bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and systemic β2‐adrenoceptor‐mediated responses to inhaled salbutamol
Authors: Fowler Stephen J. , Lipworth Brian J. 
Published: March 2003

Aims  To examine whether systemic β2‐adrenoceptor responses, such as tachycardia, tremor and hypokalaemia, can be used as a surrogate for the 20 min pharmacokinetic profile of inhaled salbutamol.Methods  A retrospective analysis of eight separate published studies in healthy volunteers was performed, each with an identical protocol evaluating the early lung absorption profile of a nominal 1200 µg dose of salbutamol given by different inhaler devices. Peak postural finger tremor, plasma potassium and heart rate were assesssed.Results  We found the maximum (Cmax) and average (Cav) plasma concentrations of salbutamol to be correlated (P < 0.0001) to change in plasma potassium (Cmaxr = 0.904; Cavr = 0.899) and tremor (Cmaxr = 0.875; Cavr = 0.857). No significant correlations existed between change in heart rate and Cmax (r = 0.425) or Cav (r = 0.415).Conclusions  Systemic β2‐adrenoceptor responses, in particular hypokalaemia and tremor, but not heart rate, appear to be good surrogates for evaluating the lung delivery of inhaled salbutamol. Consequently it is suggested that potassium or tremor responses may be used to evaluate the relative lung delivery of salbutamol from different inhaler devices.
Influence of ACE‐inhibition on salt‐mediated worsening of pulmonary gas exchange in heart failure
Authors: Guazzi Marco , Brambilla Roberto , Agostoni Piergiuseppe , Guazzi Maurizio D. 
Published: March 2003

Aims  In congestive heart failure (CHF), pulmonary gas exchange, as evaluated by carbon monoxide diffusion (DLCO), is impaired. ACE‐inhibition improves DLCO. Infusion of saline worsens DLCO, because of upregulated sodium and water transport to the alveolar interstitium, which thickens the alveolar–capillary interface and lengthens the diffusion path for gas exchange. We investigated whether enalapril can readjust the capillary permeability to sodium.Methods  In 10 NYHA class II‐III CHF patients, we measured DLCO, its two subcomponents (VC, capillary blood volume available for gas exchange, and DM, alveolar‐capillary membrane diffusion), left and right ventricular filling pressures, plasma noradrenaline, aldosterone and renin activity, at baseline and following saline infusion in the main pulmonary artery stem, before and after 1 week enalapril treatment (20 mg daily).Results  Saline (150 ml) significantly reduced DLCO (−9.1%) and DM (−9.8%) and augmented VC (+ 10.7%). Responses to 750 ml saline were somewhat greater and qualitatively similar. Enalapril produced a significant improvement of DLCO and DM at rest as well as after saline, that was not associated with variations in ventricular filling pressures, cardiac output and left ventricular ejection fraction, and was not accounted for by humoral changes.Conclusions  In CHF, ACE‐inhibition attenuates the deterioration of pulmonary gas transfer produced by saline infusion, suggesting an ability to readjust the upregulated sodium transport across the pulmonary microvascular endothelium.
Platelet CD62 expression and PDGFAB secretion in patients undergoing PTCA and treatment with abciximab
Authors: Graff J. , Andries D. , Elsner M. , Westrup D. , Bassus S. , Franz N. , Klinkhardt U. , Harder S. 
Published: March 2003

Aims  To investigate a correlation of the platelet activation marker CD62 and secretion of the growth factor PDGF from platelets in coronary patients under therapy with the GPIIb/IIIa‐inhibitor abciximab.Methods  Flow cytometric assessment of fibrinogen binding (GPIIb/IIIa‐binding site) and CD62 expression, as well as PDGF release of human platelets (immunoassay) and platelet aggregation with 20 µm ADP and 2 µg ml−1 collagen were evaluated in nine patients with stable coronary artery disease. Patients were undergoing elective balloon angioplasty and were treated with aspirin (100 mg day−1), heparin (ACT < 220 s) and abciximab (bolus and infusion over 12 h). Blood samples were obtained before initiation of abciximab therapy (under aspirin and heparin) (I), 3 h after angioplasty under abciximab (II) and 12 h after termination of abciximab infusion (III).Results  Compared with sample I before abciximab therapy, fibrinogen binding was reduced to 37% (± 34 s.d., P < 0.05) (II) and 55% (± 40 s.d., P < 0.05) (III). Reduced fibrinogen binding also led to a significant reduction of the aggregation response to ADP (down to 37% ± 20) and collagen (down to 0%). Mean fluorescence intensity of CD62‐expression was 78 units (± 20 s.d.) (I), 72 units (± 14 s.d.) (II) and 64 units (± 12 s.d., P < 0.05) (III). PDGF release from isolated, washed platelets was 99 (± 33 s.d.) ng/109 platelets at (I), 82 (± 31 s.d.) ng/109 platelets and 96 (± 30 s.d.) ng/109 platelets.Conclusions  The results indicate that despite a strong reduction of GPIIb/IIIa‐binding and platelet aggregation, CD62 as a marker of platelet secretion and the secretion product PDGF were only slightly reduced under abciximab treatment. No direct correlation between CD62 expression and PDGF release could be demonstrated.
A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers
Authors: van Kraaij D. J. W. , Hovestad‐Witterland A. H. I. , de Metz M. , Vollaard E. J. 
Published: March 2003

