European Journal of Clinical Pharmacology

Allegaert, Karel; Tibboel, Dick; Naulaers, Gunnar; Tison, Denise; De Jonge, Annick; Van Dijk, Monique; Vanhole, Christine; Devlieger, Hugo

doi: 10.1007/s00228-003-0585-3pmid: 12682806

ObjectiveTo document the effect of systematic evaluation of pain in neonates on prescription of intravenous analgesics in a level-III neonatal intensive care unit (NICU) as a marker of increased awareness of treating and preventing pain.MethodsRetrospective analysis of the number of yearly prescribed vials of intravenous analgesics in a level-III NICU during a period before (1996–1999) and after (2000 to August 2002) introduction of a multidimensional pain scale. Correction was carried out by multiple regression analysis for clinical co-variables (admissions, days on parenteral nutrition, days on respiratory support, surgical procedures), which also might explain changes in prescription of analgesics. Postoperative length (hours) of administration of analgesics was calculated in a group of infants (1996–2001) who all received cryotherapy for threshold retinopathy of prematurity (ROP) before (1996–1999) and since (2000–2001) introduction of pain evaluation.ResultsThe number of yearly prescribed vials increased from 3140±619 (mean±SD) to 5915±675 (P<0.005). There is also a significant increase in the number of surgical interventions (P<0.05) but not in days on respiratory support, days on parenteral nutrition or in number of admissions. After correction for the number of surgical procedures, the increase in prescribed vials remained significant (P<0.05). In infants who received cryotherapy, a significant increase in length of postoperative analgesia (65–107 h, P<0.01) was documented. Even after correction for the increased postoperative length of ventilation, duration of postoperative analgesia remained significantly (P<0.05) longer.ConclusionsSystematic evaluation of pain increased awareness of treating and preventing pain in neonates, even after correction for clinical co-variables. This increase was not associated with an increase in potential side-effects (length of respiratory support, length of parenteral nutrition).

Holstein, A.; Plaschke, A.; Hammer, C.; Egberts, E.-H.

doi: 10.1007/s00228-003-0592-4pmid: 12698302

A. Holstein +49-5231-721171 +49-5231-721035 [email protected] A. Plaschke C. Hammer E.-H. Egberts 1st Department of Medicine, Klinikum Lippe-Detmold, Röntgenstrasse 18, 32756, Detmold, Germany Objective. To compare the clinical characteristics and time course of severe hypoglycaemia (SH) on glimepiride and the reference drug glibenclamide. Methods. SH was defined as a symptomatic event requiring administration of i.v. glucose or of glucagon. Four hundred doctors working in acute care hospitals were randomly selected from the membership directory of the German Diabetes Association and sent a standardised questionnaire about sulphonylurea-induced SH that occurred between June 2001 and August 2002. Detailed data on history, medication, laboratory parameters, treatment and time course of the SH were analysed. Results. Altogether, 93 episodes of SH were registered, 37 on glimepiride and 56 on glibenclamide. The characteristics of the glimepiride- versus glibenclamide-induced SH were as follows: initial blood glucose 1.9±0.66 mmol/l versus 1.8±0.89 mmol/l, P =0.17; age 77±11.2 years versus 78±9.6 years, P =0.35; HbA1c 5.4±0.7% versus 5.2±0.9%, P =0.18; creatinine clearance 38±23 ml/min versus 54±32 ml/min, P =0.005; co-medication 6.2.±3 versus 3.6±3 preparations, P < 0.0001. Even very low doses of glimepiride (0.5 mg) and glibenclamide (0.88 mg) were associated with SH. Prolonged hypoglycaemia requiring more than 12 h i.v. glucose administration occurred in 8 of 37 of the glimepiride-treated subjects and 5 of 56 of those on glibenclamide. Prolonged hypoglycaemia necessitated infusion of 308±256 g (104–862 g) i.v. glucose over 43±16 h (24–64 h) in glimepiride-treated patients compared with 168±98 g (66–300 g) over 33±28 h (14–80 h) in glibenclamide-treated patients. Impaired renal function was present in 11 of 13 of all patients with prolonged hypoglycaemia and impaired liver function in 1 of 13. Conclusion. In glimepiride- and glibenclamide-treated individuals with SH, no essential differences in the clinical characteristics or time course were shown; prolonged courses also occurred on glimepiride. Even in patients with only mild renal failure both preparations should be used with caution.

