Desmethyldiazepam kinetics after intravenous,intramuscular, and oral administration of clorazepate dipotassium

Summary The pharmacokinetics and bioavailability of desmethyldiazepam (DMDZ), formed from its precursor clorazepate (CZP) dipotassium, were assessed in a series of 17 healthy volunteers aged 21–66 years. After a single 20-mg intravenous dose of CZP, mean kinetic variables for DMDZ were: volume of distribution, 1.24 l/kg; elimination half-life, 65 h; total clearance, 0.24 ml/min/kg. Among males, DMDZ half-life tended to be prolonged and clearance reduced with age, but this was not true for females. After oral administration of 20 mg CZP, appearance of DMDZ in the circulation was rapid; the mean peak plasma level was 356 ng/ml, reached an average of 0.9 h after dosage. Based on comparison with IV dosage, systemic availability of DMDZ was complete (100% absorption). Ten of the subjects also received a single 20-mg intramuscular dose of CZP. Mean peak DMDZ levels were 290 ng/ml, reaching an average of 2.7 h after dosage. Systemic availability of DMDZ was complete. Elimination half-life of DMDZ for a given individual was highly replicable from trial to trial regardless of the route of CZP administration.Part of doctoral thesis E. Steinhaus, University of Bonn 1982     

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate

Summary The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min,P<0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.Abbreviations AUC Area under curve - ISDN Isosorbide dinitrate - ISMN Isosorbide-5-mononitrate Supported in part by grant OC 10/6-4 from the Deutsche Forschungsgemeinschaft, and a grant from Boehringer Mannheim, Federal Republic of Germany     

Disposition of oxazepam in relation to age,sex, and cigarette smoking

Summary The kinetics of single 30-mg oral doses of oxazepam were determined in 22 male and nine female volunteers aged 20–86 years. Oxazepam plasma concentrations were measured in multiple plasma samples drawn during 36 h after each dose. Mean kinetic variables in males and females, respectively, were: elimination half-life, 7.5 and 8.5 h; volume of distribution, 0.96 and 1.17 l/kg; clearance, 1.48 and 1.70 ml/min/kg. Sex differences were not significant, nor were any of the kinetic variables significantly related to age. However, oxazepam clerance increased significantly with heavier cigarette smoking (r=0.48,p<0.01). Mean clearance in smokers (1.98 ml/min/kg) was significantly higher than in non-smokers (1.23 ml/min/kg,p<0.01). Thus, smoking is a more important determinant of oxazepam clearance than age or sex.Supported in part by Grant Oc 10/4 from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Federal Republic of Germany; and Grant MH-34223 from the United States Public Health Service     

Modification of gene expression of the small airway epithelium in response to cigarette smoking

The earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the small airways. To help understand how smoking modifies small airway structure and function, we developed a strategy using fiberoptic bronchoscopy and brushing to sample the human small airway (10th-12th order) bronchial epithelium to assess gene expression (Affymetrix HG-U133A and HG-133 Plus 2.0 array) in phenotypically normal smokers (n = 16, 25 +/- 7 pack-years) compared to matched nonsmokers (n = 17). Compared to samples from large (second to third order) bronchi, the small airway samples had a higher proportion of ciliated cells, but less basal, undifferentiated, and secretory cells, and contained Clara cells. Even though the smokers were phenotypically normal, microarray analysis of gene expression of the small airway epithelium of the smokers compared to the nonsmokers demonstrated up- and downregulation of genes in multiple categories relevant to the pathogenesis of chronic obstructive lung disease (COPD), including genes coding for cytokines/innate immunity, apoptosis, mucin, response to oxidants and xenobiotics, and general cellular processes. In the context that COPD starts in the small airways, these gene expression changes in the small airway epithelium in phenotypically normal smokers are candidates for the development of therapeutic strategies to prevent the onset of COPD.     

Effects of cigarette smoking or ingestion of nicotine on platelet 5-hydroxytryptamine (5-HT) levels in smokers and non-smokers

Summary Platelets of healthy smokers and nonsmokers were prepared and their content of 5-hydroxytryptamine was determined by HPLC with electrochemical detection. Platelet 5-HT levels in smokers (728 ± 156 pmol per 108 platelets, mean ±SEM, n=9) were significantly higher than those in non-smokers (353 ± 156 pmol per 10⁸ platelets, n = 11). Smoking of a single cigarette caused a transient increase in platelet 5-HT levels by about 350% in non-smokers, but had no additional effect in smokers. Similarly, chewing of nicotine gum (48 mg nicotine) resulted in a transient increase in platelet 5-HT by about 100% in non-smokers, but not in smokers. In conclusion, smoking of cigarettes can cause an increase in platelet 5-HT, most likely via an enhanced supply of 5-HT from entero-chromaffm cells which can be stimulated via nicotine receptors.Abbreviations 5-HT 5-hydroxytryptamine - 5-HIAA 5-hydroxyindoleacetic acid     

