bluuebunny/crossref_metadata_2025_split huggingface dataset:
β‐adrenoceptor blockers in chronic heart failure—a review
Authors: Krum Henry 
Published: October 2003

There are now considerable clinical trial data to support the use of β‐adrenoceptor blockers in patients with chronic heart failure due to systolic left ventricular dysfunction. Increases in ejection fraction, improved well‐being as judged by both patient and physician and reduced progression of ventricular dysfunction have been demonstrated. From meta‐analyses of available trial data, a mortality reduction of approximately 30% is obtained when these drugs are added to standard heart failure therapies. Furthermore, reductions in cardiovascular morbidity associated with decreased hospitalization rates suggest pharmacoeconomic benefits with these agents.This review addresses the following issues regarding β‐adrenoceptor blockers in chronic heart failure: the known adverse effects of chronic sympathetic activation in heart failure, the theoretical benefits of blockade of this neurohormonal system, the current clinical database of β‐adrenoceptor blockers in heart failure and practical issues regarding the administration of these agents to these patients.
Is metronidazole teratogenic? A meta‐analysis
Authors: Caro‐Patón Tomás , Carvajal Alfonso , Martín de Diego Isaac , Martín‐Arias Luis H. , Alvarez Requejo Ana , Pinilla Elvira Rodríguez 
Published: October 2003

Aim In order to assess whether the use of metronidazole during pregnancy is associated with a higher risk of congenital malformations, a meta‐analysis was conducted.Methods All epidemiological studies (cohort and case‐control) which estimate risk of congenital malformations after exposure to metronidazole during early pregnancy were included in the meta‐analysis. To obtain a summary odds ratio, the Mantel‐Haenszel method was used. A test to verify absence of heterogeneity was also performed.Results One unpublished case‐control and four published cohort studies fulfilled the inclusion criteria and were not statistically heterogeneous. A summary odds ratio was calculated for metronidazole exposure during the first trimester: OR=1.08, 95% CI: 0.90–1.29, heterogeneity test χ2=4.72, P=0.32.Conclusions This meta‐analysis did not find any relationship between metronidazole exposure during the first trimester of pregnancy and birth defects.
Evidence for both in vivo and in vitro interaction between vigabatrin and alanine transaminase
Authors: Richens Alan , McEwan Jean R. , Deybach Jean C. , Mumford John P. 
Published: October 2003

Aims Decreases in plasma alanine transaminase (ALA‐T) activity of 20–100% have been reported following the use of vigabatrin (Sabril) in patients with uncontrolled epilepsy. This effect has a potential clinical significance as it may mask signs of early, underlying hepatic disease. It is particularly significant in a patient population known to have a higher than average risk of hepatotoxicity due to treatment with other anti‐epilepsy drugs or to an independent, but concomitant, disease process. Vigabatrin is a highly specific enzyme antagonist. There is an almost 1000‐fold difference between its activity against γ‐amino butyric acid aminotransaminase and ALA‐T. However, some activity against other transaminases is not unexpected, and it is important to determine the degree of vigabatrin's effect against ALA‐T in man. Methods Two in vitro experiments, using serum samples spiked with vigabatrin, confirmed the presence of an interaction between vigabatrin and ALA‐T, and formed the basis for the design of a study in five healthy male volunteers, in whom serum ALA‐T activity was measured before and after a single dose of 1.5 g of vigabatrin. Results Serial sampling confirmed the presence of an in vivo interaction between vigabatrin and ALA‐T, causing an inhibition of enzyme activity of 30–40%. A further 20% reduction was found in vitro in samples taken at the time of the peak plasma vigabatrin concentration after they had been stored for 6 h. Conclusions The clinical significance of these findings is that the levels of ALA‐T activity determined in patients receiving vigabatrin may be inaccurate. The ‘real’ values must be assumed to be higher than those reported after routine testing. To obtain the most realistic measurement of ALA‐T activity in patients, samples should be taken at the times of trough plasma concentration and processed as soon as possible afterwards. Samples stored for any length of time at or above room temperature may also give even more false results.
Cytochromes P450 mediating the N‐demethylation of amitriptyline
Authors: Ghahramani P. , Ellis S. W. , Lennard M. S. , Ramsay L. E. , Tucker G. T. 
Published: October 2003

