bluuebunny/crossref_metadata_2025 huggingface dataset:
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).
Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency
Authors: Müller F. O. , Terblanchè J. , Schall R. , Van Zyl Smit R. , Tucker T. , Marais K. , Groenewoud G. , Porchet H. C. , Weiner M. , Hawarden D.
Published: October 2003

Aims Triptorelin is a gonadotropin‐releasing hormone (GnRH) analogue with enhanced affinity for GnRH receptors and a prolonged half‐life due to its resistance to enzymatic degradation. The sustained‐release formulation of this molecule is advantageous in conditions requiring chronic hormone suppression.

Methods This was an open study to determine the pharmacokinetics of a single i.v. bolus dose of 0.5 mg triptorelin acetate in four groups of six male subjects; namely in healthy subjects (Group I), in patients with varying degrees of renal insufficiency (Groups II and III), and in patients with hepatic insufficiency (Group IV).

Results The maximum concentrations of triptorelin were found to be similar for all four study groups (geometric mean Cmax between 41.6 mg ml−1 and 53.9 mg ml−1 ). The total clearance of triptorelin decreased with increasing renal impairment, and was even lower in patients with hepatic insufficiency (geometric mean CLtot: 210 ml min−1, 113 ml min−1, 86.8 ml min−1 and 57.3 ml min−1 for Groups I, II, III and IV, respectively). Serum triptorelin concentrations in all four groups were adequately described by a three‐compartment model. The elimination half‐life for patients with hepatic impairment was similar to that of patients with renal impairment (geometric mean t1/2, z: 6.6 h, 7.7 h and 7.6 h for Groups II, III and IV, respectively), but significantly longer than in healthy volunteers (2.8 h for Group I). The first and second distribution half‐lives were similar for the four groups studied, with geometric mean distribution half‐lives of about 0.1 h (6 min) and 0.75 h (45 min), respectively.

Conclusions Although both renal and hepatic function are important for the clearance of triptorelin, the liver plays the predominant role in subjects suffering from some degree of renal impairment.
Free radicals and antioxidants in cardiovascular disease
Authors: Maxwell Simon R. J. , Lip Gregory Y. H.
Published: October 2003

Several lines of evidence suggest that free radical‐mediated oxidative damage to lipoproteins may be an important factor predisposing them to uptake into the vascular wall. This has led to interest in the factors that determine the susceptibility of lipoproteins to oxidation and their relationship to the development of coronary heart disease. Of these factors, the lipoprotein content of natural antioxidant vitamins such as vitamin E, and beta‐carotene have aroused particular interest. Studies in animal models of atherosclerosis suggest that natural and synthetic antioxidants can retard the development of atheroma. Epidemiological comparisons between populations and studies within populations also support the contention that high plasma levels or dietary intake of natural antioxidant vitamins may protect against the development of coronary disease in man. Prospective randomized controlled trials of antioxidants in high risk groups are underway to test whether the theoretical promise of a beneficial role for antioxidants in coronary heart disease prevention will be fufilled.
Tolerance to the repolarization effects of ‘oorac‘ox‐sotalol during long‐term treatment
Authors: Padrini Roberto , Gusella Milena , Al Bunni Muhammed , Piovan Donatella , Zordan Rossella , Magnolfi Gianna , Maiolino Pietro , Ferrari Mariano
Published: October 2003

Aims To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac‐sotalol.

Methods The effect of rac‐sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6‐day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia‐related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure &bgr;‐adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship.

Results In all patients QT interval prolongation was linearly correlated with rac‐sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1±6.3%vs +14.2±3.3%; peak concentration: 1.64±0.49 mg l−1vs 1.83±0.66 mg l−1 ). Line slopes were also unchanged following chronic treatment (21.8±8.9 vs 21.1±9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long‐term &bgr;‐adrenoceptor blockade and tolerance development.

Conclusions During maintenance treatment with rac‐solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.
The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine
Authors: Eiermann Birgit , Engel Georg , Johansson Inger , Zanger Ulrich M. , Bertilsson Leif
Published: October 2003

Aims Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N‐oxide (CLZ‐NO). This study investigated the involvement of different CYP isoforms in the formation of these two metabolites.

