Ascorbic acid content and accumulation by alveolar macrophages from cigarette smokers and nonsmokers

The lung is at risk for injury from inhaled oxidants, including components of cigarette smoke; therefore, maintaining a chemical antioxidant defense would be advantageous. The potential for ascorbic acid to assume this protective role was investigated by comparing the total ascorbate content of alveolar macrophages obtained from human smokers and nonsmokers, from hamsters that were exposed to cigarette smoke for 4 to 6 weeks, and from a control group of unexposed hamsters. The abilities of alveolar macrophages from these four sources to accumulate 14C-labeled ascorbic acid and dehydroascorbate were also compared. The total ascorbate content in hamster macrophages was 19.5 +/- 1.7 and 44.3 +/- 2.8 nmol/10(7) cells for nonsmokers and smokers, (n = 5) and 73.8 +/- 13.1 nmol/10(7) cells (n = 13, p less than 0.1) for nonsmokers and smokers, respectively. In both humans and hamsters, the rates of accumulation of ascorbic acid and dehydroascorbate were significantly greater (p less than 0.05) for alveolar macrophages from smokers compared with nonsmokers of the same species. After internalization, greater than or equal to 70% of the dehydroascorbate was reduced to ascorbic acid by alveolar macrophages from nonsmokers and smokers of both species. An aqueous extract of cigarette smoke oxidized significantly more ascorbic acid to dehydroascorbate in vitro than a comparable volume of phosphate-buffered saline solution without smoke. The increased content of total ascorbate in alveolar macrophages from smokers and their enhanced ability to accumulate ascorbic acid and dehydroascorbate in vitro may reflect protective utilization of ascorbic acid under conditions of increased oxidant stress, compared with nonsmokers. In addition, alveolar macrophages may internalize dehydroascorbate that has been generated by oxidants in the alveolar space and reduce it to ascorbic acid so it can be reused as an antioxidant.     

Facilitated nitration and oxidation of LDL in cigarette smokers

BACKGROUND: Cigarette smoking increases the risk of developing atherosclerosis and ischaemic heart disease. Smoking-induced oxidative stress is considered to favour oxidation of low-density lipoprotein (LDL) and subsequently promotes the atherogenic process. We investigated whether peroxynitrite, a reaction product of cigarette smoke, is involved in facilitated oxidation of LDL in smokers. MATERIALS AND METHODS: Plasma LDL was obtained from 10 healthy asymptomatic cigarette smokers and 10 healthy nonsmokers. The state of enhanced oxidative stress in the plasma was assessed by LDL subfraction assay using anion-exchange high-performance liquid chromatography (AE-HPLC) and measurements of thiobarbituric acid-reactive substances (TBARS), 8-hydroxydeoxyguanosine (8-OHdG), vitamin E, 3-nitrotyrosine and 3-chlorotyrosine. RESULTS: Smokers showed a significantly higher level of TBARS and 8-OHdG as well as a significantly lower level of vitamin E than nonsmokers, even after stopping smoking for 10 h or more. The LDL subfraction assay demonstrated an increase in oxidatively modified LDL, as expressed by lower levels of LDL1 and higher levels of LDL2. The 3-nitrotyrosine levels in apolipoprotein B in LDL were significantly higher in smokers than nonsmokers, while the 3-chlorotyrosine levels remained unchanged. In addition, these changes observed in the smokers were further accelerated within 30 min after resumption of cigarette smoking when compared with the levels before smoking resumption. CONCLUSION: The present study suggests that peroxynitrite plays a significant role in oxidative modification of plasma LDL induced by cigarette smoking.     

Use of a noninvasive pulse CO-oximeter to measure blood carboxyhemoglobin levels in bingo players

BACKGROUND: Though smokers are known to have elevated blood carboxyhemoglobin (COHb), due to inhalation of carbon monoxide (CO) in cigarette smoke, limited data exist regarding COHb levels in nonsmokers exposed to secondhand smoke. METHODS: COHb was measured using a new noninvasive pulse CO-oximeter (Rad-57, Masimo, Irvine, California) in 38 subjects entering a bingo hall where smoking was allowed, then again as they exited 3 hours later. RESULTS: The mean +/- SD baseline COHb for the entire group was 3.3 +/- 1.8%, for the 23 nonsmokers it was 2.2 +/- 0.7%, and for the 15 smokers it was 4.9 +/- 1.9%. The nonsmokers' mean COHb was unchanged, at 2.2 +/- 0.8%, whereas the smokers' mean COHb fell to 3.2 +/- 1.9%. CONCLUSIONS: The nonsmokers were not significantly exposed to CO from secondhand smoke in the setting we tested. The smokers probably consumed fewer cigarettes while playing bingo than they did prior to arrival. The Rad-57 pulse CO-oximeter is easy to use in the ambulatory setting.     