Aims Using human liver microsomes and heterologously expressed human enzymes, we have investigated the involvement of CYPs 1A2, 2C9, 2C19, 2D6 and 3A4 in the N‐demethylation of amitriptyline (AMI), with a view to defining likely influences on its clinical pharmacokinetics. Methods The kinetics of formation of nortriptyline (NT) from AMI were measured over the substrate concentration range 1–500 μm, using liver microsomes from four extensive metabolisers (EM) and one poor metaboliser (PM) with respect to CYP2D6 activity. Results The data were best described by a two‐site model comprising a Michaelis‐Menten function for a high affinity site and a Hill function for a low affinity site. The activity at the low affinity site was eliminated by triacetyloleandomycin and ketoconazole, selective inhibitors of CYP3A4, such that the kinetics were then described by a two‐site model comprising two Michaelis‐Menten functions. A further decrease in activity was associated with the addition of the CYP2C9 inhibitor sulphaphenazole such that the residual kinetics were best described by a single Michaelis‐Menten function. The addition of quinidine, a selective inhibitor of CYP2D6, along with triacetyloleandomycin and sulphaphenazole produced an additional decrease in the rate of NT formation in all but the PM liver, but did not completely eliminate the reaction. The remaining activity was best described by a single Michaelis‐Menten function. Inhibitors of CYP1A2 (furafylline) and CYP2C19 (mephenytoin) did not impair NT formation. Microsomes from yeast cells expressing CYP2D6 and from human lymphoblastoid cells expressing CYP3A4 or CYP2C9‐Arg N‐demethylated AMI, but those from cells expressing CYPs 1A2 and 2C19 did not. Conclusions We conclude that CYPs 3A4, 2C9 and 2D6 together with an unidentified enzyme, but not CYPs 1A2 and 2C19, mediate the N‐demethylation of AMI. Thus, the clinical pharmacokinetics of AMI would be expected to depend upon the net activities of all of these enzymes. However, the quantitative importance of each isoform is difficult to predict without knowledge of the exposure of the enzymes in vivo to AMI.
Under‐reporting of adverse drug reactions in general practice
Authors: Moride Y. , Haramburu F. , Requejo A. A. , Bégaud B. 
Published: October 2003

Aims In post‐marketing setting, spontaneous reporting by physicians is a mode of surveillance of adverse effects associated with drug use. The objective of this study was to quantitatively assess under‐reporting of adverse drug reactions (ADRs) in general practice. Methods A random sample of 100 general practitioners (GPs) practising in the region of the Bordeaux pharmacovigilance centre were surveyed to obtain data on adverse effects observed. Overall, 81 GPs agreed to record during 3 non‐consecutive working days any effect they believed to be associated with drug use. The types of effects, regardless of their seriousness and labelling, and the drugs suspected were characterized and compared to spontaneous reports received from GPs by the Bordeaux pharmacovigilance centre during the reference period. Results The average number of ADRs observed per day per GP was 1.99. The estimate of the under‐reporting coefficient (U) was 24 433 (95% confidence interval: 20 702–28 837) which indicates that, as a whole, GPs might be expected to report only 1 out of every 24 433 ADRs to the pharmacovigilance centre. Under‐reporting was lowest for serious and unlabelled effects (U=4610; 95%CI: 2514–8454) and for drugs marketed recently (U=12 802; 95% CI: 8174–20 050). Conclusions Adverse effects due to drugs are part of GPs routine activities. According to the observed trend in under‐reporting, there appears to be a selection process which indicates that spontaneous reporting in general practice is not conducive to an exhaustive description of the safety profile of a drug. However, our findings are consistent with greater efficacy of spontaneous reporting in detecting serious and unlabelled effect.
The mechanism of cyclosporine toxicity induced by clarithromycin
Authors: Spicer S. T. , Liddle C. , Chapman J. R. , Barclay P. , Nankivell B. J. , Thomas P. , O'Connell P. J. 
Published: October 2003

