bluuebunny/crossref_metadata_2025_split huggingface dataset:
The risk of acute pancreatitis associated with acid‐suppressing drugs
Authors: Eland I. A. , Alvarez C. Huerta , Stricker B. H. CH. , Rodrı´guez L. A. Garcı´a 
Published: March 2003

Aims
To assess the risk of acute pancreatitis associated with use of acid‐suppressing drugs.
Methods
We conducted a retrospective cohort study with a nested case‐control design within the General Practice Research Database (GPRD) in the United Kingdom. The cohort included 180 178 persons aged 20–74 years, who had received at least one prescription of cimetidine, famotidine, nizatidine, ranitidine, lansoprazole, or omeprazole from January 1992 to September 1997 and who did not have major risk factors for pancreatic diseases. Patients with a computerized medical history compatible with idiopathic acute pancreatitis were validated through review of medical records. For the nested case‐control analysis 1000 controls were randomly selected from the study population.
Results
We identified 88 potential cases of idiopathic acute pancreatitis. Medical records were available for 86. After review of these records 36 cases of acute pancreatitis were confirmed. Seven cases occurred during nonuse, corresponding to a background incidence rate (IR) of 4.4/100 000 person‐years (PY). Six cases occurred during current use of ranitidine (IR 10.5/100 000 PY), five patients were current users of cimetidine (IR 13.9/100 000 PY), and three were current users of omeprazole (IR 7.8/100 000 PY). There were no cases among current users of famotidine, lansoprazole, or nizatidine. Relative risk (RR) compared with nonuse and corrected for age, gender, calendar year and use of medication known to be associated with acute pancreatitis was 1.3 (95% CI: 0.4,4.1) for ranitidine, 2.1 (95% CI: 0.6,7.2) for cimetidine, and 1.1 (95% CI: 0.3,4.6) for omeprazole.
Conclusions
The results of this study do not support an association between acute pancreatitis and the use of acid‐suppressing drugs, although a substantial increase in risk cannot be excluded with confidence.
Pharmacokinetics of epimeric budesonide and fluticasone propionate after repeat dose inhalation – intersubject variability in systemic absorption from the lung
Authors: Minto Charles , Li Benny , Tattam Bruce , Brown Ken , Seale J. Paul , Donnelly Richard 
Published: March 2003

Aims
Pharmacokinetic variability is likely to be a significant factor contributing to the interindividual differences in dose requirements, anti‐inflammatory response and side‐effects with inhaled corticosteroids (ICS), but there is limited information about the disposition of ICS during regular dosing with a pressurized metered dose inhaler (pMDI). This study uses a mixed effects modelling approach to quantify and compare the interindividual variability in pharmacokinetics of epimeric budesonide (BUD) and fluticasone propionate (FP) after repeat‐dose inhalation.
Methods
This pharmacokinetic substudy was part of a previously published open‐label, randomised, placebo‐controlled, 7‐period crossover study to evaluate the short‐term effects on plasma cortisol levels of inhaled BUD (400, 800, 1600 µg twice daily) and FP (375, 750, 1000 µg twice daily) via pMDI in a group of healthy male volunteers. On the fifth day of each high‐dose treatment period (BUD 1600 µg twice daily and FP 1000 µg twice daily), venous blood samples were collected in nine subjects prior to the last dose and at 15 min, 30 min, 1, 2, 4, 6 and 8 h postdose for measurement of plasma drug concentrations to determine the pharmacokinetics of epimeric BUD and FP following inhalation. Non‐compartmental analysis and a mixed effects model were used to characterize the disposition profiles.
Results
Both drugs had a rapid absorption half‐life (BUD 10 min vs FP 11.3 min), but quite different elimination half‐lives (BUD 2.4 h vs FP 7.8 h). Although there were intraindividual differences in the handling of the 22R‐and 22S‐epimers of BUD, there were no consistent pharmacokinetic differences between the two enantiomers in the group as a whole. Consistent with previous reports of FP’s higher volume of distribution (V) and lower systemic bioavailability (F), the V/F ratio was lower for BUD than FP (498 l vs 8100 l). The parameter with the greatest interindividual variability for both BUD and FP was the rate of systemic absorption from the lung.
Conclusions
This is the first report describing the pharmacokinetics of epimeric BUD and FP after repeat dose inhalation via pMDI. Three observations may be of clinical relevance: (1) there is considerable intersubject variability in the rate of absorption of both drugs from the lung; (2) in some individuals there was a long t½,z for BUD, resulting in higher and more sustained plasma drug levels in the 4–12 h postdose period than would be predicted from single‐dose pharmacokinetic data; and (3) there is evidence of diurnal variation in FP pharmacokinetics, with higher‐than‐expected plasma drug concentrations in the morning compared with the evening.
Steady‐state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam
Authors: Türck D. , Heinzel G. , Luik G. 
Published: March 2003

