bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating impossible curves using NONMEM
Authors: SCHOEMAKER RIK C. , COHEN ADAM F.
Published: October 2003

1On fitting model equations to experimental data, the situation may arise that individual subjects provide insufficient information to obtain adequate parameter estimates due to the fact that not all aspects are exhibited by all subjects or that the models are simply too complex. This may be solved by applying nonlinear mixed effect modelling to the data, which integrates the information provided by different subjects.

2We aim to provide insight into the methodology and its use in these situations, illustrated by three examples: determination of pharmacokinetics in a rising dose design, where the lower doses provide insufficient information (due to assay limitations) to estimate terminal half‐life; determination of the kinetics of the low molecular weight heparin enoxaparine (Clexane®) using anti‐Xa activity, effectively dealing with lingering low/basal activity; simultaneous estimation of the pharmacokinetics and pharmacodynamics of the low molecular weight heparin dalteparine (Fragmin®) after subcutaneous and intravenous administration.
Influence of concurrent antiepileptic medication on the pharmacokinetics of lamotrigine as add‐on therapy in epileptic children
Authors: VAUZELLE‐KERVROËDAN F. , REY E. , CIEUTA C. , PARIENTE‐KHAYAT A. , PONS G. , D′ATHIS P. , BIDAULT R. , DULAC O. , OLIVE G.
Published: October 2003

1 Lamotrigine is a new antiepileptic drug, chemically unrelated to currently used antiepileptic medication. Its pharmacokinetics can be influenced by concomitant antiepileptic medication.

2 This study was performed to assess the pharmacokinetic profile of lamotrigine in three groups of children treated with different types of comedication: drugs known to induce, to inhibit or to have no clinically significant influence on drug metabolism, respectively.

3 Thirty‐one children aged 6 months to 5 years were included and received a 2 mg kg−1 single oral dose. Lamotrigine plasma profiles were different between the three comedication groups. The half‐lives (mean±s.d.) were: 7.7±1.8 h, 21.9±6.8 h, 44.7±10.2 h in the ‘inducer’, ‘other’ and ‘inhibitor’ groups respectively.

4 Patients were then dosed to steady state, with the dosage adjusted on the basis of the single dose pharmacokinetics to achieve a minimum plasma concentration between 1.5 and 3 mg l−1. The mean minimum plasma concentration for the three groups was 2.54±1.28 mg l−1 at steady state.

5 Dosage of lamotrigine can be optimised with knowledge of the metabolic effects of antiepileptic comedication.
Pharmacokinetics of intravenous fluticasone propionate in healthy subjects
Authors: MACKIE A. E. , VENTRESCA G. P. , FULLER R. W. , BYE A.
Published: October 2003

1Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non‐compartmental analysis, in healthy male subjects over the 250 to 1000μg dose range.

2The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body (Vss 318 l), rapidly cleared (CL 1.1 l min−1) with a terminal elimination half‐life of 7.8 h and a mean residence time of 4.9 h.

3In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration‐time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non‐compartmental analysis.
Hypertensive cardiac hypertrophy—is genetic variance the missing link?
Authors: NUNEZ DEREK J. R. , PIERS CLIFFORD C. , AL‐MAHDAWI SAHAR , DUTKA DAVID
Published: October 2003

1Hypertensive cardiac hypertrophy is a major independent predictor of adverse cardiovascular events. In man the cardiac response to increased afterload is very variable, even when ambulatory blood pressure monitoring is used. Analysis of breeding experiments using normotensive and hypertensive rat strains, human twin studies and other data indicate that genetic factors play a significant role in regulating cardiac mass; in other words, a large component of total variability is accounted for by genetic variance.

2The observation that some patients with only mild‐to‐moderate hypertension exhibit gross left ventricular hypertrophy (LVH) similar to the inherited hypertrophic cardiomyopathies such as familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) has prompted us to investigate the hypothesis that genetic factors associated with excessive myocardial hypertrophy, viz. mutations in FHC and FA genes alter the hypertrophic response of the heart to pressure overload. Here we review briefly three lines of study: (i) association analysis to test whether the allele frequencies differ in hypertensive patients with or without left ventricular hypertrophy; (ii) characterization of the cardiac manifestations of FA to understand the mechanism by which the heart is affected in a disease associated with pathology in a sub‐group of neurons, and (iii) creation of transgenic models to facilitate the investigation of the interaction between hypertrophic stimuli and underlying genetic predisposition.

3Information on the nature of the cardiac‐mass‐modifying genes involved may be useful not only for selecting high risk patients in strategies aimed at preventing the development of LVH, but also in opening new avenues of research on the reprogramming of cardiac myocytes to encourage them to hypertrophy in situations where cardiac muscle has been damaged or is hypoplastic.
The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole
Authors: GILL HELEN J. , MAGGS JAMES L. , MADDEN STEPHEN , PIRMOHAMED MUNIR , PARK B. KEVIN
Published: October 2003

1Cytochrome P450‐mediated bioactivation of sulphamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co‐trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV‐infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulphamethoxazole hydroxylamine.

