bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paroxetine in human milk
Authors: Begg Evan J. , Duffull Stephen B. , Saunders Darren A. , Buttimore Rona C. , Ilett Kenneth F. , Hackett L. Peter , Yapp Patrick , Wilson Debbie A. 
Published: March 2003

Aims
The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model.
Methods
Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady‐state. The total amount of paroxetine in the milk was measured, which represented the ‘dose’ to the infant. The M/PAUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady‐state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies.
Results
The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5–1.7) of the weight adjusted maternal dose. The mean M/PAUC was 0.39 (range 0.32–0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38–2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31–3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (<4 μg l−1 ) in one infant. No adverse effects were observed in any of the infants.
Conclusions
Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered ‘safe’ during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported.
Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes
Authors: Dalén P. , Dahl M.‐L. , Andersson K. , Bertilsson L. 
Published: March 2003

Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be ‘normalised’ by low doses of the CYP2D6 inhibitor quinidine and whether this is dose‐dependent. Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4‐hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated. Results Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose‐effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1–2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively. Conclusions A dose‐effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of ‘treatment resistance’ caused by ultrarapid metabolism.
Effect of renal function on risedronate pharmacokinetics after a single oral dose
Authors: Mitchell D. Y. , St. Peter J. V. , Eusebio R.A. , Pallone K. A. , Kelly S. C. , Russell D. A. , Nesbitt J. D. , Thompson G. A. , Powell J. H. 
Published: March 2003

Aims
To determine the relationship between risedronate pharmacokinetics and renal function.
Methods
Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15–126 ml min−1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme‐linked immunosorbent assay (ELISA). Risedronate serum concentration‐time and urinary excretion rate‐time profiles were analysed simultaneously using nonlinear regression.
Results
Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min−1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min−1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population.
Conclusions
Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min−1 ).
Drug interactions avoided–a useful indicator of good prescribing practice
Authors: Williams D. , Kelly A. , Feely J. 
Published: March 2003

Aims  To develop an index of quality prescribing in general practice by investigating the incidence of potential drug interactions when medicines were coprescribed within the State supported General Medical Services (GMS) in Ireland.Methods  We determined an odds ratio (OR), as a measure of the relative risk of being exposed to a potential interaction, comparing the use of the H2‐receptor antagonist, cimetidine, with that of the noninteracting agents ranitidine, famotidine and nizatidine in users and nonusers of warfarin, phenytoin and theophylline.Results and conclusions  In 86 510 prescriptions for the H2–receptor antagonists potentially interacting drugs were dispensed to 8188 (9%) patients in the Eastern Health Board Region of the GMS. We found that prescribers were significantly less likely to use cimetidine (OR = 0.20,95% CI 0.17–0.21, P < 0.001) in those patients who were coprescribed warfarin, suggesting good prescribing practice within the GMS. Similarly there was preferential use of the noninteracting H2–receptor antagonists in patients receiving phenytoin or theophylline and the extent of this selective prescribing was in keeping with the rank order of severity of interaction with these drugs. This novel pharmacological index may be a sensitive marker of good prescribing practice.
Pharmacokinetic‐pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis
Authors: Angus B. J. , Smith M. D. , Suputtamongkol Y. , Mattie H. , Walsh A. L. , Wuthiekanun V. , Chaowagul W. , White N. J. 
Published: March 2003

Aims  Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis.Methods  Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg−1 8 hourly by bolus injection or 4 mg kg−1 h−1 by constant infusion following a 12 mg kg−1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters.Results  Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l−1, giving a target concentration CT, of 8 mg l−1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg−1, 0.058 (0.005–0.159) l kg−1 h−1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance.Conclusions  Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance =k* creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg−1 (1.9–4.6) and infusion rate I = 0.46 mg kg h−1 (0.04–1.3) (which equals 14.8 mg kg−1 day−1). A nomogram for adjustment in renal failure is given.
Pharmacokinetics and tolerability of intravenous infusion of adenosine (SUNY4001) in healthy volunteers
Authors: Uematsu Toshihiko , Kozawa Osamu , Matsuno Hiroyuki , Niwa Masayuki , Yoshikoshi Hirofumi , Oh‐uchi Mikio , Kohno Ken‐ichi , Nagashima Satoru , Kanamaru Mitsutaka 
Published: March 2003