Effects of cigarette smoking on electrodermal orienting reflexes to stimulus change and stimulus significance

Skin conductance responses (SCRs) evoked by novel, signal, and frequent tone stimuli were measured in 20 male heavy smokers and 10 male nonsmokers over two sessions. All smokers abstained from smoking for 12 hr prior to each session. Half of the smokers smoked a cigarette of their preferred brand prior to SCR measurement in the first session, whereas the remaining smokers smoked in the second session. Nonsmokers did not smoke. Results combined across the two sessions indicated that abstinence was associated with selective depression of SCRs to the novel tone. Separate analyses of results from each session revealed that, in the second session, SCRs to both novel and signal tones were depressed in abstinent smokers, partially replicating previous findings. By contrast, first session results showed no significant effects of smoking or abstinence. Results were interpreted in terms of nicotine's effects on nonspecific arousal, with some reservations.     

The effects of cigarette smoking on maximal oxygen consumption and selected physiological responses of elite team sportsmen

Summary The acute and chronic effects of cigarette smoking on selected physiological responses were determined in seven well-trained non-smokers and seven well-trained habitual smokers. Non-smokers and smokers did not differ significantly with respect to maximal oxygen consumption ( ). The acute effect of smoking two cigarettes immediately prior to a graded exercise stress test on a treadmill ergometer did not significantly alter the of either group. However, the time taken for non-smokers to reach exhaustion decreased significantly (F=5.381, P<0.05) by a mean of 0.64 min. Smokers recorded lower scores for forced vital capacity (FVC) and forced expiratory volume in the 1st s exhalation (FEV₁) than non-smokers. Only the mean FVC of smokers recorded 5 min post-exercise was significantly altered by pre-exercise smoking. No differences were found between the resting heart rates (HR) of non-smokers and smokers. Smoking two cigarettes significantly (F=44.720, P<0.01) increased the mean resting HR of smokers and non-smokers by 15.8 beats·min^–1 and 15.6 beats·min^–1 respectively. No alteration to the exercise HR of either group was found under smoking conditions of the tests.     

Interactive effect of the glutathione S-transferase genes and cigarette smoking on occurrence and severity of coronary artery risk

Cardiovascular diseases and cancer are the main causes of death in developed countries. Mortality trends for these diseases suggest that they share common pathogenetic mechanisms. Glutathione S-transferase (GST) is a family of enzymes that detoxify reactive electrophiles, particularly present in tobacco smoke. Glutathione S-transferase null M1 and T1 (GSTM1 and GSTT1) genotypes have often been associated with increased risk of developing cancer. Our hypothesis was that the polymorphic GSTM1 and GSTT1 genes modulate the risk of smoking-coronary artery disease (CAD). We evaluated the distribution of GST genotypes in 430 angiographically defined patients (308 CAD and 122 non-CAD). The frequencies of GST null genotypes did not differ significantly between patients with CAD and without CAD. However, smokers with GSTM1 and GSTT1 null genotypes had a significantly higher risk of CAD than never-smokers with these genotypes present (OR 2.2 and 3.4 for smokers with null GSTM1 and GSTT1 genes, respectively). There was also evidence of multiple interaction between GSTM1 and GSTT1 deleted genotypes and smoking. In nonsmokers carrying both null genotypes the risk of CAD was 0.66. In smokers with both present genotypes the OR was 1.5 and was significantly increased in smokers with concurrent lack for GSTM1 and GSTT1 genes (OR=4.0). Moreover, smokers lacking GST genes had both more stenosed vessels and a higher Duke score than smokers expressing the genes. We also examined the levels of DNA damage in 66 men patients using the micronucleus test, a sensitive assay for evaluating chromosome damage. Micronucleus levels were higher in smokers with null genes than in smokers with present genes. These observations suggest that GST-null genotypes strengthen the effect of smoking on CAD risk by modulating the detoxification of genotoxic atherogens.     

