bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of interaction between valaciclovir, the L‐valyl ester of aciclovir, and digoxin
Authors: Soul‐Lawton J. H. , Weatherley B. C. , Posner J. , Layton G. , Peck R. W.
Published: March 2003

Aims
 Changes in both digoxin and aciclovir renal clearance following coadministration with some other renally eliminated drugs have been reported. The potential interaction of valaciclovir, with its antiherpetic metabolite aciclovir, and digoxin was investigated.

Methods
 Twelve healthy volunteers (seven males, five females) participated in an open, randomized, four‐period crossover study. Valaciclovir, 1000 mg, was given alone on one occasion, and on another, after the second of two 0.75 mg digoxin doses administered 12 h apart. Blood samples and all urine were collected up to 12 h following the valaciclovir dose for aciclovir radioimmunoassay. On a third occasion, digoxin was given alone and on a fourth, with 1000 mg valaciclovir three times/day for 8 days starting 12 h before the first digoxin dose. Blood samples were taken up to 168 h and all urine collected up to 24 h following the second dose for digoxin radioimmunoassay.

Results
 There were no clinically significant differences in digoxin or aciclovir pharmacokinetic parameters when digoxin or valaciclovir was given alone or in combination.

Conclusions
 No dosage adjustment is required when valaciclovir and digoxin are coadministered.
New active substances authorized in the United Kingdom between 1972 and 1994
Authors: Jefferys David B. , Leakey Diane , Lewis John A. , Payne Sandra , Rawlins Michael D.
Published: March 2003

Aims
 The study was undertaken to assemble a list of all new active medicinal substances authorised in the United Kingdom between 1972 and 1994; to assess whether the pattern of introductions had changed; and to examine withdrawal rates and the reasons for withdrawal.

Methods
 The identities of those new active substances whose manufacturers had obtained Product Licences between 1972 and 1994 were sought from the Medicines Control Agency's product data‐base. For each substance relevant information was retrieved including the year of granting the Product Licence, its therapeutic class, whether currently authorised (and, if not, reason for withdrawal), and its nature (chemical, biological etc.).

Results
 The Medicines Control Agency's data‐base was cross‐checked against two other data‐bases for completeness. A total of 583 new active substances (in 579 products) were found to have been authorised over the study period. The annual rates of authorisation varied widely (9 to 40 per year). Whilst there was no evidence for any overall change in the annual rates of authorising new chemical entities, there has been a trend for increasing numbers of new products of biological origin to be authorised in recent years. Fifty‐nine of the 583 new active substances have been withdrawn (1 each for quality and efficacy, 22 for safety, and 35 for commercial reasons).

Conclusions
 For reasons that are unclear there is marked heterogeneity in the annual rates of authorisation of new active substances. Their 10 year survival is approximately 88% with withdrawals being, predominantly, for commercial or safety reasons. This confirms the provisional nature of assessments about safety at the time when a new active substance is introduced into routine clinical practice, and emphasises the importance of pharmacovigilance.
Frequency and cost of serious adverse drug reactions in a department of general medicine
Authors: Moore Nicholas , Lecointre Dominique , Noblet Catherine , Mabille Michel
Published: March 2003

Aims
 To assess the frequency and cost of drug reactions causing or prolonging hospitalization.

Methods
 All patients admitted to an internal medicine ward over 6 months were evaluated to identify serious adverse reactions. The number of drug classes on admission or at the time of the adverse drug reaction (ADR) was counted. Excess ADR‐related hospital stay was computed using a) raw excess duration of hospital stay, b) correction of duration of hospital stay by age, sex, and number of drug classes, and c) estimation by investigator of excess hospital stay.

Results
 Three hundred and twenty‐nine patients were evaluated: 212 male, 117 female, mean age 57.2 (males: 52.2, females: 66.2 (P<0.05)), range 17–95 years. They stayed a total of 3720 hospital days (mean stay 11.3 days). 298 had no ADR (mean age 55.8, taking a mean of 2.7 drug classes, 10.7 days hospital stay); 31 had ADRs: in 10, the ADR caused admission in patients with a mean age of 84 (P<0.01 vs the two other groups), taking 6.3 drug classes, who stayed a mean of 15.1 days; 21 occurred in hospital in patients with a mean age of 63.6, taking 4.2 drug classes (P<0.01), who stayed a mean of 19.2 days (P<0.01 vs patients without ADRs). In four the ADR was fatal (13% of ADRs, 40% of deaths). Raw ADR‐related excess hospital stay was 318 days (8.6% of all hospital days), after multivariate correction 282 days (7.6% of all hospital days), and with investigator estimation 197 days (5.3% of all hospital days). Point prevalence of ADRs at admission was 3%, incidence rate in hospital was 5.6/1000 patient‐days.

Conclusions
 3% of the admissions were related to ADRs. In addition, 6.6% of hospitalized patients had significant ADRs. Between 5 and 9% of hospital costs were related to ADRs. In 24 of the 31 patients with ADRs (77%), these were related to the pharmacological properties of the involved drugs, and may possibly have been avoidable.
Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children
Authors: Anderson B. J. , Holford N. H. G. , Woollard G. A. , Chan P. L. S.
Published: March 2003

Aims
 Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.