Aims
To examine the tolerability and disposition of i.v. adenosine (SUNY4001) in healthy male Japanese volunteers.
Methods
SUNY4001 was infused i.v. for 6 min at 0 (placebo), 60, 100, 120 and 140 µg kg−1 min−1 in a dose‐escalating manner in 30 healthy subjects. Adenosine and its metabolites were determined in the plasma and urine.
Results
Only plasma hypoxanthine was increased from 3 min during until 5–10 min after SUNY4001 infusion at the higher rates without any significant dose‐related changes in plasma adenosine, inosine, xanthine or uric acid, or in urinary adenosine and all metabolites compared with the placebo. There was a dose‐related increase in the incidence of subjective symptoms such as heat sensation, flushed face, dyspnoea, chest discomfort, etc. Transient and self‐subsiding episodes of second‐degree atrioventricular block were found in two subjects each at the higher doses.
Conclusions
Adenosine infusion at ≤ 140 µg kg−1 min−1 was concluded to be generally well tolerated.
Muscular and cardiorespiratory effects of pseudoephedrine in human athletes
Authors: Gill Nicholas D. , Shield Anthony , Blazevich Anthony J. , Zhou Shi , Weatherby Robert P. 
Published: March 2003

Aims
Pseudoephedrine (PSE) is a readily available over‐the‐counter nasal decongestant which is structurally similar to amphetamine and is included on the International Olympic Committee's list of banned substances. However to date, little research has supported its putative ergogenic effect. This study investigated whether a 180 mg dose of PSE ingested 45 min prior to exercise enhanced short‐term maximal exercise performance and/or altered related physiological variables.
Methods
A randomised, double‐blind, crossover study in 22 healthy male athletes.
Results
Maximum torque (mean ± s.d., n = 22) produced in an isometric knee extension exercise was 321.1 ± 62.0 Nm (PSE) and 295.7 ± 72.4 Nm (placebo), and peak power obtained on the ‘all‐out’ 30 s cycle test was 1262.5 ± 48.5 W (PSE) and 1228.4 ± 47.1 W (placebo) (P < 0.01, P < 0.03, respectively). Subjects were estimated to be producing 96.9 ± 2.4% of their maximal possible isometric leg extension force after PSE ingestion, but only 95.3 ± 2.4% when PSE was not ingested. Bench press tasks and total work during the cycle test were not affected by the ingestion of PSE. Lung function was altered following ingestion of PSE (P < 0.05) with FEV1 and FVC significantly increased (P < 0.02, P < 0.01, respectively) although the FEV1/FVC ratio was not altered. Heart rate was significantly elevated by the ingestion of PSE immediately following the 30 s cycle sprint (P < 0.01) however, lactate concentration was not altered by the ingestion of PSE.
Conclusions
The administration of a 180 mg dose of PSE increased maximum torque, produced in an isometric knee extension and produced an improvement in peak power during maximal cycle performance, as well as improving lung function.
Identification of the cytochrome P450 enzymes involved in the N‐demethylation of sildenafil
Authors: Hyland R. , Roe E. G. H. , Jones B. C. , Smith D. A. 
Published: March 2003

