bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constant rate infusion of vancomycin in premature neonates: a new dosage schedule
Authors: Pawlotsky F. , Thomas A. , Kergueris M. F. , Debillon T. , Roze J. C. 
Published: March 2003

Aims
Since vancomycin's bactericidal action has been shown to be time‐dependent, a constant rate infusion over 24 h might result in a better bactericidal efficacy. The purpose of this study was to define a new dosage schedule in prematures.
Methods
Two vancomycin 24 h constant rate infusion schedules were tested in two groups of neonates. Postconceptional age (PCA) was 27 to 41 weeks in group 1 (n=24) and 28 to 51.5 weeks in group 2 (n=29). Group 1 neonates received continuous infusion of 10 to 30 mg kg−1 day−1, adjusted for PCA and weight. Group 2 was designed to take into account the significant relationship observed in group 1 between vancomycin clearance standardized on weight and PCA and consisted of a constant loading dose of 7 mg kg−1 followed by continuous infusion of 10 to 40 mg kg−1 day−1 adjusted for PCA and weight.
Results
Mean vancomycin serum concentration at steady state was 11±3.1 mg l−1 in group 1 and 15.4±6.2 mg l−1 in group 2. Fifty‐six percent of group 1 values vs 88% of group 2 values were between 10 and 30 mg l−1 at steady state (P<0.01). Both regimens were well tolerated.
Conclusion
A loading dose of vancomycin followed by constant rate infusion of the appropriate dose adjusted for PCA and weight might improve vancomycin concentrations in neonates.
Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail
Authors: Adedoyin Adedayo , Frye Reginald F. , Mauro Kelly , Branch Robert A. 
Published: March 2003

Aims
The aim of this study was to investigate whether chloroquine can inhibit drug metabolism in humans, if such inhibition is general or selective for certain enzymes and evaluate the potential for and clinical significance of any drug‐drug interactions when chloroquine is co‐administered with other drugs.
Methods
The study was conducted in fourteen normal non‐smoking healthy male volunteers using a cocktail of five drugs consisting of caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone to assess activities of cytochromes P450 (CYP) 1A2, 2C19, 2D6, 2E1 and 3A4 respectively. Dapsone was also used to assess N‐acetyltransferase activity. The activities were assessed at baseline, after one and seven daily doses (250 mg daily) of chloroquine and 7 and 14 days after stopping chloroquine dosing.
Results
Chloroquine caused a progressive and significant decrease in CYP2D6 activity as measured by debrisoquine metabolism from first to seventh dose and the activity returned to baseline gradually over 14 days after stopping administration. There was no effect on the metabolism of any of the other probe drugs.
Conclusions
Chloroquine has been shown to be capable of inhibiting the activity of CYP2D6 in vivo in humans. This effect is selective as activities of other enzymes investigated were not affected. The effect was modest but suggests a potential for drug‐drug interactions when co‐administered with other drugs that are substrates for this enzyme. The clinical significance of such an interaction will depend on the therapeutic index of any drug involved.
The gastrointestinal passage and release of beclomethasone dipropionate from oral delivery systems in ileostomy volunteers
Authors: Burggraaf J. , Van Haarst A. D. , Fockens P. , Schoemaker H. C. , Krauwinkel W. J. J. , Cohen A. F. 
Published: March 2003

Aims
To study the delivery of 15 mg beclomethasone 17,21‐dipropionate (BDP) to the distal part of the small bowel for three oral sustained‐release formulations (I‐III) and a reference capsule in volunteer ileostomists, and to compare these findings with the in vitro dissolution profiles.
Methods
Two groups of nine ileostomy volunteers (aged 20–61 years), who were otherwise healthy, were enrolled in the study. The recovery of BDP and its metabolite beclomethasone 17‐monopropionate (B17P) in ileostomy effluent was investigated in a cross‐over study after administration of formulations I or II or a reference capsule containing micronised BDP, and in a second open study after administration of formulation III. Radio‐opaque granules were coadministered for evaluation of gastrointestinal passage. Ileostomy effluents were collected hourly for 10–12 h following drug intake. After marker beads had been counted on X‐rays, ileostomy collections were analysed for BDP and its metabolites. Cumulative recovery, lag‐time and mean transit time were determined for drug and marker beads.
Results
Gastrointestinal passage characteristics were similar for all treatments. Total drug recovery was approximately three times higher for the sustained‐release formulations than for the reference capsule. Recovery of B17P from stoma fluid samples was significantly lower for formulation III than for formulations I and II.
Conclusions
The novel oral formulations delivered substantial amounts of steroid drug at the distal small bowel/proximal colon, which may warrant further studies to evaluate clinical applicability.
Ticlopidine decreases the in vivo activity of CYP2C19 as measured by omeprazole metabolism
Authors: Tateishi Tomonori , Kumai Toshio , Watanabe Minoru , Nakura Hironori , Tanaka Masami , Kobayashi Shinichi 
Published: March 2003

