the SM homeostasis in the sciatic nerve is particularly susceptible to prenatal CO exposure resulting in maternal carboxyhaemoglobin (HbCO) levels equivalent to those found in human cigarette smokers.     

Increase in anger symptoms after smoking cessation predicts relapse

Smokers tend to increase their cigarette consumption during angry states. We sought to determine whether increases in post-quit anger symptoms predict relapse among smokers who had received 8-weeks of smoking cessation treatment (21 mg nicotine patch+smoking cessation counseling). The 15-item state anger assessment [from Spielberger, C., 1999. STAXI-2: the state trait anger expression inventory professional manual, Odessa, FL] was administered at pre-treatment (2 weeks before the target quit date; TQD) and 1 week after the TQD. Abstinence at 8-weeks post-quit was biochemically verified using carbon monoxide. Smokers who reported increases in pre- to post-quit state anger levels (n=117) were significantly more likely to relapse by 8-weeks after treatment as compared to smokers whose anger did not change or decreased after quitting (n=130) (OR=1.06; CI=1.01-1.10; p=0.01). Furthermore, smokers with increased post-quit anger relapsed almost twice as quickly than those who did not have an increase in post-quit anger symptoms (HR=1.98; CI: 1.32-2.96; p=0.001). These data suggest that anger may be an important withdrawal symptom that influences liability to relapse. Future studies are needed to evaluate treatment strategies that effectively help smokers reduce and manage post-quit anger.     

Cigarette filter vent blocking: effects on smoking topography and carbon monoxide exposure

Two studies were conducted using smokers of unventilated cigarettes to determine the effects of filter vent blocking on smoke exposure (Experiment 1) and smoking topography (Experiment 2). In both studies, subjects were exposed to ultra low yield cigarettes that had 0%, 50%, and 100% of their filter vents blocked with tape. In Experiment 1, carbon monoxide (CO) exposure from eight 60 ml puffs increased in an orderly fashion as a function of filter vent blocking. By blocking filter vents, smoke was no longer diluted with air as it passed through the filter, and hence, exposure to smoke constituents was increased. In Experiment 2, when puff and inhalation parameters were allowed to vary, subjects took significantly more puffs, and larger puffs from unblocked cigarettes than from completely blocked cigarettes, but CO exposure from the completely blocked cigarette was double that from the unblocked cigarette (8.96 ppm vs. 4.32 ppm). The increased number and volume of puffs taken from ultra low yield cigarettes with unblocked filter vents may be due to changes in physical characteristics of the cigarette, and not to smokers actively compensating for reduced smoke constituent yields.     

Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.     

Disruption of neostriatal development in rats following perinatal exposure to mild, but chronic carbon monoxide

The vulnerability of the developing neostriatum to mild, but chronic hypoxia was evaluated in weanling rats exposed only in utero or from conception through postnatal day 10 to 0, 75, 150, and 300 ppm carbon monoxide (CO). The exposure conditions produced maternal carboxyhemoglobin (HbCO) levels of about 11, 19, and 27 percent. HbCO levels of 5 percent are maintained by human cigarette smokers while comparable levels in non-smokers average less than 1%. Significant elevations in DNA and the neurotransmitter, dopamine (DA), were observed in the striatum of 21-day-old rats following the combined pre- and neonatal CO exposure. These neurochemical changes were observed 11 days after CO exposure was terminated and, therefore, cannot be interpreted as acute responses to reduced oxygen. These data indicate that the immature neostriatum is altered by even mild hypoxic insults presented during the time of neuronal proliferation and synaptogenesis.     

Screening of exhaled breath by low-resolution multicomponent FT-IR spectrometry in patients attending emergency departments

Interest in noninvasive methods for disease diagnosis is increasing. In this study, we tested the utility and potential of a portable Fourier transform infrared (FT-IR) multicomponent analyzer in the emergency rooms (ERs) of two Finnish hospitals. Major detected breath volatiles in this population were ethanol, carbon monoxide, methane, and acetone, in addition to carbon dioxide and water. The analysis of breath revealed an ethanol concentration of over 25 ppm (0.1 g/L in blood) in 56 out of 589 patients (9.5%). During nightshifts the proportion was 30% for all and 63% for trauma patients. Five-hundred eighty-four patients had measurable carbon monoxide in their breath. A breath carbon monoxide of over 4 ppm (4.4 micro g/L) differentiated smokers from nonsmokers. Methane over 2 ppm (1.3 micro g/L) was detected in the breath of 32% of the participants. Methane concentration was higher among aged patients. Two-hundred ninety-eight participants had detectable acetone in their breath. Elevated exhaled acetone [10-76 ppm (23-75 micro g/L)] was detected in 10 patients. The FT-IR method proved functional in the ER setting. A major advantage over blood sampling was fast and easy analysis performed by nonlaboratory personnel.     

