bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for involvement of human CYP3A in the 3‐hydroxylation of quinine
Authors: Zhang H. , Coville P. F. , Walker R. J. , Miners J. O. , Birkett D. J. , Wanwimolruk S.
Published: December 2004

Aims Our previous studies using in vitro hepatic microsomal preparations suggested that the hepatic metabolism of quinine to form the major metabolite 3‐hydroxyquinine is most likely catalysed by human P450 3A (CYP3A). The present study was carried out to investigate the kinetics and to identify and further characterise the human liver CYP isoforms involved in the metabolism of quinine.

Methods In vitro human microsomal techniques were employed.

Results The mean apparent Km value for 3‐hydroxyquinine formation was 83±19 (s.d.) μm, ranging from 57 μm to 123 μm in microsomes from ten human livers. There was a 6.7‐fold variation in Vmax values (mean 547±416 pmol min−1 mg−1 ). Quinine 3‐hydroxylation was inhibited by the specific CYP3A inhibitors, troleandomycin, midazolam and erythromycin. Inhibitors selective for CYP1A1/2, CYP2D6, CYP2E1, CYP2C9/10 or CYP2C19 had little or no effect on quinine 3‐hydroxylation. Using microsomes from a panel of livers, significant correlations were found only between 3‐hydroxyquinine activity and other CYP3A activities (caffeine 8‐oxidation, omeprazole sulphoxidation, midazolam 1′‐hydroxylation and midazolam 4‐hydroxylation) and immunoreactive CYP3A content. There were no statistically significant correlations with activities selective for CYP1A2, CYP2C9 and CYP2E1. Competitive inhibition of quinine 3‐hydroxylation was observed with a substrate known to be specifically metabolized by human CYP3A, i.e. midazolam, with an apparent Ki value of 11.0 μm.

Conclusions The present results strongly indicate that the conversion of quinine to 3‐hydroxyquinine is the major metabolic pathway in human liver in vitro and that the reaction is catalysed by CYP3A isoforms.
Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler
Authors: Hindle M. , Peers E. M. , Parry‐Billings M. , Chrystyn H.
Published: December 2004

Aims The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI.

Methods A randomized, double‐blind, two way crossover study compared the amount of salbutamol in the urine 30 min following inhalation of 2×100 μg salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin® (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24 h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body.

Results The mean (s.d.) 30 min post‐treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9) μg, respectively (P<0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24 h period after inhalation was 187.9 (77.6) and 137.6 (40.0) μg (P<0.05).

Conclusions The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.
Phenotyping CYP3A using midazolam in cancer and noncancer Asian patients
Authors: Lee How Sung , Goh Boon Cher , Fan Lu , Khoo Yok Moi , Wang Lingzhi , Lim Robert , Ong Ai Bee , Chua Charlotte
Published: December 2004

Aims
  To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A.

Methods
  Intravenous midazolam 2.5 mg or 2.5–8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1′‐hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1′‐hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose‐normalized plasma midazolam concentrations (concentration/per dose).

Results
  Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean ± SD, 95% confidence level) in cancer (424 ± 155, 61.3 ml min−1; 1.21 ± 0.46, 0.18 l kg−1) and noncancer (407 ± 135, 57.1 ml min−1; 1.15 ± 0.33, 0.155 l kg−1) patients, respectively, were not different and comparable with published data. Clearance variability was 4–5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the  1‐h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001.

Conclusions
  CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4–5‐fold and were not different between groups. One to two‐fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.
Planning and monitoring of placebo‐controlled survival trials: comparison of the triangular test with usual interim analyses methods
Authors: Hulot Jean‐Sébastien , Cucherat Michel , Charlesworth Andrew , Van Veldhuisen Dirk J. , Corvol Jean‐Christophe , Mallet Alain , Boissel Jean‐Pierre , Hampton John , Lechat Philippe
Published: December 2004

Aims
For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial.

Methods
We made a post hoc application of two interim analysis methods (Lan & DeMets with O’Brien–Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo‐controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect.

Results
The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method.

Conclusions
Stopping a trial early must depend on the clinical context. It is most important to stop a placebo‐controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.
Influence of captopril on symptomatic and hormonal responses to hypoglycaemia in humans
Authors: Oltmanns Kerstin M. , Deininger Eva , Wellhoener Peter , Schultes Bernd , Kern Werner , Marx Esther , Dominiak Peter , Born Jan , Fehm Horst L. , Peters Achim
Published: December 2004

Aims  Hypoglycaemic symptoms and hormonal counter‐regulation are of high importance to avoid the risk of severe hypoglycaemia in patients with diabetes mellitus. Various antihypertensive drugs, such as angiotensin‐converting enzyme (ACE) inhibitors, have been suspected for a long time to reduce this response to hypoglycaemia in diabetic subjects. Although ACE inhibitors are approved for controlling diabetic complications, previous investigations regarding this putative side‐effect are controversial.

