bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between CYP2C19 genotype and proguanil oxidative polymorphism
Authors: Coller J. K. , Somogyi A. A. , Bochner F.
Published: October 2003

Aims To examine the relationship between proguanil metabolism and the number of mutations in CYP2C19 by comparing the CYP2C19 genotype and proguanil phenotype of 10 subjects.

Methods Partial clearance and urinary metabolic ratio data were obtained from a previous study of 10 subjects [
5]. Analysis of CYP2C19 genotypes was performed using PCR amplification followed by restriction endonuclease digestion of genomic DNA from a blood sample.

Results The intrinsic partial clearance of PG to CG ranged from 0.41–10.1l h−1, and was related to the number of functional CYP2C19 alleles present. Genotypic PMs had metabolic ratios >13, while genotypic heterozygote EMs had metabolic ratios <9.

Conclusions Proguanil may be a suitable phenotyping probe for the CYP2C19 genetic polymorphism, however the exact antimode of the urinary metabolic ratio chosen to separate poor and extensive metabolisers needs further investigation.
No effect of short‐term omeprazole intake on acenocoumarol pharmacokinetics and pharmacodynamics
Authors: De Hoon J. N. J. M. , Thijssen H. H. W. , Beysens A. J. M. M. , Van Bortel L. M. A. B.
Published: October 2003

Aims To investigate the effect of omeprazole on the pharmacokinetics of R‐ and S‐acenocoumarol and on their combined anticoagulant activity.

Methods Eight healthy male subjects completed a double‐blind, randomized, placebo‐controlled, two‐way cross‐over study. Subjects were given either omeprazole 40 mg or placebo once daily for 3 days. On day 2 of each study period, a single 10 mg oral dose of racemic acenocoumarol was administered and venous blood samples were collected for pharmacokinetic and pharmacodynamic assessments. A wash‐out period of 2 weeks separated the two study periods.

Results The pharmacokinetics of R‐ and S‐acenocoumarol (AUC 3016±221 and 233±14 ng ml−1 h, respectively) did not change after omeprazole (AUC 2929±256 and 220±18 ng ml−1 h, respectively). Anticoagulant activity (INRmax 1.7±0.1) was unaffected by co‐administration of omeprazole (INRmax 1.7±0.1).

Conclusions The short‐term intake of omeprazole does not affect acenocoumarol pharmacokinetics or pharmacodynamics. These data differ from the results of previous studies on the effect of omeprazole on warfarin, suggesting a different in vivo interaction profile of omeprazole on acenocoumarol than on warfarin. Drug interaction studies with oral anticoagulants should not be restricted to the use of warfarin.
Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p‐hydroxylation
Authors: Schmider Jürgen , Greenblatt David J. , Von Moltke Lisa L. , Karsov Dmitry , Shader Richard I.
Published: October 2003

Aims Inhibition of cytochrome P450 (CYP) activity by selective serotonin reuptake inhibitors (SSRIs) has frequently been reported with regard to pathways mediated by CYP2D6, CYP3A4/5, and CYP1A2. Little data exist on the capability of SSRIs to inhibit CYP2C9.

Methods We investigated the effect of SSRIs on p‐hydroxylation of phenytoin (PPH), an established index reaction reflecting CYP2C9 activity, in an in vitro assay using liver tissue from six different human donors.

Results In control incubations (without inhibitor), 5‐( p‐hydroxy‐phenyl)‐5phenylhydantoin (HPPH) formation rates were: Vmax 0.023 nmol min−1 mg−1; Km 14.3 &mgr;m. Average inhibition constants (Ki ) differed significantly among the SSRIs, with fluvoxamine having the lowest Ki (6 &mgr;m ) followed by R‐fluoxetine (13 &mgr;m ), norfluoxetine (17 &mgr;m ), RS‐fluoxetine (19 &mgr;m ), sertraline (33 &mgr;m ), paroxetine (35 &mgr;m ), S‐fluoxetine (62 &mgr;m ), and desmethylsertraline (66 &mgr;m ). Thus, assuming comparable molar concentrations at the site of inhibition, fluvoxamine can be expected to have the highest probability of interfering with the metabolism of CYP2C9 substrates. S‐fluoxetine is on average a 5 fold weaker CYP2C9 inhibitor than either R‐fluoxetine or the racemic mixture.