Methods Human liver microsomal incubations, chemical inhibitors, specific antibodies, and different cytochrome P450 expression systems were used.

Results Km and Vmax values determined in human liver microsomes were lower for the demethylation (61±21 &mgr;m, 159±42 pmol min−1 mg protein−1 mean±s.d.; n=4), than for the N‐oxidation of CLZ (308±1.5 &mgr;m, 456±167pmol min−1 mg protein−1; n=3). Formation of DCLZ was inhibited by fluvoxamine (53±28% at 10 &mgr;m ), triacetyloleandomycin (33±15% at 10 &mgr;m ), and ketoconazole (51±28% at 2 &mgr;m ) and by antibodies against CYP1A2 and CYP3A4. CLZ‐NO formation was inhibited by triacetyloleandomycin (34±16% at 10 &mgr;m ) and ketoconazole (51±13% at 2 &mgr;m ), and by antibodies against CYP3A4. There was a significant correlation between CYP3A content and DCLZ formation in microsomes from 15 human livers (r=0.67; P=0.04). A high but not significant correlation coefficient was found for CYP3A content and CLZ‐NO formation (r=0.59; P=0.09). Using expression systems it was shown that CYP1A2 and CYP3A4 formed DCLZ and CLZ‐NO. Km and Vmax values were lower in the CYP1A2 expression system compared to CYP3A4 for both metabolic reactions.

Conclusions It is concluded that CYP1A2 and CYP3A4 are involved in the demethylation of CLZ and CYP3A4 in the N‐oxidation of CLZ. Close monitoring of CLZ plasma levels is recommended in patients treated at the same time with other drugs affecting these two enzymes.
Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method
Authors: Jerling Markus , Merlé Yann , Mentré France , Mallet Alain
Published: October 2003

Aims To evaluate the distribution of population kinetic parameters for clozapine and their relationship to age and gender in patients on continuous treatment with the drug.

Methods Retrospective therapeutic drug monitoring data (391 samples from 241 patients) were evaluated using the nonparametric maximum likelihood method. Patients treated concomitantly with drugs known to interact with clozapine were not included. The distribution of clozapine clearance was compared with the distribution of the activity of the drug metabolic enzyme CYP1A2 found in other populations, as recent studies indicate that CYP1A2 is a major determinant for clozapine elimination. The kinetic linearity for clozapine was studied in 41 patients who each provided data from more than one dose level.

Results Clozapine clearance was highly variable in the population and skewed towards high values. Men had higher clearances CL/F (median with 25% and 75% quartiles 38.2 (22.0, 60.0) vs 28.3 (15.2, 48.6) l h−1 ) and a larger volume of distribution V /F (694 (224, 970) vs 401 (189, 932) l) than women. Clearance did not decrease with age in any gender. Clozapine clearance was similarly distributed as the indices of CYP1A2‐activity found in other populations by other authors. Evidence of nonlinear kinetics was not found.

Conclusion The large kinetic variability for clozapine found in this study implies that the dose of clozapine needs to be individualised over a wide dose range. The similarity of the distribution of clozapine clearance in this study and the CYP1A2‐activity in other populations support the assumption that CYP1A2 is a major determinant for clozapine elimination.
Transplacental distribution of salbutamol enantiomers at Caesarian section
Authors: Boulton* David W. , Paul Fawcett J. , Fiddes Thomas M.
Published: October 2003

Aims To investigate the transplacental distribution of salbutamol enantiomers after administration of racemate to women prior to Caesarian section.

Methods Five women about to undergo elective Caesarian section were administered a single 0.25 mg bolus intravenous dose of (R,S)‐salbutamol. The time from drug administration to delivery was different for each woman (27–105 min). Maternal and foetal umbilical cord venous blood samples were collected immediately after delivery and the plasma fraction analysed for salbutamol enantiomer concentrations by enantioselective high pressure liquid chromatography.

Results The concentrations (mean± s.d.) of the active (R) enantiomer of salbutamol in cord and maternal plasma were 0.46±0.35 and 0.89±0.50 ng ml−1, respectively, and the difference was statistically significant (95% confidence interval (CI) of the difference: 0.12–0.74 ng ml−1 ). The corresponding concentrations of the (S) enantiomer of 0.92±0.45 and 1.11±0.67 ng ml−1, respectively, were not significantly different (95% CI of the difference −0.08–0.48 ng ml−1 ). The ratio of (R):(S) in cord plasma was significantly less than that in maternal plasma (P=0.016).

