bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double‐blind, placebo‐controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthy volunteers
Authors: Bani, M. , Colantoni A. , Guillaume M. , Macchi F. , Moroni G. , Persiani S. 
Published: March 2003

Aims
The objective of this study was to evaluate the tolerability of a novel dual ACE‐NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK).
Methods
In this randomized, placebo‐controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double‐blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once.
Results
Single oral doses of Z13752A, as high as 800 mg, were well tolerated. Only six mild‐to‐moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses ≥ 100–200 mg. NEP inhibition was indicated by elevation of ANP and cGMP plasma concentrations in almost all subjects. In the 200–800 mg dose range, Z13752A produced a 50–100% increase of plasma cGMP levels and a 50–80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half‐life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared to be dose‐independent.
Conclusions
Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in humans. The relatively slow clearance indicates that a once‐a‐day dose regimen could be considered for Z13752A.
Attitudes and knowledge of hospital pharmacists to adverse drug reaction reporting
Authors: Green Christopher F. , Mottram David R. , Rowe Philip H. , Pirmohamed Munir 
Published: March 2003

Aims  To investigate the attitudes of UK hospital pharmacists towards, and their understanding, of adverse drug reaction (ADR) reporting.Methods  A postal questionnaire survey of 600 randomly selected hospital pharmacists was conducted.Results  The response rate was 53.7% (n = 322). A total of 217 Yellow Cards had been submitted to the CSM/MCA by 78 (25.6%) of those responding. Half of those responding felt that ADR reporting should be compulsory and over three‐quarters felt it was a professional obligation. However, almost half were unclear as to what should be reported, while the time available in clinical practice and time taken to complete forms were deemed to be major deterrents to reporting. Pharmacists were not dissuaded from reporting by the need to consult a medical colleague or by the absence of a fee. Education and training had a significant influence on pharmacists' participation in the Yellow Card Scheme.Conclusions  Pharmacists have a reasonable knowledge and are supportive of the Yellow Card spontaneous ADR reporting scheme. However, education and training will be important in maintaining and increasing ADR reports from pharmacists.
Effect of dexmedetomidine, an α2‐adrenoceptor agonist, on human pupillary reflexes during general anaesthesia
Authors: Larson Merlin D. , Talke Pekka O. 
Published: March 2003

Aims  To test the hypothesis that the α2‐adrenergic agonist, dexmedetomidine, dilates the pupil and does not alter the pupillary light reflex of anaesthetized patients.Methods  Eight volunteers were administered general anaesthesia with propofol, nitrous oxide and alfentanil. One hour and 25 min after induction of anaesthesia, a 45 min infusion of dexmedetomidine was begun, targeting a plasma concentration of 0.6 ng ml−1. Pupil size, pupillary light reflex amplitude, light reflex recovery time, and reflex dilation were measured before and during dexmedetomidine infusion.Results  Dexmedetomidine produced no change in pupil size and light reflex recovery time, increased the light reflex from 0.30 ± 0.14 to 0.37 ± 0.12 mm and significantly reduced pupillary reflex dilation by 72 ± 62%.Conclusions  These pupillary effects of dexmedetomidine in humans are difficult to reconcile with the findings obtained in cats and rats that have demonstrated a direct inhibitory effect of α2‐adrenergic agonists on the pupilloconstrictor nucleus. The increase in the magnitude of the light reflex in response to dexmedetomidine does not necessarily involve an anxiolytic mechanism.
A placebo‐controlled study examining the effect of allopurinol on heart rate variability and dysrhythmia counts in chronic heart failure
Authors: Shehab Abdullah M. A. , Butler Robert , MacFadyen Robert J. , Struthers Allan D. 
Published: March 2003