Aims  To compare the effects of nabumetone and meloxicam, two cyclo‐oxygenase‐2 (COX‐2) preferential nonsteroidal anti‐inflammatory drugs (NSAIDs), on platelet COX‐1 activity and platelet function.Methods  Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross‐over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash‐out. After a second 2 week wash‐out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function. COX‐1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA‐100. Data are reported as median with range. Paired variables were analysed using Wilcoxons signed rank test.Results  TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P<0.05). Closure times increased significantly after administration of all three medications (P<0.05). Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01).Conclusions  In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX‐2 selectivity of the former. However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.
Inhaled corticosteroids and the risk of diabetes among the elderly
Authors: Dendukuri Nandini , Blais Lucie , LeLorier Jacques 
Published: March 2003

Aims  There is evidence that large doses of inhaled corticosteroids lead to an increased risk of glaucoma, cataracts and other problems associated with oral corticosteroid use. However, no formal investigation so far has been conducted into the relationship between inhaled corticosteroids and diabetes.Methods  Our nested case‐control design studied the association between current use of inhaled corticosteroids and the risk of using antidiabetic medications among a cohort of 21 645 elderly subjects. We also investigated the possibility of a dose–response relationship in users of beclomethasone. Data were obtained from the medical and pharmaceutical databases of the Regie de l'assurance maladie du Que´bec.Results  Within the cohort, we identified 1494 cases and we selected 14 931 controls using density sampling. The unadjusted rate ratio (and 95% confidence interval, CI) for developing diabetes among current users of inhaled corticosteroids was 1.4 (1.2, 1.5). After adjusting for covariates, the rate ratio (95% CI) decreased to 0.9 (0.8, 1.1). The loss of statistical significance was due in large part to adjusting for the current use of oral corticosteroids. We also did not observe a statistically significant increase in risk among users of high‐dose beclomethasone compared to nonusers, after adjusting for covariates.Conclusions  Our results do not indicate an increased risk of diabetes among current users of inhaled corticosteroids.
Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin
Authors: Faaij R. A. , Burggraaf J. , Schoemaker R. C. , Van Amsterdam R. G. M. , Cohen A.F. 
Published: March 2003

Aims
To investigate the pharmacokinetic and pharmacodynamic interaction of the antithrombotic pentasaccharide fondaparinux (Org31540/SR90107A), given subcutaneously, and oral warfarin in healthy subjects.
Methods
This study was performed according to a randomised, three‐way cross‐over, placebo‐controlled, double‐blind design in 12 healthy male subjects. The treatment consisted of five subcutaneous (s.c.) injections of fondaparinux (4 mg) or placebo at 24 h intervals. Oral dosing of warfarin or placebo was added to the fourth (15 mg) and fifth (10 mg) s.c. injection. Blood samples for pentasaccharide assay, PT and APTT were drawn before the first s.c. dose of the pentasaccharide and over a 6 day period thereafter.
Results
Fondaparinux administered to healthy male volunteers alone or in combination with oral warfarin was well tolerated and no serious adverse events were observed. No differences were found in the AUC (43 vs 44 mg l−1 h), Cmax (645 vs 678 ng ml−1) or elimination half‐life (13.8 vs 14.1 h) of fondaparinux between the pentasaccharide‐only and the combination treatment. The effect of warfarin on PT (mean maximal increase: 8.2 s.) was not influenced by the presence of the pentasaccharide (mean maximal increase in PT: 9.1 s.). After all treatments a small rise in APTT was seen. No further differences could be detected in the pharmacodynamic parameters following the three treatments.
Conclusions
The coadministration of warfarin did not influence the pharmacokinetics of fondaparinux in healthy subjects. PT can still be used to monitor the effect of oral anticoagulants during the switch from antithrombotic treatment with pentasaccharide to full oral anticoagulant therapy.
The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women
Authors: Nordmark Anna , Lundgren Stefan , Ask Birgitta , Granath Fredrik , Rane Anders 
Published: March 2003