Aims  To characterize the cytochrome P450 (CYP) enzymes responsible for the N‐demethylation of sildenafil to its main metabolite, UK‐103 320, to investigate the potential inhibitory effects of sildenafil on CYP enzymes and to evaluate the potential of selected drugs to affect sildenafil metabolism.Methods  The metabolic pathways of sildenafil N‐demethylation were studied using human liver microsomes, as well as microsomes expressing individual human CYP enzymes. Further studies to identify the individual enzymes were performed at 2.5 and 250 µm sildenafil, and employed a combination of chemical inhibition, correlation analysis, and metabolism by expressed recombinant CYP enzymes. In addition, the effect of sildenafil on the activity of the six major drug metabolizing enzymes was investigated.Results  Sildenafil conversion was found to be mediated by at least two CYP enzymes, for which the mean kinetic parameters were Km1 = 6(±3 µm), Km2 = 81(±45 µm), Vmax1 = 22(±9 pmol) and Vmax2 = 138(±77 pmol) UK‐103 320 formed min−1 mg−1. At 250 µm sildenafil, N‐demethylation was primarily mediated through the low‐affinity, high‐Km enzyme (approximately 83%), whilst at 2.5 µm there was a greater role for the high‐affinity, low‐Km enzyme (approximately 61%). Ketoconazole strongly inhibited metabolism at both sildenafil concentrations and was the only significant inhibitor at 250 µm sildenafil. At the lower sildenafil concentration, sulphaphenazole and quinidine also inhibited formation of UK‐103 320. Overall, 75% or more of the N‐demethylation of sildenafil at any concentration is probably attributable to CYP3A4. These results were supported by experiments using expressed human CYP enzymes, in which only CYP3A4 and CYP2C9 exhibited substantial sildenafil N‐demethylase activity (respective Km values of 221 µm and 27 µm). Sildenafil metabolism was inhibited by potent CYP3A4 inhibitors which are used clinically, but was found to be only a weak inhibitor of drug metabolizing enzymes itself, the strongest inhibition occurring against CYP2C9 (Ki = 80 µm).Conclusions  Evidence is provided for CYP3A4 and to a lesser extent CYP2C9‐mediated metabolism of sildenafil. There is the possibility that elevated plasma concentrations of sildenafil could occur with coadministration of known inhibitors of CYP2C9 or CYP3A4. Since peak plasma concentrations of clinical doses of sildenafil are only 200 ng ml−1 (∼0.4 µm) it is very unlikely that sildenafil will significantly alter the plasma concentration of other compounds metabolized by cytochrome P450 enzymes.
Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high‐dose chemotherapy
Authors: Huitema Alwin D. R. , Mathôt Ron A. A. , Tibben Matthijs M. , Schellens, Jan H. M. , Rodenhuis Sjoerd , Beijnen Jos H. 
Published: March 2003

Aims  To study the population pharmacokinetics of thioTEPA and its main metabolite TEPA in patients receiving high‐dose chemotherapy consisting of thioTEPA (80–120 mg m−2 day−1), cyclophosphamide (1000–1500 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) for 4 days.Methods  ThioTEPA and TEPA kinetic data were processed with a two‐compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined.Results  A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of thioTEPA (CL) was 34 l h−1 with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of thioTEPA was 47 l (IIV = 7.5%; IOV = 19%). The fraction of thioTEPA converted to TEPA divided by the volume of distribution of TEPA was 0.030 l−1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h−1 (IIV = 27%; IOV = 32%). CL of thioTEPA was correlated with alkaline phosphatase and serum albumin. The volume of distribution of thioTEPA and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively.Conclusions  A model for the description of the pharmacokinetics of thioTEPA and TEPA was developed. Factors involved in the interpatient variability of thioTEPA and TEPA pharmacokinetics were identified. Since, IOV of both thioTEPA and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.
Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects
Authors: Dingemanse Jasper , Clozel Martine , Van Giersbergen Paul L. M. 
Published: March 2003