Aims Recently a number of case reports have described the interaction of clarithromycin with cyclosporine A, resulting in cyclosporine toxicity. This interaction is presumed to take place via the hepatic cytochrome P450 enzyme system. Methods Following a case of cyclosporine toxicity and acute renal failure in a transplant patient started on clarithromycin, we investigated the effect of oral clarithromycin on the hepatic P450 system in five healthy normal male volunteers, by means of the erythromycin breath test. Results Cytochrome P4503A (CYP3A) activity was reduced in all subjects by a mean level of 26% following clarithromycin treatment. This would result in a significant reduction in cyclosporine clearance in patients receiving clarithromycin. Conclusions As clarithromycin was shown to inhibit CYP3A activity in all subjects tested, we recommend that a high degree of caution be exercised when clarithromycin is administered to patients receiving cyclosporine therapy or other drugs known to be eliminated by CYP3A‐mediated metabolism.
Predictive performance of renal function estimate equations in renal allografts
Authors: Goerdt Paul J. , Heim‐Duthoy Karen L. , Macres Mark , Swan Suzanne K. 
Published: October 2003

Aims Various mathematical models have been developed to estimate glomerular filtration rate (GFR) incorporating variables such as age, gender, height, weight, serum creatinine, and body surface area (BSA). Because adjustments in drug dosing are often based on estimated values of renal function, it is important to define which, if any, of the available models, is appropriate for a specific patient population. A study was undertaken to determine the bias and precision of four mathematical models to estimate GFR in renal allograft recipients. Methods A retrospective review of 142 stable renal allograft patients, using iohexol clearance as a determinant of GFR, was performed. Renal allograft recipients followed in an outpatient clinic setting underwent iohexol clearance studies as part of clinical monitoring in the post‐transplant period. Measured GFR values were compared with four mathematical models used to estimate GFR: the Cockcroft‐Gault equation, the Jelliffe equation, the Walser equation, and the Mawer equation. Bias and precision were determined for each model as the mean squared error and the mean squared error, respectively. Results Patients had a mean age of 44±13 years, 92 were male, and 50 were female. The serum creatinine concentration was 176.8±88.4 &mu;mol l−1 (mean±s.d.). The mean time post‐transplant was 5.1±5.0 years and 38% of patients had insulin‐requiring diabetes mellitus. The bias and precision results for the Jelliffe, Walser, Cockcroft‐Gault, and Mawer models were: −3 and 414; −5 and 381; 16 and 688; and 23 and 1084, respectively. Conclusions The Jelliffe and Walser equations gave the least biased and most precise estimations of GFR when compared with iohexol‐derived measures in patients with renal allografts.
Temporal trends in spontaneous reporting of unlabelled adverse drug reactions
Authors: Haramburu Françoise , Bégaud Bernard , Moride Yola 
Published: October 2003

Aims Trends in spontaneous reporting during the first years on the market were analyzed from a sample of selected drugs, with special attention to unlabelled effects. Methods Ten drugs were selected giving rise to approximately 100 spontaneous reports each during the first 4 years of marketing. Case reports were identified from the national pharmacovigilance database. A bibliographical score assigned at the time of reporting was used to identify unlabelled effects. Results were expressed as reporting rates. Results The average reporting rate peaked during the first year of marketing (54.6 per million treatment‐months; s.d.:62.8), then progressively decreased during the following years. Unlabelled effects represented 63% of all the spontaneous reports during the first year. Conclusions Unlabelled adverse effects represent a high proportion of spontaneous reports during the early years of marketing.
Effects of losartan on cerebral and ocular circulation in healthy subjects
Authors: Matulla Bettina , Streit Gabriele , Pieh Stefan , Findl Oliver , Entlicher Jesusa , Graselli Ursula , Eichler Hans‐Georg , Wolzt Michael , Schmetterer Leopold 
Published: October 2003

