bluuebunny/crossref_metadata_2025 huggingface dataset:
Pain‐mediated altered absorption and metabolism of ibuprofen: an explanation for decreased serum enantiomer concentration after dental surgery
Authors: Jamali Fakhreddin , Kunz‐Dober Cornelia M.
Published: March 2003

Aims Rapid onset of analgesia is essential in the treatment of acute pain. There is evidence that conditions of stress cause delayed and decreased pain relief from oral analgesic products through impaired absorption. The aim was to determine the effect of surgery for removal of wisdom teeth on the plasma concentration‐time profile of ibuprofen enantiomers.

Methods Racemic ibuprofen, 200 mg in one group (n=7) and 600 mg in another group (n=7) was administered 1 week before (control) and again after (test) surgical removal of wisdom teeth. Serum concentrations of ibuprofen enantiomers were measured for 6 h.

Results During the control phase, S‐ and R‐ibuprofen concentrations were within the suggested therapeutic range. Surgery resulted in a 2 h delay in the mean time to peak concentration, significant decreases in serum ibuprofen concentration following both doses, and a fall to sub‐optimal serum concentrations following the 200 mg dose. During the first 2 h after the 200 mg dose, dental extraction resulted in a significant reduction of the area under serum drug concentration (AUC (0, 2 h) mg l−1 h) from 5.6±2.9 to 1.6±1.8 (P<0.01) and from 5.5±3.0 to 2.1±2.0 (P<0.05) for S and R‐ibuprofen, respectively. Similar observations were made following the 600 mg dose for AUC (0, 2 h) of S‐ibuprofen (from 14.2±6.1 to 7.2±5.5 mg l−1 h, P<0.05) with no significant difference for R‐ibuprofen (from 14.4±9.5 to 5.8±7.1). AUC (0, 6 h) was also significantly reduced by surgery. The pattern of stereoselectivity in serum ibuprofen concentration was reversed by surgery such that the S enantiomer was predominant in the control phase but not in the post‐surgery phase, which is suggestive of reduced metabolic chiral inversion.

Conclusions Surgery for wisdom tooth removal resulted in substantial decreases in the serum concentration of ibuprofen enantiomers and a prolongation in the time to peak concentration. Reduced absorption and altered metabolism are the likely cause of these changes. Thus, dental patients may experience a delayed response and possible treatment failure when taking ibuprofen for pain relief after surgery. Our observation may have implications for the treatment of other diseases.
A pharmacokinetic model for alpha interferon administered subcutaneously
Authors: Chatelut Etienne , Rostaing Lionel , Grégoire Nicolas , Payen Jean‐Louis , Pujol André , Izopet Jacques , Houin Georges , Canal Pierre
Published: March 2003

Aims To model the pharmacokinetic profiles of alpha interferon (αIFN) after a single subcutaneous (s.c.) injection of 3 million units of alpha 2b interferon, to correlate the pharmacokinetic parameters with patient demographic covariates, and to develop a limiting sampling strategy for determining the αIFN plasma area under the curve of concentration vs time (AUC).

Methods The plasma αIFN pharmacokinetics were determined in 27 patients with chronic hepatitis C virus infection after the first s.c. injection of the drug. Ten patients had normal renal function and 17 were chronic haemodialysis patients. Plasma samples were assayed by an Elisa method. Concentration‐time data was analysed by a population approach using NONMEM.

Results The pharmacokinetic model which better described the concentration vs time data was a one‐compartment model with two processes of absorption: a zero‐order followed by a first‐order process. The mean clearance of dialysis patients represented 37% (with 95% confidence interval: 30%–44%) of the mean value of the patients with normal renal function. The volume of distribution was significantly correlated to the body surface area. Bayesian analysis using NONMEM allowed determination of the individual plasma AUC from three samples within the 24 h period post s.c. injection.