The effects of a combination of cigarette smoking and oral contraception on coagulation and fibrinolysis in human females

Summary Oral contraception as well as cigarette smoking influence haemostasis. The simulataneous effect of both on blood coagulation and fibrinolysis was studied in nine female smokers. While continuing oral contraception after a 4-week abstinence from smoking the concentration of fibrinogen, antithrombin III and alpha₁-Antitrypsin decreased (P<0.01 orP<0.04) and of plasminogen increased (P<0.03). The other coagulation parameters remained unchanged. Although all determinations of these parameters were in the normal range, the observed trends were statistically significant. The concentrations of the fibrinopeptide A and B 15–42 did not differ. It is concluded that the observed alteration is caused by cessation from cigarette smoking.This work has been supported by grants from Forschungsrat Rauchen und Gesundheit     

Acute ventilation-perfusion mismatching resulting from inhalative smoking of the first cigarette in the morning

Summary The effect of the first cigarette in the morning on the airway resistance (R _aw) which can be measured by body-plethysmography was investigated in 70 inhaling cigarette smokers. The test population showed a significant (P<0.0005) fall in R _aw 8 min after smoking. A further study (n = 16) showed that the fall in R _aw was most likely to be attributable to a decrease in the trapped air. The effect of the first cigarette in the morning on the arterial blood gases and on the alveolar-arterial oxygen difference P(A-a)O₂ and carbon dioxide difference P(A-a)CO₂ was investigated in 12 inhaling cigarette smokers. Smoking gave rise to a significant (P < 0.0005) fall in the partial pressure of oxygen (PaO₂) with compensatory overventilation. At the same time, the P(A-a)O₂ and the P(A-a)CO₂ increased significantly (P<0.01 and P<0.05, respectively). This effect could be observed for up to 24 min after smoking. In addition, the flow of blood in the pulmonary capillaries was measured in 28 test subjects with the nitrous oxide method ( _{N 2O}) before, and 18–22 min after, smoking the first cigarette in the morning. After smoking, there was a significant (P<0.0005) fall in the _{N 2 O} by an average of 11.3%. The decrease in the R _w the fall in the PaO₂ with compensatory overventilation, the increase in P(A-a)O₂ and P(A-a)O₂ and the decrease in the _{N 2 O} are interpreted as manifestations of pronounced acute ventilation-perfusion mismatching induced by smoking.Abbreviations Cdyn dynamic compliance - Cdyn 40a dynamic compliance at 40 breaths/min - _{N 2}O pulmonary capillary blood flow measured by the N₂O method - P(A-a)a alveolararterial pressure difference - Pa arterial partial pressure - P _AOa alveolar pressure difference measured in the pressure-flow curve at zero flow - R _awa airway resistance - sGaw specific airway conductance - SVI stroke volume index - TGV thoracic gas volume - BSA body surface area     

Effect of different levels of cigarette smoking on lipid peroxidation, glutathione enzymes and paraoxonase 1 activity in healthy people

Abstract The purpose of this study was to examine the effect of different levels of cigarette smoking on lipid peroxidation, glutathione enzymes and paraoxonase 1 (PON1) activity in a healthy population. The study included 130 subjects who were classified as mild (≤10 cigarettes daily, Group I, n=30), moderate (11–20 cigarettes daily, Group II, n=35), heavy (>20 cigarettes daily, Group III, n=33) and never smokers (controls, Group IV, n=32). Malondialdehyde (MDA) levels, PON1 and erythrocyte glutathione enzyme activities were measured. MDA levels were significantly higher in smokers than never smokers (P<0.05 for Group I, P<0.001 for Group II and III). PON1 activity was significantly lower in heavy smokers (P<0.001). Glutathione peroxidase (GSH-Px) activity was significantly lower in the smokers (P<0.0001). Glutathione reductase (GR) activity was significantly higher in smokers (P<0.0001). MDA levels negatively correlated with PON1 and GSH-PX activities (P<0.01), whereas they positively correlated with GR activities (P<0.001). At every level, cigarette smoking is associated with increased lipid peroxidation and causes an impairment in antioxidant systems.     

Effect of one hour of passive cigarette smoking on lung function and airway responsiveness in adults and children with asthma