Aims  Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF.Methods  We performed a prospective, randomized, double‐blind cross‐over study in 16 patients with NYHA Class II‐IV chronic heart failure (mean age 67 ± 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine < 150 µmol l−1) or 100 mg (if creatinine > 150 µmol l−1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI.Results  Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means ± s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean=6.5 ± 4.8 ms, P = 0.18 and 95% CI (−3.7, 17); TI mean=−2.1 ± 1.4, P = 0.16 and 95% CI (−5.2, 0.8); SDANN mean=−2.8 ± 7 ms, P = 0.68 and 95% CI (−18, 12); SDNNi mean=2 ± 6.6, P = 0.7 and 95% CI (−12, 16); RMSSD mean=−0.9 ± 2, P = 0.68 and 95% CI (−5.6, 3.7). For mean heart rate the corresponding results were 0.9 ± 1.4, P = 0.5 and 95% CI (−2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 ± 0.37, P = 0.7 and 95% CI (−0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P < 0.001).Conclusions  Allopurinol at doses, which are known to reduce oxidative stress appear to have no significant effect on resting autonomic tone, as indicated by time domain heart rate variability or on dysrhythmia count in stable heart failure patients.
The roles of CYP2D6 and stereoselectivity in the clinical pharmacokinetics of chlorpheniramine
Authors: Yasuda Sally Usdin , Zannikos Peter , Young Andrea E. , Fried Karen M. , Wainer Irving W. , Woosley Raymond L. 
Published: March 2003

Aims  To examine the stereoselective disposition of chlorpheniramine and to evaluate the role of CYP2D6 in chlorpheniramine pharmacokinetics in humans.Methods  Eight healthy volunteers (six extensive metabolizers with respect to CYP2D6 and two poor metabolizers) received a single 8 mg oral dose of rac‐chlorpheniramine either given alone or following administration of quinidine 50 mg every 6 h for 2 days prior to the study day and every 6 h thereafter until the end of the study. Plasma concentrations of (S)‐(+)‐ and (R)‐(−)‐enantiomers of chlorpheniramine were determined using liquid chromatography/mass spectrometry.Results  In extensive metabolizers, mean Cmax was greater (12.55±1.51 ng ml−1vs 5.38±0.44 ng ml−1) and CLoral was lower (0.49±0.08 l h−1 kg−1vs 1.07±0.15 l h−1 kg−1) for (S)‐(+)‐ than for (R)‐(−)‐chlorpheniramine (P<0.005). For (S)‐(+)‐chlorpheniramine, administration of quinidine, an inhibitor of CYP2D6, resulted in an increase in Cmax to 13.94±1.51 (P<0.01), a reduction in CLoral to 0.22±0.03 l h−1 kg−1 (P<0.01), and a prolongation of elimination half‐life from 18.0±2.0 h to 29.3±2.0 h (P<0.001). Administration of quinidine decreased CLoral for (R)‐(−)‐chlorpheniramine to 0.60±0.10 l h−1 kg−1 (P<0.005). In CYP2D6 poor metabolizers, systemic exposure was greater after chlorpheniramine alone than in extensive metabolizers, and administration of quinidine resulted in a slight increase in CLoral.Conclusions  Stereoselective elimination of chlorpheniramine occurs in humans, with the most pharmacologically active (S)‐(+)‐enantiomer cleared more slowly than the (R)‐(−)‐enantiomer. CYP2D6 plays a role in the metabolism of chlorpheniramine in humans.
Sirolimus steady‐state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients
Authors: Bäckman L. , Kreis H. , Morales J. M. , Wilczek H. , Taylor R. , Burke J. T. 
Published: March 2003