Conclusions The present pharmacokinetic model will allow one to obtain individual parameters such as, the area under the curve of concentration vs time from a limited‐sampling strategy, and to perform pharmacokinetic‐pharmacodynamic analysis of combined αIFN plasma concentrations and viraemic data.
Dietary caffeine as a probe agent for assessment of cytochrome P4501A2 activity in random urine samples
Authors: Nordmark Anna , Lundgren Stefan , Cnattingius Sven , Rane Anders
Published: March 2003

Aims To validate the use of randomly collected urine samples for assessment of cytochrome P4501A2 (CYP1A2) activity based on dietary caffeine (caffeine metabolic ratio, MRcaff ), and to relate the MRcaff to caffeine intake and smoking habits in a larger group of individuals.

Methods Nineteen healthy volunteers were included in the validation study. Caffeine (100 mg) was ingested and a urine sample was collected after 6 h. Within the following week a random urine sample was collected in the individuals without a preceding test dose of caffeine. Urine samples were analysed for caffeine and its metabolites by h.p.l.c. and the (AFMU+1U+1X)/1,7U metabolic ratio was used to reflect CYP1A2 activity. In an extended investigation of 522 healthy pregnant women the MRcaff was related to intake of caffeine from various sources, and to smoking.

Results The results from the random and standardised sampling methods correlate with each other (correlation coefficient of MRcaff was 0.91). The MRcaff as assessed by the random sampling method in a larger population was not affected by source or amount of caffeine ingested. Significantly higher MRcaff was found in smokers compared to non‐smokers. In the large group of individuals the random sampling method was possible to use in 80% of the cases. In the residual 20% one or several of the metabolite concentrations were too low or unmeasurable.

Conclusions Our study demonstrates that the random urine caffeine phenotyping method is possible to use in as many as 80% of the individuals when based on dietary caffeine. Our approach should prove applicable in most countries with widely spread caffeine consumption. The method is useful in larger studies of drug metabolising enzyme activities and minimises the time consumption and costs.
Transaminase elevation on placebo during Phase I trials: prevalence and significance
Authors: Rosenzweig  , Miget  , Brohier
Published: March 2003

Aims To evaluate the prevalence of transaminase elevation on placebo during Phase I trials.

Methods Retrospective review of pooled transaminase data collected on placebo during 13 Phase I trials in 93 healthy volunteers hospitalized for 14 days, with determination of the prevalence of abnormally high values.

Results 20.4% of the 93 subjects showed at least one ALT value above the upper limit of the normal range (ULN), and 7.5% had at least one value twice ULN.

Conclusions Laboratory safety results of Phase I trials should be interpreted with caution, in the light of data on placebo, to avoid premature discontinuation of the development of safe drugs wrongly believed to be hepatotoxic.
Apparent autoinduction of valproate β‐oxidation in humans
Authors: McLaughlin Daniel B. , Andrews Jaymie A. , Hooper Wayne D. , Cannell Graeme R. , Eadie Mervyn J. , Dickinson Ronald G.
Published: March 2003

Aims  The study aimed to show whether autoinduction of valproate (VPA) along its β‐oxidation pathway occurred upon chronic dosing in humans.

Methods  Twelve young volunteers without active illness took sodium valproate (NaVPA) 200 mg orally 12 hourly for 3 weeks. On days 7 and 21, serial blood samples and all urine passed over an interdosing interval from 08.00 to 20.00 h were collected for analysis of VPA and certain metabolites.

Results  Plasma AUC(0,12 h) of VPA was significantly lower on day 21 than on day 7 (2.40 vs 2.84 µmol ml−1 h, 95% CI for the difference 0.13–0.81 µmol ml−1 h). Significant differences in plasma AUC(0,12 h) of the β‐oxidation metabolites E‐2‐en‐VPA and 3‐oxo‐VPA were not found. However, formation clearances of plasma VPA to urinary E‐2‐en‐VPA and 3‐oxo‐VPA were significantly increased from day 7 to day 21 (0.010 vs 0.024 and 2.57 vs 3.60 ml kg−1 h−1, respectively, 95% CI for the differences −0.025 to −0.004 and −1.72 to −0.34 ml kg−1 h−1, respectively). Formation clearances to VPA‐glucuronide (0.534 vs 0.505 ml kg−1 h−1) and 4‐OH‐VPA (0.112 vs 0.110 ml kg−1 h−1) were not significantly different.