Conclusions These findings are consistent with published case reports describing SSRI‐related increments in plasma phenytoin levels. Because phenytoin has a narrow therapeutic index, plasma levels should be closely monitored when SSRIs are coadministered.
Consulting the oracle: a Delphi Study to determine the content of a postgraduate distance learning course in therapeutics
Authors: Boath E. , Mucklow J. , Black P.
Published: October 2003

Aims To determine the content of a distance learning course in therapeutics for general practitioners (GPs).

Methods This paper reports the results of a three‐round Delphi study. The respondent group comprised 21 GPs who were expert in their field. In the first round, the experts were interviewed to determine the knowledge, skills, competencies and attitudes required by GPs to prescribe effectively; the justification for, and scope of a distance learning course; and the preferred learning methods, format and methods of assessment. The first round generated 251 statements, which were collapsed into 108 statements covering thirteen domains. In the second and third rounds, a questionnaire was posted to the GPs. 95% responded to the second round questionnaire and agreed upon 86 statements, which were then collated into four domains. In the third round, 19 GPs rated each of the 86 statements on a five point scale. Consensus was reached for 99% of statements: 40 on the aims, design, format, organization and assessment of the course; and 45 on the knowledge and skills to be acquired by GPs who complete the course.

Results The results revealed a consensus in favour of:

• modules at regular intervals

• some flexibility in meeting deadlines

• interaction among students for mutual support

• easy access to course tutors

• some face‐to‐face contact to complement distance learning material

• clear guidance on effective and safe prescribing

• emphasis on importance of ‘people skills’

Conclusions The Delphi process can be used to determine the competencies required for continuing medical education in therapeutics.
Endotoxin depresses hepatic cytochrome P450‐mediated drug metabolism in women
Authors: Shedlofsky S. I. , Israel B. C. , Tosheva R. , Blouin R. A.
Published: October 2003

Aims In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450.

Methods Experiments were carried out in seven healthy women volunteers (ages 19–51, median 22 years). Each woman received a cocktail of the three drugs on two occassions, once after a saline injection and again after endotoxin.

Results Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor‐α, interleukin‐6, and C‐reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%–41%); hexobarbitone, 20% (95%CI 10–31%); and theophylline, 20% (95%CI 10%–30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively).

Conclusions These data show that endotoxin‐induced inflammation decreases hepatic cytochrome P450‐mediated metabolism of selected probe drugs in women as it does in men.
An investigation of hospital generated pharmaceutical care when patients are discharged home from hospital
Authors: Smith L. , McGowan L. , Moss‐Barclay C. , Wheater J. , Knass D. , Chrystyn H.
Published: October 2003

Aims To investigate how seamless pharmaceutical care could be delivered.

Methods Elderly patients discharged from hospital, to their own home, were randomized into control and study groups. Control and study group patients received the normal discharge information. The study group were also counselled about their medicines and informed about their pharmaceutical care plan. Copies of the plan were given to the study patients. All patients received a domiciliary visit between 7 and 10 days after discharge. Their current medication was compared with that on discharge and contact was made with the General Practitioner as appropriate.

Results Twenty‐eight study and 25 control patients with a mean (s.d.) age of 77.5 (7.3) and 77.6 (6.1) years completed the study. A pharmaceutical domiciliary visit was necessary for 21 (75%) and 24 (96%) of the study and control patients respectively. Compliance was better (P<0.01) in the study group. Unintentional changes to the medication of 31 (14 study and 17 control) patients were found during the visit and after contact with the prescriber all but one prescription was restored to that on discharge.

Conclusions At present it is difficult to ensure seamless pharmaceutical care. A pharmaceutical domiciliary visit may be useful to ensure seamless therapeutic care and thus avoid unnecessary healthcare events and costs after a patient is discharged home.
Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients?
Authors: Pritchard G. , Lyons D. , Webster J. , Petrie J. C. , MacDonald T. M.
Published: October 2003

Aims To assess the effect of trandolapril (2 mg once daily) and indomethacin (25 mg three times daily), alone and in combination, on renal function and renal functional reserve in hypertensive patients (DBP 95–115 mmHg) requiring regular non‐steroidal anti‐inflammatory drugs (NSAIDs).