Conclusions Transplacental distribution of salbutamol enantiomers at Caesarian section after prior administration of racemate to mothers leads to concentrations in cord plasma that are significantly less for the active (R) enantiomer and not significantly different for the (S) enantiomer than in maternal plasma presumably due to enantioselective placental‐foetal metabolism.
Metabolic interactions of selected antimalarial and non‐antimalarial drugs with the major pathway (3‐hydroxylation) of quinine in human liver microsomes
Authors: Zhao Xue‐Jun , Ishizaki Takashi
Published: October 2003

Aims Nine antimalarial (plus two metabolites of proguanil) and twelve non‐antimalarial drugs were tested for their possible interaction with CYP3A4‐catalysed 3‐hydroxylation of quinine by human liver microsomes in vitro.

Methods 3‐Hydroxyquinine was assayed in the incubation mixture by an h.p.l.c. method using fluorometric detection. The respective IC50 values were estimated for the twenty‐one drugs and two metabolites of proguanil tested herein.

Results Thirteen drugs exhibited an inhibitory effect on the 3‐hydroxylation of quinine. According to the respective mean IC50 values, the inhibitory rank order of the drugs was: ketoconazole>troleandomycin (TAO, with preincubation)> doxycycline>omeprazole>primaquine>tetracycline=TAO (without preincubation)>nifedipine>erythromycin>verapamil>cimetidine>diltiazem>oleandomycin>hydralazine. Other drugs or metabolites showed little or no inhibition of quinine metabolism (mean IC50>200 or 500 &mgr;m ). Among the antimalarial drugs, doxycycline showed relatively potent inhibition of quinine 3‐hydroxylation with a mean IC50 value of 17 &mgr;m, followed by primaquine and tetracycline, with mean IC50 values of 20 and 29 &mgr;m, respectively.

Conclusions When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, TAO and erythromycin are likely to be inhibitors of quinine metabolism in patients when the drugs are co‐administrated with quinine.
A prescription survey in a hospital hypertension outpatient clinic
Authors: Lee Pat K. F. , Li Robin K. L. , Chan Juliana C. N. , Chang Sophie , Lee S. C. , Tomlinson Brian , Critchley Julian A. J. H.
Published: October 2003

Aims The objective of this study was to investigate drug utilization in the management of hypertension in Hong Kong.

Methods We conducted a prescription survey to examine the use of antihypertensive drugs in a hypertension clinic in a regional hospital and the resulting expenditure incurred. The use of concurrent medications such as antidiabetic drugs and lipid‐lowering agents was also examined.

Results During a 7‐week study period, 530 prescriptions were collected. All except 14 patients received antihypertensive drugs with 262 (50.8%) on monotherapy and 254 (49.2%) on combination therapy. Calcium channel blocking agents and β‐adrenoceptor blocking agents were the two most popular antihypertensive drugs used in both monotherapy (38% and 31%, respectively) and combination therapy (27% and 33%, respectively). Forty‐nine patients (19%) received three antihypertensive drugs or more. The number of antihypertensive drugs showed a significant positive correlation with the duration of attendance at the clinic (r=0.88, P<0.001). Of the total 530 prescriptions, 5.6% and 10% contained antidiabetic drugs and lipid‐lowering agents, respectively. Calcium channel blocking agents, angiotensin converting enzyme (ACE) inhibitors and lipid lowering agents, accounted for 82% (HK$211 654; £1HK$12) of the total drug expenditure (HK$258 115). Seventy‐nine percent of the lipid lowering agents prescribed were hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors. Amlodipine accounted for 26% of usage but contributed to 41% of the overall costs of calcium channel blocking agents. α1‐adrenoceptor blocking agents were only used infrequently and were the most expensive class of drugs, due to the preferred use of doxazosin rather than prazosin which is far cheaper than the former.