Conclusions  Regular low dose VPA intake in humans over a period of 3 weeks appears to be associated with a small induction of its metabolism by the β‐oxidation pathway, but not by glucuronidation or 4‐hydroxylation.
Feasibility study of multicentre comparison of NHS hospital pharmacy computer data
Authors: Walker Pauline Debra , Walley Tom
Published: March 2003

Aims
This study aims to determine the feasibility of collecting, collating and analysing drug expenditure data from a sample of acute hospitals in England.

Methods
The hospital pharmacy computer system was used to report on drug expenditure from 16 hospitals throughout England for a 2 year period. These data were analysed as a whole and hospital episode statistics were correlated to hospital drug costs.

Results
Hospital outpatient costs were found to be approximately one third of hospital inpatient costs. Cardiovascular drugs accounted for the greatest increase in expenditure for both inpatients and outpatients (25%). The most expensive therapeutic area of drug use across all sites was anti‐infectives. The average daily number of occupied beds explained 55% of the variation in inpatient expenditure and the number of outpatient (including Accident and Emergency) attendances explained 60% of the outpatient drug expenditure.

Conclusions
This project has confirmed the feasibility of collecting, collating and analysing hospital drug expenditure and identified some interesting patterns and trends in hospital drug use. Hospital activity is reflected in hospital drug costs.
First trimester exposure to cefuroxime: a prospective cohort study
Authors: Berkovitch Matitiahu , Segal‐Socher Idit , Greenberg Revital , Bulkowshtein Mordechai , Arnon Judy , Merlob Paul , Or‐Noy Asher
Published: March 2003

Aims
There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime.

Methods
One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications.

Results
Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0.61, relative risk = 1.56, 95% confidence interval 0.27–9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94–11.77).

Conclusions
Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.
The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing
Authors: Allen Michael J. , Nichols Donald J. , Oliver Stuart D.
Published: March 2003

Aims
The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily.

Methods
Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 µg (n = 8), 1500 µg (n = 8), or 2500 µg (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two‐way crossover for each subject and separated by at least a 6 day washout period.

Results
Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. Ctrough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (Cmax) and the area under the concentration vs time curve (AUC(0,τ) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. Cmax occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose‐dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml−1) than on day 5 (ranging from 9.9 to 12.8 ms/ng ml−1).

Conclusions
The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.
Reducing electrostatic charge on spacer devices and bronchodilator response
Authors: Wildhaber Johannes H. , Waterer Grant W. , Hall Graham L. , Summers Quentin A.
Published: March 2003

Aims
Plastic spacers are widely used with pressurized metered dose inhalers (pMDI). Reducing electrostatic charge by washing spacers with detergent has been shown to greatly improve in vitro and in vivo drug delivery. We assessed whether this finding is associated with an improved bronchodilator response in adult asthmatics.

Methods
Twenty subjects (age 18–65 years) with a known bronchodilator response inhaled in random order salbutamol from a pMDI (Ventolin®) through an untreated new spacer (Volumatic®) and through a detergent washed spacer. Patients received the following doses of salbutamol via pMDI at 20 min intervals: 100 µg, 100 µg, 200 µg, 400 µg, 800 µg. Spirometry, heart rate and blood pressure were checked prior to each dose and 20 min after the last dose.

Results
There were no differences between baseline forced expiratory volume in 1 s (FEV1) using either spacer (2.61 ± 0.56 and 2.52 ± 0.45 l, untreated and treated with detergent, respectively; mean ± s.d.). The provocation dose required to cause a clinically significant improvement of 10% in FEV1 (PD10) was significantly lower when the detergent treated spacer was used (1505 ± 1335 and 430 ± 732 µg, untreated and treated, respectively, P < 0.002).