Methods
 Concentration‐time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg−1 were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two‐stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model.

Results
 Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2 l h−1 (CV 47%), volume of distribution 67.1 l (CV 58%) and absorption rate constant 0.77 h−1 (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).

Conclusions
 Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2 h before anticipated pain or fever in children.
Compliance with restrictions on the subsidized use of proton pump inhibitors in Australia
Authors: McManus Peter , Marley John , Birkett Donald J. , Lindner Julie
Published: March 2003

Aims
 To determine among a cohort of patients newly dispensed a prescription for a proton pump inhibitor (PPI) the extent of prior use of other less expensive agents such as antacids and H2‐receptor antagonists as evidence of a ‘stepped care’ approach to peptic ulcer and oesophageal disease.

Methods
 A retrospective drug utilization study was conducted within the Pharmaceutical Benefits Scheme (PBS) claims database in Australia. A cohort of social security recipients, who received approval for PPI supply in the month of October 1996, had no prior PPI approval in the previous 18 months and went on to have the drug dispensed, was assembled. This group of ‘new PPI starters’ was then examined for supply of less expensive prescription medicines to treat peptic ulcer and oesophageal disease in the 12 months prior to obtaining their PPI approval.

Results
 In a cohort of 4554 defined new PPI users, 1205 (26.5%) showed no use of H2‐receptor antagonists, antacids, cisapride, cytoprotectants or antiregurgitants in the 12 month period prior to commencing the PPI. The major reason for use given by prescribers for PBS supply was ‘severe refractory ulcerating oesophagitis’.

Conclusions
 Subsidized supply is currently restricted on cost‐effectiveness grounds to refractory peptic ulcer disease or severe oesophageal disease. Despite this, utilization and epidemiological data suggest that there is widespread leakage of use outside these indications particularly to less severe forms of oesophageal disease. This patient tracking study has shown within the PBS database that around a quarter of the patients are treated directly with a PPI without being prescribed less expensive agents at least in the preceding 12 months.
Stereoselective steady state disposition and action of propafenone in Chinese subjects
Authors: Li Gao , Gong Pei‐Li , Qiu Jun , Zeng Fan‐Dian , Klotz Ulrich
Published: March 2003

To investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enatiomer‐enantiomer interaction in Chinese subjects.

 Eight healthy male Chinese individuals received in a double‐blind, randomized, cross‐over study racemic propafenone (150 mg every 6 h), (S)‐, and (R)‐propafenone (150 mg each every 6 h) and placebo orally for 4 days. During the last dosing interval the plasma concentrations of both enantiomers of propafenone were measured and ECG, blood pressure (MAP) and heart rate were monitored.

 Whereas the apparent elimination half‐life (t½,z ), mean residence time (MRT) and time to reach peak concentrations (tmax ) of (S)‐ and (R)‐propafenone were similar and independent of the administered agent, significant differences were observed in the apparent oral clearance (CLO ) of the enantiomers. During dosing with racemic propafenone CLO of (S)‐ and (R)‐propafenone averaged (±s.d.) 1226±751 and 1678±625 ml min−1, respectively (P=0.024). Following the administration of the pure enantiomers CLO of (S)‐propafenone increased (P=0.007) to 2028±959 ml min−1 and that of (R)‐propafenone was reduced (P=0.042) to 1318±867 ml min−1. Both enantiomers and the racemate caused about a 10% increase in the QRS duration (P<0.05) and PR‐interval (P<0.01) when compared with placebo. The increase in maximum exercise heart rate was significantly (P<0.05) attenuated only at 3 h following the administration of the racemate and the S‐enantiomer. MAP and QTC were not affected significantly.

 These data indicate that the stereoselective disposition of propafenone is similar in Chinese and Caucasian subjects (previously published findings), the (R)‐enantiomer being cleared more rapidly. A similar enantiomer‐enantiomer interaction also occurred. Thus, when the racemate was given, the elimination of (S)‐propafenone was impaired and that of the (R)‐form accelerated compared with single enantiomer administration. The results indicate that dosage adjustments are probably not required in Chinese patients receiving propafenone.
Relationships among liver and kidney volumes, lean body mass and drug clearance
Authors: Nawaratne Sumith , Brien Jo‐anne E. , Seeman Ego , Fabiny Robert , Zalcberg John , Cosolo Walter , Angus Peter , Morgan Denis J.
Published: March 2003

Aims To determine whether lean body mass (LBM), a possible surrogate of liver and kidney volumes, correlates with hepatic and renal drug clearances.

Methods Twenty‐one disease‐free patients with a history of cancer and with normal hepatic and renal function were studied. Salivary pharmacokinetics of oral antipyrine (1200 mg) and 24 h creatinine clearance were determined following the determination of LBM by dual energy X‐ray absorptiometry and the determination of liver and kidney volumes by helical CT scanning.

