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PubMed2005

Accuracy of a semiquantitative method for Dermal Exposure Assessment (DREAM).

BACKGROUND: The authors recently developed a Dermal Exposure Assessment Method (DREAM), an observational semiquantitative method to assess dermal exposures by systematically evaluating exposure determinants using pre-assigned default values. AIM: To explore the accuracy of the DREAM method by comparing its estimates with quantitative dermal exposure measurements in several occupational settings. METHODS: Occupational hygienists observed workers performing a certain task, whose exposure to chemical agents on skin or clothing was measured quantitatively simultaneously, and filled in the DREAM questionnaire. DREAM estimates were compared with measurement data by estimating Spearman correlation coefficients for each task and for individual observations. In addition, mixed linear regression models were used to study the effect of DREAM estimates on the variability in measured exposures between tasks, between workers, and from day to day. RESULTS: For skin exposures, spearman correlation coefficients for individual observations ranged from 0.19 to 0.82. DREAM estimates for exposure levels on hands and forearms showed a fixed effect between and within surveys, explaining mainly between-task variance. In general, exposure levels on clothing layer were only predicted in a meaningful way by detailed DREAM estimates, which comprised detailed information on the concentration of the agent in the formulation to which exposure occurred. CONCLUSIONS: The authors expect that the DREAM method can be successfully applied for semiquantitative dermal exposure assessment in epidemiological and occupational hygiene surveys of groups of workers with considerable contrast in dermal exposure levels (variability between groups >1.0). For surveys with less contrasting exposure levels, quantitative dermal exposure measurements are preferable.

Clothing↗
PubMed2005

Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex.

BACKGROUND: Inhaled corticosteroids (ICS) provide short term benefits in asthma but the long term effects are still unknown. METHODS: 281 patients diagnosed with moderate to severe asthma in 1963-75 were re-examined in 1991-9. Information was collected on forced expiratory volume in 1 second (FEV(1)), bronchial hyperresponsiveness, atopy, smoking, use and dosage of oral and ICS. Patients were included in the analyses if they had at least three FEV(1) measurements during two consecutive years after the age of 30 and used ICS during follow up. RESULTS: Analyses were performed on 122 patients. During a median follow up period of 23 years, 71 men and 51 women had on average 37 and 40 individual FEV(1) measurements, respectively. Linear mixed effect models showed that men had a mean annual decline in FEV(1) of 20.6 ml/year less after ICS initiation than before (p = 0.011), and in women the decline in FEV(1) was 3.2 ml/year less (p = 0.73). In individuals with <5 pack years of smoking the decline in FEV(1) was 36.8 ml/year less after ICS institution in men (p = 0.0097) and 0.8 ml/year less in women (p = 0.94), the difference between the sexes being significant (p = 0.045). These effects were not observed in those with > or =5 pack years smoking. A higher daily dose of ICS was associated with a smaller decline in FEV(1) in men (p = 0.006), an effect not observed in women. CONCLUSION: Treatment with ICS in adult patients with moderate to severe asthma was associated with a reduction in the decline in FEV(1) over a 23 year follow up period in men who had smoked <5 pack years. This effect was dose dependent and was not present in women or in men with > or =5 pack years of smoking at follow up. The lack of effect of ICS on the decline in FEV(1) in women needs further study.

Administration, Inhalation↗
PubMed2004

Quantification of internal carotid artery stenosis with duplex US: comparative analysis of different flow velocity criteria.