2Ten healthy male volunteers were given co‐trimoxazole (800 mg sulphamethoxazole and 160 mg trimethoprim) alone or 1 h after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 h, and sulphamethoxazole and its metabolites were quantified by electrospray LC‐MS.

3Ketoconazole had no effect on the urinary recovery of sulphamethoxazole or any of its metabolites. In contrast, fluconazole significantly (P<0.001) inhibited the formation of sulphamethoxazole hydroxylamine by 50.0±15.1%. Fluconazole also inhibited the oxidation of sulphamethoxazole to the 5‐methylhydroxy and 5‐methylhydroxy acetate metabolites by 69.9±15.8% and 64.0±12.0%, respectively, but had no effect on the amount of sulphamethoxazole, N4‐acetyl sulphamethoxazole, or sulphamethoxazole N1‐glucuronide excreted in urine.

4The potential clinical benefit of using fluconazole to prevent hypersensitivity to co‐trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as end‐points.
Lack of pharmacokinetic interaction of pantoprazole with diazepam in man
Authors: GUGLER R. , HARTMANN M. , RUDI J. , BROD I. , HUBER R. , STEINIJANS V. W. , BLIESATH H. , WURST W. , KLOTZ U.
Published: October 2003

Pantoprazole, a substituted benzimidazole, is a potent and well tolerated inhibitor of the gastric H+,K+‐ATPase with a low potential to inhibit cytochrome P450. In this randomized, placebo‐controlled two‐period crossover study, 12 healthy volunteers received placebo (reference) and 240 mg of pantoprazole (test) i.v. within 2 min once daily for 7 days each. On day 4 of either period, a 1 min bolus of diazepam (0.1 mg kg−1 body weight) was additionally injected. Pantoprazole was well tolerated and did not cause clinically relevant changes in heart rate, blood pressure, ECG and routine clinical laboratory parameters. There was no effect on diazepam clearance (0.021 l h−1 kg−1 for test and reference) and elimination half‐life (36.8 h for test, 40.4 h for reference). Diazepam metabolism to desmethyldiazepam was not affected by pantoprazole. In conclusion, pantoprazole and diazepam may be administered concomitantly without dose adjustment even when high doses of pantoprazole are required.
Influence of liver cirrhosis on sertraline pharmacokinetics
Authors: DÉMOLIS JEAN‐LOUIS , ANGEBAUD PASCAL , GRANGÉ JEAN‐DIDIER , COATES PETER , FUNCK‐BRENTANO CHRISTIAN , JAILLON PATRICE
Published: October 2003

Sertraline is a serotonin reuptake inhibitor. The enhancement of serotoninergic transmission is associated with antidepressant activity. In order to determine the pharmacokinetics of sertraline in patients with chronic stable hepatic insufficiency, 10 patients were matched (age, weight, sex) with 10 healthy subjects in an open study. Each participant received a single capsule containing the equivalent of 100 mg sertraline base. Blood samples were taken during 264 h after administration for measurement of plasma concentrations of sertraline. The results confirm that the oral clearance of sertraline is reduced with a 1.7‐fold increase in Cmax and a significant prolongation in elimination half‐life in hepatically impaired patients
Characterization of angiotensin‐II effects on cerebral and ocular circulation by noninvasive methods
Authors: Krejcy Kurt , Wolzt Michael , Kreuzer Claudia , Breiteneder Helene , Schütz Wolfgang , Eichler Hans‐Georg , Schmetterer Leopold
Published: October 2003

Aims
 The role of the renin‐angiotensin‐system (RAS) in the cerebral and ocular circulation is still a matter of controversy. In vitro and animal data lead to partially contradicting results. However, direct investigation of locally generated angiotensin II (Ang II) in humans is not possible in vivo. Hence, we hypothesised that it might be possible to characterize local effects of Ang II by comparing systemic and local haemodynamic parameters during exogenous Ang II infusion.

Methods  In a placebo‐controlled, double‐blind, two‐way cross over study blood flow velocities in the middle cerebral and the ophthalmic artery and ocular fundus pulsations were measured during stepwise increasing doses of Ang II in 10 healthy subjects. Blood flow velocities were assessed by Doppler sonography, fundus pulsation amplitudes (FPA), which estimate local pulsatile ocular blood flow were measured by laser interferometry. Additionally, systemic blood pressure and pulse rate were measured.