Conclusions In view of the use of these often costly drugs for long‐term therapy, monitoring of their use and its correlation with clinical outcomes and quality of life is essential to ensure the optimal use of health care resources.
Characterization of the cytochrome P450 isoenzymes involved in the in vitroN‐dealkylation of haloperidol
Authors: Pan L. P. , Wijnant P. , De Vriendt C. , Rosseel M. T. , Belpaire F. M.
Published: October 2003

Aims The present study was carried out to identify the cytochrome P450 isoenzyme(s) involved in the N‐dealkylation of haloperidol (HAL).

Methods In vitro studies were performed using human liver microsomes and c‐DNA‐expressed human P450 isoforms. N‐dealkylation of HAL was assessed by measuring the formation of 4‐(4‐chlorophenyl)‐4‐hydroxypiperidine (CPHP).

Results There was a tenfold variation in the extent of CPHP formation amongst the nine human liver microsomal preparations. The CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. Km and Vmax values ranged respectively from 50 to 78 μm and from 180 to 412 pmol mg−1 min−1. CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N‐demethylase activity (a marker of CYP3A4 activity), but not with the activity of dextromethorphan O‐demethylase (CYP2D6), phenacetin O‐deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Ketoconazole, an inhibitor of CYP3A4, inhibited competitively CPHP formation (Ki=0.1 μm ), whereas sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine (CYP2D6) gave only little inhibition (IC50>100 μm ). CPHP formation was, moreover, enhanced by α‐naphtoflavone, an effect common to CYP3A4 mediated reactions. Anti‐CYP3A4 antibodies strongly inhibited CPHP formation, whereas no inhibition was observed in the presence of CYP2D6 antibodies. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to CPHP formation rate, with no detectable effect of other CYP isoforms (CYP1A2, CYP2D6 and CYP2C9). HAL inhibited dextromethorphan O‐demethylase (CYP2D6) with IC50 values between 2.7 and 8.5 μm, but not (IC50>100 μm ) dextromethorphan N‐demethylase (CYP3A4), phenacetin O‐deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9).

Conclusions These results strongly suggest that the N‐dealkylation of HAL in human liver microsomal preparations is mediated by CYP3A4.
Effects of IL‐3 and LPS on transcription factors involved in the regulation of IL‐6 mRNA
Authors: Tuyt Leonore M. L. , De Wit Harry , Koopmans Sicco B. , Sierdsema Siep J. , Vellenga Edo
Published: October 2003

Recently it has been demonstrated that in vivo application of interleukin‐3 (IL‐3) is associated with the release of IL‐6. This observation suggests that the transcription factors triggered by IL‐3 are in great homology with the transcription factors induced by lipopolysaccharide (LPS). The results of the present study with in vitro activated human monocytes demonstrate that IL‐3 alone is incapable of inducing IL‐6 mRNA, but primes monocytes to enhance the IL‐6 mRNA expression when co‐stimulated with LPS. The difference in effect between IL‐3 and LPS might be related to our observation that IL‐3 induces the p50 subunit of the transcription factor nuclear factor‐κB (NF‐κB), whereas LPS appears to induce both the p50 as well as the p65 subunit of NF‐κB, as demonstrated with RNA studies and electrophoretic mobility shift assays (EMSA). However, no difference was found with regard to the induction of activator protein‐1 (AP‐1) and NF‐IL6 after treatment with IL‐3 or LPS alone. Priming with IL‐3 followed by LPS stimulation is associated with a reduced expression of NF‐κB without changing the composition of the complex. In addition, a reduced expression of c‐fos and c‐jun mRNA was noticed, combined with a reduced DNA binding activity of AP‐1. However, the expression of NF‐IL6 was enhanced when priming with IL‐3 followed by LPS. Since AP‐1 has been suggested as negative regulator of the IL‐6 gene expression, it is conceivable that, after priming with IL‐3, the reduced DNA binding activity of AP‐1, in conjunction with the increased DNA binding of NF‐IL6, might result in a synergistic effect on IL‐6 mRNA expression, when compared to stimulation with LPS alone.
Serum LDH value as a predictor of clinical outcome in acute myelogenous leukaemia of the elderly
Authors: Ferrara Felicetto , Mirto Salvatore
Published: October 2003