PURPOSE: To compare 13 previously published sets of duplex ultrasonographic (US) criteria with the US criteria used at the authors' institution in terms of agreement with carotid artery angiographic results. MATERIALS AND METHODS: The authors studied 1,006 carotid arteries in 503 patients at duplex US and angiography. The degree of stenosis was determined by using duplex flow US velocities and applying 13 previously published sets of criteria and the criteria used at the authors' institution. Two independent observers evaluated the angiograms according to North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. kappa statistics, sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and generalized linear mixed regression models were used to assess agreement between duplex US and angiographic findings. RESULTS: Stenoses of 0%-29%, 30%-49%, 50%-69%, 70%-99%, and 100% could be differentiated with 73% overall agreement between duplex US and angiographic findings according to flow velocity criteria (kappa = 0.57; 95% confidence interval [CI]: 0.54, 0.60); however, with duplex US, the angiographic degree of stenosis tended to be overestimated. In the differentiation of stenoses of less than 70%, only 45% agreement (kappa = 0.26; 95% CI: 0.23, 0.29) was observed, whereas in the differentiation of high-grade (> or =70%) stenoses, 96% agreement was observed (kappa = 0.85; 95% CI: 0.83, 0.87). The PPV and NPV for the identification of 70%-99% angiographic stenosis were 69% and 98%, respectively, with use of the most sensitive duplex US criteria. CONCLUSION: Duplex US is an excellent examination to screen for high-grade carotid artery stenosis; however, it tends to lead to an overestimation of the degree of stenosis. Exclusion of 70%-99% angiographic stenosis can be achieved with a sensitivity of up to 98%.

Aged↗
PubMed2005

Prenatal and perinatal correlates of adult mammographic breast density.

BACKGROUND: Adult mammographic percent density is one of the strongest known risk factors for breast cancer. In utero exposure to high levels of endogenous estrogens (or other pregnancy hormones) has been hypothesized to increase breast cancer risk in later life. We examined the hypothesis that those factors associated with higher levels of estrogen during pregnancy or shortly after birth are associated with higher mammographic breast density in adulthood. METHODS: We analyzed data on 1,893 women from 360 families in the Minnesota Breast Cancer Family Study who had screening mammograms, risk factor data, over age 40, and no history of breast cancer. Prenatal and perinatal risk factor data were ascertained using a mailed questionnaire. Mammographic percent density and dense area were estimated from the mediolateral oblique view using Cumulus, a computer-assisted thresholding program. Linear mixed effects models incorporating familial correlation were used to assess the association of risk factors with percent density, adjusting for age, weight, and other breast cancer risk factors, all at time of mammography. RESULTS: The mean age at mammography was 60.4 years (range, 40-91 years), and 76% were postmenopausal. Among postmenopausal women, there was a positive association of birthweight with percent density (P trend <0.01), with an adjusted mean percent density of 17.1% for <2.95 kg versus 21.0% for > or = 3.75 kg. There were suggestive positive associations with gestational age (mean percent density of 16.7% for preterm birth, 20.2% for term birth, and 23.0% for late birth; P trend = 0.07), maternal eclampsia/preeclampsia (mean percent density of 19.9% for no and 14.6% for yes; P = 0.16), and being breast-fed as an infant (mean percent density of 18.2% for never and 20.0% for ever; P = 0.08). There was no association of percent density with maternal age, birth order, maternal use of alcohol or cigarettes, or neonatal jaundice. Except for being breast-fed, these associations showed similar but attenuated trends among premenopausal women, although none were statistically significant. The results for dense area paralleled the percent density results. The associations of gestational age and being breast-fed as an infant with percent density attenuated when included in the same model as birthweight. CONCLUSIONS: Birthweight was positively associated with mammographic breast density and dense area among postmenopausal women and more weakly among premenopausal women, suggesting that it may be a marker of this early life exposure. These results offer some support to the hypothesis that pregnancy estrogens or other pregnancy changes may play a role in breast cancer etiology, and suggest that these factors may act in part through long-term effects on breast density.

Adult↗
PubMed2006

Gender-specific protective effect of hemoglobin on arsenic-induced skin lesions.

