bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic models for the cardiovascular effects of moxonidine in patients with congestive heart failure
Authors: Brynne Lena , McNay John L. , Schaefer Hans G. , Swedberg Karl , Wiltse Curtis G. , Karlsson Mats O. 
Published: March 2003

Aims  To assess the pharmacodynamics of moxonidine in patients with functional NYHA Class II‐III congestive heart failure (CHF).Methods  A parallel population pharmacokinetic/pharmacodynamic (PK/PD) analysis was performed to assess the effect of moxonidine (0.1, 0.2, 0.3 mg twice daily) and placebo treatment on plasma noradrenaline (NA) levels, standing systolic blood pressure (SBP), and heart rate (HR) over 12 weeks in 97 patients with CHF using a parallel group design with dose escalation. A sequential analysis was also developed, where the relative changes in NA concentration were related to both SBP and HR.Results  In the parallel PD analysis, an effect delay was shown for all three end points (NA, SBP, and HR). An inhibitory Emax model was used to characterize the concentration‐effect relationships. For SBP and HR, the EC50 value increased over time. For NA, there was a positive baseline drift over the 12 weeks; this was interpreted as disease progression. Moxonidine delayed this increase by 9.8 weeks. For SBP, there was a circadian pattern at baseline. In the sequential PD analysis, the relationship between the drug response (NA) and SBP or HR was best described by an inhibitory Emax model. No effect delays between the response and effects were found.Conclusions  Effects of moxonidine on NA, SBP, and HR could be quantified by an effect compartment model in the presence of disease progression and circadian variations. Disease progression, as judged by increasing NA levels with time, was delayed by moxonidine. A direct relationship was found between NA and SBP/HR.
Mephenytoin as a probe for CYP2C19 phenotyping:effect of sample storage, intra‐individual reproducibility and occurrence of adverse events
Authors: Tamminga Wim J. , Wemer Johan , Oosterhuis Berend , Wieling Jaap , Touw Daan J. , De Zeeuw Rokus A. , De Leij Lou F. M. H. , Jonkman Jan H. G. 
Published: March 2003

Aims  To further evaluate mephenytoin as a probe for CYP2C19 phenotyping.Methods  Healthy subjects (n = 2638) were phenotyped using the urinary (S)‐mephenytoin to (R)‐mephenytoin ratio. This method was evaluated for (a) the stability of the S/R‐ratio following sample storage, (b) the intraindividual reproducibility of the ratio, and (c) the occurrence of adverse events.Results  After prolonged storage, the S/R‐ratio of samples from extensive metabolisers (EM) increased up to 85%. In 1.5% of the cases (1 out 66), this led to incorrect classification of phenotype. In EMs, but not in poor metabolisers (PMs), the S/R‐ratio increased after acid treatment. The intraindividual reproducibility of the mephenytoin phenotyping procedure was 28%. No major side‐effects were observed and there was no relationship between the incidence of side‐effects and the phenotype of the subject.Conclusions  After prolonged storage the S/R‐ratio significantly increased in EMs and, although low, the risk of incorrect classification should not be ignored. Our data support the use of mephenytoin as a safe drug for CYP2C19 phenotyping.
Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses
Authors: Melkersson Kristina I. , Hulting Anna‐Lena , Rane Anders J. 
Published: March 2003

