bluuebunny/crossref_metadata_2025 huggingface dataset:
The reproducibility of symptoms during a submaximal exercise test in chronic heart failure
Authors: Grant S. , McMurray J. , Aitchison T. , McDonagh T. , Christie J. , Davie A. , Dargie H. J.
Published: March 2003

Aims
 The aim of this study was to evaluate the use of a submaximal test with a symptom limited endpoint and to measure the reproducibility of symptoms in patients with CHF.

Methods
 Ten patients with chronic heart failure were studied. Based on two maximal treadmill tests an individual protocol using a constant work rate at a submaximal intensity was derived. The projected maximum treadmill time for the constant workrate was between 8 and 17 min. Tests were carried out 1, 2, 4 and 6 weeks after the maximum tests. Every 2.5 min during the submaximal test patients recorded their symptoms of breathlessness and fatigue using computer automated visual analogue (VAS) and Borg CR10 scales. The measure of reproducibility used was the proportion of total variability explained by the between subject variability.

Results
 Using the VAS scale, general fatigue was reasonably reproducible ranging from 77–86%. For VAS breathlessness reproducibility ranged from 66% to 83%. Reproducibility for breathlessness and fatigue for the Borg CR10 scale was much lower than the VAS scale. Reproducibility for the treadmill times was 51% but increased to 76% if one test of one subject was excluded.

Conclusions
 The use of the VAS during submaximal exercise offers a useful means of evaluating symptoms in CHF and potentially their response to treatment. These findings show that individual submaximal protocols can be easily prescribed for CHF patients. Using such an approach, clinically desirable tests lasting around 12 min can be developed. These tests are reasonably reproducible and may provide a useful means of assessing patient disability and the impact of treatment.
Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man
Authors: Malerczyk Claudius , Fuchs Bettina , Belz Gustav G. , Roll Susanna , Butzer Raunhild , Breithaupt‐Grögler Kerstin , Herrmann Volker , Magin Steffen G. , Högemann Anette , Voith Barbara , Mutschler Ernst
Published: March 2003

Aims
 The pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose‐effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p.l.c.

Methods
 Twelve healthy male volunteers received single oral doses of 4, 8 and 16 mg candesartan cilexetil and placebo. Plasma was obtained for h.p.l.c. and r.r.a. (receptors: rat lung; radioligand: [125I‐Sar1Ile8]‐angiotensin II).Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose‐effect curves were fitted according to an Emax model and dose ratios (DR) calculated from the antagonist induced rightward shifts.

Results
 Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6–9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4–7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent Ki‐doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible.

Conclusions
 A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off‐rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.
Start of therapy with the angiotensin II antagonist losartan after immediate switch from pretreatment with an ACE inhibitor
Authors: Scholze Juergen , Stapff Manfred
Published: March 2003

Aims
 To evaluate initial blood pressure effects of the angiotensin II antagonist losartan (L) immediately after switching from an ACE inhibitor (captopril, C).

Methods
 Two‐phase multicentre randomized study in 177 outpatients with mild to moderate essential hypertension. For 6 weeks all patients received 25 mg C twice daily. Then they were randomized double‐blind to switch for another 6 weeks to 50 mg L once daily (n=110) or to maintain C (n=55). On the first day of the switch they underwent ambulatory blood pressure measurement (ABPM).

Results
 Within 12 h of first dose, 31% of patients who switched to L had two consecutive systolic BP readings of 30 mmHg below their individual baseline value compared with 24% of patients who stayed on C. In 3% of patients with L and in 6% of the C patients systolic BP readings less than 100 mmHg were recorded within 12 h of first dose. The differences were not statistically significant. There were no clinical symptoms attributable to initial hypotension. During the 6 weeks double‐blind therapy, 9% of L patients experienced at least one adverse event, compared with 16% of patients with C.

Conclusions
 In this study the angiotensin II antagonist losartan was effective and generally well tolerated when administered immediately after pretreatment with an ACE inhibitor.
Forearm reactive hyperaemia is not mediated by nitric oxide in healthy volunteers
Authors: Nugent  , McGurk  , McAuley  , Maguire  , Silke  , Johnston
Published: March 2003

Aims To determine the role of nitric oxide (NO) in forearm reactive hyperaemia in healthy human subjects.

Methods Ten healthy subjects aged 19–34 years underwent brachial artery cannulation. Forearm circulatory arrest was achieved by means of an upper arm cuff inflated to 200 mmHg for 5 min. The blood flow responses during reactive hyperaemia were measured using venous occlusion plethysmography following a 10 min intra‐arterial influsion of 8 μmol min−1N‐monomethyl l‐arginine (‐NMMA) and following matching placebo administered in random order. Results were analysed by repeated measures anova and t‐tests.