Chronic arsenic poisoning remains a public health crisis in Bangladesh. As arsenic has been shown to bind to human hemoglobin (Hb), hematologic mechanisms may play a role in the pathway through which arsenic exerts its toxicity. Two separate studies, a case-control and a cohort, were conducted to investigate the role of Hb in the development of arsenic-induced skin lesions. In the first, conditional logistic regression was used to investigate the effect of Hb on skin lesions among 900 case-control pairs from Pabna, Bangladesh, in which individuals were matched on gender, age, and location. In the second, mixed linear regression models were used to examine the association between toenail arsenic, urinary arsenic, and Hb within a cohort of 184 individuals from 50 families in the same region who did not have arsenic-induced skin lesions. Hb was significantly associated with skin lesions but this association was gender specific. In males, a 40% reduction in the odds of skin lesions occurred for every 1 g/dL increase in Hb (odds ratio, 0.60; 95% confidence interval, 0.49-0.73). No effect was observed for females (odds ratio, 1.16; 95% confidence interval, 0.92-1.46). In the cohort of 184 individuals, no associations between toenail arsenic or urinary arsenic species and Hb levels were observed. Low Hb levels may exacerbate the detrimental health effects of chronic arsenic poisoning. Whereas providing clean water remains the optimal solution to Bangladesh's problem of arsenic poisoning, improving nutrition and reducing iron-deficiency anemia may ameliorate negative health effects, such as skin lesions in individuals who have been exposed.

Arsenic↗
PubMed1999

An individual bioequivalence approach to compare the intrasubject variability of two ciclosporin formulations, SangCya and Neoral.

A novel bioequivalence testing approach was used to determine intrasubject variability and switchability of two ciclosporin formulations, SangCya (test) and Neoral (reference). Twenty healthy volunteers were enrolled into a single-dose, randomized, open-label, 4-period, 2-sequence study with a crossover replicate design. Subject-by-formulation interaction variances were compared using a mixed effects linear model. Intrasubject variability for ln AUC(0-infinity) and ln C(max) of SangCya and Neoral were not significantly different. The 95% confidence intervals of the intrasubject variability of AUC(0-infinity) (0.94) and C(max) (1.28) as determined using the bootstrap nonparametric percentile method (n = 2,000) were below the individual bioequivalence limit estimated at 2.25. We concluded equivalent intrasubject variability of ciclosporin pharmacokinetics and switchability between SangCya and Neoral.

Adult↗
PubMed2004

Sex differences in the relation between body mass index and asthma and atopy in a birth cohort.

RATIONALE: Several studies have identified an association between asthma and obesity in women. It remains unclear if this association is due to genuine asthma or to symptoms caused by overweight, at what age the association develops, and whether it is confined to females. OBJECTIVE: To explore the relations between body mass index, asthma, and atopy in a birth cohort of approximately 1,000 individuals. METHODS: Information on asthma and measurements of lung function, airway responsiveness, and atopy were obtained on multiple occasions between ages 9 and 26. Associations between these outcomes and body mass index were analyzed using generalized mixed linear regression models. Further analyses adjusted for potential covariates including breastfeeding, birth order, parental asthma, and personal and family smoking history. MAIN RESULTS: Body mass index was positively associated with asthma, wheeze, asthma treatment, atopy, immunoglobulin E, and inversely with the FEV(1)/FVC ratio in females. There was no significant association with airway responsiveness to methacholine or salbutamol. There was little evidence of an association between body mass index and asthma or atopy in males. Analyses adjusting for potential covariates showed similar findings. Asthma was not associated with a raised body mass index in childhood and childhood asthma did not lead to being overweight as an adult. CONCLUSIONS: A raised body mass index is associated with asthma and atopy in women but not men. Population attributable fraction calculations estimate that 28% (95% confidence interval 7-45) of asthma developing in women after age 9 is due to overweight.

Adolescent↗
PubMed2004

Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis.

Based on serial lung function measurements performed in 142 children (68 males; 74 females) with cystic fibrosis (CF), prospectively evaluated over an age range of 6 to 20 years, we attempted to determine whether the lung clearance index (LCI) as a measure of ventilation inhomogeneities could be a discriminating factor of disease progression. Annual follow-up lung function measurements featuring FRC determined by whole-body plethysmography and multibreath nitrogen washouts, effective specific airway resistance, flow-volume curves, LCI, and gas exchange characteristics were analyzed by linear mixed-model analysis and Kaplan-Meier statistics. The earliest occurring and strongest factor of progression was the LCI, followed by maximal expiratory flow (MEF(50)) and FRC determined by plethysmography (p < 0.0001). Associations between onset of chronic Pseudomonas aeruginosa infection and CF transmembrane conductance regulator (CFTR) genotype with FEV(1) (p = 0.027) and FVC (p = 0.007) were identified. The study shows that the LCI predicts earlier in life and represented much better functional progression than FEV(1). Moreover, there is no single functional predictor of progression in CF, but aside from risk factors, such as onset of chronic P. aeruginosa infection and genotype, pulmonary hyperinflation, airway obstruction, and ventilation inhomogeneities are important pathophysiologic processes that should be evaluated concomitantly as determinants of lung progression in CF.