Methods  We performed clamp experiments in 16 healthy men lasting for 6 h each. The subjects were pretreated for 7 days with captopril 3 × 25 mg day−1vs placebo in a randomized, double‐blind, crossover study. Plasma glucose was decreased in a stepwise manner during a hypoglycaemic clamp session and counter‐regulatory hormones [epinephrine (adrenaline), norepinephrine (adrenaline), ACTH, cortisol, glucagon], symptoms, and haemodynamic parameters (blood pressure, heart rate] were measured.

Results  Counter‐regulatory hormone concentrations significantly increased in both sessions (ACE inhibitor vs placebo) during hypoglycaemia. The rise of counter‐regulatory hormones as well as symptom scores were equal under both ACE inhibitor and placebo treatment. Systolic blood pressure and heart rate increased (from 110 ± 3 vs 115 ± 3 mmHg to 132 ± 4 vs 133 ± 4 mmHg) whereas diastolic blood pressure slightly decreased (from 63 ± 2 vs 70 ± 3 mmHg to 61 ± 2 vs 64 ± 2 mmHg) independent of pretreatment. Systolic and diastolic blood pressure were significantly lower in the captopril session vs placebo (P < 0.05).

Conclusions  Our results demonstrate that subchronic treatment with captopril does not attenuate symptomatic and hormonal response to hypoglycaemia. Thus, to patients at risk of hypoglycaemia who require antihypertensive or nephroprotective treatment, we would continue giving an ACE inhibitor.
Aspirin for the prevention of cardiovascular disease: calculating benefit and harm in the individual patient
Authors: Loke Yoon Kong , Bell Alastair , Derry Sheena
Published: December 2004

Aims
  To estimate the absolute reduction in the risk of cardiovascular events and absolute increase in gastrointestinal haemorrhage associated with aspirin for individuals with different baseline risks.

Methods
  Calculation of absolute treatment effects from estimates of: (i) baseline risks for cardiovascular event and gastrointestinal haemorrhage; and (ii) relative risks of these events with treatment. Baseline cardiovascular risks were derived from existing risk scores, and baseline risk of gastrointestinal haemorrhage from an observational cohort study. Changes in relative risks were obtained from clinical trial data. The effects of aspirin treatment were calculated in examples of two individuals with very different baseline risks.

Results
  Treatment of a healthy  74‐year‐old man (blood pressure 144/88 mm Hg and no history of gastrointestinal disorder) would reduce his annual risk of a cardiovascular event from 2% to 1.74% (absolute risk reduction 0.26%, number needed to treat 385), but increase the gastrointestinal haemorrhage risk from 0.3% to 0.51% (absolute risk increase 0.21%, number needed to harm 476). In a  66‐year‐old obese man, following a transient ischaemic attack, and with a history of hospital treatment for a peptic ulcer, the annual risk of a cardiovascular event would be reduced from 5% to 4.35% (absolute risk reduction 0.65%, number needed to treat 153), but the risk of gastrointestinal haemorrhage would increase from 1.08% to 1.83% (absolute risk increase 0.75%, number needed to harm 133).

Conclusions
  Estimating benefit and harm by taking into account the baseline risks in each individual allows patients and doctors to judge for themselves the magnitude of the trade‐offs involved in taking aspirin.
Time effects of food intake on the pharmacokinetics and pharmacodynamics of quazepam
Authors: Yasui‐Furukori Norio , Takahata Takenori , Kondo Tsuyoshi , Mihara Kazuo , Kaneko Sunao , Tateishi Tomonori
Published: December 2004

Aims  There is little information on interaction between food and the hypnotic agent quazepam. We therefore studied the effects of food and its time interval on the pharmacokinetics and pharmacodynamics of quazepam.

Methods  A randomized three‐phase crossover study with 2‐week intervals was conducted. Nine healthy male volunteers took a single oral 20 mg dose of quazepam under the following conditions: 1) after fasting overnight; 2) 30 min after eating standard meal; or 3) 3 h after eating the same meal. Plasma concentrations of quazepam and its metabolite, 2‐oxoquazepam and psychomotor function using the Digit Symbol Substitute Test (DSST), Stanford Sleepiness Scale (SSS) and Visual Analogue Scale were measured up to 48 h.

Results  During the food treatments at 30 min and 3 h before dosing, the peak concentrations (Cmax) were 300% (95% CI 260, 340%; P < 0.001) and 250% (95% CI 210, 290%; P < 0.01) of the corresponding value during the fasting phase. For quazepam, the area under the plasma concentration–time curve from 0 to 8 h measured at 30 min and 3 h before dosing was significantly increased, with the food treatments by 2.4‐fold (95% CI 2.0; 2.8‐fold; P < 0.001) and 2.1‐fold (95% CI 1.7; 2.4‐fold; P < 0.01), respectively. In response to pharmacokinetic changes, some of the pharmacodynamics (DSST, P < 0.05; SSS, P < 0.05) differed significantly between fasted status and fed status. No difference was found in any pharmacokinetic or pharmacodynamic parameters between the two food treatment phases.