Aims
This open, controlled study investigated the effect of concomitant 15 mg oral meloxicam on the pharmacokinetics of lithium in healthy male volunteers.
Methods
On days 1–14 lithium was coadministered with meloxicam to 16 volunteers; on days 10–14 lithium was administered in individualized dosage regimes to achieve stable lithium plasma concentrations in the lower therapeutic range of 0.3–0.7 mmol l−1. A 12 h steady‐state concentration profile for lithium was obtained at day 14, after which meloxicam was withdrawn. The lithium dose remained unchanged from day 15 to day 22, at which time a second lithium concentration profile was determined.
Results
Lithium and meloxicam were well tolerated throughout the study and all 16 volunteers completed the study. Lithium predose concentrations (Cpre,ss) and area under the curve (AUCss) values both increased by 21% (paired t‐test P = 0.0002; 90% confidence intervals for test/reference ratios: 113–130% and 115–128%, respectively) when lithium was coadministered with meloxicam compared with values obtained for lithium alone. The geometric mean lithium Cpre,ss was 0.65 mmol l−1 when coadministered with meloxicam and 0.54 mmol l−1 for lithium alone. Lithium Cmax,ss values were increased by 16% by coadministration of meloxicam, from 0.97 mmol l−1 to 1.12 mmol l−1. The total plasma clearance of lithium was lower with concomitant meloxicam administration (82.5% of value for lithium alone).
Conclusions
Meloxicam (15 mg) moderately increased the plasma concentration of lithium in healthy volunteers, but by a magnitude thought to be of low clinical relevance. Nevertheless, lithium plasma concentrations should be closely monitored in patients receiving concomitant meloxicam and lithium therapy.
The effects of lamotrigine on the pharmacokinetics of lithium
Authors: Chen Chao , Veronese Laurence , Yin Yin 
Published: March 2003

Aims
The treatment of bipolar disorder often includes use of multiple drug therapies. Lithium is one of the most commonly used treatments, but has a narrow therapeutic window. Lamotrigine, an established antiepileptic drug, is emerging as a potentially important new therapy in the treatment of bipolar disorder. The objective of this two‐treatment crossover study was to determine whether lamotrigine affects lithium pharmacokinetics.
Methods
Twenty healthy adult men completed the study. Subjects took 2 g lithium gluconate anhydrous every 12 h in the morning and evening for 5 days and in the morning of day 6, with or without 100 mg lamotrigine once daily in the morning for 6 days. Blood and urine samples were collected on day 6 of both treatments to characterize the pharmacokinetics of lithium using noncompartmental methods.
Results
The geometric least‐square mean ratio for renal clearance of lithium between the combination treatment and lithium alone treatment was 0.93 (95% confidence interval 0.85–1.02). Both treatments were well tolerated.
Conclusions
Lamotrigine does not cause significant change in the pharmacokinetics of lithium.
Nebivolol decreases systemic oxidative stress in healthy volunteers
Authors: Troost R. , Schwedhelm E. , Rojczyk S. , Tsikas D. , Frölich J. C. 
Published: March 2003