Decreased leukotriene B4 synthesis in smokers' alveolar macrophages in vitro

Recent studies have shown that alveolar macrophages (AM) are able to release leukotrienes (LTs). Since cigarette smoking inhibits the cyclooxygenase pathway of arachidonic acid metabolism in the AM, we evaluated the LT production by AM from smokers and nonsmokers. AM were obtained from 35 volunteers, 16 nonsmokers, and 19 smokers. The cells were incubated under various conditions including stimulation with 30 microM arachidonic acid, 2 microM ionophore A23187, or both. Each experiment was performed in parallel using cells from a smoker and a nonsmoker. Lipoxygenase products were analyzed by reverse-phase high performance liquid chromatography. After stimulation, nonsmokers' AM produced LTB4 and 5-hydroxy-eicosatetraenoic acid (5-HETE). In incubations of AM with arachidonic acid and ionophore, the amounts of products formed were: LTB4, 317 +/- 56 pmol/10(6) cells and 5-HETE, 1,079 +/- 254, mean +/- SEM. No metabolites were generated under control conditions (no stimulation). In all incubations performed, the peptido-LTs (LTC4, LTD4, and LTE4) were undetectable. In comparison with AM from nonsmokers, those from smokers showed a 80-90% reduction of 5-HETE and LTB4 synthesis (P less than 0.05 to P less than 0.001 according to stimulatory conditions). This defective lipoxygenase metabolite production in AM from smokers was observed over a wide range of stimuli concentrations and incubation times; AM from smokers also had lower levels of intracellular (esterified) 5-HETE than nonsmokers' AM. We also studied blood polymorphonuclear leukocytes (PMNL) and no difference in the synthesis of 5-lipoxygenase products in these cells was noticed between smokers and nonsmokers. These data show that cigarette smoking causes a profound inhibition of the 5-lipoxygenase pathway in AM but not in blood PMNL.     

Transdermal nicotine mimics the smoking-induced endothelial dysfunction

BACKGROUND: Cigarette smoking is a major risk factor for coronary artery disease and causes endothelial dysfunction, perhaps by decreasing the availability of nitric oxide availability in arteries and veins. Nicotine in cigarette smoke may be responsible for this impaired endothelial response. METHODS: We studied nine healthy nonsmokers and 12 healthy mild to moderate smokers by use of the dorsal hand vein compliance technique. Dose-response curves to bradykinin and sodium nitroprusside were obtained to test the endothelium-dependent and endothelium-independent vasorelaxation before and during the use of a nicotine (21 mg) patch. Mean arterial blood pressure and heart rate were measured beat-to-beat during the 4-hour study and serial blood samples were drawn to assay plasma thromboxane B2 levels. RESULTS: Transdermal nicotine reduced the venous responsiveness to bradykinin in nonsmokers (Emax = 88.0% +/- 17.9% and 54.3% +/- 14.9%, respectively, before and after the nicotine patch; P < .05); the latter response was similar to that in smokers (Emax = 56.3% +/- 16.6%). Sodium nitroprusside-induced venodilation was unaltered. Mean arterial blood pressure increased in both smokers and nonsmokers. Transdermal nicotine increased the plasma thromboxane B2 concentrations only among nonsmokers. CONCLUSION: These findings indicate that nicotine can have a major role in the impaired endothelial function in smokers. The results probably also reflect what occurs in arterial beds because the nicotine patches increased the mean arterial blood pressure in both smokers and nonsmokers.     

Cigarette smoking and theophylline metabolism: effects of phenytoin

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 +/- 2.0 micrograms/ml) and smokers (11.5 +/- 0.9 micrograms/ml). Control theophylline elimination half-life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half-life (26.8% +/- 5.6% in smokers and 25.8% +/- 3.5% in nonsmokers) and clearance (48.0% +/- 10.1% in smokers and 39.7% +/- 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.     

