bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Pharmacology and Therapeutics—past, present and future
Authors: Reid John L. 
Published: October 2003

Aims To obtain information about the speciality of clinical pharmacology and therapeutics in the United Kingdom. Methods A survey of the views of 26 individuals in academic posts in clinical pharmacology and therapeutics was carried out by postal questionnaire. Response rate was 100%. Results Of 25 assessable responses of 25 centres, there were 35 academic staff of professorial status (median 2, range 0–5) and 61 staff of reader/senior lecturer status (median 2, range 0–5) but only 20 clinical staff in training grades in 19 institutions. All had extensive clinical commitments. Two‐thirds of respondents considered that the speciality was stable locally and nationally. However, recruitment of trainees was poor with only 8% of responders having several good applicants for each post and 90% reported that recruitment had deteriorated in the last 5–10 years. Likely good future careers for clinical pharmacologists in training were considered by 75–80% of respondents to likely lie in the pharmaceutical industry or regulatory authorities. Greater flexibility is required to facilitate training in clinical pharmacology and therapeutics. Conclusions Clincal pharmacology and therapeutics in the United Kingdom has a strong academic base but a sub‐optimal age structure. Recent experience in recruitment into training posts was disappointing. This may reflect wider problems of recruitment into academic medicine in this country.
Regional metabolism of articaine in 10 patients undergoing intravenous regional anaesthesia during day case surgery
Authors: Vree Tom B. , Simon Marc A. M. , Gielen Mathieu J. M. , Booij Leo H. D. J. 
Published: October 2003

Aims To study the pharmacokinetics of articaine and its metabolite articainic acid, in patients undergoing intravenous regional anaesthesia. Methods Ten patients (three male, seven female, ASA class 1–2), scheduled for surgery of the hand or forearm were included in the study. Articaine (40 ml, 0.5% solution (200 mg) was injected over 30 s. In total fifteen arterial blood samples were taken; one before injection and then at 10 min intervals, starting 10 min after completion of injection, until the tourniquet was released; thereafter blood samples were drawn at intervals of 1, 5, 10, 15, 20, 25, 30, 45, 60, 75 and 90 min. The tourniquet was released 30 min after completing the injection. Results During tourniquet application and regional analgesia of 30 min duration, 55% of articaine was hydrolysed by plasma (20%) and tissue (35%) esterase activity to the metabolite articainic acid. After releasing the tourniquet, articaine and its metabolite appeared in the blood; articaine was rapidly eliminated with a t1/2z of approximately 60 min. The plasma concentration of the metabolite articainic acid was the sum of the amount formed during IVRA (55%) and the amount formed after tourniquet release (45%). Conclusions Articaine is a safe agent for intravenous regional anaesthesia (IVRA) with rapid onset of good surgical anaesthesia. During tourniquet application and regional analgesia, 55% of the administered dose is already hydrolysed, thus reducing the chance of side effects after tourniquet release.
The effect of pharmacological supplementation with vitamin C on low‐density lipoprotein oxidation
Authors: Wen Y. , Cooke T. , Feely J. 
Published: October 2003

Aims Vitamin C (ascorbic acid) is a powerful antioxidant but there is limited information on its ability to prevent LDL oxidation and its interaction with other natural antioxidants in vivo. We assessed the effect of 4 weeks pharmacological supplementation with vitamin C 1 g day−1 on copper induced LDL oxidation and lipid peroxidation. Methods Blood samples were obtained at baseline and at the end of 4 weeks supplementation from 11 healthy non‐smokers and also from nine control subjects. Plasma lipid peroxides were measured as malondialdehyde (MDA) by h.p.l.c. The relationship between vitamin C and two other important antioxidants, vitamin E and glutathione, was also studied. Results There was no difference in baseline values between the two groups and the oxidizability of LDL, assessed as the lag phase of conjugated dienes production and the formation of thiobarbituric acid reactive substances (TBARS), remained unchanged after 4 weeks. In the vitamin C supplemented group only, there was a 2.2‐fold increase in plasma ascorbic acid level and a 28% increase in red cell reduced glutathione (GSH) (P<0.001). Vitamin E, measured as α‐tocopherol, in red cells increased significantly (P<0.02) and plasma MDA was reduced (P<0.01). Conclusions Vitamin C did not alter LDL oxidation but it may have a protective role against lipid peroxidation as shown by decreased plasma MDA levels and enhanced vitamin E and GSH status.
Effects of oral and inhaled corticosteroid on lymphocyte β2‐adrenoceptor function in asthmatic patients
Authors: Tan Kia Soong , McFarlane Lesley C. , Lipworth Brian J. 
Published: October 2003