Conclusions  A food effect on quazepam absorption is evident and continues at least until 3 h after food intake. The dosing of quazepam after a long period of ordinary fasting might reduce its efficacy because a 3 h interval between the timing of the evening meal and bedtime administration of hypnotics is regarded as normal in daily life.
Quality, efficacy and safety of complementary medicines: fashions, facts and the future. Part II: Efficacy and safety
Authors: Barnes Joanne
Published: December 2004

This is the second of two papers which review issues concerning complementary medicines. The first reviewed the extent of use of complementary medicines, and issues related to the regulation and pharmaceutical quality of these products; the second considers evidence for the efficacy of several well‐known complementary medicines, and discusses complementary‐medicines pharmacovigilance. The term complementary medicines describes a range of pharmaceutical‐type preparations, including herbal medicines, homoeopathic remedies, essential oils and dietary supplements, which mainly sit outside conventional medicine. The use of complementary medicines is a popular healthcare approach in the UK, and there are signs that the use of such products is continuing to increase. Patients and the public use complementary medicines for health maintenance, for the treatment or prevention of minor ailments, and also for serious, chronic illnesses. There is a growing body of evidence from randomized controlled trials and systematic reviews to support the efficacy of certain herbal extracts and dietary supplements in particular conditions. However, many other preparations remain untested. Strictly speaking, evidence of efficacy (and safety) for herbal medicines should be considered to be extract specific. Pharmacovigilance for complementary medicines is in its infancy. Data are lacking in several areas relevant to safety. Standard pharmacovigilance tools have additional limitations when applied to investigating safety concerns with complementary medicines.
A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment
Authors: Shiran M. R. , Chowdry J. , Rostami‐Hodjegan A. , Ellis S. W. , Lennard M. S. , Iqbal M. Z. , Lagundoye O. , Seivewright N. , Tucker G. T.
Published: December 2004

Aims  To assess CYP2D6 activity and genotype in a group of patients undergoing methadone maintenance treatment (MMT).

Methods  Blood samples from 34 MMT patients were genotyped by a polymerase chain reaction‐based method, and results were compared with CYP2D6 phenotype (n = 28), as measured by the molar metabolic ratio (MR) of dextromethorphan (DEX)/dextrorphan (DOR) in plasma.

Results  Whereas 9% of patients (3/34) were poor metabolizers (PM) by genotype, 57% (16/28) were PM by phenotype (P < 0.005). Eight patients, who were genotypically extensive metabolizers (EM), were assigned as PM by their phenotype. The number of CYP2D6*4 alleles and sex were significant determinants of CYP2D6 activity in MMT patients, whereas other covariates (methadone dose, age, weight) did not contribute to variation in CYP2D6 activity.

Conclusions  There was a discordance between genotype and in vivo CYP2D6 activity in MMT patients. This finding is consistent with inhibition of CYP2D6 activity by methadone and may have implications for the safety and efficacy of other CYP2D6 substrates taken by MMT patients.
Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil
Authors: Shum B. , Duffull S. B. , Taylor P. J. , Tett S. E.
Published: December 2004

Aim  To develop a population pharmacokinetic model for mycophenolic acid in adult kidney transplant recipients, quantifying average population pharmacokinetic parameter values, and between‐ and within‐subject variability and to evaluate the influence of covariates on the pharmacokinetic variability.

Methods  Pharmacokinetic data for mycophenolic acid and covariate information were previously available from 22 patients who underwent kidney transplantation at the Princess Alexandra Hospital. All patients received mycophenolate mofetil 1 g orally twice daily. A total of 557 concentration–time points were available. Data were analysed using the first‐order method in NONMEM (version 5 level 1.1) using the G77 FORTRAN compiler.

Results  The best base model was a two‐compartment model with a lag time (apparent oral clearance was 27 l h−1, and apparent volume of the central compartment 98 l). There was visual evidence of complex absorption and time‐dependent clearance processes, but they could not be successfully modelled in this study. Weight was investigated as a covariate, but no significant relationship was determined.

Conclusions  The complexity in determining the pharmacokinetics of mycophenolic acid is currently underestimated. More complex pharmacokinetic models, though not supported by the limited data collected for this study, may prove useful in the future. The large between‐subject and between‐occasion variability and the possibility of nonlinear processes associated with the pharmacokinetics of mycophenolic acid raise questions about the value of the use of therapeutic monitoring and limited sampling strategies.
Elimination of ephedrines in urine following multiple dosing: the consequences for athletes, in relation to doping control
Authors: Chester Neil , Mottram David R. , Reilly Thomas , Powell Mark
Published: December 2004

Aims  To study the elimination of ephedrines with reference to the International Olympic Committee (IOC) doping control cut‐off levels, following multiple dosing of over‐the‐counter decongestant preparations.

Methods  A double‐blind study was performed in which 16 healthy male volunteers were administered either pseudoephedrine or phenylpropanolamine in maximal recommended therapeutic doses over a 36‐h period. Urine was collected every two hours between 08:00 and 24:00 h and at 04:00 h throughout the testing period of three days. Urine drug levels were quantified using high performance liquid chromatography. Side‐effects were assessed, including heart rate and blood pressure, every four hours between 08:00 and 20:00 h.