Leslie, Stephen; Affolter, Jonathan; Denvir, Martin; Webb, David

doi: 10.1007/s00228-003-0577-3pmid: 12721772

Stephen J. Leslie Jonathan Affolter Martin A. Denvir David J. Webb +44-131-332-1205 +44-131-343-6017 [email protected] Clinical Pharmacology Unit and Research Centre, The University of Edinburgh, Western General Hospital, EH4 2XU, Edinburgh, UK Department of Cardiology, The University of Edinburgh, Western General Hospital, EH4 2XU, Edinburgh, UK Objective. To determine the reproducibility of laser Doppler flowmetry coupled with intra-dermal saline delivery. Methods. Delivery of saline was judged visually by two operators ( n =100), using a graduated syringe (Becton-Dickinson), by expelling saline onto a weighing boat. Volume was assessed by weight. Skin blood flow following intra-dermal injection of saline was assessed in 18 healthy volunteers; 10 attended twice to assess between-day reproducibility, and 8 attended once to assess between-site reproducibility. Results are expressed as mean value±SEM and 95% confidence interval for mean differences. Results. There was no difference between operators in mean injection weight, both weights being 10.3±0.1 mg (mean difference 0.08, 95% confidence interval, CI −0.23 to 0.39 mg; n =100, P =0.9). Intra-dermal saline caused a nine-fold increase in blood flow (0.03±0.003 to 0.27±0.02 perfusion units, PU; n =18, P <0.001). This response had a rapid onset, with the maximal effect seen at 4 min and a duration of greater than 30 min. There was no difference in the magnitude of the response between the dominant and non-dominant arms, AUC was 2.9±0.4 and 2.9±0.4, respectively (mean difference −0.05, 95% CI −0.8 to 0.73 PU; n =18, P =0.93). However, there was a trend towards differences between study visits 1 and 2: AUC was 3.2±0.6 and 2.0±0.5, respectively (mean difference 1.2, 95% CI −0.03 to 2.43 PU; n =10, P =0.7). There was no difference in the magnitude of responses between different sites on the forearm ( n =64, P =0.6). Conclusions. These studies demonstrate that the technique of laser Doppler flowmetry coupled with intra-dermal injection is a safe, well-tolerated technique with good reproducibility. A trend towards reduced between-day reproducibility emphasizes the importance of vehicle control sites when investigating the effects of vasoactive compounds. This technique provides a reliable method for the intra-dermal delivery of drugs, despite the direct effect of injection of saline on blood flow.

Griskevicius, Laimonas; Yasar, Ümit; Sandberg, Mia; Hidestrand, Mats; Eliasson, Erik; Tybring, Gunnel; Hassan, Moustapha; Dahl, Marja-Liisa

doi: 10.1007/s00228-003-0590-6pmid: 12684728

Several-fold differences have been observed among patients in the biotransformation of cyclophosphamide. The aim of this study was to investigate the contribution of CYP2C9 and CYP2C19 and their polymorphisms to the variability of cyclophosphamide activation. The formation of 4-hydroxycyclophosphamide was studied in microsomes from a total of 32 different genotyped human livers, as well as in yeast microsomes expressing different genetic variants of CYP2C9 and CYP2C19. The kinetic data obtained in the yeast system revealed that the intrinsic clearance (Vmax/Km) of cyclophosphamide by CYP2C9.2 and CYP2C9.3 samples was approximately threefold lower than that by CYP2C9.1. However, in liver microsomes, there were no statistically significant differences in the intrinsic clearance of 4-hydroxycyclophosphamide formation between the group of seven CYP2C9*1/*1 livers and the remaining nine with one or two variant CYP2C9 alleles (P>0.7). We found a statistically significant correlation (r s=0.65, P=0.003) between 4-hydroxylation of cyclophosphamide and 5′-hydroxylation of R-omeprazole, a measure of CYP2C19 activity in human liver microsomes (n=19). No correlation was found between 4-hydroxylation of cyclophosphamide and the formation rate of hydroxycelecoxib, mainly catalysed by CYP2C9 (r s=0.17, P=0.55, n=32). In conclusion, based on the correlation with the formation of R-5′-hydroxyomeprazole, CYP2C19 may partly contribute to the bioactivation of cyclophosphamide in human liver microsomes, while the role of CYP2C9 appears minor.

