bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study
Authors: Morain P. , Robin J. L. , De Nanteuil G. , Jochemsen R. , Heidet V. , Guez D. 
Published: March 2003

Aims  The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers.Methods  This was a double‐blind, randomized, placebo‐controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection.Results  PEP activity in plasma was dose‐dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5–2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half‐life (t½) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose.Conclusions  S 17092 had a potent, dose‐dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once‐daily dosing without any serious adverse events.
Enterocytic CYP3A4 in a paediatric population: developmental changes and the effect of coeliac disease and cystic fibrosis
Authors: Johnson Trevor N. , Tanner M. Stuart , Taylor Christopher J. , Tucker Geoffrey T. 
Published: March 2003

Aims  To investigate the effects of age and disease states on the expression and activity of intestinal CYP3A4 in a paediatric population.Methods  Duodenal biopsies and surgical sections were collected from 104 paediatric patients (age range 2 weeks to 17 years) and from 11 foetuses. An S9 fraction was prepared in each case. CYP3A4 expression was assessed by Western blotting and by immunohistochemistry; activity was measured by the rate of formation of 6β‐hydroxytestosterone from testosterone. Villin expression was used as a marker of enterocyte harvest to normalize CYP3A4 expression and activity data.Results  In the 74 histologically normal paediatric biopsies there were statistically significant increases in CYP3A4 expression (r2 = 0.19, P = 0.001) and activity (r2 = 0.17, P = 0.02) with age. CYP3A4 was practically absent in fetal duodenum and was expressed at relatively low levels in neonates (P < 0.05 between neonates and children > 5 years). Active coeliac disease resulted in significant (P < 0.001) decreases in CYP3A4 expression and activity.Conclusions  Duodenal CYP3A4 is present at significantly lower levels in neonates and in patients with active coeliac disease. This may have clinical significance with respect to the oral bioavailability of CYP3A4 substrates.
Influence of cirrhosis on lamotrigine pharmacokinetics
Authors: Marcellin P. , De Bony F. , Garret C. , Altman C. , Boige V. , Castelnau C. , Laurent‐Puig P. , Trinchet J. C. , Rolan P. , Chen C. , Mamet J. P. , Bidault R. 
Published: March 2003

Aims  Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated.Methods  Thirty‐six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period.Results  The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child‐Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child‐Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half‐life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%).Conclusions  Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child‐Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.
Pharmacokinetic/pharmacodynamic model for prednisolone inhibition of whole blood lymphocyte proliferation
Authors: Magee Mindy He , Blum Robert A. , Lates Christian D. , Jusko William J. 
Published: March 2003

Aims Mitogen‐inducedex vivowhole blood lymphocyte proliferation (WBLP) is a widely used method to assess lymphocyte responsiveness to immunosuppressive therapy. A three‐component complex model was developed to characterize effects of prednisolone on cell trafficking, transduction, and lymphocyte suppression.Methods An oral dose (0.27 mg kg−1) of prednisone was given to 32 subjects. The study consisted of baseline and prednisone phases each with 32 h of sampling. Measurements included plasma prednisolone concentrations,in vitroandex vivoWBLP, and lymphocyte cell counts during baseline and prednisone phases.Results The final model consists of a precursor‐dependent indirect response model with a first‐order periodic influx rate for lymphocyte trafficking. This accounts for the rebound phenomenon and the circadian rhythm seen in all individualex vivoWBLP effect‐time profiles. Prednisolone was modelled as inhibiting lymphocyte influx from the precursor to the blood pools. The direct suppressive effect of prednisolone on WBLP was modelled with the simple Imax model. A transduction step with rate constantktwas introduced to the simple Imax model to account for the delay (∼4 h) in reaching the maximum inhibition. The IC50values obtainedex vivowerecirca10 times lower thanin vitrovalues (3.76vs38.8 ng ml−1), suggesting additionalin vivofactors may have enhanced lymphocyte response to the inhibitory effect of prednisolone.Conclusions This integrated PK/PD model enables evaluation of multicomponent direct and indirect inhibition ofex vivoWBLP by steroids and other immunosuppressants in relation to sex and race.
Effect of the catechol‐O‐methyltransferase inhibitor entacapone on the steady‐state pharmacokinetics and pharmacodynamics of warfarin
Authors: Dingemanse Jasper , Meyerhoff Carsten , Schadrack Jan 
Published: March 2003