Aims
Nebivolol is a selective, vasodilatory β1‐adrenergic receptor antagonist which has been suggested to possess additional antioxidative properties. The aim of the present study was to assess the actions of nebivolol in antihypertensive doses on systemic oxidative stress in healthy volunteers, reflected by 24 h urinary excretion of 8‐iso‐PGF2α.
Methods
In a double‐blind, cross‐over study, 12 healthy volunteers received 5 mg nebivolol once daily or placebo for a total of 7 days, separated by a wash out period of 2 weeks. After each treatment period 24 h urinary excretion of 8‐iso‐PGF2α was determined by gas chromatography‐tandem mass spectrometry.
Results
After the 7 day treatment period nebivolol decreased significantly urinary excretion of 8‐iso‐PGF2α by 24% from 55.3 ± 5.1 pmol mmol−1 creatinine during the placebo period to 42.3 ± 4.7 pmol mmol−1 creatinine (mean ± s.e. mean, P = 0.01), a mean decrease of 13 pmol mmol−1 creatinine (95% CI: −22.8; −3.1).
Conclusions
Our data show for the first time that nebivolol decreases systemic oxidative stress in young healthy volunteers.
Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride
Authors: Niemi Mikko , Kivistö Kari T. , Backman Janne T. , Neuvonen Pertti J. 
Published: March 2003

Aims  To study the effects of rifampicin on the pharmacokinetics and pharmaco‐dynamics of glimepiride, a new sulphonylurea antidiabetic drug.Methods  In this randomised, two‐phase cross‐over study, 10 healthy volunteers were treated for 5 days with 600 mg rifampicin or placebo once daily. On day 6, a single oral dose of 1 mg glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 h.Results  Rifampicin decreased the mean area under the plasma concentration‐time curve of glimepiride by 34% (P < 0.001) and the mean elimination half‐life by 25% (P < 0.05). No significant differences in the blood glucose response to glimepiride were observed between the placebo and rifampicin phases. However, symptomatic hypoglycaemia occurred only during the placebo phase.Conclusions  The effects of rifampicin on the pharmacokinetics of glimepiride suggest that rifampicin induced the CYP2C9‐mediated metabolism of glimepiride and thereby slightly increased its systemic clearance. Because the interaction was modest and did not significantly alter the glucose‐lowering effect of glimepiride in healthy volunteers, it is probably of limited clinical significance. However, in some patients the hypoglycaemic effect of glimepiride may be reduced during concomitant treatment with rifampicin.
Identification of the human cytochrome P450 isoforms mediating in vitro N‐dealkylation of perphenazine
Authors: Olesen Ole V. , Linnet Kristian 
Published: March 2003

Aims
To identify the human cytochrome P450 (CYP) isoforms mediating the N‐dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved.
Methods
cDNA‐expressed CYP isoforms were used to identify the isoforms that are able to mediate the N‐dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N‐dealkylation reaction.
Results
CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N‐dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N‐dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1–2 µm, and Km values of CYP2C19 and CYP3A4 were 14 µm and 7.9 µm, respectively. Ketoconazole inhibition of N‐dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N‐dealkylation at therapeutically relevant concentrations.The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20–25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. HLM‐mediated N‐dealkylation of perphenazine accounted for 57% of the total amount of substrate consumed during incubation.
Conclusions
The present in vitro study suggests that CYP isoforms 1A2, 3A4, 2C19 and 2CD6 are primarily involved in the N‐dealkylation of perphenazine. The relatively modest role of CYP2D6 is at variance with in vivo studies, which indicate a greater contribution of this isoform. Alternative metabolic pathways, corresponding to 43% of the HLM‐mediated metabolism of the drug, may depend more strongly on CYP2D6.
Evaluation of a pharmacokinetic interaction between remacemide hydrochloride and phenobarbitone in healthy males
Authors: Hooper W. D. , Eadie M. J. , Blakey G. E. , Lockton J. A. , Manun'Ebo M. 
Published: March 2003