Kim, Myo-Kyoung; Cho, Joo-Youn; Lim, Hyeong-Seok; Hong, Kyoung-Seop; Chung, Jae-Yong; Bae, Kyun-Seop; Oh, Dal-Seok; Shin, Sang-Goo; Lee, Sang-Hun; Lee, Dong-Ho; Min, Bumchan; Jang, In-Jin

doi: 10.1007/s00228-003-0595-1

Centerholt, Carina; Ekblom, Marianne; Odergren, Tomas; Borgå, Olof; Popescu, Gabriela; Molz, Karl-Heinz; Couturier, Andrea; Weil, Angelika

doi: 10.1007/s00228-003-0598-ypmid: 12734608

Carina Centerholt +46-8-55326000 +46-8-55328896 [email protected] Marianne Ekblom Tomas Odergren Olof Borgå Gabriela Popescu Karl-Heinz Molz Andrea Couturier Angelika Weil , AstraZeneca R&D Södertälje, 151-85, Södertälje, Sweden , Borgå PK Consulting, Sweden , APEX GmbH, Munich, Germany Objective. Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects. Methods. Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active α-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6. Results. The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r 2 =0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation. Conclusion. The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.

Balram, C.; Zhou, Qingyu; Cheung, Yin; Lee, Edmund

doi: 10.1007/s00228-003-0594-2pmid: 12756511

C. Balram +65-64368321 +65-64368321 [email protected] Qingyu Zhou Yin Bun Cheung Edmund J. D. Lee Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, 11 Hospital Drive, 169610, Singapore Biostatistics Unit, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore Department of Pharmacology, Faculty of Medicine, National University of Singapore Objective. To determine the frequencies of two functional single nucleotide polymorphisms, CYP3A5*3 and CYP3A5*6 , in the CYP3A5 gene in three distinct Asian ethnic groups, namely, the Chinese, Malays and Indians. Methods. Single nucleotide polymorphism analyses of CYP3A5*1 , *3 and *6 were performed in 296 healthy subjects (108 Chinese, 98 Malays and 90 Indians) using the polymerase chain reaction-restriction fragment length polymorphism method. Results. The *1 allele frequency was 25% in Chinese compared with 40% in Malays and Indians ( P =0.001). The *3 allele frequency was also higher in the Chinese population, being 76% versus 60% in the Malays and Indians ( P =0.001). The Malays and Indians also had allele frequencies significantly different from Caucasian, Japanese and African-American populations (each P ≤0.001) previously published in the literature. The *6 allele was not detected in any the three Asian ethnic groups analysed. Conclusion. These results seem to suggest that genetic polymorphisms in CYP3A5 in Asians, in particular Malays and Indians but also Chinese although to a lesser extent, may be an important genetic contributor to interindividual as well as interethnic differences in clearance of CYP3A substrates.

Malm, Heli; Martikainen, Jaana; Klaukka, Timo; Neuvonen, Pertti

doi: 10.1007/s00228-003-0584-4pmid: 12700878

Heli Malm +358-9-47173938 +358-9-47174039 [email protected] Jaana Martikainen Timo Klaukka Pertti J. Neuvonen Teratology Information Service, Department of Medical Genetics, The Family Federation of Finland, Helsinki, Finland , The Social Insurance Institution, Helsinki, Finland Department of Clinical Pharmacology, Helsinki University Central Hospital, P.O. Box 340, 00029 HUS, Finland Objective. To examine the use of prescription drugs in Finnish women before and during pregnancy and lactation. Methods. A register-based study linking four nation-wide registers in Finland: the Maternal Grants Register, the Drug Prescription Register, and the Special Refund Register (all maintained by the Social Insurance Institution in Finland; KELA), and the Finnish Population Register. The study included all women applying for maternity support (maternal grants) during the year 1999, and non-pregnant control women matched by age and hospital district. Data collection included the number and type of prescription drugs purchased by the two cohorts during preconception (3 months before pregnancy), each trimester, and lactation. Results. Of the 43,470 pregnant women, 46.2% purchased at least one drug and 12.7% three or more different drugs during pregnancy. Corresponding proportions for the control cohort were 55.2% (OR 0.7, 95% CI 0.6–0.7) and 23.0% (OR 0.5, 95% CI 0.5–0.5). The drugs most frequently purchased during pregnancy were systemic antibiotics (24.1% of pregnant women vs 27.3% controls; OR 0.8, 95% CI 0.8–0.9) and gynaecological anti-infective agents (8.3% vs 1.5%; OR 5.5, 95% CI 5.5–6.5). For pregnant women, purchases of most drug groups had already declined during the first trimester, but no reduction was apparent in drugs for chronic illnesses (epilepsy, asthma, diabetes). Conclusions. Although drugs were purchased abundantly during pregnancy, a significant decline occurred for most drug groups. The medication pattern for chronic illnesses remained unchanged. The purchase of several different drugs was relatively common and raises concerns.