Adolescent↗
PubMed2005

A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population.

RATIONALE: A disintegrin and metalloprotease 33 (ADAM33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excessive decline of lung function in individuals with asthma. OBJECTIVES: To assess whether SNPs in ADAM33 are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD). METHODS: DNA was collected from subjects of the Vlagtwedde-Vlaardingen cohort participating in the last survey in 1989-1990 after a follow-up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. A total of 1,390 subjects from the cohort was genotyped for the following SNPs in ADAM33: F+1, Q-1, S_1, S_2, T_1, T_2, V_4, and ST+5. Differences in prevalence of SNPs were analyzed with chi(2) tests. Linear mixed effects models were used to analyze FEV(1) decline according to genotype. MEASUREMENTS AND MAIN RESULTS: In the whole population, mean adjusted decline was 18.7 and 12.7 ml/year in females and males, respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q-1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV(1) of, respectively, 4.9, 9.6, and 3.6 ml/year compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2, and T_2 in subjects with COPD. CONCLUSIONS: We demonstrated that SNPs in ADAM33 are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.

ADAM Proteins↗
PubMed2005

Relative change in diurnal mean ocular perfusion pressure: a risk factor for the diagnosis of primary open-angle glaucoma.

PURPOSE: To investigate diurnal change and pattern of variation in intraocular pressure (IOP) and systolic (SBP) and diastolic (DSP) blood pressures in a group with untreated primary open-angle glaucoma (uPOAG) and compare it with an age-matched, normal group. METHODS: IOP, SBP, and DBP were measured in 14 patients with uPOAG and in 14 normal subjects, every hour between 7 AM and 10 PM and the mean ocular perfusion pressure (MOPP) was calculated. Mixed-effect linear models were used to analyze the repeated-measures data in which both fixed and random effects were included. The relative diurnal change was calculated as the percentage decrease from maximum. RESULTS: The uPOAG group had the higher IOP (P < 0.001) and lower MOPP (P = 0.025). There was a significant diurnal change in IOP, SBP, DBP, and MOPP in both groups (P < 0.001). The pattern of diurnal variation in IOP (P = 0.137), SBP (P = 0.569), and DBP (P = 0.937) was not significantly different between groups but was significantly different for MOPP (P = 0.040). MOPP and IOP were most similar at 7 AM and 1 PM. Postprandial hypotension was significant for SBP, DBP, and MOPP (P < 0.001), but not IOP (P = 0.388) in both groups. The relative change in MOPP was larger in the uPOAG group (38% vs. 26%, P < 0.001), but the change in IOP was similar (42% vs. 41%, P = 0.786). There was a significant effect of DBP on IOP over the course of the day in the uPOAG group (P = 0.011) but not in the normal group (P = 0.733). CONCLUSIONS: The relative diurnal change in IOP was similar in both uPOAG and normal subjects but MOPP showed a significant difference. MOPP significantly decreased after lunch, and was at its lowest in uPOAG at 7 AM, when IOP was at its highest. A significant association was found between diurnal DBP and IOP in uPOAG.

Blood Pressure↗
PubMed2005

Anterior optic nerve capillary blood flow response to diurnal variation of mean ocular perfusion pressure in early untreated primary open-angle glaucoma.