Results Liver volume correlated with LBM (r2=0.21, P=0.04), body surface area (BSA) (r2=0.54, P<0.001), and total body weight (TBW) (r2=0.61, P<0.001). Kidney volume correlated with LBM (r2=0.49, P<0.001), BSA (r2=0.43, P=0.002) and TBW (r2=0.24, P=0.03). Stepwise multiple regression analysis, incorporating the independent variables of age, height, weight, sex, BSA, LBM, alcohol consumption, smoking status and liver volume and the dependent variable antipyrine clearance, indicated that LBM was the only independent correlate of antipyrine clearance. A stepwise multiple regression analysis with kidney volume in the independent variables, and creatinine clearance as dependent variable, showed that kidney volume and age were the only independent correlates of creatinine clearance. A nomogram using serum creatinine and LBM was comparable with the Cockcroft and Gault nomogram in calculating creatinine clearance.

Conclusions Of the anthropometric variables tested, LBM was the only determinant of antipyrine clearance, but this was not due to a relationship between LBM and liver volume. By contrast, the relationship between creatinine clearance and LBM appeared to be due to a relationship between LBM and kidney volume.
Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance
Authors: Schaber  , Stevens  , Gaertner  , Dietz  , Breyer‐Pfaff
Published: March 2003

Aims N‐Desmethylclozapine and clozapine N‐oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.

Methods From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid‐phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.

Results The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N‐desmethylclozapine 9.7%, and clozapine N‐oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N‐desmethylclozapine and clozapine N‐oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N‐desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.

Conclusions Clozapine, N‐desmethylclozapine and clozapine N‐oxide are highly protein‐bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N‐demethylation and N‐oxidation must make major contributions to the total fate of clozapine in patients.
Population pharmacokinetics and therapeutic response of CGP 56697 (artemether+benflumetol) in malaria patients
Authors: Ezzet Farkad , Mull Robert , Karbwang Juntra
Published: March 2003

Aims To investigate the pharmacokinetic and pharmacodynamic properties of artemether and benflumetol in a fixed combination tablet (CGP 56697) and to offer an explanation for the lower than expected cure rate in a Thai clinical trial.

Methods Two hundred and sixty patients were enrolled into a randomized, double‐blind, parallel group, dose‐finding trial. CGP 56697 was given orally, either as: A, 4×4 tablets over 48 h; B, 4×2 tablets over 48 h or C, 3×4 tablets over 24 h. Each tablet contained artemether 20 mg amd benflumetol 120 mg. The pharmacokinetics were determined using a population‐based approach combining full profiles (42 patients) and sparse data (218 patients). Parasite clearance time and 28 day cure rate were correlated with the derived pharmacokinetic parameters.

Results The median absorption half‐life of benflumetol was 5.3 h, with a tmax of 10 h and terminal elimination half‐life of 4.5 days. For artemether (and its metabolite, dihydroartemisinin), the corresponding values were 1.9 (1.9) h, 1.8 (1.2) h, and 0.84 (0.43) h. The variability in bioavailability of artemether and dihydroartemisinin was large both between doses and between patients, but was less pronounced for benflumetol. Compared with the first dose, benflumetol bioavailability was estimated to increase three‐fold by the third and fourth doses. Higher artemether or dihydroartemisinin AUC was found to decrease parasite clearance time. Higher benflumetol AUC was found to significantly increase the chance of cure.

Conclusions Using a population‐based approach it was confirmed that the pharmacokinetic and pharmacodynamic properties of benflumetol and artemether differ markedly. Benflumetol AUC is associated with cure and the effect of benflumetol when coadministered with artemether is to prevent recrudescence. The mode of action of benflumetol is consistent with its longer elimination half‐life. A short course of low‐dose artemether, which is rapidly absorbed and has a short elimination half‐life, produced effective parasite clearance. The complementary pharmacokinetic and pharmacodynamic properties of benflumetol and artemether was the main rationale for developing a fixed‐dose combination. While the 4×4 dose regimen is very effective in most endemic areas, the poorer absorption (2.5 fold lower than in China) and the more resistant parasites in Thailand require higher doses of this drug.
Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve
Authors: Annane  , Bellissant  , Sebille  , Lesieur  , Mathieu  , Raphael  , Gajdos
Published: March 2003

Aims To investigate the relationship between adrenal gland function and pressor response to noradrenaline in septic shock.

Methods Basal cortisol level, noradrenaline—mean arterial pressure dose‐response curve and cortisol response to intravenous corticotrophin bolus were obtained in nine patients fulfilling usual criteria for septic shock and in six normal volunteers. In patients with septic shock, dose‐response curve to noradrenaline was determined a second time 60 min after a 50 mg intravenous hydrocortisone bolus.