Aims  To determine whether bolus doses of methylprednisolone affect the steady‐state trough concentrations of sirolimus.Methods  Fourteen renal transplant recipients received concentration‐controlled sirolimus therapy in combination with azathioprine and steroids (n=8) or mycophenolate mofetil and steroids (n=6). Bolus doses of methylprednisolone (mean total dose over 1–5 days, 1694 mg; range, 500–3000 mg) were given for the treatment of acute rejection. For each patient, the sirolimus dose (mean, 24.1 mg; range, 3.3–52.5 mg) was the same before and during methylprednisolone therapy.Results  Mean sirolimus whole blood trough concentrations before and after treatment with methylprednisolone were 28.8 ng ml−1 (range, 13.9–45.3 ng ml−1), and 28.5 ng ml−1 (range, 13.0–47.9 ng ml−1), respectively (P=0.85; 95% confidence interval on the difference −3.3, 4.0 ng ml−1).Conclusions  Bolus methylprednisolone treatment does not affect steady‐state sirolimus trough concentrations.
Relationships between body composition parameters and fluorouracil pharmacokinetics
Authors: Gusella Milena , Toso Sivia , Ferrazzi Eros , Ferrari Mariano , Padrini Roberto 
Published: March 2003

Aims  To verify whether fluorouracil (FU) clearance (CL) and volume of distribution (Vss) are better correlated with specific body compartments, such as body cell mass (BCM), total body water (TBW) or fat free mass (FFM), rather than with body surface area (BSA) or total body weight (BW).Methods  Thirty‐four patients (13 females and 21 males) affected by colorectal cancer and receiving FU as adjuvant therapy entered the study. CL and Vss were determined after a 2 min i.v. injection of FU (425 mg m−2) and leucovorin (20 mg m−2). Body composition, in terms of BCM, TBW and FFM, was evaluated non‐invasively by bioelectrical impedance analysis (BIA).Results  Significant but poor correlations were found between CL or Vss and most anthropometric parameters, including BIA‐derived measures (r2 range=0.10–0.21). However, when multiple regression analysis was performed with sex, TBW and FFM as independent variables, the correlations improved greatly. The best correlation was obtained between CL and sex (r2=0.44) and between Vss and sex (r2=0.36). FFM‐normalized CL was significantly higher in women than in men (0.030±0.008 vs 0.022±0.005 l min−1 kg−1; 95% CI of difference 0.012, 0.003; P=0.003), suggesting that FU metabolism is more rapid in females. Surprisingly, Vss was highly correlated with CL (r2=0.67; CL=0.52+Vss×0.040). This finding may either be explained by extensive drug metabolism in extra‐hepatic organs or by variable inactivation on first‐pass through the lung. Both these hypotheses need experimental validation.Conclusions  The pharmacokinetics of FU are better predicted by FFM and TBW than by standard anthropometric parameters and predictions are sex‐dependent. The use of BIA may lead to improved dosing with FU.
Intestinal first pass metabolism of midazolam in liver cirrhosis – effect of grapefruit juice
Authors: Andersen Vibeke , Pedersen Natalie , Larsen Niels‐Erik , Sonne Jesper , Larsen Steen 
Published: March 2003

Aims  Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite α‐hydroxymidazolam was studied in patients with cirrhosis of the liver.Methods  An open randomized two‐way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child‐Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and α‐hydroxymidazolam.Results  Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite α‐hydroxymidazolam decreased to 25% (12, 37%) (P<0.05 for both). The ratio of the AUCs of the metabolite α‐hydroxymidazolam to midazolam decreased from 0.77 (0.46, 1.07) to 0.11 (0.05, 0.19) (P<0.05). t½ remained unaltered for both drug and metabolite. Midazolam Cmax, tmax, and α‐hydroxymidazolam tmax increased, but these changes were not statistically significant, whereas Cmax of the metabolite decreased to 30% (14, 47%) (P<0.05).Conclusions  A marked interaction between oral midazolam and grapefruit juice was found and the data are consistent with a reduced first‐pass metabolism of midazolam. This is likely to occur at the intestinal wall inhibition of CYP3A4 activity by grapefruit juice. These results indicate that patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function.
Pharmacokinetics and effects of propofol 6% for short‐term sedation in paediatric patients following cardiac surgery
Authors: Knibbe Catherijne A. J. , Melenhorst‐de Jong Gitte , Mestrom Maaike , Rademaker Carin M. A. , Reijnvaan Allart F. A. , Zuideveld Klaas P. , Kuks Paul F. M. , Van Vught Hans , Danhof Meindert 
Published: March 2003