Results  Ang II dose‐dependently decreased resistive index (RI) and increased mean flow velocities (MFV) in both arteries. Fundus pulsation amplitude was dose‐dependently decreased by Ang II, whereas mean arterial pressure (MAP) was significantly increased. Pulse pressure amplitude (PPA) was not affected by Ang II administration. There was a high degree of correlation between changes in RIs and the analogously calculated PPA/systolic blood pressure during Ang II infusion, which indicates that the changes in RI after Ang II administration can be attributed to changes in systemic haemodynamics. Calculation of total local ocular blood flow from fundus pulsation amplitudes and changes in flow pulsatility in the ophthalmic artery further argue against significant blood flow changes after Ang II administration.

Conclusions  Interpretation of data from Doppler sonography and laser interferometry must be done very carefully when concomitant changes in systemic haemodynamics occur. RI cannot necessarily be taken as an index of distal vascular resistance in these cases and changes in MFV can be caused by changes in vessel diameter or in blood flow. Moreover, FPA cannot be taken as a measure of ocular blood flow if no additional data on flow pulsatility are available. The combination of our systemic and local haemodynamic data indicates that cerebral and ocular circulation are comparably insensitive to changes in local Ang II concentrations. Fundus pulsation and blood flow velocity measurements indicate that neither choroidal nor optic nerve head blood flow are significantly affected by administration of Ang II.
Population analysis of the non linear red blood cell partitioning and the concentration‐effect relationship of draflazine following various infusion rates
Authors: Snoeck E. , Piotrovskij V. , Jacqmin P. , Van Peer A. , Danhof M. , Ver Donck K. , Woestenborghs R. , Van Belle H. , Van Bortel L. , Van Gool R. , Dupont A. G. , Heykants J.
Published: October 2003

Aims To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured adenosine breakdown inhibition (ABI).

Methods Draflazine was administered to healthy volunteers as a 15‐min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately followed by an infusion of the same dose over 1 h. Plasma and whole blood concentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The capacity‐limited specific binding of draflazine to the nucleoside transporter located on the erythrocytes was evaluated by a population approach.

Results The estimate of the population parameter typical value (%CV) of the binding constant Kd and the maximal specific binding capacity (Bmax ) was 0.385 (3.5) ng ml−1 plasma and 158 (2.1) ng ml−1 RBC, respectively. The non‐specific binding was low. The specific binding to the erythrocytes was a source of non‐linearity in the pharmacokinetics of draflazine. The total plasma clearance of draflazine slightly decreased with increasing doses, whereas the total clearance in whole blood increased with increasing doses. The sigmoidal Emax equation was used to relate the plasma and whole blood concentration of draflazine to the ex vivo determined ABI. In plasma, typical values (%CV) of Emax, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml−1 and 1.06 (3.4), respectively. The relationship in whole blood was much steeper with population parameter typical values (%CV) of Emax, IC50 and Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml−1 and 4.47 (5.5), respectively. The RBC occupancy of draflazine did not coincide with the ex vivo measured ABI. The observed relationship between RBC occupancy and ABI was not directly proportional but similar for all studied infusion schemes.

Conclusions The findings of this study show that the occupancy of the nucleoside transporter by draflazine should be at least 90% in order to inhibit substantially adenosine breakdown in vivo. On the basis of these findings it is suggested that a 15 min infusion of 1 mg draflazine followed by an infusion of 1 mg h−1 could be appropriate in patients undergoing a coronary artery bypass grafting.
Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data
Authors: Hussein Z. , Posner J.
Published: October 2003

Aims  To examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks.

Methods
 The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41–107 kg, respectively. A one‐compartment compartment model with first‐order absorption and elimination was fitted to plasma lamotrigine concentration‐time profiles from retrospective drug monitoring, using non‐linear mixed effect modelling (NONMEM), with first‐order estimation. Oral clearance (CLo ), apparent volume of distribution (V /F ) and absorption rate constant (Ka ) were the main pharmacokinetic parameters.

Results
 CLo was not significantly influenced by body weight, age, gender, oral contraceptives and dose. However, due to auto‐induction CLo increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28 l h−1, and was 28.7% lower in Asians than Caucasian. The final magnitude in interpatient variability was 32%. The effect of the covariates weight, age, race and gender on V /F was examined and none was statistically significant. The final population estimate of V /F was 77.4 l with an interpatient variability of 34%.

Conclusions  In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto‐induction on clearance are unlikely to be clinically significant and, thus, no dosage adjustment is warranted for these effects.
Pharmacokinetics and safety of JTP‐4819, a novel specific orally active prolyl endopeptidase inhibitor, in healthy male volunteers
Authors: Umemura K. , Kondo K. , Ikeda Y. , Kobayashi T. , Urata Y. , Nakashima M.
Published: October 2003

Aims To investigate the pharmacokinetics and safety profile of JTP‐4819, (‐)‐(2S)‐1‐benzylaminocarbonyl‐[ (2S)‐2‐glycoloylpyrrolidinyl]‐2‐pyrrolidinecarboxamide, a novel specific orally active prolyl endopeptidase (PEP) inhibitor.