PURPOSE: To examine the impact of diurnal variation in intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) on the variation in anterior optic nerve capillary blood flow (BF) in patients with untreated early primary open-angle glaucoma (uPOAG) and healthy volunteers. METHODS: Fourteen patients with uPOAG (age, 56.3 +/- 12 years [SD]; seven men) and 14 normal subjects (age, 57.6 +/- 9.9 years; five men) were examined. Diurnal IOP, systolic (SBP) and diastolic (DBP) blood pressures, and optic nerve head (ONH) topography were measured every hour; and diurnal BF was measured by flowmeter every 2 hours between 0700 and 2200 hours. A perfusion image analyzer was used to calculate the mean BF within the rim (mean rim flow, MRF). The local flow (LF) was calculated using the median and mean flow rates within a 10 x 10-pixel window placed on the rim in the area of maximum topography fluctuation (MTF). The MOPP was then calculated. Mixed-effect linear models were used to analyze the repeated measures data in which both fixed and random effects were included. RESULTS: IOP, BP, and MOPP had significant diurnal variation (P < 0.040). LF measured at the sector of MTF significantly changed in patients with uPOAG (P = 0.006) but not in normal subjects (P = 0.660). MRF did not show significant diurnal change in either group (P = 0.130, P = 0.770). LF increased significantly after lunch in the uPOAG group (P = 0.001). SBP had a significant effect on LF over the course of the day in the uPOAG group (P = 0.043). The diurnal change in IOP, BP, and MOPP did not have a significant effect on MTF in either group. In uPOAG, the local flow, in areas of greatest topographical change, correlated inversely with IOP at 0700 hours (P < or = 0.002). CONCLUSIONS: The mean rim flow did not change during the day, implying that the anterior optic nerve capillary blood flow was autoregulated in both normal subjects and in patients with uPOAG, despite significant changes in IOP and MOPP. However, the regions of greatest diurnal change in rim topography (MTF) had significant diurnal change in capillary blood flow in patients with uPOAG but not in normal subjects.

Blood Flow Velocity↗
PubMed1999

Pharmacokinetics of paracetamol in adults after cardiac surgery.

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (Tabs) of 2.02 h (31) with a lag time of 0.28 h. The absorption half-life for the oral preparation was 1.49 h (81) with a lag time of 0.17 h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18). Concentrations after either nasogastric or rectal paracetamol 2 g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (Tabs 0.06 to 0.7 h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.

Acetaminophen↗
PubMed2004

A model to minimize joint total costs for industrial waste producers and waste management companies.

The model LINKopt is a mixed-integer, linear programming model for mid- and long-term planning of waste management options on an inter-company level. There has been a large increase in the transportation of waste material in Germany, which has been attributed to the implementation of the European Directive 75/442/EEC on waste. Similar situations are expected to emerge in other European countries. The model LINKopt has been developed to determine a waste management system with minimal decision-relevant costs considering transportation, handling, storage and treatment of waste materials. The model can serve as a tool to evaluate various waste management strategies and to obtain the optimal combination of investment options. In addition to costs, ecological aspects are considered by determining the total mileage associated with the waste management system. The model has been applied to a German case study evaluating different investment options for a co-operation between Daimler-Chrysler AG at Rastatt, its suppliers, and the waste management company SITA P+R GmbH. The results show that the installation of waste management facilities at the premises of the waste producer would lead to significant reductions in costs and transportation.

Decision Making, Organizational↗
PubMed2006

Variation of the distal metatarsal articular angle with axial rotation and inclination of the first metatarsal.

BACKGROUND: The distal metatarsal articular angle (DMAA) is a radiographic measure of the orientation of the first metatarsal articular surface. There is debate with regards to the accuracy, reproducibility, and validity of measurement of the DMAA in the literature. This study aimed to test the validity of the measurement of the DMAA from standard radiographs, to explore the trigonometric relationship of the first metatarsal rotation and the DMAA, and to assess interobserver reliability. METHODS: Thirty-four separate dry cadaver first metatarsal bones were mounted onto a customized light-box-protractor, allowing controlled incremental changes in rotation and inclination. A series of 39 digital photographs were taken of each metatarsal in 5-degree increments of rotation between 30 degrees supination and 30 degrees pronation at 10, 20 and 30 degrees of inclination. Three reviewers performed blinded DMAA measurements from each photographic image; the data were collated for statistical analysis. The data were analysed using a mixed effects linear model comparing the DMAA with rotation of the first metatarsal. RESULTS: A strong statistically significant trend of increasing score with increasing pronation of the metatarsal was observed, the relationship was approximately linear. There was a strong effect of inclination, but the strength of this varied with rotation and was amplified at higher inclinations. Interobserver error was noted in line with other studies, but even allowing for this interobserver error, the linear relationship was maintained. CONCLUSIONS: This study showed that the DMAA varies significantly in a linear pattern with axial rotation of the first metatarsal. Inclination of the first metatarsal also affects the magnitude of the angle. This study does not refute the DMAA as an entity but does confirm the inaccuracy of extrapolating the DMAA from plain anteroposterior radiographs.