72 patients aged over 60 suffering from acute myelogenous leukaemia (AML) and treated with aggressive chemotherapy were analysed with the aim of finding factors of prognostic relevance. With regard to complete remission achievement, the only variable of statistical significance found was the karyotype at diagnosis. As far as overall survival, in multivariate analysis performed by Cox hazard regression model, unfavourable karyotype and serum lactic dehydrogenase (LDH) >400 IU/l were significantly related to an adverse clinical outcome. Finally, serum LDH was the only parameter to significantly influence disease‐free survival. We conclude that serum LDH is a main prognostic factor in AML of the elderly and a potentially useful tool for identifying subsets of patients who may obtain a substantial advantage from aggressive chemotherapy.
Mutational analysis of the p15 and p16 genes in acute leukaemias
Authors: Sill H. , Aguiar R. C. T. , Schmidt H. , Hochhaus A. , Goldman J. M. , Cross N. C. P.
Published: October 2003

Recently the p16 and related p15 genes have been described as candidate tumour suppressors at chromosome 9p21. These genes have been found to be homozygously deleted at a high frequency in several types of solid tumours and also in acute lymphoid leukaemias. In order to determine whether these genes are more widely involved in haematological malignancies, we have investigated a total of 84 samples that did not have homozygous p16 or p15 deletions from patients with acute lymphoid leukaemia (n = 13), acute myeloid leukaemia (n = 24) and chronic myeloid leukaemia in blast crisis (n = 43) as well as four haemopoietic cell lines. p15 and p16 exon 1 and exon 2 were amplified by polymerase chain reaction (PCR), analysed by single‐stranded conformation polymorphism (SSCP) and subsequently by sequencing. Within the p16 gene, a G → A polymorphism at nucleotide 436 was found in 3/80 (4%) leukaemias and the cell line HL60. This cell line had also a C → T mutation at nucleotide 232 which causes a premature stop codon. Analysis of the p15 gene revealed a C → A mutation within the noncoding sequence 27 nucleotides upstream of exon 2 in 10/80 (13%) cases. These data show that inactivation of either the p15 or p16 gene by point mutation is a very uncommon event in acute leukaemias.
Absence of mutations at the activated protein C cleavage sites of factor VIII in 125 patients with venous thrombosis
Authors: Roelse Janet C. , Koopman Maria M. W. , Büller Harry R. , Ten Cate Jan W. , Montaruli Barbara , Van Mourik Jan A. , Voorberg Jan
Published: October 2003

Resistance to activated protein C (APC), caused by a mutation at amino acid position Arg506 of the factor V gene, has recently been identified as the most prevalent genetic defect associated with venous thrombosis. Similarly to factor V, mutations at the cleavage sites of factor VIII for APC may occur in patients with venous thrombosis. Here we have analysed 125 consecutive patients with incidental or recurrent venous thromboembolism for the presence of mutations at the cleavage sites for APC at amino acid positions Arg336 and Arg562 of factor VIII. Our findings indicate that mutations at these amino acid positions of factor VIII do not occur in the patient group analysed.
Resolution of Budd‐Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria
Authors: Graham Michael L. , Rosse Wendell F. , Halperin Edward C. , Miller Cindy R. , Ware Russell E.
Published: October 2003

Thrombosis of the hepatic veins (Budd‐Chiari syndrome) is a life‐threatening thrombotic complication which can occur in patients with paroxysmal nocturnal haemoglobinuria (PNH). Despite aggressive medical and surgical therapy, mortality from Budd‐Chiari syndrome remains high. We report a boy with PNH who developed Budd‐Chiari syndrome and underwent syngeneic bone marrow transplantation (BMT). Now, 3 years following BMT, he has had dramatic clinical and radiographic evidence of resolution of the thrombosis. We suggest that BMT for PNH can successfully correct life‐threatening thrombosis in patients with PNH.
Impaired survival of bone marrow GPIIb/IIIa+ megakaryocytic cells as an additional pathogenetic mechanism of HIV‐1‐related thrombocytopenia
Authors: Zauli Giorgio , Catani Lucia , Gibellini Davide , Carla Re Maria , Vianelli Nicola , Colangeli Vincenzo , Celeghini Claudio , Capitani Silvano , La Placa Michele
Published: October 2003