Methods Randomized, double‐blind, placebo‐controlled, four way crossover design. After 3 weeks treatment renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured using the p‐aminohippurate (PAH) and inulin methods. Renal functional reserve was estimated by measuring RPF and GFR at the end of an intravenous infusion of dopamine 2 μg kg−1 and 10% amino acid solution.

Results There was no significant difference in RPF between treatments: −22.79 ml min−1 (95% CI −54.82, 9.24) for placebo and trandolapril, −10.37 ml min−1 (95% CI −30.7, 9.96) for placebo and indomethacin, −14.78 ml min−1 (95% CI −50.33, 20.77) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve RPF between treatments: −34.96 ml min−1 (95% CI −119.8, 49.88) for placebo and trandolapril, 29.78 ml min−1, −15.18, 74.74) for placebo and indomethacin, and −25.84 ml min−1 (95% CI −87.62, 35.94) for placebo and trandolapril with indomethacin. There was no significant difference in GFR between treatments: −1.01 ml min−1 (95% CI −7.45, 5.42) for placebo and trandolapril, −7.88 ml min−1 (95% CI −15.08, −0.68) for placebo and indomethacin, and −0.36 ml min−1 (95% CI −7.58, 6.86) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve GFR between treatments: 5.13 ml min−1 (95% CI −4.97, 15.23) for placebo and trandolapril, 6.31 ml min−1 (95% CI −1.88, 14.5) for placebo and indomethacin, 7.21 ml min−1 (95% CI 1.26, 13.16) for placebo and trandolapril with indomethacin.

Conclusion In hypertensives chronic treatment with NSAIDs or ACEI alone or in combination did not change RPF or GFR and did not change renal functional reserve capacity of RPF or GFR.
Pharmacokinetics of the S(+) and R(−) enantiomers of vigabatrin during chronic dosing in a patient with renal failure
Authors: Jacqz‐Aigrain Evelyne , Guillonneau Marianne , Rey Elisabeth , Macher Marie‐Alice , Montes Christine , Chiron Catherine , Loirat Chantal
Published: October 2003

Aims To study the pharmacokinetics of vigabatrin in a patient affected with tuberous sclerosis who developed major agitation and aggression, while receiving vigabatrin orally (1.5 g every 12 h) and in whom impaired renal function was diagnosed.

Methods The patient received vigabatrin (0.5 g day−1 ). A pharmacokinetic study of the S(+) and R(−) enantiomers of vigabatrin was performed before and during dialysis. Plasma concentrations were measured at 0, 1, 2, 3, 4, 6, 12, 18 and 24 h by a specific GCMS assay.

Results Before dialysis, the maximum and minimun plasma concentrations of vigabatrin at steady‐state were lower for the S(+) than for the R(−) enantiomer, while the apparent oral clearance was higher for the S(+) than for the R(−) enantiomer (2.97 vs 0.48 l h−1 ). In addition, the haemodialysis clearance was similar for the two enantiomers (4.96 vs 5.15 l h−1 ).

Conclusions Vigabatrin is an irreversible inhibitor of GABA‐transaminase, effective in the treatment of drug‐resistant epilepsy and reported to be eliminated unchanged by renal excretion. Although vigabatrin is known to have stereoselective kinetics, the difference in plasma dry concentrations and pharmacokinetics of the S(+) and R(−) enantiomers that we observed during long term administration at high doses in a patient with impaired renal function, has not been reported before. The question remains of the potential toxicity of the high levels of the R(−) enantiomer.
Single and multiple dose pharmacokinetics of felbamate in the elderly
Authors: Richens A. , Banfield C. R. , Salfi M. , Nomeir A. , Lin C. C. , Jensen P. , Affrime M. B. , Glue P.
Published: October 2003

Aims The objective of this study was to compare the pharmacokinetics, safety and tolerability of the antiepileptic drug felbamate in young and elderly healthy vounteers.

Methods The single and multiple dose pharmacokinetics of felbamate were examined in an open‐label two‐dose level parallel group study in 24 elderly (66 to 78‐year‐old) and 11 young (18 to 45‐year‐old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120 h after administration of single 600 mg or 1200 mg doses, and after multiple doses of 600 mg or 1200 mg administered every 12 h. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events.

