Acute effects of cigarette smoking on pulmonary function.

INTRODUCTION: Chronic smoking related changes in pulmonary function are reflected as accelerated decrease in FEV1 although histologic changes occur in the peripheral bronchi earlier. More sensitive pulmonary function parameters might mirror those early changes and might show a dose response. METHODS: In a randomized three-period cross-over design 57 male adult conventional cigarette (CC)-smokers (age: 45.1+/-7.1 years) smoked either CC (tar:11 mg, nicotine:0.8 mg, carbon monoxide:11 mg [Federal Trade Commission (FTC)]), or used as a potential reduced-exposure product the electrically heated smoking system (EHCSS) (tar:5 mg, nicotine:0.3 mg, carbon monoxide:0.45 mg (FTC)) or did not smoke (NS). After each 3-day exposure period, hematology and exposure parameters were determined preceding body plethysmography. RESULTS: Cigarette smoke exposure was significantly (p<0.0001) higher in CC than in EHCSS and in NS: (carboxyhemoglobin: CC: 6.4+/-1.9%; EHCSS: 1.3+/-0.6%; NS: 0.5+/-0.3%; serum nicotine: CC: 18.9+/-7.4 ng/ml; EHCSS: 8.4+/-4.3 ng/ml; NS: 1.2+/-1.6 ng/ml). Significantly lower in CC than in EHCSS and NS were specific airway conductance (0.22+/-0.09; 0.25+/-0.12; 0.25+/-0.1 1/cmH(2)O x s; CC vs EHCSS: p<0.05; CC vs NS: p<0.01), forced expiratory flow 25% (7.6+/-1.7; 7.8+/-1.7; 7.9+/-1.7 L/s; CC vs EHCSS or NS: p<0.01). Thoracic gas volume (5.1+/-1; 5+/-1.1; 5+/-1.1L/min) changed insignificantly. CONCLUSION: The data indicate acute and reversible effects of cigarette smoke exposures and no-smoking on mid to small size pulmonary airways in a dose dependent manner.

Determination of two mercapturic acids related to crotonaldehyde in human urine: influence of smoking.

Crotonaldehyde, an alpha,beta-unsaturated aldehyde, and a potent alkylating agent, is present in many foods and beverages, ambient air and tobacco smoke. A previous study indicated that two metabolites, 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) and 2-carboxyl-l-methylethylmercapturic acid (CMEMA), were excreted in rat urine after subcutaneous injection of crotonaldehyde. Herein, we report the development of a method based on liquid chromatography with tandem mass spectrometry (LC-MS/MS) and deuterated analytes as internal standards, for the determination of HMPMA and CMEMA in human urine. The limits of quantification of the method were 92 and 104 ng/mL for HMPMA and CMEMA, respectively. The calibration curves for both compounds were linear up to 7500 ng/mL with R2 >0.99. It was found that cigarette smokers excreted about three to five-fold more HMPMA, and only slightly elevated amounts of CMEMA, in their urine compared to nonsmokers. In smokers, we also found significant correlations between the urinary excretion levels of HMPMA (but not CMEMA) and several markers of exposure for smoking, including the daily cigarette consumption, carbon monoxide in exhaled breath, salivary cotinine, and nicotine plus five of its major metabolites in urine. Smoking cessation or switching from smoking conventional cigarettes to experimental cigarettes with lower crotonaldehyde delivery led to significant reductions of urinary HMPMA excretion, but not CMEMA excretion. Alcohol consumption did not influence either urinary HMPMA or CMEMA excretion. We conclude that HMPMA is a potentially useful biomarker for smoking-related exposure to crotonaldehyde.

Biomarkers of exposure and potential harm in adult smokers of 3-7 mg tar yield (Federal Trade Commission) cigarettes and in adult non-smokers.

The paper reports levels of 24-h urine nicotine and five of its major metabolites (expressed as nicotine-equivalents) and blood carboxyhaemoglobin as biomarkers of exposure to particulate- and gas-phase cigarette smoke, respectively, from an exploratory pilot study of adult smokers of 3.0-6.9 mg tar delivery (Federal Trade Commission (FTC) method) cigarettes. On multiple occasions over 6 weeks, blood high-sensitivity C-reactive protein (hs-CRP), fibrinogen, HDL- and LDL-cholesterol, and 24-h urine 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) and 11-dehydro-thromboxane B2 (11-dehydro-TxB2) were also evaluated as biomarkers of potential harm. All the biomarkers examined, except for LDL-cholesterol, discriminated with high sensitivity and specificity between adult smokers and non-smokers overall. Except for HDL-cholesterol, all biomarker medians were greater in adult smokers than in non-smokers: urine nicotine-equivalents 64.514 versus < 0.034 nmol mg-1 creatinine (p<0.001), carboxyhaemoglobin 4.0 versus 0.4% saturation (p<0.001), hs-CRP 0.27 versus 0.12 mg dl-1 (p=0.05), fibrinogen 292 versus 248 mg dl-1 (p<0.001), HDL-cholesterol 46 versus 53 mg dl-1 (p=0.003), LDL-cholesterol 119 versus 109 mg dl-1 (p=0.18), urine 8-epi-PGF2alpha 1935 versus 1034 pg mg-1 creatinine (p<0.001) and urine 11-dehydro-TxB2 973 versus 710 pg mg-1 creatinine (p<0.001). All the biomarkers of exposure and most of the biomarkers of potential harm showed no time of sampling (by visit week) effect.