Results As compared with controls, patients with septic shock had increased basal cortisol levels (mean±s.d.: 1564±818 vs 378±104 nmol l−1, P=0.002, 95% confidence interval for difference in means: [452, 1920]) and a blunted cortisol response to corticotrophin (403±461 vs 1132±195 nmol l−1, P=0.008, [−1163, −295]). Five patients had impaired adrenal function reserve. As compared with controls, septic patients displayed a moderate and non significant decrease in pressor sensitivity to noradrenaline (P=0.112). As compared with patients with adequate adrenal response, patients with impaired adrenal function reserve showed a significant decrease in pressor sensitivity to noradrenaline (P=0.038). In septic patients, hydrocortisone improved pressor response to noradrenaline (P=0.032). This effect was more marked in patients with impaired adrenal function reserve so that, as compared with patients with adequate response, the difference was no longer significant (P=0.123).

Conclusions In septic shock, impaired adrenal function reserve may partly be accounted for by the depressed pressor sensitivity to noradrenaline. The latter may be substantially improved by physiological doses of hydrocortisone.
Achilles tendinitis associated with fluoroquinolones
Authors: Van Der Linden  , Van De Lei  , Nab  , Knol  , Stricker
Published: March 2003

Aims To determine whether there is an association between use of fluoroquinolones and tendinitis in a large population under everyday circumstances.

Methods A retrospective cohort study was carried out in a dynamic population. Data came from the IPCI‐database which consists of all data on consultations, morbidity, prescriptions and other interventions, as registered by GPs in a source population of approximately 250 000 persons. For this study data were collected from 41 general practices in the period from January 1st, 1995 through December 31st, 1996. All persons treated with either fluoroquinolones, amoxicillin, trimethoprim, cotrimoxazole or nitrofurantoin were followed from the first day of treatment until the outcome of interest, death, transfer to another practice, or end of the study period, whichever came first. The risk window was defined as the legend duration +1 month. Potential cases were defined as a registration of a tendinitis or tendon rupture. Patients with a history of tendinitis or tendon rupture, preceding trauma or inadequate diagnoses were excluded on the basis of a review of the patient profiles and additional clinical data, blinded as to the exposure status. Results were adjusted for age, gender, concurrent corticosteroid exposure and number of GP visits.

Results There were 1841 users of fluoroquinolones and 9406 users of the other antibacterial drugs with an average duration of 9 and 7 days, respectively. Tendinitis or tendon rupture was registered in 97 profiles, but after review only 22 complied with the case definition. The adjusted relative risk of tendinitis to fluoroquinolones was 3.7 (95%CI: 0.9–15.1) for Achilles tendinitis and 1.3 (95%CI: 0.4–4.7) for other types of tendinitis. Achilles tendinitis to ofloxacin had a relative risk of 10.1 (95%CI: 2.2–46.0) and an excess risk of 15 cases per 100 000 exposure days.

Conclusions Although the numbers in our study are small, our results suggest that some fluoroquinolones may increase the risk of Achilles tendinitis, and that this risk increase is highest for ofloxacin.
Evidence for involvement of polymorphic CYP2C19 and 2C9 in the N‐demethylation of sertraline in human liver microsomes
Authors: Xu Zhen‐Hua , Wang Wei , Zhao Xue‐Jun , Huang Song‐Lin , Zhu Bing , He Nan , Shu Yan , Liu Zhao‐Qian , Zhou Hong‐Hao
Published: March 2003

Aims The present study was designed to define the kinetic behaviour of sertraline N‐demethylation in human liver microsomes and to identify the isoforms of cytochrome P450 involved in this metabolic pathway.

Methods The kinetics of the formation of N‐demethylsertraline were determined in human liver microsomes from six genotyped CYP2C19 extensive (EM) and three poor metabolisers (PM). Selective inhibitors of and specific monoclonal antibodies to various cytochrome P450 isoforms were also employed.

Results The kinetics of N‐demethylsertraline formation in all EM liver microsomes were fitted by a two‐enzyme Michaelis‐Menten equation, whereas the kinetics in all PM liver microsomes were best described by a single‐enzyme Michaelis‐Menten equation similar to the low‐affinity component found in EM microsomes. Mean apparent Km values for the high‐and low‐affinity components were 1.9 and 88 μm and V max values were 33 and 554 pmol min−1 mg−1 protein, respectively, in the EM liver microsomes. Omeprazole (a CYP2C19 substrate) at high concentrations and sulphaphenazole (a selective inhibitor of CYP2C9) substantially inhibited N‐demethylsertraline formation. Of five monoclonal antibodies to various cytochrome P450 forms tested, only anti‐CYP2C8/9/19 had any inhibitory effect on this reaction. The inhibition of sertraline N‐demethylation by anti‐CYP2C8/9/19 was greater in EM livers than in PM livers at both low and high substrate concentrations. However, anti‐CYP2C8/9/19 did not abolish the formation of N‐demethylsertraline in the microsomes from any of the livers.

Conclusions The polymorphic enzyme CYP2C19 catalyses the high‐affinity N‐demethylation of sertraline, while CYP2C9 is one of the low‐affinity components of this metabolic pathway.
Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline
Authors: Dilger Karin , Zheng Zhichang , Klotz Ulrich
Published: March 2003

Aims Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline.