Aims  The aim of this study was to investigate the prolactin (PRL) secretion and the growth hormone (GH)‐insulin‐like growth factor I (IGF‐I) axis in relation to gender and side‐effects and dose of antipsychotic drugs during long‐term treatment.Methods  Forty‐seven patients (21 men and 26 women), diagnosed with schizophrenia or related psychoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) criteria and treated with different classical antipsychotics, were studied. Prolactin, GH and IGF‐I were measured, as well as the serum concentration of the antipsychotics. In addition, body mass index (BMI) was calculated.Results  The median daily, as well as the median body weight, adjusted daily dose of antipsychotic drugs was twofold higher in male compared with female patients. Antipsychotic‐induced hyperprolactinaemia was more frequent and occurred at a lower daily dose of antipsychotics in women. Irrespective of sex, more than half of the patients had elevated BMI. Two patients had a slight increment in IGF‐I levels, whereas the GH concentration, as assessed on a single occasion, was normal in all patients.Conclusions  Patients on long‐term antipsychotic therapy, with doses adjusted according to therapeutic efficiency, exhibited hyperprolactinaemia and elevated BMI, but no obvious influence on the GH‐IGF‐I axis. Furthermore, it appeared that the males required twice the dose of antipsychotic compared with females.
Dopamine D2‐like receptors and amino acid‐induced glomerular hyperfiltration in humans
Authors: Luippold Gerd , Schneider Swetlana , Stefanescu Andreea , Benöhr Peter , Mühlbauer Bernd 
Published: March 2003

Aims  In rodents, blockade of dopamine D2‐like receptors abolishes both the physiological increase in glomerular filtration rate (GFR) induced by amino acids and the pathological hyperfiltration in experimental diabetes mellitus. This study addressed the contribution of dopamine D2‐like receptors to changes in renal haemodynamics after amino acid infusion in humans.Methods  Twelve healthy volunteers participated in this double‐blind, randomized, cross‐over study. GFR and renal blood flow (RPF) were assessed by renal clearance of inulin and p‐aminohippuric acid (PAH), respectively. Following infusion of 0.45% saline at baseline, an electrolyte‐balanced solution of mixed amino acids (10%) was infused. Prior to the experiments, the subjects received orally either placebo, or sulpiride (10 mg kg−1), a centrally and peripherally acting D2‐like receptor antagonist, or domperidone (1 mg kg−1) which affects only peripheral D2‐like receptors.Results  In the placebo series, amino acid infusion significantly increased GFR and RPF by up to 15.8 ± 5.3% and 14.4 ± 6.1%, respectively, while mean blood pressure and heart rate remained unchanged. Pretreatment with domperidone only marginally altered the renal response to amino acids (maximal increase by 13.2 ± 5.6 and 11.9 ± 4.0% in GFR and RPF, respectively), while sulpiride completely abolished the renal haemodynamic changes induced by amino acids. Total and fractional urinary sodium excretion as well as urinary osmolality were similar at baseline and increased in response to amino acids, to the same extent, in all series. No changes in renal dopamine excretion occurred.Conclusion  The results indicate that in man dopamine D2‐like receptors are involved in the renal haemodynamic response to amino acid infusion. Whether dopamine D2‐like receptor blockade diminishes glomerular hyperfiltration in pathological states requires clinical investigations.
Start of a selective serotonin reuptake inhibitor (SSRI) and increase of antiparkinsonian drug treatment in patients on levodopa
Authors: Van De Vijver D. A. M. C. , Roos R. A. C. , Jansen P. A. F. , Porsius A. J. , De Boer A. 
Published: March 2003

Aims  We determined whether the start of selective serotonin reuptake inhibitors (SSRI) in levodopa users was followed by a faster increase of antiparkinsonian drug treatment.Methods  Selected were all levodopa users of 55 years and older from the PHARMO prescription database. The rate of increase of antiparkinsonian drug treatment was compared using Cox's proportional hazard model for starters of SSRI (n = 15) with starters of tricyclic antidepressants (TCA) (n = 31) and with patients not using antidepressants (n = 304), and was adjusted for age, gender, and duration of levodopa use.Results  The hazard ratio for the SSRI group compared with the TCA group was 4.2 (95% confidence interval 1.4, 12.6) and compared with the second control group was 2.7 (1.2, 5.2).Conclusions  The start of SSRI therapy in levodopa users is followed by a faster increase of antiparkinsonian drug treatment.
Omeprazole hydroxylation is inhibited by a single dose of moclobemide in homozygotic EM genotype for CYP2C19
Authors: Cho Joo‐Youn , Yu Kyung‐Sang , Jang In‐Jin , Yang Byung‐Hwan , Shin Sang‐Goo , Yim Dong‐Seok 
Published: March 2003