Results ‐NMMA resulted in a significant reduction of basal forearm blood flow indicating inhibition of basal NO release (P=0.005). There was no significant difference between the blood flow responses during reactive hyperaemia following ‐NMMA and placebo (P=0.97).

Conclusions Nitric oxide production does not make a significant contribution to the vasodilatation associated with reactive hyperaemia in the human forearm.
Evaluation of noninvasive blood pressure recording by photoplethysmography in clinical studies using angiotensin challenges
Authors: Buclin  , Buchwalder‐Csajka  , Brunner  , Biollaz
Published: March 2003

Aims Continuous noninvasive blood pressure measurement by photoplethysmography has been regularly used in the experimental paradigm of angiotensin challenges, applied to the phase I clinical testing of angiotensin‐converting enzyme inhibitors and angiotensin receptor antagonists. This work aims to evaluate the performance of this measurement method, in terms of reliability, reproducibility and dependence on technical settings.

Methods Data have been gathered from 13 clinical studies on antihypertensive drugs, using the Finapres® device for measuring the response to exogenous angiotensin challenges. The agreement between simultaneous recordings at different fingers and the influence of the reading method are assessed. A literature review addresses the question of the concordance between results obtained noninvasively and through arterial cannulation.

Results The relative precision of blood pressure monitoring by photoplethysmography allows reproducible determination of angiotensin‐induced blood pressure peaks (agreement limits for systolic and diastolic peaks: 12 and 6 mmHg respectively). The reading method influences the results to a similar extent. As compared with blood pressure measured intra‐arterially, the difference is usually within limits of clinical acceptability.

Conclusions In the context of phase I studies using the angiotensin challenges methodology, the reliability and reproducibility of noninvasive blood pressure measurement appear satisfactory, despite the technical limitations of this method. The impact of selected changes in the settings and reading methods is limited.
Absorption of sunscreens across human skin: an evaluation of commercial products for children and adults
Authors: Jiang  , Roberts  , Collins  , Benson
Published: March 2003

Aims Topical sunscreens are routinely applied to the skin by a large percentage of the population. This study assessed the extent of absorption of a number of common chemical sunscreen agents into and through human skin following application of commercially available products.

Methods Sunscreen products were applied to excised human epidermis in Franz diffusion cells with the amount penetrating into and across the epidermis assessed by h.p.l.c. for 8 h following application.

Results All sunscreen agents investigated penetrated into the skin (0.25 g m−2 or 14% of applied dose), but only benzophenone‐3 passed through the skin in significant amounts (0.08 g m−2 or 10% of the applied dose). With one exception, suncreen agents in corresponding products marketed for adults and children had similar skin penetration profiles.

Conclusions Whilst limited absorption across the skin was observed for the majority of the sunscreens tested, benzophenone‐3 demonstrated sufficiently high penetration to warrant further investigation of its continued application.
Population frequency, mutation linkage and analytical methodology for the Arg16Gly, Gln27Glu and Thr164Ile polymorphisms in the β2‐adrenergic receptor among Turks
Authors: Aynacioglu  , Cascorbi  , Güngör  , Özkur  , Bekir  , Roots  , Brockmöller
Published: March 2003

Aims Inherited polymorphisms of codons 16, 27, and 164 of the β2‐adrenergic receptor (B2AR) gene may result in significantly changed functions of this receptor. The aim of the present study was to investigate the frequencies of the main mutations of the B2AR gene in Turks.

Methods A group of 104 unrelated Turkish subjects were analysed for the Arg16Gly, Gln27Glu, and Thr164Leu polymorphisms of B2AR by a newly designed polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) assay. A 242‐bp amplicon including the Arg16Gly and Gln27Glu polymorphisms was generated including an arbitrary restriction site, allowing the cleavage with Eco130I or Fnu4HI for analysis of the two polymorphic sites, respectively. For the amino acid polymorphism at codon 164 a 280‐bp fragment was generated and digested by MnlI.

Results The allelic frequencies of mutated Gly16, Glu27, and Ile164 alleles were found as 59.6%, 31.7%, and 0.5%, respectively. Although, the frequencies of the polymorphisms at codon 16 and 164 were found similar as in various Caucasian populations, the frequency of the Glu27 variant was found significantly lower than these populations.