Methods JTP‐4819 was given orally to 28 healthy male volunteers at single doses of 30 mg (n=6), 60 mg (n=6), 120 mg (n=6) and placebo (n=3) and multiple doses of 60 mg three times daily (n=5) and placebo (n=2) for 7 days to investigate its safety and pharmacokinetics following a preliminary safety evaluation of 3, 10 and 30 mg doses in six healthy volunteers. With the single dose of 60 mg, a cross‐over study was conducted to examine the effect of food on the bioavailability of the drug. The concentrations of JTP‐4819 in plasma and urine were determined by electrospray ionization‐liquid chromatography/mass spectrometry (ESI‐LC/MS) method.

Results In the multiple–dose study, the cholinesterase activity was gradually increased and reached above the normal range on days 4 to 8 in all five subjects given JTP‐4819 and gradually returned to normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of JTP‐4819, but this remains to be verified. There were no other abnormal findings in objective symptoms and laboratory findings including blood pressure, heart rate, electrocardiogram, body temperature, haematology, blood chemistry and urinalysis. The Cmax of JTP‐4819 at 30, 60 and 120 mg in fasting state were 474, 887 and 1,649 ng ml−1, respectively, at 1 h after administration, and the t1/2 was about 2 h. AUC increased in proportion to the given doses. The cumulative urinary recoveries within 24 h were approximately 66%. Cmax, AUC, t1/2 and urinary recovery were not affected by food intake. In the multiple‐dose study, there was no drug accumulation trend in plasma.

Conclusions These results indicate that JTP‐4819 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events as we verified in healthy young male volunteers.
Chloroquine‐induced pruritus in malaria fever: contribution of malaria parasitaemia and the effects of prednisolone, niacin, and their combination, compared with antihistamine
Authors: Adebayo R. A. , Sofowora G. G. , Onayemi O. , Udoh S. J. , Ajayi A. A.
Published: October 2003

Aims Chloroquine treatment of malaria fever, results in a generalized pruritus of unknown mechanism in up to 60% of adult Africans, by contrast pruritus is unusual in Caucasians following chloroquine use.

Methods We conducted a double‐blind, randomized, parallel group study to examine and compare the antipruritic effects of promethazine, niacin, prednisolone and their combination on pruritus induced by chloroquine, in 28 historical itching patients with parasitologically proven malaria fever. We also evaluated the role of the antecedent malaria parasite density in the severity of chloroquine pruritus intensity.

Results The concurrent administration of chloroquine (2.1g base total dose) with prednisolone caused a statistically significant reduction in the pruritus AUC (0, 72 h) (P<0.001 ANOVA) compared with the antihistamine promethazine alone. The areas under the pruritus intensity‐time curve were promethazine 105±28 (units h), niacin 76±22, prednisolone 28±24, and prednisolone and niacin 34±17 (P<0.001 ANOVA). The 95% confidence interval for the difference in the pruritus AUC between prednisolone and promethazine was 8.4 to 145.6 units h. There was a statistically significant and positive correlation between the pruritus intensity (AUC 0, 72 h) and the malaria parasite load in the itching subjects, not receiving prednisolone (n=9) (r=0.73, P=0.026 ANOVA).

Conclusion A single oral dose of prednisolone (10 mg) may be preferable to the antihistamine promethazine (25 mg) as an antipruritic agent for concurrent prescription with chloroquine in individuals predisposed to severe itching. Malaria parasite clearance and clinical amelioration were unaffected by any of the treatments.
Single‐dose pharmacokinetics of felbamate in patients with renal dysfunction
Authors: Glue P. , Sulowicz W. , Colucci R. , Banfield C. , Pai S. , Lin C. , Affrime M. B.
Published: October 2003

Aims The purpose of this study was to evaluate the effects of renal impairment on the single‐dose pharmacokinetics of the antiepileptic felbamate.

Methods Twelve subjects with three levels of renal dysfunction (creatinine clearance >30–80, >10–30 or 5–10 m min−1 ) and four controls with normal renal function (creatinine clearance >80 ml min−1 were studied). Plasma and urine samples were obtained for 144 h following administration of a single 1200 mg dose.

Results Compared with controls, apparent total body clearance, renal clearance and urinary excretion of felbamate were decreased, and half‐life, Cmax and AUC values were increased in subjects with renal dysfunction. The magnitude of these changes was associated with the degree of renal dysfunction. Nonrenal clearance and apparent volume of distribution values were also lower in renal dysfunction subjects, but there was no association between the extent of these changes and degree of renal dysfunction. Renal clearance of felbamate accounted for approximately 30% of apparent total body clearance in the control group and from 9–22% in the renal failure patients. Renal clearance of felbamate was significantly correlated with creatinine clearance (r2=0.75; P<0.001).