Summary We exposed 18 adults with bronchial asthma, 16 healthy controls and 11 children with asthma for 1 h either to ambient air (AA) or to environmental tobacco smoke (ETS). Exposure was performed at rest in an exposure chamber. Before and after exposure symptom scores and lung function were determined. After exposure bronchoprovocation tests with methacholine (adults) or histamine (children) were performed to determine the concentrations causing a 100% increase in SRaw (PC₁₀₀SRaw), and a 20% fall in FEV₁ (PC_2OFEV₁). In adult asthmatics mean (SD) SRaw before and after Sham was 8.8 (3.6) and 8.4 (3.6) cmH₂O · s, and mean FEV₁ (SD) was 3.18 (0.97) and 3.14 (0.9) 1, respectively. Before and after passive smoking mean SRaw (SD) was 7.5 (3.0) and 7.2 (2.7) cmH₂O · s, and mean FEV₁ (SD) was 3.31 (1.0) and 3.21 (0.88) 1, respectively. Geometric mean (SD) PC₁₀₀SRaw and PC_2OFEV₁ after Sham were 0.38 (4.5) and 0.29 (4.1) mg/ml, after passive smoking 0.39 (5.1) and 0.36 (4.7) mg/ ml, respectively. In healthy controls there was no consistent effect on the respective parameters during exposure. In children mean (SD) SRaw before and after Sham was 8.7 (3.6) and 9.0 (3.2) cmH₂O · s, and mean FEV₁ (SD) was 1.97 (0.32) and 1.98 (0.40) 1, respectively. Before and after passive smoking mean SRaw (SD) was 10.4 (5.3) and 9.4 (3.3) cmH₂O · s, and mean FEV₁ (SD) was 1.95 (0.37) and 1.94 (0.35) 1, respectively. Geometric mean (SD) PC₁₀₀SRaw and PC₂₀FEV₁ after Sham were 1.39 (3.0) and 0.70 (2.7) mg/ml, and after passive smoking 1.65 (2.5) and 0.96 (2.3) mg/ml, respectively. There were no significant differences in lung function and airway responsiveness between exposure to ambient air or ETS. The main symptoms during passive smoking were eye and nasopharyngeal irritation. Our observations suggest that in children and adults with mild to moderate bronchial asthma, 1 h of passive cigarette smoking does not cause airway obstruction or con sistent changes in bronchial responsiveness.Abbreviations AA ambient air (Sham) - ETS environmental tobacco smoke - SRaw specific airway resistance - FEV₁a one-second forced expiratory volume - PC₂₀FEV₁a provocative concentrations of histamine/methacholine to decrease FEV₁ by 20% - PC₁₀₀SRaw provocative concentrations of histamine/methacholine to increase SRaw by 100% Supported by Forschungsrat Rauchen und Gesundheit, Hamburg, Federal Republic of Germany     

慢性吸烟大鼠肺动脉平滑肌细胞钾通道Kv1.5、BKCa表达的变化

目的：观察吸烟对大鼠肺动脉平滑肌大电导的钙激活的钾通道（BK_Ca）和电压依赖性延迟整流钾通道Kv1.5蛋白和mRNA表达的影响，以阐明吸烟引起的肺血管反应性改变中钾通道表达的变化。方法：复制大鼠的慢性吸烟模型，采用HE染色、免疫组织化学染色、原位杂交等方法。结果：（1）慢性吸烟可降低大鼠肺动脉平滑肌 BK_Ca 蛋白和mRNA表达；（2）慢性吸烟可降低大鼠肺动脉平滑肌Kv1.5蛋白和mRNA表达；（3）大动脉 BK_Ca的降低程度大于Kv1.5，小动脉 BK_Ca和Kv1.5的降低程度无明显差异。结论：慢性吸烟可下调大鼠肺动脉平滑肌钾通道 BK_Ca和Kv1.5的表达水平，是导致肺血管反应性增高的机制之一。     

Longevity-associated mitochondrial DNA 5178 A/C polymorphism influences effects of cigarette smoking on serum protein fraction levels in Japanese men

Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism is reportedly associated with longevity and susceptibility to age-related diseases in Japanese individuals. We previously reported an association between mt5178 A/C polymorphism and serum protein fraction levels in healthy Japanese women. An association between habitual smoking and serum protein fraction levels has also been reported previously. The aim of this study was to examine whether mt5178 A/C polymorphism influenced the effects of habitual smoking on serum protein fraction levels in 321 healthy Japanese men. In mt5178C genotype men, alpha-1 and alpha-2 globulin levels were higher in smokers than in nonsmokers (P<0.001, and P=0.002, respectively). The influence of smoking on these globulin levels depended on cigarette consumption. However, in mt5178A genotype men, no significant difference was observed in alpha-1 or alpha-2 globulin levels between smokers and nonsmokers. These results suggest that longevity-associated mt5178 A/C polymorphism may influence the effects of cigarette smoking on serum protein fraction levels in healthy Japanese men.     