Conclusions Obviously there are interethnic differences in functionally relevant B2AR variants which may have implications for drug treatment and disease susceptibility.
The use of atypical antipsychotics in the management of schizophrenia
Authors: Campbell  , Young  , Bateman  , Smith  , Thomas
Published: March 2003

Long‐term drug treatment of schizophrenia with conventional antipsychotics has limitations: an estimated quarter to one third of patients are treatment‐resistant; conventional antipsychotics have only a modest impact upon negative symptoms (poverty of thought, social withdrawal and loss of affect); and adverse effects, particularly extrapyramidal symptoms (EPS). Newer, so‐called atypical, antipsychotics such as olanzapine, risperidone, sertindole and clozapine (an old drug which was re‐introduced in 1990) are claimed to address these limitations. Atypical agents are, at a minimum, at least as effective as conventional drugs such as haloperidol. They also cause substantially fewer extrapyramidal symptoms. However, some other adverse effects are more common than with conventional drugs. For example, clozapine carries a significant risk of serious blood disorders, for which special monitoring is mandatory; it also causes troublesome drowsiness and increased salivation more often than conventional agents. Some atypical agents cause more weight gain or QT prolongation than older agents. The choice of therapy is, therefore, not straightforward. At present, atypical agents represent an advance for patients with severe or intolerable EPS. Most published evidence exists to support the use of clozapine, which has also been shown to be effective in schizophrenia refractory to conventional agents. However, the need for compliance with blood count monitoring and its sedative properties make careful patient selection important. The extent of any additional direct benefit offered by atypical agents on negative symptoms is not yet clear. The lack of a depot formulation for atypical drugs may pose a significant practical problem. To date, only two double‐blind studies in which atypical agents were compared directly have been published. Neither provides compelling evidence for the choice of one agent over another. Atypical agents are many times more expensive than conventional drugs. Although drug treatment constitutes only a small proportion of the costs of managing schizophrenia, the additional annual cost of the use of atypical agents in, say, a quarter of the likely U.K. schizophrenic population would be about £56 M. There is only limited evidence of cost‐effectiveness. Atypical antipsychotics are not currently licensed for other conditions where conventional antipsychotics are commonly used, such as behaviour disturbance or dementia in the elderly. Their dose, and place in treatment in such cases have yet to be determined.
Record‐linkage for pharmacovigilance in Scotland
Authors: Evans Josie M. M. , MacDonald Thomas M.
Published: March 2003

Record‐linkage is the linkage of patient‐specific information that is stored separately. Recent advances in computerization have meant that record‐linkage techniques in medical research are increasingly being used and refined. In particular, they have made a significant contribution to pharmacovigilance, which involves linking drug exposure to outcomes data. In this article, the contribution of record‐linkage in Scotland to medical research is described. The two organizations that utilize record‐linkage techniques are the Medicines Monitoring Unit (MEMO) of the University of Dundee and the Information and Statistics Division (ISD) of the NHS in Scotland. Pharmacovigilance is MEMO’s main concern (using data from the Tayside region of Scotland), while ISD link health care datasets for Scotland for general health care research. The experience of the two groups is now being combined to carry out drug safety studies in the entire population of Scotland.
Comparison of urinary 6β‐hydroxycortisol/cortisol ratio between neonates and their mothers
Authors: Nakamura Hiroyoshi , Hasegawa Atsushi , Kimura Maharu , Yamagata Shin‐ichi , Nakasa Hiromitsu , Osada Hisao , Sekiya Souei , Ohmori Shigeru , Kitada Mitsukazu
Published: March 2003

Aims To assess CYP3A enzyme activity in human neonates by measuring the urinary 6β‐hydroxycortisol/cortisol (6β‐OHF/C) ratio.

Methods Fifty‐six mature male neonates with normal delivery, seventeen of their mothers and twenty‐four healthy non‐pregnant young women participated in this study. Urinary 6β‐OHF/C ratio was determined on the day of birth in neonates and their mothers. In addition, changes in the ratio after birth were determined in neonates.

Results On the day of birth, the urinary 6β‐OHF/C ratio of neonates was significantly higher than that of their mothers (20.5 vs 6.9). In contrast, no significant difference was observed in the mean ratio of urinary 6β‐OHF/C between women with and without pregnancy (6.9 vs 9.0). The urinary 6β‐OHF/C ratio after birth was decreased day by day in neonates.

Conclusion These results indicate that the high urinary 6β‐OHF/C ratio in mature neonates on the day of birth is independent of the activity of CYP3A enzyme in their mothers.
Role of nitric oxide in isoprenaline and sodium nitroprusside‐induced relaxation in human hand veins
Authors: Chalon Stephan , Tejura Bina , Moreno Jr Heitor , Urae Akinori , Blaschke Terrence F. , Hoffman Brian B.
Published: March 2003

Aims Recent reports, largely in animal models, have suggested that either inhibition of nitric oxide (NO) synthase or endothelium removal in arteries inhibits the response to isoprenaline, a β‐adrenoceptor agonist, and also enhances the response to sodium nitroprusside, a nitrovasodilator. This in vivo study was designed to determine whether NG‐monomethyl‐l‐arginine (l‐NMMA), an inhibitor of NO synthesis, influences relaxation of human hand veins mediated by isoprenaline or by sodium nitroprusside.