Response to marijuana as a function of potency and breathhold duration

The present study examined the effects of systematic manipulation of breathhold duration (0 and 20 s) on the physiological and subjective response to active (M; 2.3% delta-9-THC) and placebo (P; 0.0% delta-9-THC) marijuana in a group of ten regular marijuana smokers. During the eight-session experiment, subjects were exposed twice to each of four experimental conditions (P0, P20, M0, M20), scheduled according to a randomized block design. A controlled smoking procedure was used in which the number of puffs and puff volume were held constant. Expired-air carbon monoxide (CO) levels were used to monitor smoke intake. Breathhold duration affected CO absorption; significantly more CO was absorbed from both P and M smoke after 20 s of breathholding (mean CO boost=6.9 ppm) than after no breathholding (mean=4.4 ppm). Heart rate was minimally affected by the breathhold manipulation. Effects of marijuana on mood were not consistently affected by breathhold duration. The results confirm previous findings that prolonged breathholding does not substantially enhance the effects of inhaled marijuana smoke.     

An investigation into the direct and indirect venoconstrictor effects of endothelin-1 and big endothelin-1 in man.

1. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide that is generated through cleavage of its precursor big endothelin-1 by 'endothelin converting enzyme' (ECE) in resistance vessels, including those of the forearm vascular bed. In some animal tissues, but not in resistance vessels of healthy human subjects, endothelin-1 appears to potentiate the actions of the sympathetic nervous system. We examined whether ECE activity is present in human hand veins and whether endothelin-1 or big endothelin-1 potentiate sympathetically mediated venoconstriction. 2. Six healthy subjects received dorsal hand vein infusion of local, non-systemic doses of endothelin-1 (5 pmol min-1), big endothelin-1 (50 pmol min-1) and, as a control, sodium chloride (0.9%; w/v) for 90 min. Vein diameter was measured using the Aellig displacement technique. Sympathetically mediated venoconstriction was elicited using the single deep breath reflex. 3. Endothelin-1 caused a progressive decrease in hand vein diameter, by 49% at 90 min (95% confidence intervals [CI]: -68 to -30%; P = 0.0001). Vein diameter did not change significantly after 90 min infusion of big endothelin-1 (+3%; CI: -11 to +17%; P = 0.0007 vs endothelin-1; P = 0.40 vs baseline) or sodium chloride (+2%; CI: -12 to +16%; P = 0.0002 vs endothelin-1; P = 0.60 vs baseline). Venoconstriction to deep breath was not potentiated by endothelin-1. 4. These results suggest that, in contrast to the situation in forearm resistance vessels, there is little or no local ECE activity in human hand veins and that endothelin does not potentiate sympathetic responses in these cutaneous capacitance vessels.     

Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats.

Twenty-eight 42-day-old pups/sex/group (F0) were exposed to toluene diisocyanate vapor (TDI; 80% 2,4-TDI, 20% 2,6-TDI) by inhalation at 0.0, 0.02, 0.08, or 0.3 ppm, 6 h/day, 5 days/week, for 10 weeks, then mated within groups for 3 weeks, with exposure 7 days/week during mating, gestation, and lactation. F0 maternal animals were not exposed from gestational day (gd) 20 through postnatal day (pnd) 4; maternal exposures resumed on pnd 5. Twenty-eight weanlings/sex/group continued exposure for 12 weeks (starting on pnd 28) and were bred as described above. F0 and F1 parents and ten F1 and F2 weanlings/sex/group were necropsied, and adult reproductive organs, pituitary, liver, kidneys, and upper respiratory tract (target organs) were evaluated histologically in ten/sex/group. Adult toxicity was observed in both sexes and generations at 0.08 and 0.3 ppm, including occasional reductions in body weights and weight gain, clinical signs of toxicity at 0.08 and 0.3 ppm, and histologic changes in the nasal cavities at 0.02, 0.08, and 0.3 ppm (including rhinitis, a nonspecific response to an irritating vapor, at all concentrations). There was no reproductive toxicity, reproductive organ pathology, or effect on gestation or lactation at any exposure concentration. Postnatal toxicity and reduced body weights and weight gains during lactation occurred only in F2 litters at 0.08 and 0.3 ppm. Therefore, under the conditions of this study, a no observed adverse effect level (NOAEL) was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 0.3 ppm, and the NOAEL for postnatal toxicity was 0.02 ppm.     

Transplacental passage of dichloromethane and carbon monoxide

Maternal blood dichloromethane concentrations were higher than fetal blood dichloromethane concentrations and maternal and fetal blood carbon monoxide concentrations were the same in pregnant rats exposed to 500 ppm of dichloromethane. Fetal blood carbon monoxide concentrations were higher than maternal blood carbon monoxide concentrations in pregnant rats exposed to 20 ppm of carbon monoxide. These results show that maternal exposure to dichloromethane is accompanied by fetal exposure to both dichloromethane and carbon monoxide.     