Conclusions
We have demonstrated an improvement in bronchodilator response, in adult asthmatics, after reducing the electrostatic charge in a spacer device by washing it with ordinary household detergent. This finding stresses the importance of an optimal choice of delivery device for asthma medication.
Quinapril and its metabolite quinaprilat in human milk
Authors: Begg E. J. , Robson R. A. , Gardiner S. J. , Hudson L. J. , Reece P. A. , Olson S. C. , Posvar E. L. , Sedman A. J.
Published: March 2003

Aims  To measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure.

Methods  A single dose of quinapril 20 mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks. Blood was sampled for the measurement of quinapril and quinaprilat at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h. Milk was collected for measurement of quinapril and quinaprilat concentrations over the periods −4–0, 0–4, 4–8, 8–12, 12–18, 18–24 h. The areas under the plasma and milk concentration‐time curves were estimated and an M/P ratio derived for both quinapril and quinaprilat.

Results  The M/P ratio for quinapril was 0.12 (95% CI 0.09,0.14). No quinapril was detected in milk after 4 h. No quinaprilat was detected in any of the milk samples. The estimated ‘dose’ of quinapril that would be received by the infant was 1.6% (95% CI 1.0,2.2) of the maternal dose, adjusted for respective weights.

Conclusions  Quinapril appears to be ‘safe’ during breastfeeding according to conventional criteria, although as always, the risk:benefit ratio should be considered when it is to be given to a nursing mother.
Drug expenditure in hospitals: what do German ward physicians know?
Authors: Schnurrer J. U. , Stichtenoth D. O. , Troost R. , Frölich J. C.
Published: March 2003

Aims
Ward physicians hold key positions in the course of efforts to reduce drug expenditures in hospitals. This study evaluated the knowledge of German hospital physicians with respect to the daily therapeutic costs of 21 frequently used drugs.

Methods
A questionnaire survey was carried out among 168 ward physicians from university and municipal hospital departments of internal medicine.

Results
One hundred and twenty‐seven physicians returned a completed questionnaire, a response rate of 75.6%. On average the physicians successfully identified both low cost and expensive drugs. The prices of inexpensive and moderately expensive drugs were generally overestimated whereas those for the expensive and highly expensive drugs were underestimated in 35% and 68% of respondents, respectively.

Conclusions
The results of this survey of German hospital physicians suggest that a more economically efficient use of drugs could be achieved by an improved knowledge of daily therapeutic costs.
A randomized controlled assessment of the effects of different dosing regimens of budesonide on the HPA‐axis in healthy subjects
Authors: Andersson Norma , Källén Anders , Thorsson Lars
Published: March 2003

Aims  To investigate the effect on the hypothalamo‐pituitary‐adrenal (HPA) axis of treatment with budesonide, 400 µg once daily, morning or evening, or 200 µg twice daily, and 800 µg twice daily via Turbuhaler in a randomized, placebo‐controlled, double‐blind, double‐dummy crossover study.

Methods  Healthy men received budesonide, 400 µg in the morning (08.00–09.00 h) or evening (20.00–21.00 h), budesonide, 200 µg twice daily, 800 µg twice daily, and placebo twice daily, for 1 week each. Plasma and urine samples were obtained over 24 h on day 7 for cortisol determination. Twenty‐five subjects completed all treatments, and 27 were included in the analysis.

Results  The 24 h plasma cortisol concentrations vs placebo (95% CI) were 98% (89, 108) for 400 µg in the morning, 92% (83, 100) for 400 µg in the evening, 95% (86, 104) for 200 µg twice daily, and 76% (70, 84) for 800 µg twice daily.

Conclusions  Budesonide at a dose of 400 µg day−1 via Turbuhaler had no statistically significant effect on 24 h cortisol production, irrespective of whether treatment is given once or twice daily, whereas a dose of 800 µg twice daily resulted in a statistically significant suppression vs placebo. Neither could a significant difference be found between morning and evening dosing.
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. ⧫▵ FEV, A, ▪▵ FEV, B, ▴▵ FVCA, *▵ 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

Results 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

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.
Allogeneic bone marrow transplantation for systemic AL amyloidosis
Authors: Gillmore Julian D. , Davies John , Iqbal Adil , Madhoo Sheril , Russell Nigel H. , Hawkins Philip N.
Published: March 2003