Methods Using the dorsal hand vein technique, full dose‐response curves to bradykinin (0.27–278 ng min−1, n=6), isoprenaline (2.12–271 ng min−1, n=8) and sodium nitroprusside (0.01–634 ng min−1, n=7) were generated on separate occasions before and after l‐NMMA co‐infusion (50 μg min−1 ).

Results In veins preconstricted with the α1‐adrenoceptor‐selective agonist phenylephrine, the three vasodilators induced maximal responses (Emax ) of 119±35, 72±18 and 103±17%, respectively. l‐NMMA inhibited relaxation to bradykinin by 64% (P=0.014) but did not influence relaxation induced by isoprenaline. The sensitivity to sodium nitroprusside was significantly enhanced by l‐NMMA co‐infusion (concentration shift of 2.3, P=0.031).

Conclusions We conclude that in human veins, spontaneously released NO does not play a major role in isoprenaline‐induced relaxation. Our results also suggest that the effects of sodium nitroprusside in this vascular bed may be attenuated by endothelium‐derived NO.
Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole
Authors: Brynne  , Böttiger  , Hallén  , Bertilsson
Published: March 2003

Aim To investigate the in vivo effect of treatment with tolterodine on debrisoquine 4‐hydroxylation (an index of CYP2D6 activity), omeprazole 5‐hydroxylation (CYP2C19), omeprazole sulphoxidation (CYP3A4) and caffeine N3‐demethylation (CYP1A2).

Methods Twelve healthy male volunteers (eight extensive metabolisers [EMs] and four poor metabolisers [PMs] with respect to CYP2D6) received 4 mg tolterodine l‐tartrate orally twice daily for 6 days. All subjects were EMs with respect to CYP2C19. The subjects received single oral doses of debrisoquine (10 mg), omeprazole (20 mg) and caffeine (100 mg) for determination of the appropriate metabolic ratios (MR). The drugs were given on separate consecutive days, before, during and after the co‐administration of tolterodine.

Results Mean serum tolterodine concentrations were 5–10 times higher in PMs than in EMs. Serum concentrations of the active 5‐hydroxymethyl metabolite of tolterodine, 5‐HM, were not quantifiable in PMs. The mean MR of debrisoquine (95% confidence interval) during tolterodine treatment was 0.50 (0.25–0.99) and did not differ statistically from the values before [0.49 (0.20–1.2)] and after tolterodine administration [0.46 (0.14–1.6)] in EMs. The mean MR of omeprazole hydroxylation and sulphoxidation or caffeine metabolism were not changed in the presence of tolterodine in either EMs or PMs. Debrisoquine and caffeine had no significant effect on the AUC(1,3 h) of either tolterodine or 5‐HM, but during omeprazole administration small decreases (13–19%) in these parameters were seen.

Conclusions Tolterodine, administered at twice the expected therapeutic dosage, did not change the disposition of the probe drugs debrisoquine, omeprazole and caffeine and thus had no detectable effect on the activities of CYPs 2D6, 2C19, 3A4 and 1A2. Alteration of the metabolism of substrates of these enzymes by tolterodine is unlikely to occur.
Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people
Authors: Wilkinson Tim J. , Begg Evan J. , Winter Anna C. , Sainsbury Richard
Published: March 2003

Aims To establish the incidence, time course and risk factors of hyponatraemia complicating treatment with fluoxetine or paroxetine in an elderly population.

Methods Retrospective descriptive and case control study in an inpatient/outpatient assessment and rehabilitation service for people aged 65 years and over. Fourteen elderly patients with hyponatraemia complicating treatment with fluoxetine or paroxetine, matched with 56 controls drawn from 845 patients treated with fluoxetine or paroxetine over 3.5 years. No other SSRI antidepressants were used over the study period.

Results The incidence of hyponatraemia was 4.7/1000 people treated/year (6.3/1000 for fluoxetine and 3.5/1000 for paroxetine). Hyponatraemia was detected at a median 13.5 (mean 18.6, range 4–64) days after commencing the drug. Mean (95% confidence intervals) body weights were lower in cases at 53.0 (95% CI 46.5–59.5) kg compared with controls at 64.5 (95% CI 60.1–68.4) kg (P<0.01). 71% of cases were women compared with 45% of controls (P=0.07) but the effect of gender was confounded by body weight. There were trends for cases to be older (odds ratio 1.10: 95% CI 0.99, 1.23) and lighter (odds ratio 0.92, 95% CI 0.86, 0.99).