Aims  The pharmacokinetics of omeprazole and its metabolites in healthy subjects were evaluated to determine if a single dose of moclobemide inhibited CYP2C19 activity.Methods  Sixteen volunteers, of whom eight were extensive metabolizers (EM) and eight were poor metabolizers for CYP2C19, participated in two studies. Venous blood samples were collected for 24 h after oral ingestion of 40 mg omeprazole with or without 300 mg moclobemide coadministration. The pharmacokinetic change of omeprazole, omeprazole sulphone and 5‐hydroxyomeprazole concentrations were assessed to test for an interaction between omeprazole and moclobemide.Results  The coadministration of moclobemide in EMs approximately doubled the mean AUC (from 1834 to 3760 ng ml−1 h) and Cmax (from 987 to 1649 ng ml−1) of omeprazole, and increased the AUC of omeprazole sulphone without changing AUC ratio of omeprazole to omeprazole sulphone. Moclobemide coadministration more than doubled the AUC ratio of omeprazole to 5‐hydroxyomeprazole (from 2.5 to 5.3) in EMs, too. There was a significant decrease in Cmax and AUC of 5‐hydroxyomeprazole in PMs but no significant changes were seen in the results for omeprazole and omeprazole sulphone AUCs.Conclusions  A single dose of moclobemide resulted in significant suppression of CYP2C19 activity in EMs. We conclude that physicians prescribing moclobemide should pay attention to its pharmacokinetic interactions even on the first day of coadministration with CYP2C19 substrates.
Population pharmacokinetics model and limited sampling strategy for intravenous vinorelbine derived from phase I clinical trials
Authors: Nguyen Laurent , Tranchand Brigitte , Puozzo Christian , Variol Philippe 
Published: March 2003

Aims a) To characterize the pharmacokinetics of intravenous vinorelbine, b) to use a population analysis for the identification of patient covariates that might appreciably influence its disposition and c) to define a limited sampling strategy for further Bayesian estimation of individual pharmacokinetic parameters.Methods All data were collected from 64 patients (99 courses) entered in three different phase I trials that have been previously reported. All patients received vinorelbine as a 20 min infusion with dose levels ranging from 20–45 mg m−2. The population pharmacokinetic model was built in a sequential manner on a subset of two‐thirds of the data, starting with a covariate‐free model then progressing to a covariate model using the nonlinear‐mixed effect methodology. The remaining one‐third of the data were used to validate several sparse sampling designs.Results A linear three‐compartment model characterized vinorelbine blood concentrations (n=1228). Two primary pharmacokinetic parameters (total clearance and volume of distribution) were related to various combinations of covariates. The relationship for total clearance (CLtotal(l h−1)=29.2×BSA×(1−0.0090 Plt)+6.7×Wt/Crs) was dependent on the patient's body surface area (BSA), weight (Wt), serum creatinine (Crs) and platelet count before administration (Plt). The optimal limited sampling strategy consisted of a combination of three measured blood concentrations; the first immediately before the end of infusion or 20 min later, the second at either 1 h, 3 h or 6 h and the third at 24 h after drug administration.Conclusions A population pharmacokinetic model and a limited sampling strategy for intravenous vinorelbine have been developed. This is the first population analysis performed on the basis of a large phase I database that has identified clinical covariates influencing the disposition of i.v. vinorelbine. The model can be used to obtain accurate Bayesian estimates of pharmacokinetic parameters in situations where extensive pharmacokinetic sampling is not feasable.
Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers
Authors: Gandon J. M. , Allain H. 
Published: March 2003