Aims  The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, during chronic infusions in healthy male subjects.Methods  Tezosentan was infused at a rate of 100 mg h−1 for 6 h (study A, six subjects) and at a rate of 5 mg h−1 for 72 h (study B, eight subjects). Both studies had a randomized, placebo‐controlled, double‐blind design. Tolerability and safety were monitored by the recording of vital signs, ECG, adverse events and clinical laboratory parameters. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin‐1 concentrations.Results  In both studies tezosentan was well tolerated with headache the most frequently reported adverse event (incidence of 75–100% for tezosentan and 50% for placebo). Plasma concentrations of tezosentan rapidly approached steady state (3000 and 125 ng ml−1 in study A and B, respectively) and did not change upon prolonged infusion. A two‐compartment model could describe its pharmacokinetic profile. The half‐lives of the two disposition phases were approximately 0.10 and 3.2 h. Endothelin‐1 concentrations increased rapidly 11‐ and 2‐fold compared with pre‐dose values in study A and B, respectively, during infusion of tezosentan and did not change during the 72 h infusion.Conclusions  On the basis of these results, dose finding studies with tezosentan in acute heart failure can be initiated in the dose range 5–100 mg h−1.
Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady‐state dose
Authors: Sallustio Benedetta C. , Westley Ian S. , Morris Raymond G. 
Published: March 2003

Aims  1) To develop an estimate of oral clearance ( /F) for the antianginal agent perhexiline based on the ratio of cis‐OH‐perhexiline metabolite/parent perhexiline plasma concentrations at steady‐state

. 2) To determine whether the ratio measured in the first fortnight of treatment

may be used to guide patient dosing with perhexiline, a drug with a narrow therapeutic index, long half‐life and saturable metabolism via CYP2D6.Methods  Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis‐OH‐perhexiline concentrations.Results  Study 1 (n=70). At steady‐state, the frequency distributions of

/F and

/ were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by

/F≤50 ml min−1 or

/≤0.3. A group of patients with

/F≥950 ml min−1 may have been ultra‐rapid metabolizers. In this group, the high

/F values suggest extensive first‐pass metabolism and poor bioavailability. In patients with therapeutic plasma perhexiline concentrations (0.15–0.60 mg l−1), the variability in dose appeared directly proportional to

/F (r2=0.741, P<0.0001). Study 2 (n=23). Using

/ patients were tentatively identified as poor, extensive and ultra‐rapid metabolizers, with

/F of 23–72, 134–868 and 947–1462 ml min−1, respectively, requiring doses of 10–25, 100–250 and 300–500 mg day−1, respectively.Conclusions  The cis‐OH‐perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.
Dose–response relationships between individual nonaspirin nonsteroidal anti‐inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta‐analysis based on individual patient data
Authors: Lewis S. C. , Langman M. J. S. , Laporte Joan‐Ramon , Matthews John N. S. , Rawlins Michael D. , Wiholm Bengt‐Erik 
Published: March 2003

Aims
To define by amalgamation of data obtained in contemporaneous case‐control studies, the risks associated with individual nonaspirin nonsteroidal anti‐inflammatory drugs (NANSAIDs) according to doses used.
Methods
Meta‐analysis of individual patient data from three retrospective case‐control studies using similar data collection protocols was carried out in hospitals in Catalonia, England, Scotland and Sweden. 2472 cases of upper gastrointestinal bleeding and 5877 controls were studied. Main outcome measures were risks associated with individual NANSAIDs according to dose used and the period of time for which they were given.
Results
Ibuprofen showed the lowest odds ratio (OR = 1.7; 95% confidence interval 1.1, 2.5), followed by diclofenac (4.9; 3.3, 7.1), indomethacin (6.0; 3.6, 10.0), naproxen (9.1; 6.0–13.7), piroxicam (13.1; 7.9–21.8) and ketoprofen (34.9; 12.7, 96.5). Striking dose–response relationships were seen with four to eight‐fold increases in risk within conventionally used dose ranges for all except ketoprofen, where numbers were too few to allow dose analysis. Across the class, risk was highest during the first week of use (11.7; 6.5, 21.0), decreased thereafter with continuing use (5.6; 4.6, 7.0), and fell to 3.2 (2.1, 5.1) 1 week after discontinuing use. Concurrent use of more than one NANSAID substantially increased risk.
Conclusions
The risk of upper gastrointestinal bleeding with NANSAIDs varies twenty‐fold depending on the drug, and by three to seven‐fold depending on the dose chosen. Risk is maximal during the first week and decreases thereafter. Paracetamol (acetaminophen) is not associated with upper gastrointestinal bleeding at any dose and should be the first‐line analgesic wherever possible.