Conclusions These data suggest that initial dosage and titration of felbamate may require adjustment in patients with renal dysfunction.
Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets
Authors: Osamah Hussein , Mira Rosenblat , Sorina Schlezinger , Shlomo Keidar , Michael Aviram
Published: October 2003

Aims High plasma cholesterol concentration and increased platelet activity are two major risk factors for atherosclerosis. Lovastatin, the lipophilic drug was shown to inhibit platelet aggregation whereas pravastatin, the hydrophilic drug had no such effect. Analysis of the effect of fluvastatin which is both a lipophilic and hydrophilic drug, on platelet aggregation was the goal of the present study.

Methods Fluvastatin 40 mg daily was administered to 25 patients with hypercholesterolaemia for up to 24 weeks. Normal subjects acted as controls. The influence of fluvastatin on plasma lipids and on platelet aggregation and fluidity was studied. The direct effect of fluvastatin on platelets was compared with that of other statins.

Results Fluvastatin therapy (40 mg day−1 for a period of 4 weeks) in hypercholesterolaemic patients resulted in a 23% and 29% reduction in plasma levels of total cholesterol and LDL‐cholesterol respectively. Platelet cholesterol/phospholipids molar ratio was reduced by 26% and platelet aggregation was significantly (P<0.02) reduced by 10% after 4 weeks of fluvastatin treatment. On continuing fluvastatin therapy for additional 20 weeks, no further decrement in plasma LDL cholesterol levels or in platelet cholesterol/phospholipid ratio were noted. However, platelet aggregation was further significantly (P<0.01) reduced by up to 15%. Incubation of platelets with increasing concentrations of fluvastatin or lovastatin, demonstrated a dose‐dependent reduction in platelet aggregation, whereas pravastatin showed no effect. This inhibitory effect of fluvastatin or lovastatin on platelet aggregation (up to 34% or 22% respectively at a concentration of 1 μg statin ml−1 ) was found both in platelet rich plasma and in washed platelet suspensions. Fluvastatin and lovastatin (but not pravastatin), seem to share similar platelet binding sites, as non labelled fluvastatin or lovastatin were able to displace []>
3H]‐labeled‐fluvastatin from its binding sites on platelets.

Conclusions Fluvastatin therapy reduces platelet aggregation via a dual effect which involves its in vivo hypocholesterolaemic action on platelet cholesterol content, and also a direct effect of the drug binding to the platelets. The antiatherogenicity of fluvastatin may be related, in addition to its plasma cholesterol lowering ability, to its inhibitory effect on platelet activation.
Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19
Authors: Bertilsson Leif , Tybring Gunnel , Widén Jolanta , Chang Ming , Tomson Torbjörn
Published: October 2003

Aims Omeprazole has been shown previously to be metabolized by the two cytochrome P450 isoforms CYP2C19 (hydroxylation) and CYP3A4 (sulphoxidation). The objective of this study was to test the inducibility of these enzymes by carbamazepine (CBZ).

Methods Omeprazole was given as a single oral dose before and after 3 weeks of treatment of five patients with CBZ (400–600 mg daily).

Results Mean area under the plasma concentration vs time curve (AUC) between 0 and 8 h after drug intake, decreased by about 40% for omeprazole and its hydroxy metabolite and increased for its sulphone metabolite, but the changes were not statistically significant. The ratio of the AUCs of omeprazole and its sulphone, used as an index of CYP3A4 activity, decreased in all patients (P=0.052), while there was no change in the omeprazole/hydroxyomeprazole AUC ratio used as an index for CYP2C19 activity. There was a significant decrease in the mean ratio of the AUC of the hydroxy and sulphone metabolites from 2.58 to 0.93 (P=0.046) with a mean difference of 1.79 (95% CI: 0.07 to 3.50) showing that the induction was more pronounced for CYP3A4 than for CYP2C19.

Conclusions CBZ induces CYP3A4, but not, or to a lesser extent, CYP2C19. The induction of the sulphoxidation of omeprazole by CBZ seems to have no major clinical implication.
Disposition and effects of flurbiprofen enantiomers in human serum and blister fluid
Authors: Oelkers R. , Neupert W. , Williams K. M. , Brune K. , Geisslinger G.
Published: October 2003

Aims To investigate the pharmacokinetics of the enantiomers of flurbiprofen and inhibition of prostanoid production in blister fluid and serum.

Methods Eleven healthy volunteers received 75 mg R‐, 75 mg S‐flurbiprofen or no medication in a randomized 3‐way cross‐over study. Flurbiprofen concentrations were determined by h.p.l.c. TXB2 and PGE2 were determined by enzyme immunoassay and chemiluminescence immunoassay respectively.