Aims  Levocetirizine (R‐cetirizine), is the active enantiomer of cetirizine, an antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic urticaria. The purpose of this trial was to analyse the effects of levocetirizine single and multiple doses on CNS using integrated measures of cognitive and psychometric performance.Methods  A battery of psychometric tests was used: critical flicker fusion (CFF), choice reaction time (CRT), body sway (BS), learning memory test (LMT) and subjective assessments of alertness compared with placebo. Nineteen (19) healthy male volunteers received either levocetirizine 5 mg (therapeutic dose), diphenhydramine 50 mg or placebo once daily for 5 consecutive days (3‐way cross‐over). Diphenhydramine was used as a positive control. CFF tests were performed on days 1 and 5 at baseline and up to 24 h following drug intake. Subjects used the Bond‐Lader visual analogue scales (VAS) to assess their mood and vigilance.Results  In contrast to diphenhydramine, when compared with placebo, levocetirizine did not modify the CFF (primary endpoint), regardless of the dosing scheme (−1.62 Hz [−2.61, −0.64] and −0.81 Hz [−1.80, 0.19], respectively, 3 h after dosing on day 1). CRT was decreased with both levocetirizine and placebo up to 5 h after dosing on day 1 and up to 3 h after dosing on day 5. Body sway data were similar with levocetirizine and placebo but increased with diphenhydramine. LMT was similar in all three groups. No relevant difference between placebo and levocetirizine was recorded by the subjects on their assessment of alertness using the VAS, whilst decreased alertness was reported following diphenhydramine 50 mg.Conclusions  This study showed that levocetirizine does not produce any deleterious effect on cognitive and psychometric functions compared with placebo in healthy male volunteers.
Lack of pharmacokinetic interaction between the oral anti‐influenza neuraminidase inhibitor prodrug oseltamivir and antacids
Authors: Snell Paul , Oo Charles , Dorr Al , Barrett Joanne 
Published: March 2003

Aims
Oseltamivir is an oral ester prodrug of its active metabolite Ro 64–0802, a potent and selective neuraminidase inhibitor of the influenza virus. The object of this study was to evaluate whether the oral absorption of oseltamivir was reduced in the presence of two main classes of antacid, Maalox® suspension (containing magnesium hydroxide and aluminium hydroxide) and Titralac® tablets (containing calcium carbonate).
Methods
Twelve healthy volunteers completed a randomized, single dose, three‐period crossover study. Each volunteer received in a fasted state, 150 mg oseltamivir alone (Treatment A), 150 mg oseltamivir with a 20 ml Maalox® suspension (Treatment  B),  and  150 mg  oseltamivir  with  four  Titralac® tablets  (Treatment  C),  with 7–10 days washout in between treatments. Plasma and urine concentrations of oseltamivir  and  Ro  64–0802  were  measured  using  a  validated  h.p.l.c./MS/MS assay. Pharmacokinetic parameters were calculated for oseltamivir and Ro 64–0802. Since antacids are locally acting drugs and generally not expected to be absorbed substantially into the systemic system, no plasma or urine concentrations of antacids were measured.
Results
Bioequivalence was achieved for the primary pharmacokinetic parameters Cmax and AUC(0,∞) of Ro 64–0802 following administration of oseltamivir with either Maalox® suspension or Titralac® tablets vs administration of oseltamivir alone. The bioavailability (90% confidence intervals) of Ro 64–0802 following administration of oseltamivir together with Maalox® suspension vs administration of oseltamivir alone, was 90% (83.6, 96.9%) for Cmax and 94.1% (91.4, 96.9%) for AUC(0,∞); similarly, for Titralac® tablets, the equivalent values were 95.1% (88.3, 102%) for Cmax and 94.7% (91.9, 97.5%) for AUC(0,∞).
Conclusions
The coadministration of either Maalox® suspension or Titralac® tablets with oseltamivir has no effect on the pharmacokinetics of either oseltamivir or Ro 64–0802, and conversely, there is no evidence that coadministration with oseltamivir has an effect on the safety and tolerability of either Maalox® suspension or Titralac® tablets. There was no pharmacokinetic interaction between oseltamivir with either antacid, demonstrating that the oral absorption of oseltamivir was not impaired in the presence of antacids containing magnesium, aluminium or calcium.
Population PKPD modelling of the long‐term hypoglycaemic effect of gliclazide given as a once‐a‐day modified release (MR) formulation
Authors: Frey N. , Laveille C. , Paraire M. , Francillard M. , Holford N. H. G. , Jochemsen Roeline 
Published: March 2003