Risha, P.; Vervaet, C.; Vergote, G.; Bortel, L.; Remon, J.

doi: 10.1007/s00228-003-0587-1pmid: 12721773

P. G. Risha C. Vervaet G. Vergote L. Van Bortel J. P. Remon +32-9-2648054 +32-9-2228236 [email protected] Department of Pharmaceutics, Faculty of Pharmacy, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, 9000, Ghent, Belgium Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium Rationale. Objective. The quality of drugs imported into developing countries having a tropical climate may be adversely affected if their formulations have not been optimized for stability under these conditions. The present study investigated the influence of tropical climate conditions (class IV: 40°C, 75% relative humidity) on the drug content, in vitro dissolution and oral bioavailability of different formulations of two essential drugs marketed in Tanzania: diclofenac sodium and ciprofloxacin tablets. Methods. Before and after 3 and 6 months storage under class IV conditions the drug content and in vitro dissolution were evaluated using United States Pharmacopoeia (USP) 24 methods. Following a randomized four-period cross-over study, the pharmacokinetic parameters of drug formulations stored for 3 months under class IV conditions were compared with those stored at ambient conditions. Results. Drug content and drug release from all tested ciprofloxacin formulations were within USP-24 requirements and remained stable during storage at simulated tropical conditions. Oral bioavailability was also not influenced by tropical conditions. The dissolution rate of two diclofenac formulations (Diclo 50 manufactured by Camden and Dicloflame 50 manufactured by Intas) reduced significantly during storage under class IV conditions. After oral administration Camden tablets stored for 3 months under class IV conditions showed a reduction in C max (90% CI of C max ratio: 0.59 – 0.76). This reduction was smaller than expected based on the in vitro tests. Conclusions. Some drug formulations imported into Tanzania are not optimized for stability in a tropical climate. Manufacturers and regulatory authorities should pay more attention to the WHO recommendations for testing the stability of drugs under tropical climate conditions. Efforts should be made to improve the in vitro tests to better predict the bioavailability.

Gilså Hansen, Dorte; Søndergaard, Jens; Vach, Werner; Freng Gram, Lars; Rosholm, Jens-Ulrik; Kragstrup, Jakob

doi: 10.1007/s00228-003-0593-3pmid: 12721774

Dorte Gilså Hansen +45-655-03039 +45-659-18296 [email protected] Jens Søndergaard Werner Vach Lars Freng Gram Jens-Ulrik Rosholm Jakob Kragstrup Research Unit of General Practice, University of Southern Denmark, Winsløwparken 19, DK-5000, Odense C, Denmark Clinical Pharmacology, University of Southern Denmark, DK-5000, Odense C, Denmark Department of Statistics and Demography, University of Southern Denmark, DK-5000, Odense C, Denmark Objective. The use of antidepressants (ADs) has escalated and prompted considerable debate. Many depressed patients go unrecognised or under-treated and the area of indication of the new ADs is widening. The aim of this study was to analyse (i) the variation in general practitioners' prescribing of ADs by comparing with prescribing of other drug groups and (ii) whether the general prescribing behaviour, practice activity and demography are associated with the AD prescribing. Methods. Analysis of AD prescribing patterns among 174 general practices (93.5%) in the County of Funen, Denmark. Age- and sex-standardised 1-year incidences and prevalences of AD prescribing for patients listed were calculated using individual prescription data from Odense University Pharmacoepidemiologic Database. Data about health services and practice demography were obtained from the Health Insurance Register. The variation in AD 1-year prevalence was compared with other drug groups by a variation index (90%/10% percentile). Univariate linear regression analysis was used to examine associations between practice characteristics and prescribing. Results. The 1-year prevalence of AD prescribing varied sixfold, no more than the prevalence of five other drug groups. Practices with high yearly: general prescribing prevalence, mean number of drugs per medicated patient, number of surgery consultations/100 patients and counsellings/100 surgery consultations showed the highest yearly prevalence of AD prescribing. Single-handed practices had higher AD prescribing rates than partnerships. The relative use of selective serotonin re-uptake inhibitors and other new ADs showed only little variation (10% and 90% percentiles as close as 66–86%), but practices with high 1-year prevalence and incidence most often chose the new ADs. Conclusion. Analysis of inter-practice variation showed no extraordinary quality problems with regard to AD prescribing, but does not exclude that there might be problems. The general prescribing pattern of the general practitioners seems essential to their attitude to AD prescribing. The relationship between counselling and prescribing was a feature specific to ADs and deserves further investigation. Quality indicators are needed to understand differences in AD prescribing, and studies based on prescription data have to be supplemented with individual clinical data.