Aims
This paper describes the pharmacokinetics and effects of propofol in short‐term sedated paediatric patients.
Methods
Six mechanically ventilated children aged 1–5 years received a 6 h continuous infusion of propofol 6% at the rate of 2 or 3 mg kg−1 h−1 for sedation following cardiac surgery. A total of seven arterial blood samples was collected at various time points during and after the infusion in each patient. Pharmacokinetic modelling was performed using NONMEM. Effects were assessed on the basis of the Ramsay sedation score as well as a subjective sedation scale.
Results
The data were best described by a two‐compartment pharmacokinetic model. In the model, body weight was a significant covariate for clearance. Pharmacokinetic  parameters in the weight‐proportional model were clearance (CL) = 35 ml kg−1 min−1, volume of central compartment (V1) = 12 l, intercompartmental clearance (Q) = 0.35 l min−1 and volume of peripheral compartment (V2) = 24 l. The interindividual variabilities for these parameters were 8%, < 1%, 11% and 35%, respectively. Compared with the population pharmacokinetics in adults following   cardiac   surgery   and   when   normalized   for   body   weight,   statistically   significant    differences   were   observed   for   the   parameters   CL   and  V1   (35  vs 29 ml kg−1 min−1 and 0.78 vs 0.26 l kg−1P < 0.05), whereas the values for Q and V2 were similar (23 vs 18 ml kg−1 min−1 and 1.6 vs 1.8 l kg−1, P > 0.05). In children, the   percentage   of   adequately   sedated   patients   was   similar   compared   with   adults (50% vs 67%) despite considerably higher propofol concentrations (1.3 ± 0.10 vs 0.51 ± 0.035 mg l−1, mean ± s.e. mean), suggesting a lower pharmacodynamic sensitivity  to propofol in children.
Conclusions
In children aged 1–5 years, a pharmacokinetic model for propofol was described using sparse data. In contrast to adults, body weight was a significant covariate for clearance in children. The model may serve as a useful basis to study the role of covariates in the pharmacokinetics and pharmacodynamics of propofol in paediatric patients of different ages.
The prevalence of CYP2C19 genotypes in a population of healthy Dutch volunteers and apparent gender differences in phenotypes
Authors: Tamminga Wim J. , Wemer Johan , Oosterhuis Berend , De Zeeuw Rokus A. , De Leij Lou F. M. H. , Jonkman Jan H. G. 
Published: March 2003

We reported the prevalence of poor metabolizers of CYP2C19 to be 1.8% in a sample of the Dutch population (n=4301; [1]). These data were obtained by phenotyping. In that study pronounced oral contraceptive related gender differences for CYP2C19 activity were reported. The present study was performed to estimate the prevalence of non‐coding mutations of CYP2C19 leading to the poor metabolizer phenotype. Furthermore, the data were analysed for gender differences.Seven hundred and sixty‐five unrelated healthy volunteers were evaluated for their CYP2C19 status. Subjects were phenotyped using mephenytoin. Genotyping was performed by the polymerase chain reaction (PCR) and restriction analysis for the most common null alleles.For CYP2C19*2 and CYP2C19*3 a frequency of 13.3% and 0.2%, respectively, was observed. The S/R‐ratio was significantly higher in heterozygous subjects (S/R‐ratio=0.22) compared with homozygous wild type subjects (S/R‐ratio=0.11). Comparison of all subjects below 45 years showed a significantly higher S/R‐ratio in females compared with males especially in heterozygous subjects (S/R‐ratio: 0.39 vs 0.19; P<0.001).The frequencies of CYP2C19 allelic variants in a population of Dutch healthy volunteers were in accordance with data on other European populations. Assessment of *2 and *3 for CYP2C19 predicted the phenotype with an accuracy of over 98.6%. Gene‐dose effect existed for CYP2C19. CYP2C19 heterozygous females had a decreased CYP2C19 activity that may be at least partly due to the use of oral contraceptives.
Does the change of omeprazole to pantoprazole affect clozapine plasma concentrations?
Authors: Mookhoek E. J. , Loonen A. J. M. 
Published: March 2003