The effect of cigarette smoking on salivation and esophageal acid clearance

To further define the influence of cigarette smoking on the pathophysiology of gastroesophageal reflux disease, studies were done to evaluate acid clearance in the esophagus and the salivary titratable base secretion of chronic smokers as compared to those of nonsmokers, and to ascertain the acute effects of smoking on these variables. Eight nonsmoking volunteers and 16 cigarette smokers without symptoms of gastroesophageal reflux disease were studied. All studies were initiated after a 6-hour fast, with the smokers also having refrained from smoking. Of the 16 smokers half smoked three cigarettes in the course of the experiments and half did not smoke. The immediate effects of cigarette smoking were a prolongation of the acid clearance time and a diminution of the secretion of salivary titratable base. However, both of these effects were overshadowed by greater baseline differences between the populations of smokers and nonsmokers. As a population the smokers had only 60% of the titratable base secretion of nonsmokers and acid clearance times that were 50% longer than those of nonsmokers. These effects were presumably long-lasting effects of cigarette smoking, although the duration of the effect was not defined. The observed differences in acid clearance are most likely the result of diminished salivary base secretion, since good correlation existed between these parameters.     

Oral nitric oxide during plaque deposition

BACKGROUND: Nitric oxide (NO) is one of the most powerful antibacterial compounds. We investigated if NO oral production increases during dental plaque deposition. MATERIALS AND METHODS: Oral NO and salivary nitrite were measured in 31 healthy subjects - 11 smokers and 20 nonsmokers - with natural healthy teeth, in the morning after tooth cleaning (baseline), after withdrawal of oral hygiene for 24 h and again after tooth cleaning. RESULTS: NO and nitrite were significantly higher during plaque deposition than with clean teeth: mean NO values +/- SEM were 44.3 +/- 4.9 parts per billion (ppb) at baseline, 58.8 +/- 3.7 ppb with plaque and 43.6 +/- 3.7 ppb after tooth cleaning, P < 0.05; nitrite values were 32.9 +/- 5.5 microm at baseline, 66.4 +/- 8.2 with plaque and 37.5 +/- 5.5 after tooth cleaning, P < 0.01. During plaque deposition, oral NO was significantly directly related to salivary nitrite (r = 0.497, P = 0.002) and so were their respective changes after tooth cleaning (r = 0.577, P < 0.001). Smokers had significantly lower oral NO than nonsmokers, with both clean and dirty teeth (P < 0.001), and higher bacteria counts in the plaque (38.6 +/- 11.5 vs. 19.9 +/- 2.3, P = 0.046). CONCLUSIONS: Oral NO production increases during de novo deposition of dental plaque. NO might be an early host defence mechanism against bacterial proliferation in the plaque. Such a mechanism is inhibited by cigarette smoking.     

Cigarette smoking and plasma total homocysteine levels in young adults with type 1 diabetes

OBJECTIVE: The purposes of this study were to compare plasma total homocysteine (tHcy) levels, a recognized cardiovascular risk factor, in nondiabetic subjects and type 1 diabetic patients, and to evaluate whether chronic cigarette smoking had a deleterious effect on plasma tHcy levels in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Plasma tHcy concentrations were measured in 60 young type 1 diabetic patients without clinical evidence of macroangiopathy and in 30 healthy control subjects who were matched for age, sex, BMI, and smoking habit. RESULTS: Plasma tHcy levels were significantly higher in type 1 diabetic patients than in control subjects (12.5 +/- 4.8 vs. 10.3 +/- 2.2 micromol/l, P = 0.01). After stratification by smoking status, diabetic smokers had values for age, sex, BMI, lipids, creatinine, blood pressure, glycometabolic control, diabetes duration, and microvascular complications that were superimposable on their nonsmoking counterparts. Nevertheless, plasma tHcy levels were markedly elevated in diabetic smokers versus nonsmokers (15.5 +/- 5.7 vs. 10.6 +/- 3 pmol/l, P < 0.0001) in a dose-dependent fashion (P < 0.0001, by analysis of variance when subjects were categorized for the number of cigarettes smoked daily). CONCLUSIONS: Chronic cigarette smoking seems to adversely affect plasma tHcy levels in young adults with type 1 diabetes.     

Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men

The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.     