Aims We have previously demonstrated that a single dose of oral prednisolone but not single doses of inhaled fluticasone had facilitatory effects on lymphocyte β2‐adrenoceptor (AR) function. To address possible differences in steady‐state time‐course, the aim of this study was to determine if repeated dosing with inhaled fluticasone would have facilitatory effects on lymphocyte β2‐AR. Plasma cortisol was also evaluated as a measure of systemic bioactivity. Methods Ten asthmatic subjects, mean (s.e.mean) age 29 (3) years, FEV1 89 (5) % predicted, were randomised in a double‐blind crossover study to receive inhaled placebo (PL), inhaled fluticasone 1000 μg day−1 (F1000) and inhaled fluticasone 2000 μg day−1, each for 4 days and also a single dose of oral prednisolone 50 mg (PRED). Prednisolone was given as open medication. The last dose of study drug was taken at 22.00 h and subjects attended the laboratory at 08.00 h the following day. Results β2‐AR density (Bmax; fmol/106 cells) was significantly increased after PRED compared with PL and inhaled fluticasone. Bmax (geometric mean) after each treatment were: PL 1.51, F1000 1.20, F2000 1.20 and PRED 2.14 (a 1.4 fold difference PRED vs PL; 95% CI 1.05 to 1.95; P<0.001). There was significant (P<0.001) suppression of plasma cortisol (nmol l−1 ) following F2000 and PRED compared with PL: 393.8, F1000 302.1, F2000 205.0 (95% CI F2000 vs PL 58.1 to 319.4) and PRED 87.0 (95% CI PRED vs PL 176.2 to 437.5). The estimated milligram equivalence ratio for adrenal suppression was calculated at 1:11 for fluticasone vs prednisolone. Conclusions Repeated dosing with high‐dose inhaled fluticasone did not up‐regulate lymphocyte β2‐AR as compared with a single dose of oral prednisolone, despite having significantly suppressed early morning plasma cortisol. This study confirms our previous finding of a dissociation in sensitivity between effects of inhaled corticosteroid on adrenal suppression and lymphocyte β2‐AR regulation, at least for doses up to 2 mg day−1 of fluticasone.
Enantioselective pharmacokinetics of mefloquine during long‐term intake of the prophylactic dose
Authors: Hellgren Urban , Berggren‐Palme Ingela , Bergqvist Yngve , Jerling Markus 
Published: October 2003

Aims To investigate the kinetics of the (+)RS‐ and (−)SR‐enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.Results A two‐compartment model adequately described the disposition of (+)RS‐MQ. CL/F was 6.5±1.8 l h−1, Vss/F 815±165 l, and k 0.0081± 0.0023 h−1. The kinetics of (−)SR‐MQ were time‐ and/or concentration dependent with a lower oral clearance (0.92±0.25 vs 2.14±0.63 l h−1, 95% CI for the difference 0.86–1.60 l h−1 ) and a longer half‐life (345 vs 185 h, 95% CI for the difference 47–291 h) after the last dose compared with the first dose. Clearance of (+)RS‐MQ and (−)SR‐MQ was significantly correlated within subjects (r=0.69, P<0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS‐MQ and 12.3% for (−)SR‐MQ. The elimination of MMQ was disposition rate‐limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.Conclusions The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.
Omeprazole, other antiulcer drugs and newly diagnosed gout
Authors: Meier Christoph R. , Jick Hershel 
Published: October 2003