吸烟对人精子单倍染色体的影响

目的　为了探讨吸烟与精子染色体畸变的关系。方法　采用异种体外授精技术制备人精子单倍染色体 ,对比分析吸烟对精子单倍染色体的致畸变效应。结果　轻度吸烟组 (2 0支 /d)和重度吸烟组 (4 0支 /d)结构畸变精子率分别为8 31%和 13 83% ,明显高于对照组 (4 0 5 % ) (P <0 .0 5 ,P <0 .0 1)。各组间结构畸变类型以无着丝粒断片为主。在重度吸烟组检出三射体、双着丝粒体等半稳定畸变。对照组、轻度吸烟组和重度吸烟组精子染色体断裂均数分别为 0 0 4 6 ,0 0 98,0 14 2 ,差异显著 (P <0 .0 5 ,P <0 .0 1) ,各组间性别比无明显差异。结论　吸烟可导致人精子单倍染色体畸变 ,吸烟量与精子染色体畸变率的升高成正相关。     

Effect of extracellular potassium on the loss of potassium from human red blood cells treated with propranolol

The Ca⁺⁺-dependent propranolol-induced increase of K⁺ permeability of human red blood cells, well documented in previous studies, was found to depend on extracellular K⁺. This was shown by studying the passive transport of ⁸⁶Rb and the loss of bulk cellular K⁺ in both K⁺-free and K⁺-containing media. The maximal effect of propranolol was achieved with 5–10 mM K⁺ in incubation media. The external K⁺ could be substituted with TI⁺, but not with Na⁺. When added after propranolol, extracellular K⁺ failed to initiate the effect of propranolol on membrane permeability. The cell/medium distribution of permeant ²⁰⁴TI showed that the propranolol-induced increase of K⁺ permeability did not result in considerable hyperpolarization of the red blood cell membrane. The data obtained seem to be more consistent with a counter-transport model for explaining the propranolol effect than with a mechanism based on free diffusion of K⁺ through the membrane.     

某边防部队489名战士吸烟状况调查分析

目的　了解某部官兵的吸烟状况及吸烟心理。方法　采用自拟的问卷调查表 ,调查了某部 489名官兵。结果　本次调查战士的吸烟率为 5 2 .1 5 % ,而战士年龄越大、级别越高 ,吸烟率也越高 ,吸烟人数随着战士服役时间的延长则逐步增加。结论　部队战士的吸烟率较高 ,应采取相应的控烟措施 ,降低战士的吸烟率 ,使更多的战士远离香烟     

Race moderates the effects of Motivational Interviewing on smoking cessation induction

ObjectiveHealth disparities necessitate exploration of how race moderates response to smoking cessation treatment. Data from a randomized clinical trial of Motivational Interviewing (MI) for smoking cessation induction were used to explore differential treatment response between African American (AA) vs Non-Black (NB) smokers.MethodsAdult tobacco smokers (138 AA vs 66 NB) with low desire to quit were randomly assigned to four sessions of MI or health education (HE). Outcomes (e.g., quit attempts) were assessed 3- and 6-months.ResultsThere was evidence of a Race by Treatment interaction such that MI was less effective than HE in AA smokers. Mean Cohen's d for the interaction effect was −0.32 (95% CI [−0.44, −0.20]). However, the race interaction could be accounted for by controlling for baseline relationship status and communication preference (wants directive approach).ConclusionsMI may be less effective for smoking cessation induction in AA vs NB smokers when compared to another active and more directive therapy. The differential response between races may be explained by psychosocial variables.Practice implicationsMI may not be an ideal choice for all African American smokers. Patients' relationship status and preference for a directive counseling approach might explain disparities in response to MI treatment.     

Effect of different levels of cigarette smoking on lipid peroxidation, glutathione enzymes and paraoxonase 1 activity in healthy people

The purpose of this study was to examine the effect of different levels of cigarette smoking on lipid peroxidation, glutathione enzymes and paraoxonase 1 (PON1) activity in a healthy population. The study included 130 subjects who were classified as mild (20 cigarettes daily, Group III, n=33) and never smokers (controls, Group IV, n=32). Malondialdehyde (MDA) levels, PON1 and erythrocyte glutathione enzyme activities were measured. MDA levels were significantly higher in smokers than never smokers (P<0.05 for Group I, P<0.001 for Group II and III). PON1 activity was significantly lower in heavy smokers (P<0.001). Glutathione peroxidase (GSH-Px) activity was significantly lower in the smokers (P<0.0001). Glutathione reductase (GR) activity was significantly higher in smokers (P<0.0001). MDA levels negatively correlated with PON1 and GSH-PX activities (P<0.01), whereas they positively correlated with GR activities (P<0.001). At every level, cigarette smoking is associated with increased lipid peroxidation and causes an impairment in antioxidant systems.