Results S‐flurbiprofen produced almost complete (>99%vs baseline) inhibition of thromboxane B2 (TXB2 ) in serum in all volunteers and significant inhibition of prostaglandin E2 (PGE2 ) generation in blister fluid, but there was a considerable inter‐individual variation in the response ranging from −78 to +190% change from control PGE2 AUC. After administration of R‐flurbiprofen, there was a mean maximum TXB2 inhibition of 65.2±15.0% in serum but no significant changes of PGE2 levels in blister fluid were observed. The pharmacokinetic parameters in serum and blister fluid were not significantly different between enantiomers. R‐ to S‐inversion did not occur to a clinically relevant extent. For R‐flurbiprofen, the complex rate constant of transfer into blister fluid was greater at the u.v.‐exposed site (0.110±0.050) than at the control site (0.079±0.026, P<0.05) which corresponded to a higher AUC and Cmax of R‐flurbiprofen in u.v.‐exposed blister as compared with control. For inhibition of TXB2 generation after administration of S‐flurbiprofen, a sigmoidal log‐linear concentration–response relationship was established in all subjects (EC50: 0.123±0.092 μg ml−1 ). In contrast, inhibition of PGE2 production in blister showed no clear concentration‐response relationship when correlated with concentrations of S‐flurbiprofen in either serum or blister fluid. After administration of R‐flurbiprofen, no concentration‐effect relationship could be established.

Conclusions It is concluded that the blister model may have value for studying the pharmacokinetics and pharmacodynamics of antiinflammatory drugs in humans. Interestingly, inter‐individual variation in the pharmacokinetics of flurbiprofen enantiomers could not account for the variability in response observed in the blister model.
Comparison of two Bayesian approaches to dose‐individualization for once‐daily aminoglycoside regimens
Authors: Duffull S. B. , Kirkpatrick C. M. J. , Begg E. J.
Published: October 2003

Aims Bayesian dose‐individualization methods have been shown to have good predictive performance using minimal data points, and are now used widely in clinical practice. This study was designed to compare two computerised Bayesian dose‐individualization methods, ABBOTTBASE and SeBA‐GEN, in once‐daily dosing of aminoglycosides.

Methods ABBOTTBASE uses the maximum a posteriori estimator (MAP) algorithm which analyses all available serum drug concentration data for individual patients simultaneously, while the prior model remains unchanged. SeBA‐GEN analyses each data set sequentially while continually modifying the individual patient's prior model, allowing within‐patient variability to be modelled. One hundred consecutive patients who received once‐daily dosing of aminoglycosides were prospectively dose‐individualized using either of these methods. Retrospectively the alternative dosing method was used to provide comparative data. The ability of the methods to predict subsequent serum aminoglycoside concentration data was assessed in terms of their predictive performance, bias and precision.

Results From the 100 patients, 277 serum aminoglycoside concentrations were available. Ninety‐eight patients had serum concentrations available from the first dose and 55 from the second dose. Gentamicin was used in 96 patients. There was no significant bias when predicting peak concentrations from the prior model using either SeBA‐GEN or ABBOTTBASE. The prior model used by ABBOTTBASE did, however, significantly underpredict the mid‐dose concentration (mean bias=−0.79 mg l−1, 95% Confidence Interval [CI]: −1.3 to −0.3). When using the Bayesian algorithms for prediction of the second set of concentrations neither method was biased when predicting the peak concentration. ABBOTTBASE significantly overpredicted the mid‐dose concentration (mean bias=0.38 mg l−1, 95% CI: 0.03 to 0.74). The prior model used by SeBA‐GEN was more precise at predicting both peak and mid‐dose concentrations (P<0.01), indicating better use of covariates. There was no difference between the methods in terms of estimation of the value of volume of distribution, but they differed significantly in the estimation of clearance (mean difference=0.24 l h−1 for SeBA‐GEN‐ABBOTTBASE, 95% CI: 0.05 to 0.43).

Conclusions Bayesian techniques appear to work well with once‐daily aminoglycoside dosing. The method of incorporation of individual patient information into the prior model appears to be important in the optimum choice of the first dose. SeBA‐GEN has an advantage in this and in the lack of bias related to predicting low concentrations compared with ABBOTTBASE.
Non‐linear pharmacokinetics of high‐dose intravenous verapamil
Authors: Toffoli G. , Robieux I. , Fantin D. , Gigante M. , Frustaci S. , Nicolosi G. L. , De Cicco M. , Boiocchi M.
Published: October 2003

Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil.

Methods We studied nine patients [
seven males, two females; median age 46 years (range, 31–57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg−1 followed by 12 h continuous i.v. infusion at 0.20 mg kg−1 h−1 ), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1 ). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and urine collections were taken every 12 h. Verapamil and nor‐verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL=ko/Css ) and renal clearance (CLr) of verapamil and nor‐verapamil. The Cssvs rate relationship was fitted to a Michaelis‐Menten equation: Css=ko(Km+Css )/(V Vm ).