Aims  To investigate the influence of the CYP1A2*1F mutation on CYP1A2 activity in smoking and nonsmoking pregnant women.Methods Pregnant women (n = 904) who served as control subjects in a case‐control study of early fetal loss were investigated. They were phenotyped for CYP1A2 using dietary caffeine and the urinary ratio AFMU + 1X + 1 U/1,7 U. An assay for CYP1A2*1F using 5′‐nuclease assay (Taqman) was developed to genotype the population.Results  The frequencies of *1 A and *1F alleles among Swedish women were 0.29 and 0.71, respectively. There was no statistically significant difference in CYP1A2 activity between the genotypes, although a trend towards enhanced activity was observed in *1F/*1F (log MRc 0.77) and *1F/*1 A (log MRc 0.82) genotypes compared with the *1 A/*1 A genotype (log MRc 0.71) (anovaP = 0.07). The mean difference between the *1 A homozygotes and the heterozygotes was 0.11 [95% confidence interval of the difference: (−0.21, −0.01)] and that between the *1 A and *1F homozygotes was 0.05 [95% confidence interval of the difference: (−0.13, 0.03)]. No significant effect (P = 0.22) of the *1F on CYP1A2 activity was observed in smokers, tested using an interaction term (smoking * genotype) in the anova model (*1F/*1F log MRc 0.79, *1F/*1 A log MRc 0.86, and *1 A/*1 A log MRc 0.73). In smokers, there was no difference in ratio between homozygotes for the *1 A and *1F alleles [mean difference −0.06; 95% confidence interval of the difference: −0.22, 0.11] or between *1 A/*1 A and *1 A/*1F genotypes [mean difference −0.13; 95% confidence interval of the difference: −0.29, 0.04].Conclusions  The effect of the CYP1A2*1F mutation on CYP1A2 activity in smoking pregnant women could not be confirmed.
The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus; a systematic review
Authors: Wulffelé M. G. , Kooy A. , De Zeeuw D. , Stehouwer C. D. A. , Gansevoort R. T. 
Published: March 2003

The UKPD S 34 [1] indicated that intensive treatment with metformin (M) significantly reduces stroke, diabetes‐related endpoints and all‐cause mortality in newly diagnosed type 2 diabetics compared with intensive treatment with insulin or sulfonylurea derivates, despite similar glycaemic control. How this should be explained is yet unclear. Some reports suggested an intrinsic positive effect of M on blood pressure [2] and lipid profile [3]. In an attempt to quantify the effects of M on these parameters we systematically reviewed the literature for randomized controlled trials (RCTs) with M and pooled the obtained data in a meta‐analysis.To identify all RCTs we conducted electronic searches using the bibliographic databases Medline and Embase, contacted the manufacturer and checked the obtained publications for cross‐references. We only included trials with M treatment in type 2 diabetes mellitus of at least 6 weeks. Parallel as well as crossover trials were eligible. Statistical analysis was performed using Review Manager 4.1 and Metaview 4.1. In case data were missing in a specific RCT the investigators were contacted.Of 77 possibly eligible studies, 32 were included in our analyses with a total of 2452 patients. Thirty‐two studies were excluded because the investigators did not or could not provide the desired data and six because of other reasons. Only a small, non‐significant effect was found on systolic and diastolic blood pressure, and HDL cholesterol (−1.37 mmHg, P=0.30; −1.21 mmHg, P=0.10; +0.02 mmol l−1, P=0.20, respectively). Compared with control treatments M decreased triglycerides, total cholesterol and LDL cholesterol significantly (−0.12 mmol l−1, P=0.03; −0.20 mmol l−1, P= 0.0002; −0.25 mmol l−1, P=0.00001, respectively). We found no indications for publication bias. Of note, glycaemic control was also better with M vs control treatments (−0.80 percent point glyHb; P<0.00001). When studies were subdivided according to tertiles of glycaemic control, it appeared that M had no effect vs control treatments on triglycerides in the tertile where they had similar glycaemic control, whereas in this tertile there still was a significant effect on total and LDL cholesterol. Furthermore, a positive dose‐response relationship was observed between M and total and LDL‐cholesterol.Metformin has no intrinsic effect on blood pressure, HDL cholesterol and triglycerides in patients with type 2 diabetes. Total and LDL cholesterol however, are significantly reduced by this drug, independent of its effect on glycaemia. Whether these latter effects are clinically relevant is questionable considering the limited effect‐size.
A population pharmacokinetic model for Cremophor EL using nonlinear mixed‐effect modeling: model building and validation
Authors: Van Den Bongard H. J. G. D. , Mathôt R. A. A. , Van Tellingen O. , Schellens J. H. M. , Beijnen J. H. 
Published: March 2003