Aims To examine the effect of ticlopidine administration on the activities CYP2C19 and CYP3 A in vivo using omeprazole as a model substrate.Methods A single dose of 40 mg omeprazole was administered orally with or without ticlopidine (300 mg daily for 6 days) to six Japanese extensive metabolisers with respect to CYP2C19. Blood samples were taken for the measurement of plasma concentrations of omeprazole, 5‐hydroxyomeprazole and omeprazole sulphone.Results Ticlopidine administration increased omeprazole Cmax (1978±859/ 3442±569 (control phase/ticlopidine phase, nm )) and decreased the oral clearance of omeprazole (CL/F; 25.70±16.17/10.76±1.16 (control phase/ticlopidine phase, l h−1 )) significantly. The 5‐hydroxyomeprazole to omeprazole AUC ratio (0.817±0.448/0.236±0.053 (control phase/ticlopidine phase)) and the 5‐hydroxyomeprazole to omeprazole sulphone AUC ratio (1.114±0.782/0.256±0.051 (control phase/ticlopidine phase)) were decreased significantly after ticlopidine administration. The decrease in omeprazole CL/F and the 5‐hydroxyomeprazole to omeprazole AUC ratio correlated significantly with their respective absolute values when the drug was given alone. The decrease in CL/F following ticlopidine administration correlated with that in the 5‐hydroxyomeprazole to omeprazole AUC ratio.Conclusions These findings suggest that ticlopidine inhibited the in vivo activity of CYP2C19, but not, or to a lesser extent CYP3 A4, and that the magnitude of inhibition by ticlopidine is related to the in vivo activity of CYP2C19 before inhibition.
Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies
Authors: Jorga Karin , Fotteler Bärbel , Banken Ludger , Snell Paul , Steimer Jean‐Louis 
Published: March 2003

Aims To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under‐ or over‐exposure to this catechol‐O‐methyltransferase (COMT) inhibitor. Methods Four hundred and twelve patients participated in three multicentre, parallel, double‐blind, placebo‐controlled, dose‐finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. Results The pharmacokinetic model which best described the data was a two‐compartment open model with first‐order absorption and possibly a lag‐time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10–20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4.5–5 l h−1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half‐life in patients of approximately 5–8 h. Conclusions Using sparse concentrations and mixed effect‐effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under‐ or over‐exposure to tolcapone.
Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes
Authors: Davis, Timothy M. E. , Daly, Frank , Walsh, John P. , Ilett, Kenneth F. , Beilby, John P. , Dusci Leon J. , Barrett P. Hugh R. 
Published: March 2003

Aims
Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes.
Methods
Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero‐hepatic recirculation was fitted to group mean serum gliclazide profiles.
Results
The Caucasians were older than the Aborigines (mean ± s.d. age 53.4 ± 12.2 vs 40.3 ± 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between‐group differences in gliclazide kinetics. Post‐breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 ± 0.4 vs 2.2 ± 0.3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model‐derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively.
Conclusions
Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect.
Nonspecific binding of drugs to human liver microsomes
Authors: McLure James A. , Miners John O. , Birkett Donald J. 
Published: March 2003