Glycoproteic (GP) IIb/IIIa+ megakaryocytic cells were purified from the bone marrow (BM) of 15 HIV‐1 seropositive thrombocytopenic patients, eight HIV‐1 seronegative patients affected by immune thrombocytopenic purpura (ITP) and 14 HIV‐1 seronegative normal donors. The presence of apoptosis was evaluated in freshly isolated GPIIb/IIIa+ cells by flow cytometry after propidium iodide staining and electron microscopy. GPIIb/IIIa+ cells from HIV‐1 seropositive thrombocytopenic patients showed a significant ( P < 0.001) increase of apoptosis with respect to both HIV‐1 seronegative ITP patients and normal donors. Moreover, the degree of apoptosis in bone marrow GPIIb/IIIa+ cells purified from HIV‐1 seropositive thrombocytopenic patients was inversely ( P < 0.01) related to the count of circulating platelets, whereas it did not show any significant correlation with the absolute number of circulating CD4 T cells, the CD4/CD8 ratio or the presence of proviral gag DNA sequences. Therefore neither an advanced stage of HIV‐1 disease nor a direct infection with HIV‐1 seems to play a primary role in the impaired survival of BM GPIIb/IIIa+ megakaryocytic cells. These findings strengthen the notion that, besides the immune targeting of peripheral platelets, an impairment of the bone marrow megakaryocyte compartment may also contribute to the pathogenesis of HIV‐1 related thrombocytopenia.
Response of myelodysplastic syndrome marrow progenitor cells to stimulation with cytokine combinations in a stroma‐free long‐term culture system
Authors: Soligo D. A. , Campiglio S. , Servida F. , Bossolasco P. , Romitti L. , Cortelezzi A. , Lambertenghi Deliliers G.
Published: October 2003

The effect of an ex vivo expansion culture system using multiple cytokine combinations was evaluated in 38 cases of myelodysplastic syndrome (MDS) with the aim of overcoming the defective in vitro growth of haemopoietic progenitor cells. A combination of four growth factors (GF) including SCF, IL‐3, IL‐6 and GM‐CSF was identified as the optimal combination for expanding clonogenic progenitor cells in MDS bone marrow liquid cultures. The cultures of 50% of the patients (19/38) responded to GF stimulation (mean CFU‐GM fold increase 15.65 ± 48 at week 4) and showed morphological features of normal and/or dysplastic myeloid differentiation. In 12/38 cases (31%), complete unresponsiveness to multiple cytokine stimulation was observed; a small number of patients (7/38) showed progressive leukaemic growth along the cultures with the presence of 100% immature blasts at week 4. GM‐CSF and c‐kit receptors, analysed by immuno‐histochemistry in 10 patients, were over‐expressed in responding patients and either lacking or down‐regulated in non‐responders. Fluorescence in situ hybridization (FISH) analysis of cultured interphase cells of nine patients (trisomy 8 in eight patients) showed a clear‐cut increase in the percentage of cells with three signals in the two responding patients, thus indicating the expansion of a MDS clone.  Multiple cytokine liquid cultures seem to be able to override the refractoriness of MDS progenitor cells to GF stimulation in many cases, revealing a heterogeneity which may have prognostic implications and should be considered in ex‐vivo and in vivo clinical trials with cytokine combinations.
Effect of platelet phospholipid exposure on activated protein C resistance: implications for thrombophilia screening
Authors: Luddington Roger , Brown Karen , Baglin Trevor
Published: October 2003

The effect of platelet contamination and freeze‐thawing on the activated protein C sensitivity ratio (APCsr) was determined. With increasing platelet count there was a progressive reduction in the ratio. Filtration of samples through a 0.2 μm filter before or after freeze‐thawing abolished the development of resistance to the addition of activated protein C indicating that the phenomenon is due to the presence of a particulate factor. Contamination of normal plasma with platelets from a patient with homozygous factor V (FV) deficiency was also associated with the same development of resistance to activated protein C, indicating that the phenomenon was not due to exposure of platelet‐derived factor V that might be inaccessible to APC.