Results Single dose felbamate pharmacokinetic parameters differed between young and elderly subjects; compared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1 ml min−1; 90% CI −11.4 to −0.9; P=0.02) and a trend towards a greater half‐life (18.6 vs 21.0 h; 90% CI −0.6 to 5.4; P=0.11). Mean AUC and Cmax values were also higher in elderly subjects. No gender differences were noted for weight‐adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. This may be due to age‐related pharmacokinetic differences, to the rapid dose titration schedule used in this study, and/or to altered sensitivity to felbamate’s pharmacodynamic effects.

Conclusions These findings imply that elderly subjects require lower initial dosing and slower dose titration of felbamate than non‐elderly subjects.
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 μmol 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.
Drug treatment in acute porphyria
Authors: Gorchein A.
Published: October 2003

The acute hepatic porphyrias are rare pharmacogenetic diseases inherited as autosomal dominant conditions of low penetrance. The genetic defect is a 50% deficiency of an enzyme of the haem biosynthetic pathway. Patients may develop ‘neurovisceral attacks’ which include severe abdominal pain, neuropsychiatric manifestations and potentially fatal respiratory paralysis. Attacks occur generally after puberty, are much commoner in females and may be precipitated by endogenous hormonal changes, dieting, alcohol, severe infections, and many drugs. Treatment includes analgesia, early administration of haem, and general supportive measures. Patients are at greater risk of a severe attack on first presentation since an abdominal emergency may be simulated and inappropriate medication, including that for general anaesthesia may exacerbate the crisis. The urine should be tested for raised porphobilinogen, which is pathognomonic of the acute attack, if there is the slightest doubt about diagnosis. The genotype of blood relatives of index cases must be determined so that carriers may avoid drug and other precipitants. Some drugs have been established as safe or unsafe by clinical use, but information about many drugs is not available or is based only on their properties in rodents or in tissue culture systems. The relevance of these to the human condition remains controversial, but drugs shown to be porphyrinogenic in animal systems should be avoided if there is a known safe alternative. Where it is essential to use a drug not known to be safe, close biochemical and clinical observation may warn of an impending attack.
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.
Dose‐ and time‐dependency of the dilator effects of the endothelin antagonist, BQ‐123, in the human forearm
Authors: Berrazueta José R. , Bhagat Kiran , Vallance Patrick , MacAllister Raymond J.
Published: October 2003

Aims Endothelin‐1 is a potent endogenous vasoconstrictor that acts on the endothelin A (ETA ) receptor. The dose‐response and time‐course of the dilator effect of the ETA receptor antagonist, BQ‐123, was investigated in the forearm of healthy volunteers.

Methods Forearm blood flow was measured using mercury‐in rubber strain gauge venous occlusion plethysmography.

Results Following intra‐arterial infusion of BQ‐123 (50 nmol min−1 ) for 5 min, forearm blood flow increased by approximately 60% over the next 60 minutes; lower doses were without significant effect. The degree of dilatation was similar to that observed in previous studies using 20‐fold larger doses.

Conclusions This study confirms that basal endothelin‐1 has a role in the physiological regulation of vascular tone. It is possible that at low doses, BQ‐123 might be a more sensitive pharmacological tool for the detection of abnormal endothelin‐1 mediated constriction.
Elevated serum levels of soluble ICAM‐1 in non‐Hodgkin’s lymphomas correlate with tumour burden, disease activity and other prognostic markers
Authors: Christiansen Ilse , Gidlöf Cecilia , Kälkner Karl‐Michael , Hagberg Hans , Bennmarker Helge , Tötterman Thomas
Published: October 2003