Aims The introduction of specific inhibitors of AT1 receptors, such as losartan, has enabled the investigation of the renin‐angiotensin‐system (RAS) in humans in vivo. We studied the role of the RAS in the cerebral and ocular circulation in healthy subjects. Haemodynamic effects of orally administered losartan were investigated with non‐invasive methods. Methods In a placebo‐controlled randomized, double‐blind two way crossover design losartan (100 mg orally) or placebo was administered in 10 healthy subjects. The effect of losartan was studied at hourly intervals for 8 h. In addition, the effect of losartan on haemodynamic changes induced by exogenous angiotensin II (Ang II) was assessed. Blood flow velocities in the ophthalmic and the middle cerebral artery (OA, MCA) were measured with Doppler sonography. Pulsatile choroidal blood flow was estimated with laser interferometric measurement of fundus pulsation. Results Losartan significantly increased fundus pulsation amplitude (+11%, 95% CI: 5 to 16%P<0.0001), tended to increase resistive index in the ophthalmic artery (+12%, 95% CI: 0 to 23%) and tended to decrease mean arterial pressure (−15%, 95% CI: −23 to −1%). Ang II induced effects on cerebral, ocular and systemic haemodynamics were prevented by preceding administration of losartan. Conclusions The present data suggest that Ang II is not a major determinant of cerebral and ocular blood flow in vivo. The observed changes in cerebral and ocular haemodynamic parameters after losartan administration reflect effects on systemic blood pressure.
Effects of tedisamil, atenolol and their combination on heart andrate‐dependent QT interval in healthy volunteers
Authors: Démolis Jean‐Louis , Martel Christine , Funck‐Brentano Christian , Sachse Alisia , Weimann Hans‐Joseph , Jaillon Patrice 
Published: October 2003

Aims Tedisamil is a new blocker of K+ currents in cardiac tissues, exerts bradycardic effects and has shown clinical efficacy in angina pectoris. Theoretically, when coadministered with a &bgr;‐adrenoceptor blocker the tedisamil combination could induce dangerous bradycardia and QT interval prolongation. Therefore, the aim of this study was to evaluate the effects of tedisamil and atenolol alone and in combination, on heart rate and QT interval duration at rest and during exercise tests. Methods The effects of tedisamil (100 mg twice daily) and atenolol (50 mg twice daily) on heart rate and QT interval duration were analysed in a three‐period crossover study in healthy male volunteers. Results This study showed that tedisamil exerted a significant (P<0.05) bradycardic action at rest (−10 beats min−1; 95% CI: ‐6 to ‐15 beats min−1 ) similar to atenolol (−14 beats min−1; ‐11 to ‐17) and drug combination (−9 beats min−1; ‐6 to ‐12). During exercise, at the highest comparable workload, heart rate did not decrease significantly with tedisamil but decreased significantly with atenolol (−42 beats min−1; ‐37 to ‐47) and combination (−47 beats min−1; ‐41 to 52). Atenolol did not modify QT interval duration. Tedisamil alone and in combination with atenolol increased QT interval duration by 12% (95% CI: 7 to 17%) and 12% (8 to 16) respectively at RR=1000ms, but not at RR<700ms (combination). Tedisamil alone and in combination induced a reverse rate‐dependent QT interval prolongation. Conclusions These results indicate that the combination of tedisamil and atenolol is not associated with excessive bradycardia or excessive QT interval prolongation in healthy subjects.
Effect of high‐fat, high‐protein, and high‐carbohydrate meals on the pharmacokinetics of a small dose of ethanol
Authors: Jones A. W. , Jönsson K. Å. , Kechagias S. 
Published: October 2003