Haptoglobin 2-2 phenotype is associated with decreased ferroxidase activity in smokers

BACKGROUND: Cigarette smoking and the inheritance of Hp 2-2 phenotype have been separately linked to cardiovascular disease. In this study, the combined effects of smoking and the presence of Hp 2-2 type on predisposition to cardiovascular disease were investigated. METHODS: Fasting blood specimens were collected from 489 Jordanian males (228 smokers and 261 nonsmokers). Haptoglobin phenotype was determined by electrophoresis, and lipid profile and ferroxidase activity were determined by spectrophotometric methods. RESULTS: The results show that, irrespective of Hp type, total- and LDL-cholesterol levels were significantly higher in smokers compared with nonsmokers, while levels of HDL-cholesterol and ferroxidase activity were lower in smokers. There was no significant difference between the three Hp types in nonsmokers regarding the lipid profile and ferroxidase activity. In the smokers group, however, serum ferroxidase activity was significantly lower in individuals with Hp 2-2 type compared with that in Hp 1-1 and Hp 2-1 smoker individuals. Smokers with the Hp 2-2 type have significantly higher levels of total- and LDL-cholesterol and lower HDL-cholesterol levels compared with that in nonsmokers expressing the same Hp type. CONCLUSION: These findings demonstrate that smokers with Hp 2-2 phenotype have a decreased antioxidant capacity suggesting that smoking coupled with the inheritance of an Hp-2-2 type predispose to more oxidative stress and cardiovascular disease.     

Circulating concentrations of C-reactive protein and total sialic acid in tobacco smokers remain unchanged following one year of validated smoking cessation

BACKGROUND: Elevated plasma concentrations of C-reactive protein (CRP) and total sialic acid (TSA) have been associated with increased cardiovascular risk. Additionally, levels of both CRP and TSA have been reported to be significantly elevated in smokers. However, it is not clear if the raised TSA and CRP levels noted in smokers are directly attributable to the smoking experience, or if they may be elevated due to a secondary mechanism(s), such as smoking-induced tissue inflammation. SUBJECTS AND METHODS: We measured the plasma concentration of CRP and TSA in a group of smokers at baseline and following one year of validated smoking cessation (n = 30) and in a control group of tobacco users who continued to smoke over the year (n = 30). RESULTS: The baseline concentration of TSA and CRP was 67.2 mg dL(-1) and 1.91 mg L(-1), respectively (n = 60). No significant dose-dependent relationship was noted between baseline CRP or TSA concentration and either plasma cotinine, expired-air CO or daily cigarette consumption. There was no difference in the mean change in CRP level in the quitters over one year (- 0.2 mg L(-1)) compared to the continuing smokers (+ 0.5 mg L(-1)), P = 0.80, or in the change in concentration of TSA in the quitters (- 2.7 mg dL(-1)) compared to the continuing smokers (+ 0.4 mg dL(-1)), P = 0.26. CONCLUSIONS: As the circulating concentrations of both CRP and TSA remain unchanged following one year of smoking cessation, these results would suggest that the elevated levels noted in smokers are not directly attributable to tobacco use and are more likely to be elevated due to a secondary process that is yet to be established.     

Complex assessment of nicotine dependence using questionnaires and measurement of carbon oxide concentration in exhaled air

AIM: To study nicotine dependence (ND) basing on special questionnaires and measurement of CO concentrations in the exhaled air. MATERIAL AND METHODS: 350 smokers (318 males and 32 females) aged 20-57 years (mean age 37.1 +/- 7.3 years) were studied. ND was assessed by Fagerstrom test (FT), motivation to smoke and to quit tests, smoking history and exhaled CO measurement. In addition, respiratory complaints and ventilation parameters such as peak expiratory flow (PEF) and forced expiratory volume per 1 sec (FEV1) were measured. RESULTS: Mean daily cigarette number was 14.2 +/- 7.3; smoking duration 16.3 +/- 7.8 years and smokers index 170.9 +/- 87.8. Smoking women differed from smoking men in ND, PEF% and FEV1% decline as well as CO level. Exhaled CO was 21.1 +/- 9.5 ppm, on the average, corresponding to moderate dependence. ND and daily cigarette number produced a direct impact on the exhaled CO level. FT findings directly correlated with the number of daily cigarettes and CO level (mean 3.2 +/- 2.3). Among motivation to smoke factors was the demand to release tension. CONCLUSION: ND varies considerably among smokers by severity. Smoking men and women differ considerably by ND. Along with dependence tests, exhaled CO measurement provides objective verification of ND.     