Low‐intensity chemotherapy is ineffective in most patients with AL amyloidosis, probably because clinical benefit requires regression of the amyloid deposits, and this occurs only very gradually after the underlying plasma cell dyscrasia has been suppressed. We report the first successful allogeneic bone marrow transplant (allo‐BMT) for AL amyloidosis, which after 3 years was associated with complete clinical recovery. This supports the idea that there may be a brief window of opportunity in patients with AL amyloidosis during which dose‐intensive chemotherapy is feasible and most likely to produce clinical benefit.
A 5′ splice region G → C mutation in exon 3 of the human β‐spectrin gene leads to decreased levels of β‐spectrin mRNA and is responsible for dominant hereditary spherocytosis (spectrin Guemene‐Penfao)
Authors: Garbarz Michel , Galand Colette , Bibas Dominique , Bournier Odile , Devaux Isabelle , Harousseau Jean‐Luc , Grandchamp Bernard , Dhermy Didier
Published: March 2003

We studied a family with autosomal dominant hereditary spherocytosis (HS) associated with a mild spectrin deficiency. Linkage analysis using two microsatellite markers (D14S63 and D14S271) very close to the β‐spectrin gene (SPTB) showed that HS co‐segregated with alleles of these microsatellite markers and the linkage between the marker and HS was statistically significant. The presence of a β‐spectrin protein polymorphism (β‐spectrin Vay; A1880V) in trans of the HS allele was not itself deleterious, but allowed the detection of decreased membrane expression of the spherocytic β‐spectrin allele in two HS‐affected subjects. Direct sequencing of the coding exons of the β‐spectrin gene in one affected subject showed the presence of a G → C transversion at the terminal nucleotide of exon 3, which did not change the leucine codon 100 (CTG → CTC). The presence of the mutation was confirmed by restriction enzyme digestion at the DNA level in all affected SH members of the family. The G → C mutation severely reduced the utilization of the 5′ splice site and resulted in aberrant mRNA splicing with intron 3 retention.
Establishment of a GM‐CSF‐dependent megakaryoblastic cell line with the potential to differentiate into an eosinophilic lineage in response to retinoic acids
Authors: Ma Feng , Koike Kenichi , Higuchi Tsukasa , Kinoshita Tatsuya , Takeuchi Kouichi , Mwamtemi Hadija Hemed , Sawai Nobukuni , Kamijo Takehiko , Shiohara Masaaki , Horie Shiro , Kawa Shigeyuki , Sasaki Yumiko , Hidaka Eiko , Yamagami Osamu , Yamashita Tetsuji , Koike Tadashi , Ishii Eizaburo , Komiyama Atsushi
Published: March 2003

We recently established a human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐dependent cell line (HML) from colony‐constituent cells grown by peripheral blood cells of a patient with acute megakaryoblastic leukaemia. The HML cells possessed megakaryocytic features, as determined by cytochemical, electron microscopic and flow cytometric analysis. In the present study we examined the effects of retinoic acid (RA) on the development of HML cells. All‐trans‐RA, 13‐cis‐RA and 9‐cis‐RA at 10−8 mol/l to 10−5 mol/l inhibited the GM‐CSF‐dependent cell growth. Some of the RA‐treated cells contained prominent azurophilic granules and were positive for peroxidase. They also reacted with Biebrich scarlet, Luxol fast blue and a monoclonal antibody against eosinophil peroxidase. In addition, exposure to RA increased the frequency and the intensity of major basic protein‐positive cells. However, eosinophil‐derived neurotoxin and eosinophil cationic protein were not detected or were only detected at a low level in the lysates of the HML cells treated with RA. Although IL‐5 alone could not stimulate cell growth, the addition of IL‐5 to the cultures containing stem cell factor + all‐trans‐RA was required for the expression of the eosinophilic phenotype. These results suggest that the HML cell line is a megakaryoblastic cell line with the potential to differentiate into the eosinophilic lineage. HML cells may be a useful model for elucidating the eosinophilic differentiation programme.