Conclusions Approximately 1 in 200 elderly people treated per year with fluoxetine or paroxetine developed complicating hyponatraemia. Low body weight was a particular risk factor. Most cases occurred within 3 weeks of treatment.
Chronopharmacology of intravenous and oral modified release verapamil
Authors: Dilger Karin , Eckhardt Klaus , Hofmann Ute , Kucher Klaus , Mikus Gerd , Eichelbaum Michel
Published: March 2003

Aims Using a stable isotope technique which allows simultaneous and differential measuring of orally and intravenously administered drugs we compared the pharmacokinetics and pharmacodynamics of unlabelled modified release verapamil p.o. (steady state) and deuterated verapamil i.v. (single dose) following morning and evening administration.

Methods Twelve female and 12 male healthy volunteers were studied in a randomized, crossover design. During the last day of each treatment period (day 6 and day 10) pharmacokinetics and pharmacodynamics (PR interval) of verapamil were assessed; 1 h before ingestion of a new R/S‐verapamil 240 mg modified release formulation (08.00 h vs 20.00 h) a single dose of 10 mg d7‐R/S‐verapamil was administered intravenously. Serum levels of unlabelled and labelled R/S‐verapamil were measured by gas chromatography/mass spectrometry. In selected samples of serum which were chosen at tmin,po and tmax,po the enantiomers were separated by chiral high‐performance liquid chromatography in order to calculate R‐ to S‐verapamil serum concentration ratios.

Results We observed no significant differences in pharmacokinetics (AUCpo, Cmax, tmax, CLo, F and R/S enantiomer ratio) between morning and evening treatment with modified release verapamil and there was no influence of time of dosing on mean prolongation of PR interval. AUCiv, CL, Vss and d7‐R/d7‐S enantiomer ratio following verapamil i.v. did not show circadian variation. t1/2 was slightly but statistically significantly increased after the morning infusion. PR‐prolongation was significantly greater after verapamil i.v. in the morning than in the evening. The 90% confidence intervals of the differences between morning and evening administration in AUCpo, Cmax and AUCiv were within the equivalence range of 0.8–1.25.

Conclusions Time of dosing has no significant influence on pharmacokinetics and pharmacodynamics of this new modified release formulation of verapamil. Circadian variation in presystemic metabolism of verapamil was not observed.
Integrated modelling of the clinical pharmacokinetics of SDZ HTF 919, a novel selective 5‐HT4 receptor agonist, following oral and intravenous administration
Authors: Appel‐Dingemanse Silke , Lemarechal Marie‐Odile , Kumle Anette , Hubert Martine , Legangneux Eric
Published: March 2003

Aims The purpose of the present study was to assess the pharmacokinetics of the novel selective 5‐HT4 receptor agonist SDZ HTF 919 (HTF) including food effect, absolute bioavailability, interoccasion and intersubject variabilities.

Methods In the randomized, open‐label, three treatment, four period crossover study, HTF was administered to 12 young healthy male subjects as a 12 mg tablet (twice under fasted and once under fed conditions) and a 3 mg intravenous (i.v.) infusion over 40 min (fasted). Pharmacokinetic parameters were obtained by noncompartmental methods. A more comprehensive pharmacokinetic characterization was achieved by integrated modelling of oral (p.o.) and i.v. data. To describe the absorption phase a Weibull function and a classical first order input function were compared.

Results Noncompartmental pharmacokinetic analysis revealed a rapid absorption (tmax 1.3 h, fasted), an absolute bioavailability of 11±3%, a biphasic disposition phase with a terminal half‐life of 11±5 h, a clearance of 77±15 l h−1, and a volume of distribution at steady state of 368±223 l. The coefficients of interoccasion and interindividual variability in Cmax and AUC ranged between 17 and 28%. Food intake caused a delay (tmax 2.0 h) and decrease in absorption with consequently lower systemic exposure (≈5% absolute bioavailability). Integrated p.o./i.v. pharmacokinetic modelling with a Weibull input function allowed accurate description of individual profiles. Modelling of the data from the p.o. dosing improved the description of the terminal phase by inclusion of the i.v. data and additionally provided quantitative characterization of the absorption phase.

Conclusions The pharmacokinetics of HTF could be well described by an integrated modelling approach for both p.o. and i.v. data. The derived model will provide guidance in the design of future studies.
Prediction of the international normalized ratio and maintenance dose during the initiation of warfarin therapy
Authors: Vadher  , Patterson  , Leaning
Published: March 2003

Aims A pharmacokinetic/pharmacodynamic model, with Bayesian parameter estimation, was used to retrospectively predict the daily International Normalized Ratios (INRs) and the maintenance doses during the initiation of warfarin therapy in 74 inpatients.