Aims  To investigate the influence of a multiple‐dose regimen with the catechol‐O‐methyltransferase inhibitor entacapone on the pharmacokinetics and pharmacodynamics of warfarin.Methods  In a randomized, double‐blind, two‐way cross‐over study, 12 healthy subjects (gender ratio 1 : 1) received treatment for 1 week with either entacapone 200 mg four times daily or placebo during individually optimized treatment with warfarin (INR 1.4–1.8). The effect of entacapone on the steady‐state pharmacokinetics of both R‐ and S‐warfarin was determined and, in addition, INR values were measured. The key pharmacokinetic variables were AUCss, Cmax and tmax.Results  Entacapone increased the exposure to R‐warfarin by 18% (90% CI: 111, 126%), and caused a 13% (6, 19%) increase in INR values. No effect was seen on the pharmacokinetics of the pharmacologically more potent S‐enantiomer. Safety and tolerability variables did not show any difference between the treatment phases.Conclusions  In healthy subjects, entacapone displays a slight pharmacokinetic interaction with R‐warfarin but, based on the lack of a clinically relevant pharmacodynamic interaction, it appears that it can also be used safely in Parkinson's disease patients who are receiving warfarin.
Prior iontophoresis of saline enhances vasoconstriction to phenylephrine and clonidine in the skin of the human forearm
Authors: Drummond Peter D. 
Published: March 2003

Aims  To determine whether postjunctional α1‐ and α2‐adrenoceptors mediate vasoconstrictor responses in the cutaneous vasculature of the human forearm.Methods  Drugs were administered transdermally by iontophoresis in the forearm of 20 healthy participants. Phenylephrine and clonidine were administered at sites pretreated with the relevant antagonist (terazosin and rauwolscine), and at additional untreated sites and sites pretreated with saline. To enhance the contrast between sites, the forearm was heated to 42° C before flow was measured with the laser Doppler technique.Results  After the iontophoresis of phenylephrine, blood flow at the site pretreated with terazosin was 24±37% (±95% confidence interval) greater than flow at the reference site, whereas flow was 53±24% lower than reference flow at the previously untreated site and 77±10% lower than reference flow at the site pretreated with saline (P<0.001). After the iontophoresis of clonidine, blood flow at the site pretreated with rauwolscine was 25±21% greater than flow at the reference site, whereas flow was 56±15% lower than reference flow at the previously untreated site and 72±8% lower than reference flow at the site pretreated with saline (P<0.001). The saline pretreatment enhanced vasoconstriction to phenylephrine (P<0.05) and clonidine (P=0.05).Conclusions  Pre‐treatment with the appropriate antagonist blocked vasoconstrictor responses to phenylephrine and clonidine, consistent with the presence of both α‐adrenoceptor subtypes in cutaneous vessels of the human forearm. In addition, iontophoretic pretreatment with saline facilitated vasoconstrictor responses, suggesting that a nonspecific effect of iontophoresis may enhance drug penetration through the stratum corneum.
Single‐ and multiple‐dose pharmacokinetics of bosentan and its interaction with ketoconazole
Authors: van Giersbergen Paul L. M. , Halabi Atef , Dingemanse Jasper 
Published: March 2003

Aims  The present study was conducted to characterize the single‐ and multiple‐dose pharmacokinetics of bosentan, a dual endothelin receptor antagonist, and to investigate a possible pharmacokinetic interaction with ketoconazole.Methods  In a randomized, two‐way crossover study, 10 healthy male subjects received treatments A and B. Treatment A consisted of a single dose of 62.5 mg bosentan on day 1 followed by 62.5 mg twice daily for 5.5 days. Treatment B consisted of bosentan (62.5 mg twice daily) for 5.5 days plus concomitant ketoconazole (200 mg once daily) for 6 days. Plasma concentrations of bosentan and its three metabolites were measured on days 1 and 7 of treatment A and on day 6 of treatment B.Results  Bosentan was absorbed and eliminated with a tmax of 4.5 h (range 3.5–6.0 h) and a t½ of 5.4 h (95% CI; 4.5, 6.6). Upon multiple dosing, the exposure to bosentan was reduced by 33% without change in tmax and t½. Concomitant administration of ketoconazole increased the Cmax and AUC of bosentan 2.1‐ (95% CI; 1.5, 2.7) and 2.3‐fold (95% CI; 1.8, 2.9), respectively. Exposure to the metabolites was low and represented less than 25% of that to bosentan both after single and multiple doses. In the presence of ketoconazole, formation of the metabolites was inhibited.Discussion  The multiple‐dose pharmacokinetics of bosentan are consistent with the phenomenon of auto‐induction. In the presence of CYP3A4 inhibitors, bosentan concentrations may be increased 2‐fold.
Pharmacokinetics and pharmacodynamics of low‐dose methotrexate in the treatment of psoriasis
Authors: Chládek Jaroslav , Grim Jiøı´ , Martínková Jiøina , Šimková Marie , Vanı`èková Jaroslava , Koudelková Vı`ra , Noièková Marie 
Published: March 2003