Effects of cigarette smoking on short-term variability of blood pressure in smoking and non smoking healthy volunteers

The present trial was planned to study the effects of smoking on short-term variability of blood pressure and on haemodynamic parameters after an overnight cessation and after one day of repeated smoking in healthy cigarette smoking volunteers, compared to a control group of non-smokers who were not asked to smoke. 40 healthy male volunteers, 20 smokers and 20 non-smokers, participated in an open study with two period of measurements over a single day (morning and afternoon). Blood pressure and heart rate were measured using standard and finger recordings over 6 min before and 10 min after smoking one cigarette (in smokers only). During the two periods, smokers were asked to smoke 4 cm of a cigarette containing 1 mg of nicotine in 2 min, and a blood sample was taken for a plasma nicotine assay. In the smoking group, smoking the first cigarette of the day caused a significant increase of systolic blood pressure (+7%), diastolic blood pressure (+10%) and heart rate (+25%). The blood pressure variability in the frequency range of the Mayer waves (66-129 mHz) was increased after an overnight cessation of smoking in the smoking group in comparison to the non-smokers, and decreased significantly after the first cigarette of the day (7.1 +/- 4.0 to 3.2 +/- 1.8 mmHg2; P < 0.01). The changes observed in the afternoon after continuous smoking were significantly less important (3.8 +/- 1.9 to 3.2 +/- 1.9 mmHg2; NS). In the non-smoking group, the different parameters remained stable between the different measurements. These results suggest that an overnight cessation of smoking in smoking subjects is associated with a increase in sympathetic activity to the vascular system in the morning, which is released by smoking the first cigarette. This effect of smoking is reduced in the afternoon after a continuous nicotinic impregnation.     

Deficiency of vitamin E in the alveolar fluid of cigarette smokers. Influence on alveolar macrophage cytotoxicity.

Cigarette smoking produces oxidant-mediated changes in the lung important to the pathogenesis of emphysema. Since vitamin E can neutralize reactive oxygen species and prevent peroxidation of unsaturated lipids, it may constitute an important component of the lung's defense against oxidant injury. To better characterize the antioxidant protective role of vitamin E, young asymptomatic smokers and nonsmokers were evaluated by bronchoalveolar lavage before and immediately after a 3-wk course of oral vitamin E (2,400 IU/d). Smoker alveolar fluid at baseline was relatively deficient in vitamin E compared with nonsmoker fluid (3.1 +/- 0.7 ng/ml vs. 20.7 +/- 2.4 ng/ml, P less than 0.005). Although smoker alveolar fluid vitamin E levels increased to 9.3 +/- 2.3 ng/ml after supplementation, the levels remained significantly lower than nonsmoker baseline levels (P less than 0.01). This deficiency was explained, in part, by the increased oxidative metabolism of vitamin E to the quinone form in the lungs of smokers compared with nonsmokers. Although the significance of a lower concentration of alveolar fluid vitamin E is unclear, it may compromise the antioxidant protection afforded by the alveolar fluid as it coats the lung's epithelial surface. The protective role of vitamin E was assessed by cytotoxicity experiments, which demonstrated that the killing of normal rat lung parenchymal cells by smoker alveolar macrophages was inversely related to the vitamin E content of the parenchymal cells. These findings suggest that vitamin E may be an important lower respiratory tract antioxidant, and that the deficiency seen in young smokers may predispose them to an enhanced oxidant attack on their lung parenchymal cells.     

Effects of passive smoking on theophylline clearance

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.     

Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706

PURPOSE: We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers. METHODS: Six healthy nonsmokers and six smokers inhaled 50 to 400 mg FK706 in two different doses. Series of plasma concentrations of the SSS form of FK706 (pharmacologically active epimer) were analyzed model dependently and independently. Pharmacokinetic parameters obtained from each group were compared after standardization by doses. RESULTS: The plasma concentration-time curve of inhaled FK706 was apparently different between smokers and nonsmokers. The maximum plasma concentrations (Cmax) were significantly higher in the smokers than in the nonsmokers (smokers, 1.47 +/- 0.62 ng/mL/mg; nonsmokers, 0.49 +/- 0.14 ng/mL/mg [mean +/- SD; P < .01]). The time to reach Cmax (tmax) and elimination half-life (t1/2) were statistically smaller in the smokers compared with the tmax and elimination t1/2 in the nonsmokers (tmax in smokers, 0.44 +/- 0.27 hours; tmax in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t1/2 in smokers, 1.23 +/- 0.40 hours; t1/2 in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area under the plasma concentration-time curve and plasma clearance were not significantly different between the two groups. Model-dependent pharmacokinetic analysis, assuming a flip-flop model, revealed that the absorption rate constant (ka) was about 10 times greater in smokers than the ka in nonsmokers. CONCLUSION: Significant increases of Cmax and ka and reductions of tmax and elimination t1/2 of the inhaled FK706 were observed in the healthy smokers, suggesting that the smoking habit accelerates the drug absorption after inhalation. These results suggest that we should pay attention to the drug-related adverse events caused by smoking, especially when the drug has a narrow therapeutic range.     