Cadaver↗
PubMed2001

Elevated baseline triglyceride levels modulate effects of HMGCoA reductase inhibitors on plasma lipoproteins.

BACKGROUND: The response in levels of very-low-density (VLDL) and low-density (LDL) lipoproteins varies substantially among hyperlipidemic patients during treatment with HMGCoA reductase inhibitors. Apolipoprotein E genotype and gender are known to contribute to the regulation of steady state levels of plasma lipoproteins. This study explores the effect of these and other potential determinants of the response of VLDL and LDL to treatment with reductase inhibitors. METHODS: Using mixed linear statistical models, the response of lipoprotein lipid values was studied in 142 hyperlipidemic individuals who were treated with reductase inhibitors. Patients received one or more of the following drugs individually for a total of 623 treatment observations: lovastatin, pravastatin, simvastatin, or atorvastatin. For evaluation of the effects of treatment in the aggregate, actual doses were expressed as equivalent doses of atorvastatin, using factors based on random assignment comparisons in 16 reported studies. The analysis factors considered were apolipoprotein E genotype, baseline average triglycerides >170 mg/dL (vs less), and gender. RESULTS: Presence of an apo epsilon4 allele was associated with a trend toward greater reduction of triglyceride levels and a diminished ability of the reductase inhibitors to reduce LDL cholesterol levels. Gender had only minimal effect on the response of either LDL cholesterol or triglycerides. However, the effect of elevated baseline triglycerides on the response of both triglycerides and LDL cholesterol was striking and was exerted in opposite directions. The triglyceride-lowering effect of reductase inhibitors was greater in patients with initial triglyceride levels above 170 mg/dL (P=0.0001). The effect was even greater in patients with initial triglyceride levels over 250 mg/dL (P=0.015). Conversely, for LDL cholesterol levels, elevated baseline triglycerides were associated with a significantly decreased response to the drugs (P=0.0015). CONCLUSIONS: These findings indicate that baseline triglyceride levels are an important predictor of response of plasma lipoproteins to HMGCoA reductase inhibitors, perhaps reflecting fundamental differences in mechanism underlying the hyperlipidemic phenotype.

Apolipoproteins E↗
PubMed2006

A pharmacokinetic study investigating the rate of absorption of a 500 mg dose of a rapidly absorbed paracetamol tablet and a standard paracetamol tablet.

OBJECTIVE: A rapidly absorbed tablet formulation of paracetamol containing sodium bicarbonate (PS) has been previously shown to be absorbed at least twice as fast as a standard paracetamol tablet (P) at a 1 g dose. In South America and Asia it is customary for patients to take a 500 mg dose of analgesic. The objective of this pharmacokinetic study was to compare the rate of absorption of PS versus P at a 500 mg dose. RESEARCH DESIGN AND METHODS: An open, randomized, single dose, cross-over study. Thirty Hispanic healthy volunteers randomly received a 500 mg dose taken orally with 50 mL of water 2 h after a standard breakfast. Blood samples were taken up to 10 h post-dose. Plasma concentrations of paracetamol were determined by HPLC with UV detection. MAIN OUTCOME MEASURES: AUC(0-30 min), C(plasma 30 min) and T(max) were analyzed non-parametrically by the Wilcoxon's rank sum test. A linear mixed effects model was used to analyze the logarithmically transformed AUC(0-alpha) and C(max). Bioequivalence was accepted if the 90% confidence intervals (CI) for the ratio of the means of the primary pharmacokinetic variable AUC(0-alpha) lay completely within the range 0.80-1.25. RESULTS: AUC(0-30 min) and C(plasma 30 min) were significantly greater and T(max) was significantly shorter (all p < 0.0001) for PS versus P. The formulations were bioequivalent for AUC(0-alpha) (90% CI 0.99:1.05) and no statistical difference was seen for C(max) (95% CI 0.91:1.14). CONCLUSIONS: Paracetamol was absorbed at least twice as fast from PS compared to P at a 500 mg dose. The extent of absorption was equivalent for both formulations.