82% (96/117) of FVQ506 and 32% (138/430) of FV R506 individuals had APC resistance on analysis of unfiltered plasma. However, 85% (42/50) of FVQ506 individuals had APC resistance on analysis of filtered plasma, whilst only 1/50 FV R506 individuals had APC resistance after filtration. For the purpose of identifying individuals at increased risk of venous thromboembolism due to the presence of the FVQ506 and associated APC resistance a PCR‐based genotypic analysis is recommended.
Monoclonal antibody 197 (anti‐FcγRI) infusion in a patient with immune thrombocytopenia purpura (ITP) results in down‐modulation of FcγRI on circulating monocytes
Authors: Ericson S. G. , Coleman K. D. , Wardwell K. , Baker S. , Fanger M. W. , Guyre P. M. , Ely P.
Published: October 2003

A 44‐year‐old woman with refractory immune thrombocytopenia purpura was treated with the murine monoclonal antibody 197 in a phase I trial. In vitro studies have demonstrated that the monoclonal antibody 197 (subclass IgG2a) binds to two distinct epitopes of FcγRI, with the constant domain binding to the Fc‐binding portion of the FcγRI and the variable domain binding to a different epitope, resulting in crosslinking and modulation of this receptor. The monoclonal antibody 197 was administered on days 1, 3 and 5 at doses of 0.25 mg/kg, 0.35 mg/kg and 0.45 mg/kg, respectively. The infusions were well tolerated with transient facial flushing, and wheal‐and‐flare rash during the first infusion, which resolved with a slower infusion rate and the administration of diphenhydramine and acetaminophen. Although a marked clinical improvement did occur with resolution of oral ecchymoses and epistaxis after the first mAb infusion, the initial platelet count of 6×109 l did not change appreciably over the 5 d course of monoclonal antibody treatment. Binding of fluorescein‐labelled monoclonal antibody 197 to peripheral monocytes showed a rapid and persistently decreased mean fluorescence intensity, indicating binding of administered 197 to the monocytes in vivo. Indirect staining for FcγRI using fluorescein‐labelled goat anti‐mouse immunoglobulin was also decreased, suggesting modulation of the receptor. The patient experienced monocytopenia which persisted throughout the 5 d of monoclonal antibody 197 therapy, but reversed following institution of intravenous IgG. These data indicate that intravenous monoclonal antibody 197 induces specific down‐modulation of FcγRI expression on monocytes.
Atypical chronic myeloid leukaemia, a distinct clinical entitity related to the myelodysplastic syndrome?
Authors: Oscier D. G.
Published: October 2003

The FAB group has recently published guidelines for distinguishing chronic granulocytic leukaemia (CGL) from chronic myelomonocytic leukaemia (CMML) and atypical chronic myeloid luekaemia (aCML). Whereas CGL is generally recognized to be a distinct entity, there is debate as to whether CMML and aCML are separate disorders or part of a spectrum of myeloproliferative disorders with dysplastic features. Data are presented on 10 cases who developed features of aCML during the course of their disease but who presented with a normal or low leucocyte count without a monocytosis and were diagnosed as refractory anaemia. This suggests that, at least in some cases, aCML represents an unusual evolution of MDS, and even though these patients have a uniformly poor prognosis it may be premature to regard aCML as a distinct clinical entity.
Heart valve and arterial tissue engineering
Authors: Sarraf C. E. , Harris A. B. , McCulloch A. D. , Eastwood M.
Published: October 2003

Abstract.  In the industrialized world, cardiovascular disease alone is responsible for almost half of all deaths. Many of the conditions can be treated successfully with surgery, often using transplantation techniques; however, autologous vessels or human‐donated organs are in short supply. Tissue engineering aims to create specific, matching grafts by growing cells on appropriate matrices, but there are many steps between the research laboratory and the operating theatre. Neo‐tissues must be effective, durable, non‐thrombogenic and non‐immunogenic. Scaffolds should be bio‐compatible, porous (to allow cell/cell communication) and amenable to surgery. In the early days of cardiovascular tissue engineering, autologous or allogenic cells were grown on inert matrices, but patency and thrombogenicity of grafts were disappointing. The current ethos is toward appropriate cell types grown in (most often) a polymeric matrix that degrades at a rate compatible with the cells’ production of their own extracellular matrical proteins, thus gradually replacing the graft with a living counterpart. The geometry is crucial. Computer models have been made of valves, and these are used as three‐dimensional patterns for mass‐production of implant scaffolds. Vessel walls have integral connective tissue architecture, and application of physiological level mechanical forces conditions bio‐engineered components to align in precise orientation. This article reviews the concepts involved and successes achieved to date.