Results  Mean (95% CI) total phenylpropanolamine and pseudoephedrine eliminated unchanged was 75 (88, 61) and 81 (92, 71)%, respectively. Maximum urine concentrations of phenylpropanolamine and pseudoephedrine were 112.1 (164.2, 59.9) and 148.5 (215.0, 82.1) mg.l−1, respectively. A peak in drug urine concentration occurred four hours following the final dose. There were no adverse cardiovascular effects and only mild CNS stimulation was evident.

Conclusions  Following therapeutic, multiple dosing, drug levels remain above the IOC cut‐off levels for a minimum of 6 h and 16 h following final doses of phenylpropanolamine and pseudoephedrine, respectively. Athletes require informed advice on this from their healthcare professionals.
Effect of age on the pharmacokinetics of duloxetine in women
Authors: Skinner Michael H. , Kuan Han‐Yi , Skerjanec Andrej , Seger Mary E. , Heathman Michael , O'Brien Lisa , Reddy Shobha , Knadler Mary P.
Published: December 2004

Aims  The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.

Methods  Twenty‐four healthy subjects (12 women 65–77 years, and 12 women 32–50 years) were given a single 40‐mg oral dose of duloxetine in Study 1. Plasma concentration‐time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24–77 years) who received duloxetine 20 mg day−1, 30 mg day−1, or 40 mg day−1 in Study 2A and 128 women (28–64 years) who received duloxetine 20 mg day−1, 40 mg day−1, or 80 mg day−1 in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed‐effects modelling program (NONMEM).

Results  In Study 1, the elderly (≥ 65 years) exhibited a statistically significant slower elimination rate constant λz compared with younger subjects {elderly‐younger difference = −0.022 h−1[95% confidence interval (CI) − 0.036, − 0.008]}. However, no statistically significant differences in either CL/F [elderly‐younger difference = −17.4 l h−1 (95% CI − 41.1, 6.23)] or V/F [elderly‐younger difference = 115.9 l (95% CI − 168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non‐elderly participants in these studies.

Conclusions  Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower λz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.
The Regulation of Medical Products
Authors: Nigel Baber
Published: December 2004

Edited by J P, Griffin and J, O'Grady  BMJ Books, 2003 ISBN 0‐7279‐1780‐3
Influence of mild liver impairment on the pharmacokinetics of tezosentan, a drug excreted unchanged into bile
Authors: Dingemanse Jasper , Van Giersbergen Paul L. M.
Published: December 2004

Aims  To investigate the effect of mild liver impairment on the pharmacokinetics of tezosentan.

Methods  Eleven patients with mild liver impairment and eight healthy subjects received an intravenous infusion of 50 mg h−1 tezosentan for 1 h. Plasma and urine concentrations were determined during and following termination of the infusion.

Results  The pharmacokinetic parameters presented as geometric means [95% confidence interval (CI)] for clearance, volume of distribution and terminal half‐life were 30 (22, 40) and 42 (36, 48) l h−1, 28 (19, 42) and 19 (16, 23) l, and 4.5 (2.9, 7.0) and 3.6 (2.9, 4.5) h in liver patients and healthy subjects, respectively. The ratios (liver patients/healthy subjects) of these geometric means (95% CI) were 0.71 (0.47, 1.1), 1.5 (0.87, 2.6), and 1.3 (0.69, 2.3), respectively. A two‐compartment model accurately fitted the concentration–time data. In both groups approximately 4% of the dose was excreted unchanged into urine.

Conclusions  Although there was a slight trend towards a decreased clearance, the pharmacokinetics of tezosentan in patients with mild liver impairment were similar to those in healthy subjects. Therefore, no dose adaptation seems to be needed in this patient population.
Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic–pharmacodynamic data
Authors: Kerbusch Thomas , Milligan Peter A. , Karlsson Mats O.
Published: December 2004

Aims  To describe the population pharmacokinetic–pharmacodynamic relationship between darifenacin (UK‐88,525) and its hydroxylated metabolite (UK‐148,993), and the reduction in salivary flow (SF, a M3‐mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug.

Methods  A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct‐effect, indirect‐effect, link and binding model) using NONMEM.

Results  The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding‐corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50‐fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first‐pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.–oral crossover study was necessary for the estimation of the relative potency.

Conclusions  Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.
The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive
Authors: Simonson Steven G. , Martin Paul D. , Warwick Mike J. , Mitchell Patrick D. , Schneck Dennis W.
Published: December 2004

Aims

To assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed.

Methods

This open‐label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri‐Cyclen®) on Days 1–21 and placebo OCS on Days 22–28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1–21 of Cycle B.

Results

Co‐administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co‐administration increased AUC[0–24] for ethinyl oestradiol (26%; 90% CI ratio 1.19–1.34), 17‐desacetyl norgestimate (15%; 90% CI 1.10–1.20), and norgestrel (34%; 90% CI 1.25–1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17–1.33) and norgestrel (23%; 90% CI 1.14–1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle‐stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6β‐hydroxycortisol. Rosuvastatin significantly decreased low‐density lipoprotein cholesterol [‐55%], total cholesterol [‐27%], and triglycerides [‐12%], and significantly increased high‐density lipoprotein cholesterol[11%]. Co‐administration was well tolerated.