Aims To study the relationship between the pharmacokinetics (PK) of gliclazide and its long‐term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability.Methods A PKPD database of 634 Type 2 diabetic patients with a total of 5258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease‐progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR.Results Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half‐life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l−1 year−1 (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1‐year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control.Conclusions This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long‐term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control.
A case of guttate psoriasis following Kawasaki disease
Authors: Han M-H. , Jang K-A. , Sung K-J. , Moon K-C. , Koh J-K. , Choi J-H. 
Published: March 2003

Abstract
We report a case of guttate psoriasis following Kawasaki disease, in a patient with Staphylococcus aureus demonstrated in a throat swab. We suggest that preceding staphylococcal infection can play a key role in the pathogenesis of some cases of guttate psoriasis, possibly by the production of superantigens.
Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia‐associated invasive fungal infections
Authors: Leenders Alexander C. A. P. , Daenen Simon , Jansen Rob L. H. , Hop Wim C. J. , Lowenberg Bob , Wijermans Pierre W. , Cornelissen Jan , Herbrecht Raoul , Lelie Hans Van Der , Hoogsteden Henk C. , Verbrugh Henri A. , Marie Siem De 
Published: March 2003

It has been suggested that a better outcome of neutropenia‐associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P = 0.09);P = 0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P = 0.05 andP = 0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status,P = 0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P < 0.001).The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety.
Transplantation for Fanconi's anaemia: long‐term follow‐up of fifty patients transplanted from a sibling donor after low‐dose cyclophosphamide and thoraco‐abdominal irradiation for conditioning
Authors: SociÉ Gérard , Devergie AgnÈs , Girinski Théodore , Piel Gaelle , Ribaud Patricia , Esperou Hélène , Parquet Nathalie , Maarek Odile , Noguera Maria‐Helena , Richard Patrice , Brison Olivier , Gluckman Eliane 
Published: March 2003

We describe the long‐term follow‐up of 50 Fanconi's anaemia patients who were transplanted from a related donor with a median follow‐up of >6 years. The survival estimate was 74.4% at 54 months and 58.5% at 100 months. All patients were conditioned with low‐dose cyclophosphamide and thoraco‐abdominal irradiation. Acute graft‐versus‐host disease (GvHD) of grade II or more developed in 26 patients and chronic GvHD developed in 30/43 (69.9%) patients. The survival of patients without chronic GvHD (n = 13) was 100%. In addition to chronic GvHD, 20 pre‐transplant transfusions was shown to have an adverse impact on survival by multivariate analysis (relative risk = 7.08, P = 0.0003). Prospective follow‐up of growth and endocrine function could be performed in 31 patients. Of 20 boys, six have already reached normal puberty within the expected time. Among the 11 girls, three were at the pubertal age at the time of analysis. Growth retardation was common, whereas late complications (e.g. peripheral hypothyroidism, cataract) were rare. However, the most important long‐term complication was the occurrence of cancer in seven patients (8‐year projected incidence 24%).Among the 32 survivors, 27 (84.5%) had a normal and four a moderately reduced performance status, and all achieved complete engraftment with donor cells. Therefore transplantation was able to cure these patients who remain at high risk for developing late complications. Clearly, a genetic predisposition and chronic GvHD could have led to the development of these cancers. However, we cannot completely rule out irradiation as a cofactor in the genesis of these cancers, and therefore no longer use irradiation for the conditioning of Fanconi's anaemia patients.