Many chronic psychiatric inpatients suffer from schizophrenia and gastric disorders. Some of them are therefore treated with a combination of clozapine and an acid pump inhibitor. The atypical antipsychotic clozapine is metabolized by CYP1A2, CYP3A4 and CYP2D6. The acid pump inhibitor omeprazole can inhibit the activity of CYP2C19 and induce the activity of CYP2C8‐9, CYP3A4 and CYP1A2. The acid pump inhibitor pantoprazole is largely devoid of these activities. The possibility of pharmacokinetic drug drug interactions with psychotropic drugs lead in Spring 2000 to the replacement of omeprazole by pantoprazole in the drug formulary of Delta Psychiatric Hospital. In this hospital the plasma concentrations of clozapine and its primary metabolite are measured at regular intervals on a routine basis. This offers the opportunity to investigate the possible consequences of the change of acid pump inhibitor.The aim was to retrospectively assess the possible effect of the change of omeprazole to pantoprazole on the plasma concentrations of clozapine.The medication records of all long‐stay psychiatric in‐patients were checked and those patients were selected who used omeprazole and clozapine on April 4, 2000 and who were changed to pantoprazole for the rest of the year. The medical records of these patients were searched for data on clozapine plasma concentrations before and at least 6 weeks after the change, necessary changes of the clozapine dosage due to a changed clinical condition, and possibly reported adverse events. The data were controlled for co‐medication that influences the activity of CYP isoforms and for smoking habits.Out of 430 long‐stay patients 49 used omeprazole and 15 also used clozapine. Of these, 13 were finally evaluable. The 13 patients used 423±153.6 mg clozapine per day (mean±s.d.). Before the change, the clozapine concentrations measured 382±190.6 µg l−1. After the change, these concentrations measured 382±158.9 µg l−1. In five patients an increase in plasma concentrations was observed. Three of them were non‐smokers. A significant correlation (Pearson Rank, −0.615, P=0.025) was found between the second clozapine concentration and the amount of tobacco smoked per day. There existed no reports of changes in the medical condition, particularly the occurrence of relevant adverse events, that could be attributed to a change in clozapine plasma concentrations.No relevant changes were observed retrospectively in the plasma concentrations and clinical effects of clozapine due to the alteration of omeprazole to pantoprazole in this small patient population. However, there appears to exist a relationship between the smoking habits and the sensitivity to this change. This might be due to the CYP inducing activity of tobacco smoke, which may be more important than the CYP inducing activity of omeprazole.
In vitro permeation of β‐lactam antibiotics across rat jejunum and its correlation with oral bioavailability in humans
Authors: Saitoh Hiroshi , Aungst Bruce J. , Tohyama Masashi , Hatakeyama Yuko , Ohwada Keiko , Kobayashi Michiya , Fujisaki Hiroko , Miyazaki Katsumi 
Published: March 2003

Aims
To investigate the correlation between in vitro permeation of 11 β‐lactam antibiotics across rat jejunum and their oral bioavailability in humans.
Methods
The absorptive and secretory permeation across rat jejunum was evaluated and apparent permeability coefficients (Papp) were determined.
Results
A steep, sigmoid‐type curve was obtained for the relationship between Papp in the absorptive permeation and human oral bioavailability. When the ratios of Papp in the absorptive direction to Papp in the secretory direction were plotted against human oral bioavailability, a much improved correlation was obtained (r = 0.98, P < 0.001). The addition of glycylglycine to both mucosal and serosal media modi­fied the permeation of ceftibuten and cephalexin from the absorptive to the secretory direction.
Conclusions
For 11 β‐lactam antibiotics rat intestinal permeation correlated well with human oral bioavailability, especially when corrected for secretory transport.