Conclusions

Rosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid‐regulating effect was observed in this study, and there was no evidence of an altered lipid‐regulating effect with OCS coadministration.
Tizanidine is mainly metabolized by cytochrome P450 1A2 in vitro
Authors: Granfors Marika T. , Backman Janne T. , Laitila Jouko , Neuvonen Pertti J.
Published: December 2004

Aims

To identify the cytochrome P450 (CYP) enzyme(s) that catalyze the metabolism of tizanidine in vitro.

Methods

The effect of CYP isoform inhibitors on the elimination of tizanidine was studied using pooled human liver microsomes. The metabolism of the drug by a range of human recombinant CYP isoforms was then investigated.

Results

Incubation of tizanidine (80 nm) with human liver microsomes resulted in time‐ and NADPH‐dependent substrate consumption with a half‐life of 50 min, initial reaction velocity of 1.1 pmol min−1 mg−1 protein and intrinsic clearance of 17 ml min−1 kg−1. The predicted in vivo hepatic clearance (CLh) of tizanidine using the well‐stirred and parallel‐tube model was close (68% and 82%, respectively) to its estimated in vivo CLh. Fluvoxamine and furafylline strongly inhibited tizanidine metabolism. Inhibitors specific to isoforms other than CYP1A2 had no substantial effect. Recombinant CYP1A2 metabolized tizanidine to a substantial degree (35% in 45 min), but other recombinant CYPs had little metabolic capacity for the drug.

Conclusions

CYP1A2 is primarily responsible for the metabolism of tizanidine. CYP1A2 inhibitors may inhibit its metabolism also in vivo.
Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese
Authors: Fukazawa Ichiro , Uchida Naoki , Uchida Eiji , Yasuhara Hajime
Published: December 2004

Aims

To investigate the effects of repeated grapefruit juice (GFJ) intake on the pharmacokinetics of atorvastatin and pravastatin in Japanese subjects.

Methods

Two randomized, two‐way crossover studies were performed. GFJ or water was given to two groups of 10 subjects each three times daily for 2 days. On the third day, single 10 mg doses of atorvastatin or pravastatin were orally administered with GFJ or water, and an additional 250 ml of GFJ or water was taken before lunch and dinner. Plasma concentrations of atorvastatin and its metabolites were determined over 48 h postdosing and of pravastatin and its metabolites over 24 h postdosing.

Results

Compared with in the water group, the AUC(0,48 h) of atorvastatin acid significantly increased by 1.40 fold (95% CI 1.02, 1.92; P < 0.05) when atorvastatin was taken with GFJ. AUC(0,48 h) and Cmax of atorvastatin lactone significantly increased by 1.56 (95% CI 1.33, 1.83; P < 0.001) and 1.29 fold (95% CI 1.09, 1.51; P < 0.01), respectively, when atorvastatin was taken with GFJ. No significant changes were detected in any pravastatin pharmacokinetic parameter examined when pravastatin was taken with GFJ. However, AUC(0,24 h) of pravastatin lactone increased 1.31 fold (95% CI 1.01, 1.71; P < 0.05) with GFJ intake.

Conclusions

GFJ was confirmed to significantly affect the pharmacokinetics of atorvastatin but had little or no effect on those of pravastatin in Japanese subjects.
Protein binding and α : β anomer ratio of dihydroartemisinin in vivo
Authors: Batty Kevin T. , Ilett Kenneth F. , Davis Timothy M. E.
Published: December 2004

Aims

To determine the ratio of α : β anomers and the protein binding of dihydroartemisinin (DHA) in vivo.

Methods

10‐[3H]‐DHA was synthesized by reduction of artemisinin with sodium boro‐[3H]‐hydride and purified with preparative thin layer chromatography. A solution of 3H‐DHA (2000 ng in 20 µl) was added to 2 ml whole blood from 15 healthy volunteers and 22 Vietnamese patients with falciparum or vivax malaria. The blood was centrifuged and the plasma stored at −25 °C until analysed by HPLC with radiochromatographic detection. Protein‐free ultrafiltrate of the plasma was assayed to determine the free fraction of DHA and the in vivo ratio of α‐DHA : β‐DHA.

Results

The DHA fraction unbound (mean ± SD) was 0.068 ± 0.032 in Vietnamese patients with falciparum malaria (n = 17), 0.065 ± 0.009 in Vietnamese patients with vivax malaria (n = 5), 0.117 ± 0.015 in Vietnamese volunteers (n = 7) and 0.092 ± 0.020 in Caucasian volunteers (n = 8). The ratios of α‐DHA : β‐DHA for the four groups were 6.3 ± 0.9, 6.9 ± 0.8, 6.9 ± 0.6 and 5.4 ± 0.8, respectively.

