bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.