Cremophor EL is a polyethoxylated castor oil that is used for the formulation of a variety of hydrophobic drugs. Recently, it has been demonstrated that the pharmacokinetic (PK) behaviour of Cremophor EL influences the disposition of paclitaxel [1]. Consequently, assessment of the clinical PK of Cremophor EL during paclitaxel administration is of major importance. The purpose of the present study was to develop a population PK model of Cremophor EL as a solubilizing agent for paclitaxel.Plasma concentration‐time data (85 courses) of Cremophor EL concentrations were collected from 71 patients with solid tumours treated with paclitaxel dissolved in Cremophor EL. Cremophor EL was intravenously infused during 3, 24 and 96 h (doses ranging from 8.3–20.8 ml m−2). Population PK analysis of plasma concentration‐time data was performed using the nonlinear mixed effect modeling software program NONMEM. Thirteen covariates were investigated for their influence on the PK parameters of Cremophor EL. The stability of the final model was evaluated by bootstrapping. The median parameter estimates obtained from 1000 bootstrap replicates were compared with those obtained from the original data set.The data were fitted to a 3‐compartment model with Michaelis‐Menten elimination from the central compartment. The following PK parameters were estimated: volume of the central compartment V1=2.59 l), volume of the first peripheral compartment (V2=1.81 l), volume of the second peripheral compartment (V3=1.61 l), intercompartmental clearance between the central compartment and the first peripheral compartment (Q12=1.44 l h−1) and the second peripheral compartment (Q13=0.16 l h−1), maximal elimination rate (Vmax=0.19 ml h−1), and the plasma concentration at half of the Vmax (Km=0.12 ml l−1). Interindividual variability (IIV) was estimated using an exponential error model, and was quantified for V1 (25%), V2 (36%), and Vmax (31%). Residual variability was small with a combined additional and proportional error of 0.095 ml l−1 and 7%, respectively. Significant relationships (P<0.001) between the covariates and the PK parameters were determined between V1 and sex, between V2 and BSA, and between Vmax and performance status. The median PK parameter values from the bootstrap procedure were in accordance with the parameter estimates of the population PK model.The non‐linear PK of Cremophor EL could adequately be described by the developed population PK model. Sex, BSA and PS partially explained the IIV in V1, V2 and Vmax, respectively. The PK model may be used when studying the clinical PK of paclitaxel.
Pharmacodynamic effects of albuterol nebulization in hospitalized COPD‐patients because of an exacerbation with blocked gastrointestinal absorption
Authors: Cromheecke H. , Grouls R. , Creemers J. , Smeenk F. , Verboom L. , Ackerman E. 
Published: March 2003

Despite major improvements in drug output of new nebulizers and differences between nebulizers [1], doses of albuterol nebulizing therapy of hospitalized COPD‐patients has not changed in the last decades.The objective was to determine the optimal dose in the current setting according to a standardized protocol (10 min at flow 8 l min−1, MICRO MIST nebulizer, Hudson RCI).After a washout of bronchodilators patients nebulized 5 mg (group A; n=21. FEV1=47.4 ± 2.9% predicted; Tiffeneau=48.1 ± 2.5%) or 10 mg (group B; n=21, FEV1=50.5 ± 3.8% predicted; Tiffeneau=49.5 ± 3.4%) albuterol (t=−10 to 0 min). Pulmonary function (PF) (FEV1, FVC, Tiffeneau), dyspnoea (modified Borg scale) and heart‐frequency (HF), blood pressure (BP), breathing‐frequency (BF), serum potassium (K), fingertremor, QTc‐interval, were measured at t=−30, 10, 30, 60, 120, 240 min. Charcoal was administered to prevent gastrointestinal absorption (t=−10; 10 min (5 g) and 60 min (10 g). Pharmacodynamic (PD)‐effects, relative to baseline, and correlation between effects, severeness of COPD and patient characteristics were analysed.FEV1 and FVC increased significantly (FEV1: (A) 10–120 min; (B) 10–240 min; Figure 1), leaving Tiffeneau unchanged. FVC at t=10 is significantly greater for group B compared to A (P=0.009). PD‐parameters (Table 1) showed significant changes.Mean FEV1, FVC in groups A and B. &lozf;&utri; FEV, A, &squf;&utri; FEV, B, &utrif;&utri; FVCA, &ast;&utri; FVCB.image