Conclusions

DHA is approximately 93% protein‐bound in patients with malaria infection and there is a preferential existence in vivo of the α‐DHA anomer. Knowledge of this stereochemistry may be valuable in elucidation of the mechanisms of DHA action and/or toxicity, and in the synthesis of new trioxane antimalarials.
Paclitaxel activity for the treatment of non‐Hodgkin's lymphoma: final report of a phase II trial
Authors: YOUNES ANAS , AYOUB JEAN‐PIERRE , SARRIS ANDREAS , HAGEMEISTER FREDERICK , NORTH LUCILLE , PATE ODEAL , MCLAUGHLIN PETER , RODRIGUEZ M. ALMA , ROMAGUERA JORGE , KURZROCK RAZELLE , PRETI ALEJANDRO , BACHIER CARLOS , SMITH TERRY , CABANILLAS FERNANDO
Published: December 2004

In order to determine the activity of paclitaxel in patients with relapsed or refractory non‐Hodgkin's lymphoma (NHL), we conducted a phase II clinical trial in which eligible patients received paclitaxel 200 mg/m2 intravenously over 3 h. Treatment was repeated every 3 weeks. Patients achieving complete or partial responses after two courses of paclitaxel continued to receive therapy for a maximum of eight courses, otherwise they were removed from the study. Of 96 evaluable patients, 45 (47%) had primary refractory disease, and 51 (53%) had relapsed lymphoma. The median number of prior treatment regimens was two (range one to 10 regimens). 45 patients had low‐grade, 44 had intermediate‐grade, and seven had mantle cell lymphoma. 24/96 patients responded (10 complete and 14 partial remissions) for an overall response rate of 25% (95% CI 17–35%). Patients with relapsed lymphoma had a higher response rate than those with primary refractory disease (19/51=37% v 5/45 =11%; P < 0.01), and patients with relapsed intermediate‐grade lymphoma had a higher response than those with relapsed low‐grade lymphoma (9/18=50% v 10/31 = 32%; P = 0.22). The treatment was very well tolerated with the most common side‐effects being alopecia (100%), peripheral neuropathy (35% of ≥ grade II), and arthralgia/myalgia (25% of ≥ grade II). After the first course of paclitaxel, grade III/IV thrombocytopenia and neutropenia were observed in 21% and 23% of the patients respectively. 23 episodes of neutropenic fever developed after 250 courses of paclitaxel therapy (8%). We conclude that paclitaxel, at this dose and schedule, is an active new drug for the treatment of non‐Hodgkin's lymphoma. The activity of paclitaxel combination programmes are currently under investigation.
PCR‐positivity in harvested bone marrow predicts relapse after transplantation with autologous purged bone marrow in children in second remission of precursor B‐cell acute leukaemia
Authors: VERVOORDELDONK SUSAN F. , MERLE PAULINE A. , BEHRENDT HENK , STEENBERGEN ERIC J. , VAN DEN BERG HENK , VAN WERING ELISABETH R. , KR. VON DEM BORNE ALBERT E. G. , VAN DER SCHOOT C. ELLEN , VAN LEEUWEN ELEONORE F. , SLAPER‐CORTENBACH INEKE C. M.
Published: December 2004

Purging of autologous bone marrow (BM) grafts of children in second remission after a relapse of precursor B acute lymphoblastic leukaemia (ALL) in the BM has been carried out in our laboratory since 1987, initially by complement mediated cell lysis. This protocol was extended by performing an immunorosette depletion before lysis with complement. The aim of the present study was to assess by polymerase chain reaction the presence of residual leukaemic cells in the BM grafts before and after purging. The results were then correlated to clinical outcome. In 24/28 patients a PCR product was obtained by amplification of IgH and/or TcR junctional regions. BM before purging was available for analysis in 13 patients. We found that leukaemic cells could be detected in 8/13 (62%) of these grafts before purging . All these eight patients experienced a relapse, regardless of whether the purging procedure had been successful (defined as achievement of PCR‐negativity) or not. In contrast, none of the five patients with PCR‐negative grafts before purging relapsed (P = 0.0008). One patient died due to transplant‐related toxicity. Of the remaining 23 patients, nine patients received a PCR‐positive BM graft after purging. All these nine patients experienced a relapse as compared to 6/14 whose BM was PCR‐negative after purging (P = 0.0072). Two of eight PCR‐positive BM grafts could be purged to PCR‐negativity. Thus, improvements both in treatment of leukaemia and in purging efficacy are still needed.
Persistent polyclonal B‐cell lymphocytosis in identical twins
Authors: CARR ROBERT , FISHLOCK KEITH , MATUTES ESTELLA
Published: December 2004