Methods Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double‐blind, four‐period, placebo‐controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8–10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady‐state (day 10).

Results In all periods, point estimates and 90% confidence intervals of the area under the concentration‐time curves (AUC), maximum steady‐state concentrations and peak‐trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87–0.97), 0.90 (0.85–0.95) and 1.00 (0.95–1.06) for omeprazole, lansoprazole and pantoprazole, respectively.

Conclusions Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline.
Pharmacokinetic‐pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers
Authors: Blin  , Jacquet  , Callamand  , Jouve  , Habib  , Gayraud  , Durand  , Bruguerolle  , Pisano
Published: March 2003

Aims To describe the pharmacokinetic‐pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers.

Methods This was a randomized double‐blind, placebo‐controlled two‐way cross‐over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures.

Results The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml−1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks.

Conclusions The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines.
Attitudinal survey of voluntary reporting of adverse drug reactions
Authors: Eland  , Belton  , Van Grootheest  , Meiners  , Rawlins  , Stricker
Published: March 2003

Aims Voluntary adverse drug reaction (ADR) reporting schemes have operated since the early sixties in many Western countries. It is generally recognized, however, that only a small proportion of ADRs is actually reported. The current survey was conducted to assess attitudes towards reporting of ADRs, and to study which types of ADRs are reported.

Methods A questionnaire seeking reasons for nonreporting was sent to a random sample of 10% of medical practitioners in The Netherlands in October 1997. After 6 weeks, a reminder was sent to those who had not responded.

Results One thousand four hundred and forty‐two (73%) questionnaires were returned, of which 94% were complete. The percentage of GPs (51%) which had ever reported an ADR to the national reporting centre was significantly higher than the percentage of specialists (35%), who reported more often to the pharmaceutical industry (34%vs 48%). 86% of GPs, 72% of surgical specialists and 81% of medical specialists had ever diagnosed an ADR, which they had not reported. Uncertainty as to whether the reaction was caused by a drug (72%), the ADR being trivial (75%) or too well known (93%) were the most important reasons for not reporting. 18% were not aware of the need to report ADRs, 22% did not know how to report ADRs, 38% did not have enough time, 36% thought that reporting was too bureaucratic and only 26% of Dutch physicians knew which ADRs to report. A serious ADR, an unlabelled ADR, an ADR to a new drug, history of reporting of one or more ADRs, and specialty were all independently associated with reporting of 16 hypothetical ADRs. Surgical and medical specialists tended to report less often than GPs.

Conclusions There is a considerable degree of underreporting, which might partly be explained by lack of knowledge and misconceptions about spontaneous reporting of adverse drug reactions.
Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5‐HT1B‐ and 5‐HT1F‐receptor activation
Authors: Razzaque  , Heald  , Pickard  , Maskell  , Beer  , Hill  , Longmore
Published: March 2003

Aims Sumatriptan is a 5‐HT1B/1D‐receptor agonist which also has affinity for 5‐HT1F‐receptors. The vasoconstrictor effects of sumatriptan are thought to be 5‐HT1B‐receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5‐HT1F‐receptors has also been identified and this study addresses the possibility of whether 5‐HT1F‐receptor activation contributes to vasoconstriction.

Methods The ability of two selective 5‐HT1B/1D‐receptor antagonists (GR125,743 and GR127,935) with no affinity for 5‐HT1F‐receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5‐HT1B/1D‐receptor agonists (sumatriptan, zolmitriptan, CP122,288, L‐741,519 and L‐741,604), some with high affinity for 5‐HT1F‐receptors and the non‐selective 5‐HT‐receptor agonists 5‐HT and 5‐CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5‐HT1B‐, 5‐HT1D‐and 5‐HT1F‐receptors expressed in CHO cell lines.

Results GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan‐induced responses in a non‐competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5‐HT1B‐receptor affinity (r=0.93, P=0.002) but not with 5‐HT1D‐ or 5‐HT1F‐receptor affinity (r=0.74, P=0.06; r=0.31, P=0.49, respectively).

Conclusions These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan‐like agents is 5‐HT1B‐receptor mediated with little if any contribution from 5‐HT1F‐receptor activation.
Evaluation of the effect on heart rate variability of a β2‐adrenoceptor agonist and antagonist using non‐linear scatterplot and sequence methods
Authors: Hanratty  , Silke  , Riddell
Published: March 2003

Aims To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac β2‐adrenoceptor in healthy volunteers, using standard time‐domain summary statistics and non‐linear methods (scatterplot and quadrant analysis).

Methods Under double‐blind and randomised conditions (Latin square design), 17 normal volunteers received placebo, salbutamol (β2‐adrenoceptor partial agonist), ICI 118,551 (specific β2‐adrenoceptor antagonist), or salbutamol plus ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22.30 h, with HRV assessed from the sleeping heart rates.