Aims Case‐reports describing patients who developed a first episode of acute gout while being treated with the proton pump inhibitor omeprazole led us to compare incidence rates of newly diagnosed gout cases among omeprazole, ranitidine and cimetidine users.Methods We conducted a cohort study with a nested case‐control analysis using the UK‐based General Practitioner Research Database (GPRD). The study encompassed a cohort of more than 53 000 subjects who received some 185 000 prescriptions for the three study drugs.Results Neither current omeprazole vs recent use (age‐ and sex‐adjusted relative risk 1.1, 95% CI 0.5–2.1), nor current omeprazole use in comparison with current use of the two histamine H2‐receptor blockers was associated with an increased risk of developing newly diagnosed gout. Higher age (RR 2.4, 95% CI 1.5–3.9), male gender (RR 5.4, 95% CI 2.8–10.3), high body mass index (OR 3.3, 95% CI 1.0–10.9) and hypertension (OR 4.5, 95% CI 1.6–12.9) were all important risk factors for gout.Conclusions While other known risk factors were significantly associated with gout, current omeprazole use was not materially associated with an increased gout incidence.
The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis
Authors: Van Miert M. M. , Eastwood N. B. , Boyd A. H. , Parker C. J. R. , Hunter J. M. 
Published: October 2003

Aims To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide.Methods We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child‐Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end‐tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train‐of‐four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg−1 was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c.Results The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T1:T0, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T1:T0, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T1:T0, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T4:T1 to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg−1 min−1; P<0.005). The central (V1 ) and steady state volumes of distribution (Vss ) did not differ significantly between the groups. The slow redistribution (t½,λ1 ) and elimination (t½,z ) half‐lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P<0.005; and 143 (80) vs 92 (40) min, P<0.05 respectively). The exit rate constant for the effect compartment keo was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min−1; P<0.05), but cirrhosis had no significant effect on the parameters of the concentration‐effect relationship Cpss50 and γ.Conclusions Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.
Pharmacokinetics of digoxin‐specific Fab: effects of decreased renal function and age
Authors: Renard C. , Grene‐Lerouge N. , Beau N. , Baud F. , Scherrmann J. M. 
Published: October 2003

Aims To study the influence of age and renal function on digoxin‐specific Fab (DS‐Fab) pharmacokinetics.Methods Sixteen patients (35–91 years) with creatinine clearance ranging from 10.6 to 122.1 ml min−1 who had been admitted to hospital with severe digoxin or digitoxin self‐poisoning were treated with DS‐Fab (80 to 800 mg). Plasma DS‐Fab concentrations were determined by radioimmunoassay.Results The mean (±s.d.) distribution and elimination half‐lives, apparent volume of distribution and total body clearance were 1.1±0.4 h, 20.2±7.3 h, 13.1±5.8 l, and 17.6±10.8 ml min−1, respectively. Interindividual variability of DS‐Fab total body clearance was linked linearly with the decrease in creatinine clearance or with the increase in age and DS‐Fab distribution volume was not dependent on creatinine clearance or age.Conclusions The data suggest that DS‐Fab should be given to elderly and renal‐impaired patients at doses similar to those given to younger or normal renal function patients.
Bradykinin‐induced venodilation is not different in blacks
Authors: Vajo Zoltan , McDonald Mark , Takahashi Bruce , Zafar Haider , Srivathsan Komandor , Dachman William D. 
Published: October 2003

Aims The aim of this study was to determine whether young, normotensive blacks who have been recently demonstrated to have a venodilator response to isoprenaline decreased compared with whites, also have an decreased vasodilatory response to bradykinin. Methods Eleven black and 11 white subjects were studied. Full dose‐response curves to bradykinin (dosing range 0.5–500 ng min−1 ) were generated in hand veins preconstricted with phenylephrine (dosing range 20–6800 ng min−1 ). Results The groups had a similar maximal response to bradykinin (57.6±32.2%vs 67.8±49.3%, P=NS 95% confidence interval for the difference (CI): −47.3, 26.8). Also, the log of the dose that produced half maximal response to bradykinin was similar for the two groups (0.89±0.58 vs 0.78±0.61 ng min−1, P=NS, 95% CI: −0.42, 0.64). There was no difference between the two groups in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein. Conclusion Diminished vasodilatory response to endothelium‐derived relaxing factor (EDRF) does not seem to be associated with the increased prevalence of hypertension in blacks.
Forearm endothelium‐dependent vascular responses and the potassium‐ATP channel
Authors: McAuley D. , McGurk C. , Nugent A. G. , Hanratty C. , Maguire S. , Johnston G. D. 
Published: October 2003