Risk factors for emphysema. Cigarette smoking is associated with a reduction in the association rate constant of lung alpha 1-antitrypsin for neutrophil elastase.

The increased risk of developing emphysema among individuals who smoke cigarettes and who have normal levels of alpha 1-antitrypsin (alpha 1AT) is hypothesized to result from a decrease in the antineutrophil elastase capacity of the lower respiratory tract alpha 1AT of smokers compared with nonsmokers. To evaluate this hypothesis we compared the time-dependent kinetics of the inhibition of neutrophil elastase by lung alpha 1AT from healthy, young cigarette smokers (n = 8) and nonsmokers (n = 12). alpha 1-antitrypsin was purified from lavage fluid using affinity and molecular sieve chromatography, and the association rate constant (k assoc) for neutrophil elastase quantified. The k assoc of smoker plasma alpha 1AT (9.5 +/- 0.5 X 10(6) M-1s-1) was similar to that of nonsmoker plasma (9.3 +/- 0.7 X 10(6) M-1s-1, P greater than 0.5). In marked contrast, the k assoc of smoker lower respiratory tract alpha 1AT was significantly lower than that of nonsmoker alpha 1AT (6.5 +/- 0.4 X 10(6) M-1s-1 vs. 8.1 +/- 0.5 X 10(6) M-1s-1, P less than 0.01). Furthermore, the smoker lower respiratory tract alpha 1AT k assoc was significantly less than that of autologous plasma (P less than 0.01). When considered in the context of the concentration of alpha 1AT in the lower respiratory tract epithelial lining fluid, the inhibition time for neutrophil elastase of smoker lung alpha 1AT was twofold greater than that of nonsmoker lung alpha 1AT (smoker: 0.34 +/- 0.05 s vs. nonsmoker: 0.17 +/- 0.05 s, P less than 0.01). Consequently, for concentrations of alpha 1AT in the lower respiratory tract it takes twice as long for an equivalent amount of neutrophil elastase to be inhibited in the smoker's lung compared with the nonsmoker's lung. These observations support the concept that cigarette smoking is associated with a decrease in the lower respiratory tract neutrophil elastase inhibitory capacity, thus increasing the vulnerability of the lung to elastolytic destruction and thereby increasing the risk for the development of emphysema.     

Disposition of nicotine and eight metabolites in smokers and nonsmokers: identification in smokers of two metabolites that are longer lived than cotinine

The disposition of a single intravenous dose of 14C-nicotine was investigated in six cigarette smokers and six nonsmokers. Plasma and urinary elimination of both nicotine and cotinine was faster in smokers than in nonsmokers. In the urine of both smokers and nonsmokers, we identified nicotine and eight metabolites, including two new metabolites: metabolite A (3-hydroxycotinine glucuronide) and metabolite G (demethylcotinine delta 2',3'-enamine). Metabolites A and G were of particular interest because, in smokers, they both persisted longer than cotinine. This property renders them more sensitive than cotinine as potential indicators of passive exposure to cigarette smoke.     

Smoking,von Willebrand factor and ADAMTS-13 in healthy males

While von Willebrand factor (vWF) has been reported to be elevated in smokers, there are no reports on the effects of smoking on its cleaving protease ADAMTS-13, particularly in subjects of Arab ethnicity. This study was conducted to determine the effects of smoking on vWF and ADAMTS-13 antigen and activity levels in Arab males. Venous blood samples from 80 smoking (at rest) and 80 non-smoking healthy males were collected after asking subjects to fast and refrain from smoking for 8 hours. Similar sampling was done for 40 smokers (acute smokers), who were asked to smoke one cigarette immediately before blood collection. Plasma was used to measure ADAMTS-13 antigen and activity levels, as well as vWF antigen and collagen binding activity levels using commercial ELISA kits. Compared to non-smokers, ADAMTS-13 and vWF activities were significantly lower in smokers at rest (p < 0.05). Acute smokers had significantly higher levels of vWF activity and ADAMTS-13 antigen and activity levels (p < 0.01), compared to smokers at rest. Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules. If not followed by a subsequent smoke, the activities of both proteins subside. It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers (at rest) compared to nonsmokers who do not experience a similar (repeated) injury to the endothelium.