Carbon monoxide-induced cardiac hypertrophy is not reduced by alpha- or beta-blockade in the rat

The stimulus for carbon monoxide-induced cardiac hypertrophy was investigated. Two experiments were carried out in which adult male Sprague-Dawley rats were exposed continuously to 700 ppm CO for 30 days (CO) or inhaled room air (Air). In each experiment, 2/3s of the rats received either the beta-1-adrenergic blocker, atenolol, or the alpha-1 adrenergic blocking agent, prazosin, in the food daily, at low and high doses. Systolic blood pressure (SBP) was significantly lowered (20–25 mmHg) by CO alone. Atenolol alone lowered SBP, but only at the high dose. Low dose and particularly high dose atenolol, lowered SBP even more in the CO rats. Prazosin lowered SBP, particularly at the high dose and further lowered SBP in the CO rats. Heart rate was significantly lowered by atenolol and prazosin alone at both doses in the Air rats. Heart rate remained the same or was slightly elevated by CO exposure. Heart rate in the presence of CO was significantly depressed by prazosin, but not by atenolol. Carbon monoxide alone resulted in 30–43% and 18–25% weight increases in right ventricle free-wall (RV) and left ventricle + septum (LV+S), respectively, relative to untreated controls. Neither low nor high dose prazosin significantly decreased RV and LV+S weights in the CO rats. Low dose atenolol failed to alter RV and LV+S weights in the CO rats; however, high dose atenolol, significantly (P < 0.01) increased RV weight in the CO rats. Right ventricle weight was positively correlated with SBP lowering by CO and/or atenolol, or prazosin. Carbon monoxide exposure increased lung/body weight ratio; atenolol, but not prazosin, attenuated this effect. Hematocrit increased from 50% in the Air to 77% in the CO rats; it was unaltered by prazosin or atenolol treatment. Thus, CO-induced cardiac hypertrophy develops in spite of lowered SBP (i.e. lowered LV afterload), and the blockade of either alpha or beta-1 receptors. It is suggested that the increased ventricular preload caused by atenolol and prazosin is directly responsible for the cardiac hypertrophy, regardless of the ameliorating effects of decreased inotropicity and heart rate produced by the adrenergic blocking agents. The results suggest the potentially powerful role of enhanced preload in driving myocardial hypertrophy.     

12-week clinical exposure evaluation of a third-generation electrically heated cigarette smoking system (EHCSS) in adult smokers

This randomized, controlled, forced-switching, open-label, parallel-group, single-center study in 90 male and female adult smokers evaluated six biomarkers of tobacco smoke exposure over a 12-week period of unrestricted smoking in the participants' normal life setting. Baseline biomarker levels were measured, then participants were randomly assigned to switch to an electrically heated cigarette smoking system (EHCSS, Series K) or to continue smoking a conventional cigarette (CC) of similar tar yield (Federal Trade Commission method) for 12 weeks. Compared to Baseline, adult smokers who switched to the EHCSS for 12 weeks in their normal life setting had significantly reduced nicotine equivalents (-33%), total NNAL (a biomarker for NNK, -63%), 1-OHP (a surrogate biomarker for polycyclic aromatic hydrocarbons, -38%), carboxyhemoglobin (a biomarker for carbon monoxide, -23%), 3-HPMA (a biomarker for acrolein, -25%) and S-PMA (a biomarker for benzene, -49%), whereas exposure was stable in the CC control group.     

Utility and accuracy of collateral reports of smoking status among 256 abstinent alcoholic smokers treated for smoking cessation

This study examined the utility and accuracy of collateral reports of smoking status among 256 abstinent alcoholic smokers (140 males, 116 females) treated for smoking cessation. Data were gathered prospectively from two randomized clinical trials of behavioral smoking cessation treatment conducted in San Diego, CA. The mean age of the participants was 42.0 years (S.D.= 10.0) and 93% were Caucasian. Self-reported smoking status was obtained at posttreatment (1 week after the target quit date) and at 1 year. Collateral reports obtained by telephone and expired air carbon monoxide (CO) levels of < 10 ppm were used to confirm self-reported smoking status. Collateral reports were available for 89.1% of subjects at posttreatment and 90.6% of subjects at 1 year. The smoking abstinence rates were similar when using collateral reports or CO confirmation of smoking status at both time points. Collateral reports refuted self-reported abstinence as often or more than CO levels, and showed relatively high concordance with CO levels. In conclusion, collateral reports have utility and are reasonably accurate for confirming self-reported smoking status in clinical trials of smoking cessation for abstinent alcoholic smokers.