Aims Vasodilation to acetylcholine is mediated at least in part by endothelium‐derived hyperpolarising factor (EDHF) which causes membrane hyperpolarisation by activating potassium channels. It is however uncertain which potassium channel mediates this effect. The aim of this study was to determine the role of the potassium‐ATP (K+‐ATP) channel in mediating endothelium‐dependent vascular responses to acetylcholine. Methods In 10 healthy volunteers acetylcholine, an endothelium‐dependent vasodilator, and sodium nitroprusside as a control assessing endothelium‐independent vasodilatation were infused into the non‐dominant brachial artery. Forearm blood flow (FBF) in response to each dose was measured by strain‐gauge venous occlusion plethysmography. The K+‐ATP channel blocker glipizide (2.5 mg) was then administered orally. After 45 min the infusions with FBF measurements were repeated. Results Acetylcholine (P<0.01) and sodium nitroprusside (P<0.01) both caused an increase in FBF. There was no significant difference in vascular responses to acetylcholine (P >0.05) or sodium nitroprusside (P >0.05) following K+‐ATP channel blockade. Conclusions The K+‐ATP channel does not modulate forearm arteriolar endothelium‐dependent responses in healthy volunteers and therefore does not play a role in membrane hyperpolarisation.
Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects
Authors: Thorsson L. , Dahlström K. , Edsbäcker S. , Källén A. , Paulson J. , Wirén J‐E. 
Published: October 2003

Aims The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. Methods Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 &;mgr;g) of FP via Diskhaler and repeated inhalations (1000 &;mgr;g twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 μg FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. Results The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6–18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20–65]% and 95 [93–97]% for the single and repeated doses, respectively. Conclusions To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.
Indices and graphical approaches for the detection of interindividual and interethnic variations in codeine metabolism
Authors: Yue Q. Y. , Iselius L. , Säwe J. 
Published: October 2003

Aims To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various urinary metabolic ratios (MR) for codeine O‐demethylation were also compared for their ability to determine phenotype. Methods Frequency histograms, normal test variable (NTV) plots and admixture analysis were used to examine the distributions of the urinary MRs for codeine O‐demethylation, N‐demethylation and glucuronidation in 132 Caucasian and 222 Chinese subjects. Results In the Caucasian population, apparent bimodality was shown in both a frequency histogram and NTV plot of the log MR of codeine O‐demethylation (codeine/(morphine (M)+M‐3 and M‐6‐glucuronide (M3G and M6G)+ normorphine (NM)). Admixture analysis confirmed the co‐segregation of codeine O‐demethylation and debrisoquine hydroxylation. The antimode for the codeine O‐demethylation MR between extensive and poor metabolisers was located between 5.5 and 8.3. A simplified MR for codeine O‐demethylation (codeine/M3G) demonstrated a similar correlation with the debrisoquine MR to the more complex MR, allowing a simplification of the analytical method for phenotyping. The Chinese population had significantly higher median MRs for codeine N‐demethylation, O‐demethylation and glucuronidation, which was shown clearly in the frequency histograms, but not in the NTV plots. Conclusion A histogram seems preferable over a NTV plot for assigning phenotype using the codeine O‐demethylation MR, because it is clear and simple. Interethnic difference in the metabolism of codeine are also better visualised from the histograms.
The pharmacokinetics of methadone in healthy subjects and opiate users
Authors: Wolff K. , Rostami‐Hodjegan A. , Shires S. , Hay A. W. M. , Feely M. , Calvert R. , Raistrick D. , Tucker G. T. 
Published: October 2003

Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).