Aims To investigate whether the relative amounts of fat, carbohydrate (CHO), or protein in a meal influence the pharmacokinetics of a small dose of ethanol. Methods Nine healthy men received ethanol (0.30 g kg−1 body weight) on five occasions in a randomized cross‐over fashion. On three occasions the dose of ethanol was consumed within 15 min of eating a standardized breakfast of similar volume and calorific value but containing different amounts of fat, CHO, and protein. On two other occasions the same dose of ethanol was ingested on an empty stomach (overnight fast) or administered by intravenous (i.v.) infusion over 30 min. Results The blood‐ethanol profiles showed large inter and intraindividual variations, especially when ethanol was ingested after eating food. The peak blood‐alcohol concentrations (BAC) were 16.6±4.0, 17.7±7.1, and 13.3±4.0 mg dl−1 (mean±s.d.) after fat, CHO, and protein‐rich meals and 30.8±4.3 and 54.3±6.4 mg dl−1 after fasting and i.v. infusion, respectively. The corresponding areas under the concentration‐time profiles (AUC) were 1767±549, 1619±760, 1270±406 mg dl−1 min after fat, CHO, and protein‐rich meals compared with 3210±527 and 4786±446 mg dl−1 min after fasting and i.v. infusion, respectively. The time required to eliminate ethanol from the blood was shortened by 1–2 h in the fed‐state. Conclusions Drinking ethanol after eating a meal, regardless of the nutritional composition, decreases the systemic availability of ethanol. Because gastric emptying is slow and more prolonged with food in the stomach, the delivery of ethanol to the duodenum and the liver will be highly variable as will the hepatic clearance of ethanol. Provided that portal venous BAC remains fairly low and ethanol metabolizing enzymes are not fully saturated then part of the dose of ethanol can be cleared by hepatic first‐pass metabolism (FPM), as one consequence of Michaelis‐Menten elimination kinetics.
Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment
Authors: Püchler K. , Eckl K. M. , Fritsche L. , Renneisen K. , Neumayer H.‐H. , Sierakowski B. , Lavrijssen A. T. J. , Thomsen T. , Roots I. 
Published: October 2003

Aims The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat. Methods Non‐compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CLCR, ≥60 ml min−1 ) and impaired renal function (CLCR 40–59, 20–39, <20 ml min−1 ) after 14 once daily oral doses of 10 mg temocapril hydrochloride. Results For temocapril, there were no statistically significant differences in median tmax or mean Cmax, AUCSS, t½,Z, CL/F between the four groups. Renal clearance, CLR, for temocapril showed a linear decreasing trend with decreasing CLCR [

mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min−1]. Steady‐state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean Cmax or median tmax were detected. With decreasing mean CLCR, mean AUCSS for temocaprilat increased statistically significantly although only 2.4‐fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml−1 h] and t½,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CLR for temocaprilat showed a linear decreasing trend with decreasing CLCR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min−1]. Conclusions These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.
Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme
Authors: Wojnar‐Horton R. E. , Kristensen J. H. , Yapp P. , Ilett K. F. , Dusci L. J. , Hackett L. P. 
Published: October 2003

Aims Methadone is widely used in maintenance programs for opioid‐dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug. Methods Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20–80 mg (0.3–1.14 mg kg−1 ). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms. Results The mean (95% CI) milk/plasma ratio was 0.44 (0.24–0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15 l kg−1 day−1 and a bioavailability of 100% was 17.4 (10.8–24) μg kg−1 day−1. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07–3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5 μg l−1. Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen. Conclusions We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.
Effect of buffering on pharmacokinetics of ketoprofen enantiomers in man
Authors: Fuder H. , Stiegler S. , Wetzelsberger N. , Wieckhorst G. , Lange R. , Lücker P. W. 
Published: October 2003

Aims Concomitant administration of magnesium hydroxide may affect the rate or extent of absorption of non‐steroidal anti‐inflammatory drugs. In order to find out whether or not buffering modifies the pharmacokinetics of ketoprofen, plasma concentration‐time courses resulting from oral administration of unbuffered formulations were compared with those of buffered formulations. Methods Two groups of 12 healthy and young male subjects were included in two randomized cross‐over studies and received single oral doses of ketoprofen 12.5 or 25 mg, respectively, given as tablets which were either unbuffered or buffered with magnesium hydroxide/citrate. Ketoprofen enantiomers in plasma were determined by h.p.l.c. up to 24 h post‐dose. Results Maximum plasma concentrations (Cmax ) of both the (R)‐ and (S)‐enantiomer, observed after administration of the buffered formulations (12.5 and 25 mg), were higher compared with the unbuffered tablets by about 50–80%. The area under concentration‐time data (AUC) was unaffected, and, hence, Cmax/AUC was increased by buffering. Time to Cmax (tmax ) and mean residence time (MRT) tended to be or was shortened by buffering. Conclusions It is concluded that buffering of two ketoprofen formulations with magnesium hydroxide/citrate enhanced the concentration maximum by increasing the rate of absorption and leaving AUC unaffected.