The serum levels of soluble ICAM‐1 (CD54) were significantly elevated in patients with non‐Hodgkin’s lymphomas (NHL, n = 127) and hairy cell leukaemia (HCL, n = 15) compared with healthy controls (n = 31). In high‐grade malignant NHL (n = 79) the sICAM‐1 levels correlated with the tumour mass as reflected in the Ann Arbor staging system but not with bulky disease. Further, the sICAM‐1 levels correlated with disease activity as reflected by the presence of B symptoms and with other known prognostic markers, in particular serum thymidine kinase (sTK). In patients with low‐grade malignant NHL (n = 48) a trend towards higher serum levels of sICAM‐1 was found in patients with advanced stage and B symptoms. In both low‐ and high‐grade malignant NHL, elevated levels of sICAM‐1 were associated with poorer overall and disease‐free survival. The present results indicate that sICAM‐1 levels have a prognostic power equal to that of other serum markers claimed to be of prognostic value in NHL, namely serum lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), beta‐2‐microglobulin (β2m), serum thymidine kinase (sTK), albumin and orosomucoid. The cellular origin and the possible interactions between soluble and surface ICAM‐1 and its ligands needs further exploration.
Early suppressive effects of chemotherapy and cytokine treatment on committed versus primitive haemopoietic progenitors in patient bone marrow
Authors: Schwartz G. N. , Hakim F. , Zujewski J. , Szabo J. M. , Cepada R. , Riseberg D. , Warren M. K. , Mackall C. L. , Setzer A. , Noone M. , Cowan K. H. , O’Shaughnessy J. , Gress R. E.
Published: October 2003

These studies investigated the effectiveness of in vivo administration of cytokines in ameliorating potential marrow damage induced by chemotherapy. Breast cancer patients received 5‐fluorouracil, leucovorin, doxorubicin and cyclophosphamide (FLAC) followed by either GM‐CSF, PIXY321, or no cytokine. Marrow was obtained before and after one or two cycles of FLAC once blood cell counts had recovered. Colony‐forming units for granulocytes and macrophages (CFU‐GM) were used to indicate the effect of therapy on recovery of committed progenitor cells responsible for early blood cell recovery. The frequency and number of CFU‐GM in marrow obtained after FLAC + PIXY321 were significantly lower than in marrow obtained after FLAC + GM‐CSF or FLAC without cytokine. CD34+ cell numbers were also reduced after FLAC + PIXY321. CFU‐GM production in marrow long‐term cultures (LTC) was used to assess the effect of therapy on primitive progenitors. After 5 weeks the number of CFU‐GM in LTC of post‐therapy marrow from all three treatment arms was < 15% of the number in pre‐therapy LTC. Suppressive effects of FLAC on primitive progenitors were observed even when committed progenitors and CD34+ cells had recovered to pre‐therapy levels. These results demonstrate that cytokine treatment did not ameliorate suppressive or toxic effects of FLAC on the functional integrity of the marrow.
Remission maintenance therapy with histamine and interleukin‐2 in acute myelogenous leukaemia
Authors: Brune Mats , Hellstrand Kristoffer
Published: October 2003

Peripheral blasts recovered from patients with acute myelogenous leukaemia (AML) were efficiently lysed by interleukin‐2 (IL‐2)‐activated heterologous natural killer (NK) cells in vitro. The IL‐2‐induced killing of AML blasts was inhibited by monocytes, recovered from peripheral blood by centrifugal elutriation. Histamine, of concentrations within the micromolar range, abrogated the monocyte‐induced inhibition of NK‐cells; thereby, histamine and IL‐2 synergistically induced NK‐cell‐mediated killing of AML blasts. The effect of histamine was apparently mediated by H2‐type histamine receptors (H2R), since the H2R antagonist ranitidine completely blocked the response.

Based on these in vitro findings, seven patients with AML in first (n=2), second (n=3) or third (n=2) complete remission (CR) were given home therapy with interleukin‐2 (IL‐2; 0.9×106 IU×2 s.c.) and histamine (0.4–0.7 mg×2 s.c.) in cycles of 21 d, separated by 6‐week intervals. The patients also received treatment with low‐dose cytarabine and thioguanine between cycles of histamine/IL‐2. Toxicity was moderate and included local reactions to IL‐2 at the site of injection and short‐lasting flush, hypotension, and headache to histamine. The addition of histamine to treatment with IL‐2 significantly enhanced the accumulation of CD25+ T cells in peripheral blood as compared to treatment with IL‐2 alone (P<0.003). Five patients remain in complete remission at 9, 18, 21, 24 and 26 months; the two patients in CR3 relapsed after 8 and 33 months, respectively. In the five patients with earlier relapse, the duration of remission after treatment with histamine/IL‐2 has in each case exceeded that of previous remissions. We conclude that (i) histamine and IL‐2 synergize to kill human AML blasts in vitro, and (ii) histamine/IL‐2 is a safe and feasible approach to immunotherapy of AML which merits further investigation.