Results Salbutamol reduced the long‐term (SDNN: 135 ms [120, 156], SDANN: 107 ms [89, 124]) time‐domain indicators of HRV compared with placebo (SDNN: 39 [24, 55], SDANN 42 [29, 56], {mean difference [95% confidence intervals of difference]}). Alone, ICI 118,551 did not effect HRV, but in combination blocked the actions of salbutamol. Scatterplot length (944 ms [869, 1019]) and area (222*103 ms2 [191, 253]) were reduced by salbutamol compared with placebo; (length difference (164 [98, 230]) and area difference 59 [36, 83]). Scatterplot width (dispersion) was lower at both low (width RR‐1 25% salbutamol 277 ms [261, 293]: salbutamol minus placebo 14 ms [0, 28]) and high (width 75% salbutamol 417 [391, 443]: salbutamol minus placebo 41 [20, 62]) heart rates. ICI 118,551 alone did not alter scatterplot parameters but in combination blocked the effect of salbutamol. Cardiac acceleration episodes (i.e. consecutive ΔRR and ΔRRn+1 shorten) were increased following salbutamol 7288 [6089, 8486] compared with placebo −1890 [−2600, −1179]; the beat‐to beat difference (ΔRRn+1 ) was reduced after salbutamol compared with the other treatments. ICI 118,551 did not effect acceleration episodes but reduced the effect of salbutamol when used in combination.

Conclusions Agonism at the cardiac β2‐adrenoceptor in healthy volunteers with salbutamol altered autonomic balance towards sympathetic dominance; this re‐balancing was blocked by ICI 118,551 given in combination with salbutamol. However antagonism at the β2‐adrenoceptor with ICI 118,551 alone did not significantly alter the HRV. The β2‐adrenoceptor modulates HRV in healthy volunteers; the implications of agonism and antagonism at the β2‐adrenoceptor in cardiovascular disease states warrants further investigation.
Glomerular, tubular and interstitial nephritis associated with non‐steroidal antiinflammatory drugs. Evidence of a common mechanism
Authors: Ravnskov Uffe
Published: March 2003

Aims To study the mechanisms behind NSAID‐associated nephropathy.

Methods Analysis of published case reports satisfying strict criteria for NSAID nephropathy.

Results Ninety‐seven cases with acute nephritis (AN; 19 patients), minimal change nephropathy (MC; 38 patients), membranous glomerulonephritis (MGN; 19 patients), focal sclerosis (FS; 13 patients) and other glomerulonephritis subgroups (8 patients) were identified. Hypersensitivity reactions were seen in all groups, most often in AN. Proteinuria was more severe in MC and FS than in MGN and unrelated to amount of glomerular deposits. The mean NSAID treatment time was 1.7 months in AN, 8.2 months in MC and 39 months in MGN and associated with amount of glomerular deposits, fusion of podocytes and proteinuria, and inversely associated with hypersensitivity, interstitial damage and renal failure. Rheumatic diseases were common in MGN. At follow‐up 68 of 72 patients who had discontinued NSAID treatment had improved, 57 with normal renal function.

Conclusions NSAID nephropathy may be caused by hypersensitivity. The reaction is milder than in drug‐induced acute tubulointerstitial nephritis, probably because the offending drug inhibits the inflammatory reaction it has started itself. Heavy proteinuria is probably due to lymphokines produced as a result of the immunological response. If the allergic reaction is strong, AN is produced rapidly with severe renal failure but little proteinuria; if it is less violent, immunocompetent cells may develop to produce lymphokines and proteinuria. Immune complexes may be formed eventually, secondary to the increased glomerular permeability, more easily in patients with a hyperactive immune system and with little consequence for renal function.
Is reporting rate a good predictor of risks associated with drugs?
Authors: Pierfitte Corinne , Bégaud Bernard , Lagnaoui Rajaa , Moore Nicholas D.
Published: March 2003

Aims Uncertainty as to relative under‐reporting plagues the comparisons of spontaneous reporting rates as a tool for decision‐making in pharmacovigilance. However, it is generally accepted that under‐reporting should be reasonably similar for similar drugs sharing the same indication, country and period of marketing. To test this, we compared the adverse drug reaction reporting rates to the French regional pharmacovigilance centres for six pairs of identical drug marketed at the same time by different companies under different brand names (co‐marketing).

Methods All reaction reports were related to sales, to compute reporting rate; within each pair, the reporting rate ratio and its confidence interval were calculated.

Results The rate ratios were all between 0.76 and 1.33. Two of them were significantly different from 1 (1.28; 95% C.I. [1.01; 1.60] and 1.33; 95% C.I. [1.06; 1.74]).

Conclusions These small differences in reporting rates would not warrant regulatory action and support the usual assumption of similar reporting for similar drugs.
Midazolam effects on prepulse inhibition of the acoustic blink reflex
Authors: Schächinger Hartmut , Müller Beatrice U. , Strobel Werner , Langewitz Wolf , Ritz Rudolf
Published: March 2003

Aims The eye‐blink response following sudden acoustic noise bursts is part of the startle reflex. The magnitude of the startle response can be attenuated by presentation of a weak stimulus before the ‘startle‐eliciting’ stimulus (prepulse inhibition, PPI). PPI is a stable finding in awake humans but may be altered by anaesthetic drugs. We investigated whether the application of benzodiazepines altered the magnitude of PPI in healthy male volunteers.