Results CL was dose‐dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL±s.d. were 0.51±0.31, 0.38±0.16, 0.32±0.18, and 0.27±0.11 l h−1 kg−1, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1; P=0.0001). Css increased more than proportionally to the dose rate and the Cssvs rate relationship was best defined by a Michaelis‐Menten equation (Km=730 μg l−1; V Vm=0.55 mg kg−1 h−1 ), (r=0.994; P=0.006). CLr of verapamil and nor‐verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose.

Conclusions These findings suggest a non‐linear, capacity‐limited metabolic clearance of high‐dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500–2500 ng ml−1 ) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.
Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma
Authors: Roberts Michael S. , Wu Zhen Y. , Rivory Laurent P. , Smithers B. Mark , Egerton William S. , Weiss Michael
Published: October 2003

Aims We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing.

Methods A bolus of injectate containing [
 51Cr] labelled red blood cells, [14C]‐sucrose and [3H]‐water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [ 51Cr] or beta [ 14C and 3H] counting. The moments of the outflow fraction‐time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions).

Results The availability, mean transit time and normalised variance (CV2 ) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients.

Conclusions The vascular space is not well‐stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow‐limited blood‐tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.
Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity
Authors: Lennard L. , Welch J. C. , Lilleyman J. S.
Published: October 2003

Aims The response to 6‐mercaptopurine (6MP) is highly variable. Its antileukaemic effect can be related to drug derived 6‐thioguanine nucleotides (TGNs). The inherited level of thiopurine methyltransferase (TPMT) activity may be a major factor in the clinical response to 6MP because TPMT forms methylmercaptopurine metabolites (MeMPs) at the expense of TGNs. The aim of this study was to explore the clinical importance of TPMT phenotype.

Methods Thiopurine metabolism was studied in a consecutive cohort of children with acute lymphoblastic leukaemia (ALL) treated according to the Medical Research Council trial UK ALL XI. TPMT phenotype was measured in 38 children at diagnosis, and thiopurine metabolites were measured at defined times during 2 years treatment in 29 of these children.

Results TPMT activities at diagnosis ranged from 5.5 to 18.5 units ml−1 packed RBCs, no different from the range of activities reported in healthy children. TGNs and MeMPs measured during the first 6MP cycle at 75 mg m−2 ranged from 187 to 594 pmol 6TGNs, median 327, and 0.5 to 22.0 nmol MeMPs, median 4.5, per 8×108 RBCs. TPMT activity was not significantly related to the generation of MeMPs (rs=0.06), but was negatively correlated to 6TGNs (rs=−0.44, P<0.025, n=29). TGNs were related to neutropenia at the point of dose reduction (rs=−0.5, P<0.01). TPMT activity was also inversely related to the duration of cytopenia driven 6MP withdrawal (rs=−0.41, P<0.05).

Conclusions These findings support the suggestion that the inherited activity of TPMT in a given individual can modulate the cytotoxic effect of 6MP, and this information may help in clinical management.
Integrated pharmacokinetics and pharmacodynamics of Ro 48–6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects
Authors: Dingemanse J. , Van Gerven J. M. A. , Schoemaker R. C. , Roncari G. , Oberyé J. J. L. , Van Oostenbruggen M. F. , Massarella J. , Segala P. , Zell M. , Cohen A. F.
Published: October 2003

Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48–6791, compared with midazolam, in healthy subjects during first administration to man studies.

Methods The study was double‐blind and five‐way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48–6791 was administered as a slow i.v. infusion in doses of 0.1–0.3–1 mg in the first group, and 1–2–3 mg in the second. Midazolam was infused at 0.1 mg kg−1. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min−1 ) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two‐compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (&bgr;‐power). These parameters were used for pharmacokinetic/pharmacodynamic modelling.

Results Ro 48–6791 and midazolam were both well tolerated. Most clinical events were dose‐dependent central depressant effects. The volume of distribution (Vss ) and plasma clearance of Ro 48–6791 were on average markedly larger than those of midazolam (171±65 vs 41±10 l and 2.2±0.9 vs 0.42±0.11 l min−1, respectively). The doses of Ro 48–6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48–6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in &bgr;‐power than Ro 48–6791 at the highest administered dose. Ro 48–6792, a metabolite of Ro 48–6791, showed a considerably longer half‐life than the parent compound. Although there were no indications of a discernable effect of Ro 48–6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further.

Conclusions This first study with Ro 48–6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.
Integrated pharmacokinetics and pharmacodynamics of Ro 48–8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects
Authors: Van Gerven J. M. A. , Roncari G. , Schoemaker R. C. , Massarella J. , Keesmaat P. , Kooyman H. , Heizmann P. , Zell M. , Cohen A. F. , Dingemanse J.
Published: October 2003

Aims This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48–8684, compared with midazolam, in healthy subjects during first administration to man.