Aims  To characterize the nonspecific binding to human liver microsomes of drugs with varying physicochemical characteristics, and to develop a model for the effect of nonspecific binding on the in vitro kinetics of drug metabolism enzymes.Methods  The extent of nonspecific binding to human liver microsomes of the acidic drugs caffeine, naproxen, tolbutamide and phenytoin, and of the basic drugs amiodarone, amitriptyline and nortriptyline was investigated. These drugs were chosen for study on the basis of their lipophilicity, charge, and extent of ionization at pH 7.4. The fraction of drug unbound in the microsomal mixture, fu(mic), was determined by equilibrium dialysis against 0.1 m phosphate buffer, pH 7.4. The data were fitted to a standard saturable binding model defined by the binding affinity KD, and the maximum binding capacity Bmax. The derived binding parameters, KD and Bmax, were used to simulate the effects of saturable nonspecific binding on in vitro enzyme kinetics.Results  The acidic drugs caffeine, tolbutamide and naproxen did not bind appreciably to the microsomal membrane. Phenytoin, a lipophilic weak acid which is mainly unionized at pH 7.4, was bound to a small extent (fu(mic) = 0.88) and the binding did not depend on drug concentration over the range used. The three weak bases amiodarone, amitriptyline and nortriptyline all bound extensively to the microsomal membrane. The binding was saturable for nortriptyline and amitriptyline. Bmax and KD values for nortriptyline at 1 mg ml−1 microsomal protein were 382 ± 54 µm and 147 ± 44 µm, respectively, and for amitriptyline were 375 ± 23 µm and 178 ± 33 µm, respectively. Bmax, but not KD, varied approximately proportionately with the microsome concentration. When KD is much less than the Km for a reaction, the apparent Km based on total drug can be corrected by multiplying by fu(mic). When the substrate concentration used in a kinetic study is similar to or greater than the KD (Km ≥ KD), simulations predict complex effects on the reaction kinetics. When expressed in terms of total drug concentrations, sigmoidal reaction velocity vs substrate concentration plots and curved Eadie Hofstee plots are predicted.Conclusions  Nonspecific drug binding in microsomal incubation mixtures can be qualitatively predicted from the physicochemical characteristics of the drug substrate. The binding of lipophilic weak bases is saturable and can be described by a standard binding model. If the substrate concentrations used for in vitro kinetic studies are in the saturable binding range, complex effects are predicted on the reaction kinetics when expressed in terms of total (added) drug concentration. Sigmoidal reaction curves result which are similar to the Hill plots seen with cooperative substrate binding.
Antihypertensive drugs and the risk of idiopathic aplastic anaemia
Authors: Myers Marian Wald , Vasilakis Catherine , Kaufman Matthew R. , Jick Hershel 
Published: March 2003

Aims
A recent report has raised concern that nifedipine may be associated with an increased risk of aplastic anaemia. This large population‐based study evaluated the risk of idiopathic aplastic anaemia in users of calcium channel blockers compared with that of other antihypertensive drugs.
Methods
The study was based on information derived from the General Practice Research Database. We conducted a follow‐up study with a nested case‐control analysis of 322 448 subjects who received antihypertensive drugs. Cases were people who had a first‐time diagnosis of aplastic anaemia during January 1, 1988 through September 30, 1997. The risk estimate of aplastic anaemia was calculated for all antihypertensive drugs. For the nested case‐control analysis, six controls were matched to each case on age, sex and general practice attended. Odds ratios compared the risk of idiopathic aplastic anaemia for all antihypertensive drugs relative to nonusers.
Results
There were 13 cases of newly diagnosed idiopathic aplastic anaemia. The estimated risk of aplastic anaemia per 100 000 users was 0.8 (95% CI 0.1, 4.7) for calcium channel blockers, 1.4 (95% CI 0.5, 4.1) for β‐adrenoceptor blockers, 2.3 (95% CI 0.6, 8.6) for angiotension‐converting enzyme (ACE) inhibitors and 5.9 (95% CI 1.6, 21.5) for users of other antihypertensive drugs. In the case‐control analysis of 13 cases and 77 controls, the odds ratio was 0.3 (95% CI 0.02, 3.3) for calcium channel blockers, 0.5 (95% CI 0.1, 2.5) for β‐adrenoceptor blockers, 0.7 (95% CI 0.1, 5.6) for ACE inhibitors, 1.2 (95% CI 0.1, 11.8) for users of other antihypertensive drugs and 0.7 (95% CI 0.1, 7.2) for users of multiple drugs with a calcium channel blocker compared with nonusers.
Conclusions
The present study suggests that the use of calcium channel blockers is not associated with an increased risk of aplastic anaemia.
Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients
Authors: Sam W. J. , Aw M. , Quak S. H. , Lim S. M. , Charles B. G. , Chan S. Y. , Ho P. C. 
Published: March 2003