Absorption↗
PubMed2005

Acute effects of cigarette smoking on inflammation in healthy intermittent smokers.

BACKGROUND: Chronic smoking is the main risk factor for chronic obstructive pulmonary disease. Knowledge on the response to the initial smoke exposures might enhance the understanding of changes due to chronic smoking, since repetitive acute smoke effects may cumulate and lead to irreversible lung damage. METHODS: We investigated acute effects of smoking on inflammation in 16 healthy intermittent smokers in an open randomised cross-over study. We compared effects of smoking of two cigarettes on inflammatory markers in exhaled air, induced sputum, blood and urine at 0, 1, 3, 6, 12, 24, 48, 96 and 192 hours and outcomes without smoking. All sputum and blood parameters were log transformed and analysed using a linear mixed effect model. RESULTS: Significant findings were: Smoking increased exhaled carbon monoxide between 0 and 1 hour, and induced a greater decrease in blood eosinophils and sputum lymphocytes between 0 and 3 hours compared to non-smoking. Compared to non-smoking, smoking induced a greater interleukin-8 release from stimulated blood cells between 0 and 3 hours, and a greater increase in sputum lymphocytes and neutrophils between 3 and 12 hours. CONCLUSION: We conclude that besides an increase in inflammation, as known from chronic smoking, there is also a suppressive effect of smoking two cigarettes on particular inflammatory parameters.

Acute Disease↗
PubMed2006

Decorin and TGF-beta1 polymorphisms and development of COPD in a general population.

BACKGROUND: Decorin, an extracellular matrix (ECM) proteoglycan, and TGF-beta1 are both involved in lung ECM turnover. Decorin and TGF-beta1 expression are decreased respectively increased in COPD lung tissue. Interestingly, they act as each other's feedback regulator. We investigated whether single nucleotide polymorphisms (SNPs) in decorin and TGF-beta1 underlie accelerated decline in FEV1 and development of COPD in the general population. METHODS: We genotyped 1390 subjects from the Vlagtwedde/Vlaardingen cohort. Lung function was measured every 3 years for a period of 25 years. We tested whether five SNPs in decorin (3'UTR and four intron SNPs) and three SNPs in TGF-beta1 (3'UTR rs6957, C-509T rs1800469 and Leu10Pro rs1982073), and their haplotypes, were associated with COPD (last survey GOLD stage = II). Linear mixed effects models were used to analyze genotype associations with FEV1 decline. RESULTS: We found a significantly higher prevalence of carriers of the minor allele of the TGF-beta1 rs6957 SNP (p = 0.001) in subjects with COPD. Additionally, we found a significantly lower prevalence of the haplotype with the major allele of rs6957 and minor alleles for rs1800469 and rs1982073 SNPs in TGF-beta1 in subjects with COPD (p = 0.030), indicating that this association is due to the rs6957 SNP. TGF-beta1 SNPs were not associated with FEV1 decline. SNPs in decorin, and haplotypes constructed of both TGF-beta1 and decorin SNPs were not associated with development of COPD or with FEV1 decline. CONCLUSION: Our study shows for the first time that SNPs in decorin on its own or in interaction with SNPs in TGF-beta1 do not underlie the disturbed balance in expression between these genes in COPD. TGF-beta1 SNPs are associated with COPD, yet not with accelerated FEV1 decline in the general population.

Decorin↗