Methods INRs and maintenance doses predicted by the model were compared with the actual INRs and the eventual maintenance dose. Cases with drugs or medical conditions interacting with warfarin or receiving concurrent heparin therapy were not excluded. As the study was retrospective, model predictions of the maintenance dose were not those that were administered. Mean prediction error (MPE) and percentage absolute prediction errors (PAPE) were used to assess the model predictions.

Results INR MPE ranged from −0.07 to 0.06 and median PAPE from 10% to 20%. Dose MPE ranged from −0.7 to 0.17 mg and median PAPE from 16.7% to 37.5%. Accurate and precise dose predictions were obtained after 3 or more INR feedback’s.

Conclusions This study shows that the model can accurately predict daily INRs and the maintenance dose in this sample of cases. The model can be incorporated into computer decision‐support systems for warfarin therapy and may lead to improvement in the initiation of warfarin therapy.
Status of new medicines approved by the European Medicines Evaluation Agency regarding paediatric use
Authors: Impicciatore Piero , Choonara Imti
Published: March 2003

Aims To evaluate the activity of the European Medicines Evaluation Agency with regard to the registration for paediatric use of new medicines granted a marketing authorization.

Methods European Public Assessment Reports published on the Internet from January 95 until April 98 have been analysed using the browser Microsoft Explorer and the software Adobe Acrobat Reader.

Results Of the 45 new substances licensed since January 95, 29 (64%) were of possible use in children but only 10 were licensed for paediatric use. For the 19 drugs of possible use in children, but not approved for such a use, in nine instances (47%) their summary of product characteristics reported that their use in children has not been established.

Conclusions A change of practice by pharmaceutical companies and regulatory authorities is imperative so that children are not precluded from having the same rights to medicines as adults.
Enantiomeric disposition of inhaled, intravenous and oral racemic‐salbutamol in man — no evidence of enantioselective lung metabolism
Authors: Ward Jonathan K. , Dow James , Dallow Nigel , Eynott Paul , Milleri Stefano , Ventresca G. Pietro
Published: March 2003

Aims To establish whether enantioselective metabolism of racemic (rac )‐salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes.

Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 μg) with or without oral charcoal and intravenous (500 μg) rac‐salbutamol. Systemic exposure (plasma AUC(0,∞) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)‐salbutamol both in plasma (AUC(R)‐/AUC(S)‐ ) and urine (Au(R)‐/Au(S)‐ ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route.

Results AUC(R)‐/AUC(S)‐ [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h.

Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)‐ and (S)‐enantiomers are present in similar quantities in the airways following inhaled rac‐salbutamol.
Non‐linear pharmacokinetics of MDMA (‘ecstasy’) in humans
Authors: De La Torre R. , Farré M. , Ortuño J. , Mas M. , Brenneisen R. , Roset P. N. , Segura J. , Camí J.
Published: March 2003

Aims 3,4‐Methylenedioxymethamphetamine (MDMA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetics, in humans in controlled settings. A clinical trial was designed for the evaluation of MDMA pharmacological effects and pharmacokinetics in healthy volunteers.

Methods A total of 14 subjects were included. In the pilot phase six received MDMA at 50 (n=2), 100 (n=2), and 150 mg (n=2). In the second phase eight received MDMA at both 75 and 125 mg (n=8). Subjects were phenotyped for CYP2D6 activity and were classified as extensive metabolizers for substrates, such as MDMA, whose hepatic metabolism is regulated by this enzyme. Plasma and urine samples were collected throughout the study for the evaluation of MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4‐methylenedioxyamphetamine (MDA), 4‐hydroxy‐3‐methoxy‐methamphetamine (HMMA) and 4‐hydroxy‐3‐methoxy‐amphetamine (HMA).

Results As the dose of MDMA administered was increased, volunteers showed rises in MDMA concentrations that did not follow the same proportionality which could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing MDMA recovery seems to point towards a saturation or an inhibition of MDMA metabolism (the demethylenation step). These observations are further supported by the fact that urinary clearance was rather constant while nonrenal clearance was dose dependent.

Conclusions It has previously been postulated that individuals genetically deficient for the hepatic enzyme CYP2D6 (about 10% of the Caucasian people) were at risk of developing acute toxicity at moderate doses of MDMA because the drug would accumulate in the body instead of being metabolized and inactivated. The lack of linearity of MDMA pharmacokinetics (in a window of doses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It implies that relatively small increases in the dose of MDMA ingested are translated to disproportionate rises in MDMA plasma concentrations and hence subjects are more prone to develop acute toxicity.
The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium
Authors: Apseloff G. , Mullet D. , Wilner K. D. , Anziano R. J. , Tensfeldt T. G. , Pelletier S. M. , Gerber N.
Published: March 2003

Aims  To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.

Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day− 1, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day− 1, given as two divided daily doses, on days 9–11 followed by 80 mg day− 1, given as two divided daily doses on days 12–15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.

Results  Ziprasidone administration was associated with a 0.07 mmol l− 1 (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l− 1 (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h− 1 (5%) in the ziprasidone group and by 0.14 l h− 1 (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.

Conclusions  Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.
A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives
Authors: Farmer R. D. T. , Lawrenson R. A. , Todd J.‐C. , Williams T. J. , MacRae K. D. , Tyrer F. , Leydon G. M.
Published: March 2003

Aims
 In October 1995 in response to the results of three studies, the Committee on the Safety of Medicines advised doctors and pharmacists that oral contraceptives containing desogestrel (DSG) and gestodene (GST) were associated with around a two‐fold increase in the risk of thromboembolism compared with those containing other progestogens. The objective of this study was to estimate the risk of idiopathic venous thromboembolic disease (VTE) in users of combined oral contraceptives (COCs), to compare the risk between formulations and to examine the effect of using age banding as opposed to matching by exact year of birth.

Methods
 A nested case control study was conducted using the General Practice Research Database. Women with a VTE event recorded between 1992 and 1997, who were treated with an anticoagulant, from consideration of their prescription records were likely to have been using a COC prescription on the day of the event and also had no exclusion factors, were deemed cases. For comparison with the previous studies, two nested case control studies were undertaken. Study 1 used controls matched by practice and year of birth. Study 2 used controls matched by practice and within 5 years age bands.

Results
 We found an incidence of idiopathic VTE amongst users of combined oral contraceptives of 3.8 per 10 000 exposed women years. Incidence rates increased markedly after 35 years of age. The nested case‐control study using controls matched by year of birth showed no significant difference in risk between the major COC formulations. With levonorgestrel (LNG) 150 µg and ethinyloestradiol (EE) 30 µg as the reference, the adjusted ORs for GST 75 µg and EE 30 µg was 1.3 (95% CI 0.8, 2.1), for DSG 150 µg and EE 30 µg it was 1.0 (95% CI 0.7, 1.7) and for DSG 150 µg and EE 20 µg it was 0.8 (95% CI 0.4, 1.6). Using less rigorous matching criteria, matching controls to cases within 5 years age bands, the ORs increased. When a mixed group of COCs, characterized by having LNG as the progestogen component was used as the reference category, there was an elevation in the ORs for the newer products. We found a significant association between idiopathic VTE and current smoking (OR 2.0 (1.4, 2.7)), BMI over 35 (OR 3.8 (1.8, 8.0)) and asthma (OR 1.9 (1.3, 2.9)). The OR for women who had proxy evidence of general ill health (indicated by the number of prescriptions issued) was 2.2 (1.7, 3.7).

Conclusions
 The results of this study indicate that a number of the characteristics of the women taking COCs affect the risk of VTE. There is no evidence to support the hypothesis that there is any difference in risk between COC formulations containing under 50 µg ethinyloestradiol.
Absorption of lefradafiban from different sites of the gastrointestinal tract
Authors: Drewe Jürgen , Narjes Hans , Heinzel Günther , Brickl Rolf‐Stefan , Rohr Andrea , Beglinger Christoph
Published: March 2003

Aims
Fibrinogen receptor antagonists show a close relationship between plasma concentrations and inhibitory effect. Optimal efficacy at an acceptable bleeding risk requires low inter‐ and intrasubject variability on low peak trough fluctuation in receptor occupancy and therefore also of plasma concentrations. Therefore, the enteral absorption of lefradafiban, an orally available fibrinogen receptor antagonist prodrug, was investigated after local administrations to different sites of the gastrointestinal tract in order to investigate the feasibility of an oral extended release formulation.

Methods
Twelve healthy male subjects received in a randomised, open‐labelled, four‐period crossover trial four consecutive administrations of lefradafiban: 1. orally; 2. administration into the jejunum, 3. administration into the lower jejunum/ileum (300 cm distally to the teeth), and 4. administration into the lumen of the sigmoid region (30 cm proximally to the anus). Local intestinal administrations were performed through a gastrointestinal tube.

Results
Compared with oral administration, ratios [mean (two‐sided 90% confidence intervals)] of maximum drug plasma concentrations and AUC(0,24 h) of fradafiban were 1.05 (0.80,1.39) and 1.06 (0.85,1.31) after jejunal, 0.98 (0.75,1.30) and 0.98 (0.79,1.21) after ileal, 0.52 (0.39,0.69) and 0.68 (0.55,0.85) after colonic administration. Urinary excretion of fradafiban was about 16% of the dose after oral, jejunal and ileal applications whereas after rectal administration about 11% were excreted.