Aims  The purpose of this study was to describe the population pharmacokinetics of intravenous and oral tacrolimus (FK506) in 20 Asian paediatric patients, aged 1–14 years, following liver transplantation and to identify possible relationships between clinical covariates and population parameter estimates.Methods  Details of drug dosage histories, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data accumulated for at least 4 days after surgery. Before analysis, patients were randomly allocated to either the population data set (n = 16) or a validation data set (n = 4). The population data set was comprised of 771 concentration measurements of patients admitted over the last 3 years. Population modelling using the nonlinear mixed‐effects model (NONMEM) program was performed on the population data set, using a one‐compartment model with first‐order absorption and elimination. Population average parameter estimates of clearance (CL), volume of distribution (V) and oral bioavailability (F) were sought; a number of clinical and demographic variables were tested for their influence on these parameters.Results  The final optimal population models related clearance to age, volume of distribution to body surface area and bioavailability to body weight and total bilirubin concentration. Predictive performance of this model evaluated using the validation data set, which comprised 86 concentrations, showed insignificant bias between observed and model‐predicted blood tacrolimus concentrations. A final analysis performed in all 20 patients identified the following relationships: CL (l h−1) = 1.46 *[1 + 0.339 * (AGE (years) −2.25)]; V (l) = 39.1 *[1 + 4.57 * (BSA (m2)−0.49)]; F = 0.197 *[1 + 0.0887 * (WT (kg) −11.4)] and F = 0.197 *[1 + 0.0887 * (WT (kg) −11.4)]*[1.61], if the total bilirubin ≥ 200 µmol l−1. The interpatient variabilities (CV%) in CL, V and F were 33.5%, 33.0% and 24.1%, respectively. The intrapatient variability (s.d.) among observed and model‐predicted blood concentrations was 5.79 ng ml−1.Conclusions  In this study, the estimates of the pharmacokinetic parameters of tacrolimus agreed with those obtained from conventional pharmacokinetic studies. It also identified significant relationships in Asian paediatric liver transplant patients between the pharmacokinetics of tacrolimus and developmental characteristics of the patients.
A comparison of oral artesunate and artemether antimalarial bioactivities in acute falciparum malaria
Authors: Suputtamongkol Yupin , Newton Paul N. , Angus Brian , Teja‐Isavadharm Paktiya , Keeratithakul Duangsuda , Rasameesoraj Maneerat , Pukrittayakamee Sasithon , White Nicholas J. 
Published: March 2003

Aims  Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives.Methods  The pharmacokinetic properties of oral artesunate and artemether (4 mg kg−1) were compared in a randomized cross‐over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay.Results  Despite a 29% lower molar dose, oral artesunate administration resulted in significantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (P ≤ 0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40–76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the first day of treatment, 31 (17–100)%, compared to the second day, 72 (44–118)% (P = 0.018). In vivo parasite clearance and time above the in vitro IC90 were similar for the two drugs, despite considerable differences in Cmax and AUC.Conclusions  The oral antimalarial bioavailability following artemether was significantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.
Time trends in lipid lowering drug use in The Netherlands. Has the backlog of candidates for treatment been eliminated?
Authors: Mantel‐Teeuwisse Aukje K. , Klungel Olaf H. , Verschuren W. M. Monique , Porsius Arijan J. , De Boer Anthonius 
Published: March 2003

Aims  To assess time trends in lipid lowering drug use in The Netherlands.Methods  Data were obtained from the PHARMO‐database, comprising pharmacy records of approximately 300 000 people in The Netherlands. In the period from 1991–98, we estimated prevalence of lipid lowering drug use on the first Wednesday of October. A patient was defined as incident user if (s)he filled a prescription for lipid lowering medication after a 360 days lipid lowering drug free interval. Both prevalence and incidence estimates were weighted for the sex and age distribution of the general Dutch population.Results  From 1991 to 1998, the prevalence of lipid lowering drug use increased from 0.5% (95% confidence interval (CI): 0.5, 0.6) to 2.3% (95% CI: 2.2, 2.4) in women and from 0.6% (95% CI: 0.6, 0.6) to 2.9% (95% CI: 2.8, 3.0) in men. Prevalence increased with increasing age and was highest in the age category 60–69 years (in 1998: 9.9% (95% CI: 9.4, 10.4) in women and 11.6% (95% CI: 11.0, 12.1) in men). In 1992, the estimated incidence of lipid lowering drug use was 251(95% CI: 226, 277)/100 000 person years in women and 251(95% CI: 225, 276)/100 000 person years in men. The largest incidence estimates were observed in 1996 (685(95% CI: 644, 726)/100 000 person years in women and 881(95% CI: 834, 928)/100 000 person years in men). After 1996, incidence stabilized in 1997 and decreased in 1998 to 599(561, 637)/100 000 person years in women and 731(688, 773)/100 000 person years in men. Most of the patients (approximately 95%) were treated with one lipid lowering agent. Statins were used by over 90% of patients from 1996 onwards. In 1998, 35% of the patients started with a statin that was not a first choice drug (mainly atorvastatin).Conclusions  In the period from 1991–98, prevalence of lipid lowering drug use significantly increased in The Netherlands. However, incidence stabilized and decreased after 1996 which may be explained by the fact that the number of patients eligible for treatment was reached. The question remains whether lipid lowering medication was targeted to the appropriate patients.