Evaluation of urinary 1-hydroxypyrene, S-phenylmercapturic acid, trans,trans-muconic acid, 3-methyladenine, 3-ethyladenine, 8-hydroxy-2'-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke.

The objective was to evaluate the utility of urinary 1-hydroxypyrene (1-OHP), S-phenylmercapturic acid (S-PMA), trans,trans-muconic acid (t,t-MA), 3-methyladenine (3-MeAd), 3-ethyladenine (3-EtAd), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and thioethers as biomarkers for assessing the exposure in adult smokers who switched from smoking conventional cigarettes to candidate potential reduced exposure products (PREP) or who stopped smoking. Two electrically heated smoking systems (EHCSS) were used as prototype cigarettes that have significant reductions in a number of mainstream smoke constituents as measured by smoking machines relative to those from conventional cigarettes. Urine samples were collected from a randomized, controlled, forced-switching study in which 110 adult smokers of a conventional cigarette brand (CC1) were randomly assigned to five study groups. The groups included the CC1 smoking group, a lower-tar conventional cigarette (CC2) smoking group, EHCSS1 group, EHCSS2 group and a no smoking group that were monitored for 8 days. Biomarkers were measured at baseline and day 8. The daily excretion levels of these biomarkers were compared among the groups before and after switching, and the relationships between the daily excretion levels of these biomarkers and cigarette smoking-related exposure were investigated using Pearson product-moment correlation and multiple regression analyses. It was concluded that under controlled study conditions: (1) 1-OHP, S-PMA and t,t-MA are useful biomarkers that could differentiate exposure between smoking conventional and EHCSS cigarettes or between smoking conventional cigarettes and no smoking; between S-PMA and t,t-MA, the former appeared to be more sensitive; (2) 3-MeAd could only differentiate between smoking conventional cigarettes and no smoking; the results for 3-EtAd were not conclusive because contradictory results were observed; (3) 8-OHdG had a questionable association with smoking and therefore the utility of this biomarker for smoking-related exposure could not be established; and (4) urinary excretion of thioethers as a biomarker lacked sensitivity to demonstrate a clear dose-response relationship in conventional cigarette smokers, although it could differentiate the excretion levels between those subjects who smoked a conventional cigarette and those who stopped smoking.

Bioavailability of a new liquid formulation of penicillin V (Isocillin syrup) and the influence of ethanol on bioavailability of penicillin V.

In an open, randomized four-way crossover study, four different formulations of penicillin V each containing 1.2 mega units were tested: A) new liquid formulation of Isocillin syrup, B) new liquid formulation of Isocillin syrup plus ethanol, C) commercially available penicillin V syrup containing ethanol as solubilizer and D) Isocillin film tablets. Six male and eight female healthy volunteers participated in the study. Serum concentration and urinary excretion of penicillin V were measured by HPLC or bioassay. The new liquid formulation of Isocillin syrup showed highest Cmax and AUC values. Correspondingly, urinary excretion of the new liquid formulation of Isocillin syrup was highest (38% of the given dose). Mean pharmacokinetic data of the new liquid formulation of Isocillin syrup were: tmax (h) = 0.81, Cmax (mg/l) = 9.92, AUC0-8h (mgh/l) = 13.67, lambda z (h) = 0.68, Cltot/f (ml/min) = 964. Ethanol (4.6%) had no absorption-enhancing effects. From a clinical point of view, all four formulations investigated in this trial showed serum concentrations well above bactericidal concentrations (greater than 1 mg/l) for more than 3 h. Although the interindividual variability of serum levels was high, the levels observed would guarantee therapeutic efficacy against penicillin sensitive bacterial strains.

The concentration of prealbumin in cerebrospinal fluid (CSF), indicator of CSF circulation disorders.

Prealbumin, was determined in serum, lumbar and ventricular cerebrospinal fluid (CSF) and compared with albumin and IgG. The measured concentrations of prealbumin in the CSF indicate that there are two sources of prealbumin: a minor fraction enters the CSF via the blood-cerebrospinal fluid (B-CSF) barrier like albumin, and the major fraction enters the CSF at the ventricles, probably during production of the CSF in the ventricles. The two fractions can be calculated from the CSF concentration of prealbumin, serum prealbumin and the concentration gradient (serum/CSF) of albumin. The B-CSF barrier-independent prealbumin can be used as an indicator of CSF circulation. This was proved by the investigation of several special cases.