Conclusions
Lefradafiban is absorbed throughout the entire gastrointestinal tract. Therefore, an extended release formulation seems to be feasible with regard to bioavailability.
The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19 087 patients in general practice in England: cohort study
Authors: Martin Richard M. , Biswas Pipasha , Mann Ronald D.
Published: March 2003

Aims
Meloxicam is a novel nonsteroidal anti‐inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo‐oxygenase‐2 relative to the constitutive isoform, cyclo‐oxygenase‐1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam.

Methods
As part of the national prescription‐event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription.

Results
There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient‐months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20–30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three‐fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1).

Conclusions
In the absence of gastro‐intestinal risk factors the incidence of gastro‐intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam.
Influence of asimadoline, a new κ‐opioid receptor agonist, on tubular water absorption and vasopressin secretion in man
Authors: Kramer H. J. , Uhl W. , Ladstetter B. , Bäcker A.
Published: March 2003

Aims
The purpose of the study was to investigate the effects of asimadoline, a new κ‐opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects.

Methods
In a placebo‐controlled, randomised, double‐blind crossover design we studied the effects of single oral doses of 1, 5, and 10 mg of asimadoline, in 24 healthy volunteers. Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5% saline was given i.v. at a rate of 0.3 ml min−1 kg−1 during another 2 h urine collection. Blood was obtained hourly. Arginine‐vasopressin (AVP), atrial natriuretic peptide (α‐hANP), endothelin (ET‐1) and cAMP were determined by r.i.a. or ELISA.

Results
GC‐MS measurements revealed Cmax values of asimadoline in plasma ranging from 18 ng ml−1 at the 1 mg dose, 91 ng ml−1 at the 5 mg dose, to 214 ng ml−1 at the 10 mg dose after an average of 1.1–1.4 h. Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1–2 h after administration of 5 and 10 mg asimadoline from 3.3 ± 1.3 to 5.6 ± 1.4 (P < 0.05) and from 3.2 ± 1.6 to 5.5 ± 2.2 ml min−1 (P < 0.01), respectively. CH2O rose from 0.2 ± 1.5 to 2.0 ± 1.6 (P < 0.05) and from 0.6 ± 1.6 to 3.0 ± 1.6 ml min−1 (P < 0.01). Urinary excretion of AVP was suppressed only with the 10 mg dose from 46 ± 23 to 25 ± 15 fmol min−1 (P < 0.05) without and from 410 ± 206 to 181 ± 125 fmol min−1 (P < 0.05) with stimulation by 2.5% saline. Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion. Changes in the α‐hANP or ET‐1 systems were not affected by asimadoline.

Conclusions
Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level. Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline.
The xenobiotic inhibitor profile of cytochrome P4502C8
Authors: Ong Chin‐Eng , Coulter Sally , Birkett Donald J. , Bhasker C. Ramana , Miners John O.
Published: March 2003

Aims   To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate specificity of CYP2C8 and CYP3A).

Methods   CYP2C8 and NADPH‐cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8‐catalysed torsemide tolylmethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure.

Results   At concentrations of the CYP inhibitor ‘probes’ employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by > 10%. Ketoconazole, at an added concentration of 10 µm, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent Ki values of 2.5 µm. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82–91% of control activity) of CYP2C8 at concentrations five‐fold higher than the known CYP3A Km. Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent Ki values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 µm.

Conclusions   Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.
Frequency of cytochrome P450 2C9 mutant alleles in a Korean population
Authors: Yoon Young‐Ran , Shon Ji‐Hong , Kim Moon‐Kyung , Lim Young‐Chai , Lee Hye‐Rang , Park Ji‐Young , Cha In‐June , Shin Jae‐Gook
Published: March 2003

Aims  To determine the frequencies of CYP2C9 variants in the Korean population and compare them with the frequencies in other ethnic populations.

Methods  Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was carried out in 574 Korean subjects by PCR and restriction fragment length pattern analysis.

Results  Thirteen of 574 subjects (2.3%) were heterozygous for CYP2C9*3 (Ile359Leu), but no subjects with a CYP2C9*2 allele or homozygous for CYP2C9*3 were identified. The allele frequency of CYP2C9*3 in Korean subjects (0.0113, 95% CI 0.0066–0.0193) was similar to that of other East Asian populations, but was considerably lower than that of Caucasian populations.

Conclusions  CYP2C9*3 seems to be an allelic variant related to the functional polymorphism of CYP2C9, but this variant is rarely seen among Koreans compared with Caucasians. Routine genotyping of the CYP2C9*2 allele is considered to be unnecessary in Korean and East Asians, because this allele appears to be extremely rare or absent in these populations.