Methods In an open‐label noncontrolled investigation, the effect of the benzodiazepine agonist midazolam on PPI was assessed in the absence and presence of the antagonist flumazenil. After an initial control period of 60 min three consecutive periods, each of 60 min, with progressively increasing concentrations of midazolam were studied (0.02, 0.06, 0.14 mg kg−1 h−1 ). A final 60 min period during the administration of flumazenil (0.004 mg kg−1 h−1 ) and while the agonist was still present was also studied. Drug was administered intravenuously as a combination of bolus, 50% of total dose and continuous infusion over the 60 min period. Electromyographic (EMG) response of the right orbicularis oculi muscle was used to assess the startle response to noise bursts of 50 ms duration (95 dB(A)). Noise bursts were randomly preceded by nonstartling prepulses (800 Hz sinus, 50 ms duration, 65 dB(A), prepulse to noise interval 120 ms). The magnitude of PPI was calculated by dividing the EMG response to nonprepulsed stimuli by the response to prepulsed stimuli for each individual and period. Eleven subjects participated in the study, two of them were excluded from the statistical analysis because startle responses could not be reliably elicited (final sample size n=9).

Results The magnitude of PPI was inversely related to the concentration of midazolam. This relationship was described by a sigmoidal Emax model, giving an Emax of 0.65±0.13, an ED50 of 33.9±10.9 ng ml−1 and gamma of 3.5±1.0. During infusion of flumazenil and in the presence of midazolam, the magnitude of PPI increased by 0.11 (95% CI, 0–0.22, P≤0.04), which is consistent with its mode of action as a benzodiazepine antagonist.

Conclusions In healthy male volunteers the magnitude of PPI varies according to agonism and antagonism of benzodiazepine receptors, suggesting that the assessment of PPI may be potentially useful to monitor the sedative effect of benzodiazepines in the clinical setting.
Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers
Authors: Fukuda Tsuyoshi , Yamamoto Isamu , Nishida Yuko , Zhou Qian , Ohno Masako , Takada Kanji , Azuma Junichi
Published: March 2003

Aims Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O‐desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population.

Methods Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I‐RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h.

Results The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively.

Conclusions These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.
Effect of troglitazone on plasma lipid metabolism and lipoprotein lipase
Authors: Kobayashi Junji , Nagashima Izumi , Hikita Minoru , Bujo Hideaki , Takahashi Kazuo , Otabe Masako , Morisaki Nobuhiro , Saito Yasushi
Published: March 2003

Aims To clarify how troglitazone, an insulin‐sensitizing agent, affects lipid metabolism and postheparin plasma lipoprotein lipase (LPL).

Methods Fifteen patients (3 male, 12 female) (the average age 62±7 years; the mean body mass index (BMI) 25±3 kg/m2 ) were recruited for this study. The serum lipids and postheparin plasma lipoprotein lipase (LPL) mass before and 4 weeks after oral administration of troglitazone (200 mg day−1 ) were measured. A mouse preadipocyte cell line, 3T3‐L1, was incubated with troglitazone and LPL enzyme protein mass in the culture media was measured by an enzyme linked immunosorbent assay. A reverse transcription polymerase chain reaction (RT‐PCR) using primers specific for the carboxyl terminal 135 amino acid of mouse LPL cDNA was used to evaluate the effect of troglitazone on expression of LPL and Northern blot analysis carried out to determine expression of LPL.

Results The average levels before treatment of fasting serum total cholesterol, triglycerides, high density lipoprotein cholesterol, plasma glucose and glycohaemoglobin A1c were 5.6±0.9, 1.8±1.0, 1.5±0.5, 8.1±1.7 mmol l−1 and 7.8±1.6% respectively. Four weeks after treatment, those levels were 5.4±0.9, 1.2±0.3 (P=0.004), 1.6±0.5 (P=0.02) mmol l−1, 7.7±2.3 mmol l−1 and 7.3±0.6% (P=0.01), respectively. The postheparin plasma LPL mass increased from 226±39 to 257±68 ng ml−1 (P=0.03) during that period. The LPL mass in the media of 3T3 L1 cells cultured in the presence of 10, 20 or 30 μm of this compound increased in a dose dependent manner. RT‐PCR revealed that the area of the bands of the RT‐PCR products on 1.5% agarose gel analyzed with NIH image from the cell extracts cultured in the presence of 10 μm troglitazone was significantly larger (P=0.0069) than that in the absence of this compound. Northern blot analysis revealed that in the cultured 3T3‐L1 cells, the expression of LPL was enhanced in the presence of 10 μm troglitazone.