This is the first report of the unusual syndrome of persistent polyclonal B‐cell lymphocytosis occurring in monozygotic twins. The syndrome is characterized by a lymphocytosis, with circulating atypical, binucleated lymphocytes, mild splenomegaly and raised serum IgM. It occurs predominantly in females, with serological evidence of previous EBV infection, and is associated with cigarette smoking and HLA‐DR7 phenotype. The association with DR7 suggests a genetic predisposition. Its occurrence in identical twins, documented here, provides stronger support for a hereditary/genetic basis for the syndrome.
Prospective Randomized Study Comparing the Efficacy of Bioequivalent Doses of glycosylated and nonglycosylated rG‐CSF for Mobilizing Peripheral Blood Progenitor Cells
Authors: DE ARRIBA F. , LOZANO M. L. , ORTUÑO F. , HERAS I. , MORALEDA J. M. , VICENTE V.
Published: December 2004

Thirty patients diagnosed with breast cancer were included in a prospective randomized study comparing the in vivo priming effect of bioequivalent doses of glycosylated (lenograstim) and nonglycosylated (filgrastim) rG‐CSF administration. Analysis of the efficacy of equivalent biological doses of both rG‐CSFs showed no significant differences either in the mobilization of the subpopulations of PBPC considered (CD34+, CD34+/38−, CD34+/DR−), the content of such CD34+ cell subsets in the leukapheresis product, or the cost of the mobilization and collection procedures between both recombinant molecules. These results suggest that priming with bioequivalent doses of the two commercially available forms of glycosylated or nonglycosylated rG‐CSF has a similar in vivo effect on PBPC mobilization.
Allogeneic bone marrow transplantation versus chemotherapy in high‐risk childhood acute lymphoblastic leukaemia in first remission
Authors: UDERZO CORNELIO , VALSECCHI MARIA GRAZIA , BALDUZZI ADRIANA , DINI GIORGIO , MINIERO ROBERTO , LOCATELLI FRANCO , RONDELLI ROBERTO , PESSION ANDREA , ARCESE WILLIAM , BACIGALUPO ANDREA , POLCHI PAOLA , ANDOLINA MARINO , MESSINA CHIARA , CONTER VALENTINO , ARICÓ MAURIZIO , GALIMBERTI STEFANIA , MASERA GIUSEPPE
Published: December 2004

We compared the outcome of children with high‐risk acute lymphoblastic leukaemia (HR‐ALL) in first complete remission (first CR) treated with chemotherapy (CHEMO) or with allogeneic bone marrow transplantation (BMT) in a multicentre study.  All children treated by the Italian Paediatric Haematology Oncology Association for HR‐ALL in first CR between 1986 and 1994 were eligible for the study. 30 children were given BMT at a median of 4 months from first CR, with preparative regimens including total‐body irradiation (n =25/30). 130 matched controls for BMT patients were identified among 397 HR‐ALL CHEMO patients. Matching on main prognostic factors and duration of first CR was adopted to control the selection and time‐to‐transplant biases. The comparative analysis was based on the results of a stratified Cox model. The estimated hazard ratios of BMT versus CHEMO at 6 months, 1 year and 2 years after CR were 1.38 (CI 0.59–3.24), 0.69 (CI 0.27–1.77) and 0.35 (CI 0.06–1{\raise 5mu ..91), with an overall non‐significant difference between the two groups (P = 0.34). With a median follow‐up of 4 years, the disease‐free survival was 58.5% (SE 9.3) in the BMT group and 47.7% (SE 4.8) in the CHEMO group, at 4 years from CR. Non‐leukaemic death occurred in 4% of CHEMO and 10% of BMT patients. In the BMT group the estimated cumulative incidence of relapse at 1.5 years from CR was 31.5% (SE 8.8) and did not change thereafter, whereas in the CHEMO group the corresponding figure was 29.2% (SE 4.1) and the incidence continued to increase thereafter (48.2% (SE 4.8) at 4 years from CR).  The results of this study suggest that, with respect to the CHEMO group, the higher risk of early failure in the BMT group is outweighed by the lower risk of relapse after 1 year. Results prompt the need for a prospective study, in order to demonstrate the likely advantage of BMT in HR childhood ALL in first CR.
Conventional induction treatments do not influence overall survival in multiple myeloma
Authors: BOCCADORO MARIO , PALUMBO ANTONIO , ARGENTINO CHIARA , DOMINIETTO ALIDA , FRIERI ROBERTO , AVVISATI GIUSEPPE , COMOTTI BENEDETTO , LAUTA VITO MICHELE , LIBERATI MARINA , MARMONT FILIPPO , MUSTO PELLEGRINO , TRIBALTO MAURIZIO , PILERI ALESSANDRO
Published: December 2004