Aims  To determine whether there is a pharmacokinetic interaction between the antiepileptic drugs remacemide and phenobarbitone.Methods  In a group of 12 healthy adult male volunteers, the single dose and steady‐state kinetics of remacemide were each determined twice, once in the absence and once in the presence of phenobarbitone. The effect of 7 days remacemide intake on initial steady‐state plasma phenobarbitone concentrations was also investigated.Results  Apparent remacemide clearance (CL/F) and elimination half‐life values were unchanged after 7 days intake of the drug in the absence of phenobarbitone (1.25 ± 0.32 vs 1.18 ± 0.22 l kg−1 h−1 and 3.29 ± 0.68 vs 3.62 ± 0.85 h, respectively). Concomitant administration of remacemide with phenobarbitone resulted in an increase in the estimated CL/F of remacemide (1.25 ± 0.32 vs 2.09 ±0.53 l kg−1 h−1), and a decreased remacemide half‐life (3.29 ± 0.68 vs 2.69 ± 0.33 h). The elimination of the desglycinyl metabolite of remacemide also appeared to be increased after the phenobarbitone intake (half‐life 14.72 ± 2.82 vs 9.61 ± 5.51 h, AUC 1532 ± 258 vs 533 ± 281 ng ml−1 h). Mean plasma phenobarbitone concentrations rose after 7 days of continuing remacemide intake (12.67 ± 1.31 vs 13.86 ± 1.81 μg ml−1).Conclusions  Phenobarbitone induced the metabolism of remacemide and that of its desglycinyl metabolite. Remacemide did not induce its own metabolism, but had a modest inhibitory effect on the clearance of phenobarbitone.
Co‐prescribing of SSRIs and TCAs in Australia: how often does it occur and who is doing it?
Authors: McManus Peter , Mant Andrea , Mitchell Philip , Birkett Don , Dudley John 
Published: March 2003

Aims  To determine the frequency with which the selective serotonin re‐uptake inhibitor (SSRI) antidepressants are used as add‐on therapy to the tricyclic antidepressants (TCA) rather than as replacement therapy.Methods  The data analysed were profiles of prescription records by date of supply to the patient. From within the national administrative dispensing claims database, the subset eligible for social security entitlements was identified as individuals by means of their coded permanent identification numbers (PINs). Following the initial supply of an SSRI in January 1996, the subsequent 6 months dispensing of SSRI and TCA antidepressants to these individuals was examined. The main outcome measure was the proportion of individuals to whom SSRIs and TCAs were dispensed concurrently, as an indirect measure of coprescription. In instances where a patient was receiving prescriptions for SSRIs and TCAs that had been written by the one doctor only, the major specialty of the doctor was investigated.Results  55 271 PINs were dispensed 63 865 SSRI prescriptions in January 1996 which represented over half (52%) of the total community SSRI prescriptions dispensed in that month. The number of these patients meeting the criteria for coprescription of SSRIs and TCAs over the next 6 months was 2773 (5%). The coprescribing instances were highest in Queensland and the prescribers most frequently involved had psychiatry major specialty codes.Conclusions  Among SSRI users there is a cohort of patients who, within the same time frame, are receiving supplies of a TCA, the nonselective drug that the SSRIs were designed to replace. This is indirect evidence of probable coprescription. Such combination use is of uncertain clinical and cost effectiveness, and carries additional risks. The SSRIs were included on the subsidy list in Australia on the basis of reasonable cost effectiveness as monotherapy compared with the TCAs. Our data imply that for some patients, antidepressant prescribing is inconsistent with the basis on which government subsidy was approved.
Lack of effect of ondansetron on the pharmacokinetics and analgesic effects of morphine and metabolites after single‐dose morphine administration in healthy volunteers
Authors: Crews, Kristine Radomski , Murthy, Bindu P. , Hussey Elizabeth K. , Passannante Anthony N. , Palmer Jonathan L. , Maixner William , Brouwer Kim L. R. 
Published: March 2003