Conclusions Troglitazone improves plasma triglyceride‐rich lipoproteins metabolism by enhancing the expression of LPL in adipocytes.
Methadone N‐demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4
Authors: Foster David J. R. , Somogyi Andrew A. , Bochner Felix
Published: March 2003

Aims To investigate the kinetics of CYP‐mediated N‐demethylation of methadone in human liver microsomes, and examine the role of stereoselectivity and CYP isoforms involved.

Methods The kinetics of 2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP) formation via N‐demethylation of rac‐, (R)‐ and (S)‐methadone in human liver microsomes prepared from six liver samples were determined by h.p.l.c., and inhibition of metabolic function was studied using isoform‐specific chemical inhibitors and monoclonal antibodies. Microsomes containing expressed CYP3A4, CYP2D6 and CYP2C19 were also used to examine the formation of EDDP.

Results The V max, Km, and CLint values for the formation of EDDP from rac‐, (R)‐ and (S)‐methadone were in the ranges of 20–77 nmol mg−1 protein h−1, 125–252 μm, and 91–494 ml h−1 g−1 protein. Km and CLint values for (R)‐ and (S)‐methadone were not statistically significantly different (P >0.05), while V max values for (S)‐methadone were 15% (P=0.045) lower than for (R)‐methadone. Expressed CYP3A4 and CYP2C19 showed similar reaction rates for both (R)‐ and (S)‐methadone, while CYP2D6 did not catalyse this reaction. Selective chemical inhibitors of CYP3A (troleandomycin, ketoconazole) and monoclonal human CYP3A4 antibodies significantly inhibited (P<0.05) the formation of EDDP in a concentration dependent manner by up to 80%. Sulphaphenazole (CYP2C9) also significantly inhibited (P<0.05) EDDP formation (range 14–25%). There were no statistically significant differences in the inhibition observed between the three substrates. Selective inhibitors of CYP1A2 (furafylline), CYP2A6 (coumarin), CYP2C19 ((S)‐mephenytoin), CYP2D6 (quinidine) and CYP2E1 (diethyldithiocarbamic acid sodium salt and monoclonal human CYP2E1 antibodies) had no significant (P >0.05) effect.

Conclusions The N‐demethylation of methadone in human liver microsomes is not markedly stereoselective, and is mediated mainly by CYP3A4 with the possible involvement of CYP2C9 and CYP2C19. Thus, the large interindividual variation reported for methadone pharmacokinetics may be due to variability in the expression of these CYP isoforms, and the reported stereoselectivity in the systemic clearance of methadone in vivo is not due to stereoselectivity in N‐demethylation.
Pharmacokinetic‐pharmacodynamic profile of systemic nitric oxide‐synthase inhibition with L‐NMMA in humans
Authors: Mayer Bernhard X. , Mensik Christa , Krishnaswami Sriram , Derendorf Hartmut , Eichler Hans‐Georg , Schmetterer Leopold , Wolzt Michael
Published: March 2003

Aims It has been demonstrated that inhibition of endothelium derived nitric oxide with NG‐monomethyl‐l‐arginine (l‐NMMA) results in a different cardiac and peripheral vascular response. The purpose of this study was to investigate the pharmacokinetic‐pharmacodynamic profile of l‐NMMA and pharmacokinetic interactions with l‐arginine in healthy subjects.

Methods Plasma pharmacokinetics were analysed from two different studies: In study 1, 3 mg kg−1 l‐NMMA was administered i.v. over 5 min and systemic haemodynamics, cardiac output (CO), fundus pulsation amplitude (FPA), and NO‐exhalation (exhNO) were measured at baseline and 15, 65, 95, 155, and 305 min after start of drug administration (n=7). In study 2, 17 mg kg−1 min−1 of the physiologic substrate for nitric oxide synthase, l‐arginine, was coinfused i.v. over 30 min with a primed constant infusion of 50 μg kg−1 min−1 l‐NMMA (n=8).

Results Bolus infusion of l‐NMMA resulted in a maximum plasma concentration of 12.9±3.4 μg ml−1 (mean±s.d.) with elimination half‐life of 63.5±14.5 min and clearance of 12.2±3.5 ml min−1 kg−1 and caused a small hypertensive response, decreased CO by 13%, FPA by 26%, exhNO by 46% and increased systemic vascular resistance by 16% (P<0.05 each) 15 min after start of drug administration. Although only limited data points were available in the l‐NMMA plasma concentration range between 0 and 4 μg ml−1, drug effects over time were in good agreement with an Emax model (r2>0.98 each), which also suggested that concentrations producing half‐maximum effects were higher for FPA than for CO and exhNO. The coinfusion with l‐arginine caused a nearly two‐fold increase in plasma l‐NMMA levels, indicating a pharmacokinetic interaction.

Conclusions In the absence of a systemic hypertensive response, l‐NMMA significantly decreased CO, exhNO, and FPA. The concentration calculated to produce a half maximal effect was equivalent for exhNO and CO, but markedly higher for FPA. Furthermore, measurement of FPA is susceptible to changes in l‐NMMA levels at small plasma concentrations.