A retrospective analysis was performed on two subsequent myeloma patient series treated with the same conventional induction treatments, melphalan and prednisone or alternating VMCP/VBAP: 273 were enrolled in the multicentre M83 trial (M83 trial group) from 1983 to 1986; 160 were referred to a single institution (Haemat.To group) from 1986 to 1994. Response to treatment was very similar in the two groups (53% v 50.3%). Remission duration curves merely overlapped (median 20 v 21 months). However, overall survival was significantly longer in the Haemat.To group (43.2 v 33 months, P < 0.04). This difference was due to a prolonged period from relapse or progression to death (21 v 8 months, P < 0.01; 20.8 v 7 months, P < 0.009). Prolonged survival was also observed in poor‐prognosis patients with a serum β2‐microglobulin level > 3 mg/l, in the Haemat.To group (31.8 v 24.2 months, P < 0.04). The same induction treatments produced almost identical response rate and remission duration in both groups, but overall survival was 10 months longer for one group. However, it could be argued that treatment salvage modalities and support therapies have been improved in a decade. Lastly, induction treatments did not influence overall survival.
A new c‐kit mutation in a case of aggressive mast cell disease
Authors: PIGNON JEAN‐MICHEL , GIRAUDIER STÉPHANE , DUQUESNOY PHILLIPPE , JOUAULT HÉLÈNE , IMBERT MICHÈLE , VAINCHENKER WILLIAM , VERNANT JEAN‐PAUL , TULLIEZ MICHEL
Published: December 2004

Systemic mast cell disease (SMCD) is a disorder characterized by a mast cell proliferation in various tissues. Mast cells express the c‐kit proto‐oncogene. A few cases of c‐kit mutations have been described in SMCD. We report an aggressive SMCD in a patient who presented with a bone marrow infiltration by abnormal mast cells. Molecular studies of mast cell DNA and RNA revealed a new c‐kit heterozygous mutation (Asp820Gly). This mutation leads to a drastic amino‐acid change and is located close to the highly oncogenic Asp816Val. These findings suggest that the Asp820Gly has a potential role in c‐kit activation.
Biological diagnosis of primary intraocular lymphoma
Authors: Merle‐Béral Hélène , Davi Frédéric , Cassoux Nathalie , Baudet Sylvie , Colin Chantal , Gourdet Thomas , Bodaghi Bahram , LeHoang Phuc
Published: December 2004

Primary intraocular lymphoma (PIOL) is a rare presentation of lymphoma that is particularly difficult to recognize. In our institution, 36 cases of PIOL were diagnosed between March 1997 and July 2002. The recognition of lymphoma cells by cytology with or without immunophenotyping on slides generated a strong suspicion of the diagnosis in 34 of 36 cases. The diagnosis was confirmed by measurement of interleukin‐10 (IL‐10) in the vitreous humour or aqueous humour; high levels were observed in 35 of 36 cases, all were of B‐cell origin. As expected, the only case with T‐cell lymphoma had a very low level of IL‐10. Furthermore, IL‐10 levels excluded this diagnosis in two cases that were incorrectly suspected of PIOL after cytological examination. Finally, detection of clonality by polymerase chain reaction techniques, performed in 29 cases, represented a helpful tool in diagnosing PIOL as this approach definitively confirmed the diagnosis of B‐ or T‐cell lymphoma in 17 cases.
Computer‐assisted training system for pars plana vitrectomy
Authors: Jonas Jost B. , Rabethge Stefan , Bender Hans‐Joachim
Published: December 2004

Purpose:  To evaluate whether microsurgical steps in vitreoretinal surgery can be taught by a computer‐assisted training system.

Methods:  This prospective, randomized experimental study included 14 ophthalmic residents and medical students who were completely inexperienced in microsurgery. They were randomized into two groups. The study group underwent training programmes in a computer‐assisted training system for simulation of pars plana vitrectomy. The control group did not participate in any in vitro training. In the second phase of the study, participants of both groups performed a pars plana vitrectomy in three pig eyes, which included picking a metallic foreign body from the retinal surface.

Results:  The amount of retinal detachment and the number of retinal defects at the end of the vitrectomies were smaller, the time needed to remove the foreign body was shorter, the number of retinal lesions associated with the foreign body removal was lower, and the mark given was better in the trained study group than in the untrained group. The relatively small number of study participants did not allow the differences between the study and control groups to reach the 5% level of error probability.

Conclusions:  In an animal model, training by a computer‐based medical work station for simulation of pars plana vitrectomy showed better outcome measures for trained study participants compared with untrained study participants. Future studies may show whether further refinements of such training programmes will result in statistically significantly better results in surgical outcome parameters.
Myopia and natural lighting extremes: risk factors in Finnish army conscripts
Authors: Vannas Antti E. , Ying Gui‐Shuang , Stone Richard A. , Maguire Maureen G. , Jormanainen Vesa , Tervo Timo
Published: December 2004

Purpose:  To establish whether features of environmental lighting in far northern latitudes might be associated with prevalence of myopia.

Methods:  Using both questionnaires and military medical examinations, this cross‐sectional survey of Finnish conscripts assessed both light exposure and conventional risk factors for myopia.

Results:  While myopia was not associated with the month of birth, there was a trend towards a higher prevalence of myopia among conscripts living above the Arctic Circle, consistent with the hypothesis that ambient lighting might influence refractive development. Other novel associations with myopia were decreased sunglasses use and brown iris colour. As indicated by other reports, myopia was found to be associated with family history, education and nearwork.

Conclusion:  Although constraints inherent in surveying this military population may have limited our ability to detect associations, the positive findings suggest that studying northern populations may prove useful in clarifying any potential role of the light/dark cycle in refractive development.