Methods The study was double‐blind and five‐way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48–8684 was infused in doses of 0.1–0.3–1 mg in the first group, and 1–3–10 mg in the second, with different infusion rates (expressed as mg min−1 ) among doses. Midazolam was infused at 0.1 mg−1 kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article.

Results Ro 48–8684 caused dose‐dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48–8684 were larger than of midazolam (337±114 vs 50±12 l and 2.4±0.5 vs 0.47±0.11 l min−1, resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48–8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48–8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48–8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration–effect‐relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48–8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4‐fold (range 1.6, 7.3 times), with doses of Ro 48–8684 increasing from 1 to 10 mg. The metabolite Ro 61–2466 had a longer half‐life than the parent compound Ro 48–8684. The influence of this metabolite during prolonged administration should be further investigated.

Conclusions These results show that Ro 48–8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48–8684 with repeated administration of rising doses due to as yet undetermined factors.
Chronic myelomonocytic leukaemia with t(8;9)(p11;q34) in childhood: an example of the 8p11 myeloproliferative disorder?
Authors: Nakayama Hideki , Inamitsu Takeshi , Ohga Shouichi , Kai Takeshi , Suda Masahiro , Matsuzaki Akinobu , Ueda Kohji
Published: October 2003

We describe the case of a 10‐year‐old girl with chronic myelomonocytic leukaemia with the chromosomal translocation t(8;9)(p11;q34), who had developed tonsillar lymphoma as extramedullary involvement at the initial presentation. The cytogenetic study of the cells in both bone marrow and tonsils demonstrated t(8;9)(p11;q34), despite no malignant features in the bone marrow specimens. She developed acute leukaemic transformation 8 months after diagnosis during chemotherapy for lymphoma. Although etoposide reduced the number of blasts, t(8;9)(p11;q34)‐bearing cells were not eradicated. Complete remission was obtained following an unrelated bone marrow transplantation. The clinical characteristics of this patient are similar to those of the patients with t(8;9)(p11;q34 or q32) or t(8;13)(p11;q11 or q12) reported previously. The unusual progression of the disease might be associated with the presence of t(8;9)(p11;q34), suggesting a part in the 8p11 myeloproliferative syndrome.
Elevated plasma levels of vascular cell adhesion molecule‐1 (VCAM‐1) in diabetic patients with microalbuminuria: a marker of vascular dysfunction and progressive vascular disease
Authors: Schmidt Ann Marie , Crandall Jill , Hori Osamu , Cao Rong , Lakatta Edward
Published: October 2003

Advanced glycation endproducts (AGEs), which accumulate in diabetic vasculature, result in enhanced expression of endothelial cell‐associated vascular cell adhesion molecule‐1 (VCAM‐1) as well release of a soluble form of VCAM‐1 (sVCAM‐1) into culture supernatants. We hypothesized that sVCAM‐1 in diabetic plasma might reflect early vascular perturbation in diabetic vasculopathy. Diabetic patients with microalbuminuria, a group with a high incidence of vascular complications, had increased plasma levels of sVCAM‐1, ∼1.5‐fold greater than diabetic patients without microalbuminuria; P < 0.05. sVCAM‐1 may be an indicator of ongoing cellular dysfunction in diabetes, as well as a dynamic surrogate marker for the effectiveness of therapeutic interventions.
Mammary epithelial stem cells: transplantation and self‐renewal analysis
Authors: Smith Gilbert H. , Boulanger Corinne A.
Published: October 2003

Abstract.  An entire mammary epithelial outgrowth, capable of full secretory differentiation, may be comprised of the progeny of a single cellular antecedent. This conclusion is based upon the maintenance of retroviral insertion sites within the somatic DNA of successive transplant generations derived from a single mammary fragment. In addition, dissociation of these clonal dominant glands and implantation of dispersed cells at limiting dilution demonstrated that both duct‐limited and lobule‐limited outgrowths were developed, as well as complete, fully differentiated glands. Thus, transplantation has revealed three distinct mammary epithelial progenitors in the mouse. Similar studies have extended this observation to rat mammary tissue. Recently, using cre‐lox conditional activation of reporter genes, a new epithelial progenitor, specific for mammary secretory epithelium in postlactation females has been uncovered. In situ, these cells were shown to regenerate secretory lobules upon successive pregnancies. In transplant studies, they demonstrated the capacity for self‐renewal and contributed to the new generation of all of the known epithelial cell types among mammary epithelium. In limiting dilution, the parity‐induced progenitors were capable of engendering lobule‐limited and duct‐limited outgrowths in their entirety, but not completely developed glands. Serial transplant studies indicate that these progenitors have a significant but limited capacity for self‐renewal.