Aims  The aim of this 13 week, randomized, parallel‐group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low‐dose intermittent oral methotrexate (LDMTX) in patients with psoriasis.Methods  Twenty‐four psoriatic patients (15 male and 9 female, aged 31–73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASI‐scoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times.Results  The comparison of the areas under the plasma concentration‐time curve (AUCMTX) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two‐way anova (factors: subject and the week of therapy) on the log‐transformed AUCMTX showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUCMTX was at least 4‐fold less than the interindividual variability (F‐test; P<0.01). The steady‐state total plasma clearance of MTX ranged from 5.0 to 18.2 l h−1 and was proportional to the renal clearance (r2=0.45, P<0.001) which accounted for 65±20% of the former. The renal clearance of 7‐OHMTX was approximately 4–8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady‐state AUCMTX (rs=−0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)≥700 nmol l−1 h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l−1 h were responders (P<0.01, Fisher's exact test).Conclusions  A strong correlation was observed between the pharmacokinetics (AUCMTX at the steady state) and antipsoriatic effect (PASI‐score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUCMTX values of 700 nmol l−1h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.
Interaction between saquinavir soft‐gel and rifabutin in patients infected with HIV
Authors: Moyle G. J. , Buss N. E. , Goggin T. , Snell P. , Higgs C. , Hawkins D. A. 
Published: March 2003

Aims  To evaluate the potential pharmacokinetic interaction between the HIV protease inhibitor saquinavir and rifabutin.Methods  Fourteen HIV‐infected patients provided full steady‐state pharmacokinetic profiles following administration of rifabutin alone (300 mg once daily) or saquinavir soft‐gel formulation (1200 mg three times daily) plus rifabutin (300 mg once daily) in this open label, partially randomized study.Results  Coadministration of saquinavir and rifabutin resulted in a reduction in saquinavir AUC(0,8 h) and Cmax(0,8 h) of 47% (95% CI 30, 60%) and 39% (95% CI 11, 59%), respectively. Rifabutin AUC(0,24 h) and Cmax(0,24 h) was increased by an average of 44% (95% CI 17, 78%) and 45% (95% CI 14, 85%), respectively. Saquinavir in combination with rifabutin was well tolerated. Gastrointestinal intolerance and asymptomatic increases in liver enzymes were the only adverse events of note.Conclusions  Administration of rifabutin with saquinavir may decrease the efficacy of this HIV protease inhibitor.
Enantioselective distribution of albendazole metabolites in cerebrospinal fluid of patients with neurocysticercosis
Authors: Takayanagui O. M. , Bonato P. S. , Dreossi S. A. C. , Lanchote V. L. 
Published: March 2003

Aims Albendazole (ABZ) is effective in the treatment of neurocysticercosis. ABZ undergoes extensive metabolism to (+) and (−)‐albendazole sulphoxide (ASOX), which are further metabolized to albendazole sulphone (ASON). We have investigated the distribution of (+)‐ASOX (−)‐ASOX, and ASON in cerebrospinal fluid (CSF) of patients with neurocysticercosis.Methods Twelve patients with a diagnosis of active brain parenchymal neurocysticercosis treated with albendazole for 8 days (15 mg kg−1 day−1) were investigated. On day 8, serial blood samples were collected during the dose interval (0–12 h) and one CSF sample was taken from each patient by lumbar puncture at different time points up to 12 h after the last albendazole dose. Albendazole metabolites were determined in CSF and plasma samples by h.p.l.c. using a Chiralpak AD column and fluorescence detection. Population curves for CSF albendazole metabolite concentrationvstime were constructed.Results The mean plasma/CSF ratios were 2.6 (95% CI: 1.9, 3.3) for (+)‐ASOX and 2.7 (95% CI: 1.8, 3.7) for (−)‐ASOX, with the two‐tailedP value of 0.9873 being non‐significant. These data indicate that the transport of ASOX through the blood–brain barrier is not enantioselective, but rather depends on passive diffusion. The present results suggest the accumulation of the (+)‐ASOX metabolite in the CSF of patients with neurocysticercosis. The CSF AUC(+)/AUC(−)ratio was 3.4 for patients receiving albendazole every 12 h. The elimination half‐life of both ASOX enantiomers in CSF was 2.5 h. ASOX was the predominant metabolite in the CSF compared with ASON; the CSF AUCASOX/AUCASONratio was approximately 20 and the elimination half‐life of ASON in CSF was 2.6 h.Conclusions We have demonstrated accumulation of the (+)‐ASOX metabolite in CSF, which was about three times greater than the (−) antipode. ASOX concentrations were approximately 20 times higher than those observed for the ASON metabolite.
Use of nonsteroidal anti‐inflammatory drugs and the risk of first‐time acute myocardial infarction
Authors: Schlienger Raymond G. , Jick Hershel , Meier Christoph R. 
Published: March 2003