Aims  The purpose of this investigation was to study the influence of ondansetron on the single‐dose pharmacokinetics and the analgesic effects elicited by morphine and the 3‐ and 6‐glucuronide metabolites of morphine in healthy volunteers.
Methods
This was a randomized, double‐blind, placebo‐controlled, two‐way crossover study in which six male and six female subjects were administered a single 10 mg intravenous dose of morphine sulphate, followed 30 min later by a single 16 mg intravenous dose of ondansetron hydrochloride or placebo. Serum and urine concentrations of morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) samples were quantified over 48 h using high performance liquid chromatography with detection by mass spectrometry. Analgesia was assessed in the volunteers with a contact thermode device to provide a thermal pain stimulus. Four analgesic response variables were measured including thermal pain threshold, thermal pain tolerance, temporal summation of pain and mood state.
Results
The two treatments appeared to be equivalent based on the 90% confidence intervals (0.6, 1.67) of the least squares means ratio. All least squares means ratio confidence intervals for each parameter, for each analyte fell within the specified range, demonstrating a lack of an interaction.
Conclusions
The results of this study suggest that administration of ondansetron (16 mg i.v.) does not alter the pharmacokinetics of morphine and its 3‐ or 6‐glucuronide metabolites to a clinically significant extent, nor does it affect the overall analgesic response to morphine as measured by the contact thermode system.
Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind‐up of the second pain response in healthy male volunteers
Authors: Hughes A. M. , Rhodes J. , Fisher G. , Sellers M. , Growcott J. W. 
Published: March 2003

Aims  The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind‐up of second pain response in healthy male volunteers.Methods  The trial was a randomized, double‐blind, placebo‐controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg−1 dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg−1 ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind‐up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDICTM thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.Results  Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind‐up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (−5.52, 4.24) and 11.75 vs 15.25 (−11.89, 4.90) for left‐ and right‐hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind‐up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left‐ and right‐hand, respectively.Conclusions  Wind‐up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind‐up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.
An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria
Authors: Matthews Angela , Johnson Trevor N. , Rostami‐Hodjegan Amin , Chakrapani Anupam , Wraith J. Edward , Moat Stuart J. , Bonham James R. , Tucker Geoffrey T. 
Published: March 2003

Aims  To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of betaine in the treatment of classical homocystinuria due to cystathionine β‐synthase (CβS) deficiency with a view to optimizing the dosage regimen.Methods  Betaine was given as a single oral dose of 100 mg kg−1 to six patients (age range 6–17 years) who normally received betaine but whose treatment had been suspended for 1 week prior to the study. Plasma betaine and total homocysteine concentrations were measured by high performance liquid chromatography (h.p.l.c.) at frequent intervals over 24 h. The best‐fit PK model was determined using the PK‐PD program Win‐Nonlin and the concentration‐time‐effect data analysed by an indirect PD model. Using the PK and PD parameters, simulations were carried out with the aim of optimizing betaine dosage.Results  Betaine PK was described by both mono‐ and bi‐exponential disposition functions with first order absorption and a lag time. The correlation coefficient between betaine oral clearance and body weight was 0.6. Mean betaine clearance was higher in males than in females (P=0.03). PK‐PD simulation indicated minimal benefit from exceeding a twice‐daily dosing schedule and a 150 mg kg−1 day−1 dosage for betaine.Conclusions  PK‐PD modelling allows recommendations for optimal dosage of betaine in the treatment of homocystinuria, that have the potential for improved patient compliance and both therapeutic and pharmacoeconomic benefit.