PD‐parameter differences relative to t=−30 min, group A and B

t=10
t=30
t=60
t=120
t=240

ΔHF (beats min−1)
A
4.1±1.5^
6.0±1.9*^
7.8±2.0*
8.5±1.9*
4.2±1.4*

B
12.5±2.6*
15.1±3.0*
14.0±2.4*
10.0±2.0*
7.6±2.3*

ΔQTc (ms)
A
8.3±4.0*^
6.5±9.0^
28.2±8.0*
14.3±6.0*
7.3±4.7

B
26.0±6.0*
30.7±6.0*
20.0±6.8*
16.5±5.6*
18.0±6.3*

ΔK+ (mmol l−1)
A
−0.1±0.1
−0.2±0.0*
−0.5±0.1*
−0.2±0.1
−0.1±0.1*

B
−0.2±0.1*
−0.5±0.1*
−0.3±0.1*
−0.3±0.1*
−0.1±0.1

Significant within group;

significant between groups; P<0.05.

All changes in group B had an earlier onset and were of the same or longer duration. Parameters not mentioned did not change clinically significant. FEV1‐ and dyspnoeic‐changes and FEV1 and FVC changes had a significant correlation in both groups. No other correlations or differences were seen.Group B shows no greater PF improvements, only significant and clinical relevant greater changes in some side effects. In moderate to severe COPD‐patients 5 mg albuterol is the highest recommended dose, lower doses should be investigated.
Calcipotriol ointment and cream or their vehicles applied immediately before irradiation inhibit ultraviolet B-induced erythema
Authors: De Rie M.A. , Di Nuzzo S. , Brands S. , Hansen A.B. , Bos J.D. 
Published: March 2003

AbstractResults of ultraviolet (UV) B phototherapy can be improved by the application of calcipotriol, but studies are needed to decide how the two treatments should be combined. We studied the effect of UVB after application of calcipotriol ointment (50 μg g−1) and calcipotriol cream (50 μg g−1) and determined the optimal time of application of calcipotriol when combined with UVB phototherapy (280–350 nm), in a single-blinded randomized vehicle-controlled study of 37 healthy adult volunteers. Calcipotriol ointment or cream was applied randomly on five areas on the back at different time intervals from UVB irradiation. One area was left untreated as the control. Application times were the evening before, the morning before, 2 h before, immediately before, and immediately after irradiation. UVB irradiation was administered by TL20W/12 fluorescent tube lamps at increasing doses (20, 25, 32, 40, 50 and 64 mJ cm−2) to six subunits of each test area. Clinical assessment was performed 24 h after UVB irradiation by a blinded investigator. Calcipotriol ointment and cream were applied in 19 and 18 subjects, respectively, and erythema was measured for each application time quantified. We found that erythemal reactions were significantly smaller when calcipotriol ointment or cream was applied immediately before irradiation compared with all other application times. To explain these findings, a vehicle control study was performed. No difference in erythema was seen between calcipotriol medication and the vehicle controls. Spectrophotometric analysis of the calcipotriol cream and ointment showed no UV absorbance in the UVB range. No signs of photosensitization were noted. In conclusion, the vehicles of the calcipotriol ointment and cream inhibit the induction of erythema by UVB irradiation if applied immediately before phototherapy. Consequently, calcipotriol ointment and cream should not be applied directly before UVB irradiation; however, they may be applied at any time up to 2 h prior to or immediately after UVB irradiation. Possible explanations for this sunscreen activity are discussed.
Linear eruptions of the nose in childhood: a form of lichen striatus?
Authors: Lee M-W. , Choi J-H. , Sung K-J. , Moon K-C. , Koh J-K. 
Published: March 2003

Abstract
We report four children with linear eruptions on the nose, with overlapping features of lichen striatus and linear cutaneous lupus erythematosus. However, linear lupus erythematosus has rarely been reported, and lichen striatus, although classically linear, rarely affects the face. The linear distribution of lesions from the glabella to the ala nasi may represent distribution following Blaschko’s lines.