Aims
Aspirin decreases the risk of clinical manifestations of atherothrombosis. This effect is mainly due to inhibition of platelet aggregation and potentially due to anti‐inflammatory properties of aspirin. To evaluate whether use of non‐aspirin non‐steroidal anti‐inflammatory drugs (NSAIDs) may also be associated with a decreased risk of first‐time acute myocardial infarction (AMI), we performed a population‐based case‐control analysis using the United Kingdom‐based General Practice Research Database (GPRD)
Methods
We identified first‐time AMI‐patients free of preexisting diagnosed cardiovascular or metabolic diseases. We compared use of NSAIDs prior to the index date between cases and control patients who were matched to cases on age, gender, practice and calendar time.
Results
A total of 3319 cases (≤75 years) with a diagnosis of first‐time AMI between 1992 and 1997 and 13139 controls (matched to cases on age, sex, general practice attended, calendar time, years of prior history in the GPRD) were included. Overall, the relative risk estimate of AMI (adjusted for smoking, body mass index, hormone replacement therapy and aspirin) in current NSAID users was 1.17 (95% CI 0.99, 1.37). Long‐term current NSAID use (≥30 prescriptions) yielded an adjusted odds ratio (OR) of 1.20 (95% CI 0.94, 1.55). Stratification by age (<65 years vs≥65 years) and sex did not materially change the results.
Conclusions
Our findings indicate that current NSAID exposure in patients free of diagnosed cardiovascular or metabolic conditions predisposing to cardiovascular diseases does not decrease the risk of AMI.
Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects
Authors: Omori Hisako , Nagashima Hirotaka , Tsurumi Yukio , Takagi Atsushi , Ishizuka Naoko , Hagiwara Nobuhisa , Kawana Masatoshi , Kasanuki Hiroshi 
Published: March 2003

Aims
HMG‐CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol‐lowering effect.
Methods
We investigated the effect of a single dose of cerivastatin on vascular endothelial function by measuring flow‐mediated dilatation of the brachial artery on ultrasound in 30 healthy volunteers with normal serum cholesterol concentrations. They were randomized to either placebo group (n = 15) or cerivastatin group (n = 15), and flow‐mediated dilatation and endothelium‐dependent dilatation were evaluated at before and 1 h, 3 h, 6 h, and 12 h after administration of placebo or cerivastatin.
Results
There were no differences in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, malondialdehyde‐LDL, and high‐sensitivity C‐reactive protein before and after administration of placebo or cerivastatin. Cerivastatin significantly increased flow‐mediated dilatation at 3 h (P < 0.001), and this increase rapidly returned to the baseline level 6 h after administration. Endothelium‐­independent dilatation of brachial artery was not altered.
Conclusions
A single dose of cerivastatin increased vascular endothelial responsiveness. Our data suggest that cerivastatin has a direct effect on the blood vessels that is independent of its lipid‐lowering effect, and thus can be considered as a vascular statin.
Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2
Authors: Han Xing‐Mei , Ouyang Dong‐Sheng , Chen Xiao‐Ping , Shu Yan , Jiang Chang‐Hong , Tan Zhi‐Rong , Zhou Hong‐Hao 
Published: March 2003

Aims  To evaluate the effect of the CYP1A2*1C and CYP1A2*1F polymorphisms on the inducibility of CYP1A2 by omeprazole in healthy subjects.Methods  Mutations of CYP2C19 and CYP1A2 were identified by PCR‐RFLP. Omeprazole, 120 mg day−1, was given to 12 extensive metabolizers (EM) with respect to CYP2C19 (six CYP1A2*1F/CYP1A2*1F and six CYP1A2*1C/CYP1A2*1F of CYP1A2) for 7 days. CYP1A2 activity was determined on three occasions, namely on day 1, day 9 and day 16 using the caffeine plasma index (the ratio of the concentrations of paraxanthine to caffeine), 6 h after oral administration of 200 mg caffeine.Results  There was a significant difference (P = 0.002) between the caffeine ratios for CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes on day 9, but not on day 1 or day 16 (P > 0.05). The changes in the ratios from day 9 to day 1 (48% ± 20%vs 19% ± 20%) and from day 9 to day 16 (50% ± 31%vs 15% ± 22%) were significantly different (P < 0.05) between the CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes.Conclusion  The CYP1A2*1C and CYP1A2*1F genetic polymorphisms influenced the induction of CYP1A2 activity in vivo by omeprazole.