bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and pharmacodynamic effects of ABT‐627, an oral ETA selective endothelin antagonist, in humans
Authors: Verhaar Marianne C. , Grahn Amy Y. , Van Weerdt Anton W. M. , Honing Marina L. H. , Morrison Paul J. , Yang Yonghong P. , Padley Robert J. , Rabelink Ton J. 
Published: March 2003

Aims  Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT‐627 in healthy humans.Methods  Healthy volunteers were included in two studies with cross‐over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT‐627 or matched placebo, in a dose range of 0.2–40 mg. The pharmacokinetics of ABT‐627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET‐1 were assessed.Results  ABT‐627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62%vs 4% during placebo, P < 0.05, for Study 1 and in 42%vs 60%, P = 0.2, for Study 2). ABT‐627 was rapidly absorbed, reaching maximum plasma levels at ≈ 1 h post dose. Single dose ABT‐627, at a dose of 20 and 40 mg, inhibited ET‐1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT‐627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET‐1. ABT‐627 caused a significant reduction in peripheral resistance as compared with placebo (16 ± 1 vs 19 ± 1, 18 ± 2 vs 23 ± 3, 15 ± 1 vs 17 ± 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 ± 2 vs 84 ± 3, 80 ± 4 vs 90 ± 5, 75 ± 3 vs 79 ± 1 at 1, 5, 20 mg in Study 2). ABT‐627 caused a moderate dose‐dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level).Conclusions  The oral ETA receptor blocker ABT‐627 is well tolerated, rapidly absorbed, effectively blocks ET‐1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT‐627 may be a valuable tool in treatment of cardiovascular disease.
In vitroinhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6
Authors: Ko, Jae Wook , Desta, Zeruesenay , Soukhova, Nadia V , Tracy Timothy , Flockhart David A 
Published: March 2003

Aims To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s)in vitrousing human liver microsomes (HLMs) and recombinant human CYP450s.Methods Isoform‐specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (Kivalues) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin.Results TCL was a potent, competitive inhibitor of CYP2C19 (Ki = 1.2 ± 0.5 µm) and of CYP2D6 (Ki = 3.4 ± 0.3 µm). TheseKivalues fell within the therapeutic steady‐state plasma concentrations of TCL (1–3 µm). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 ± 19 µm) and a weak inhibitor of CYP2C9 (Ki > 75 µm), but its effect on the activities of CYP2E1 (Ki = 584 ± 48 µm) and CYP3A (> 1000 µm) was marginal.Conclusions TCL appears to be a broad‐spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.
Diurnal variation in the quantitative EEG in healthy adult volunteers
Authors: Cummings L. , Dane A. , Rhodes J. , Lynch P. , Hughes A. M. 
Published: March 2003

Aims
To define the change in power in standard waveband frequencies of quantitative cortical electroencephalogram (EEG) data over a 24 h period, in a drug free representative healthy volunteer population.
Methods
This was an open, non randomised study in which 18 volunteers (9 male and 9 female) were studied on 1 study day, over a 24 h period. Volunteers had a cortical EEG recording taken at 0, 2, 4, 6, 8, 10, 12, 16 and 24 h. Each recording lasted for 6 min (3 min eyes open, 3 min eyes closed). All EEG recordings were taken in a quietened ward environment with the curtains drawn round the bed and the volunteer supine. During the 3 min eyes open, volunteers were asked to look at a red circle on a screen at the foot of the bed, and refrain from talking.
Results
Plots produced of geometric mean power by time of the standard wave band frequencies gave some indication of a circadian rhythm over the 24 h period for θ (4.75–6.75 Hz), α1 (7.0–9.5 Hz) and β1 (12.75–18.50 Hz) wavebands. Mixed models were fitted to both the eyes open and eyes closed data which confirmed a change in mean waveband power with time with statistical significance at the conventional 5% level (P < 0.05).
Conclusions
These data indicate the presence of a diurnal variation in the cortical quantitative EEG. They support the use of a placebo control group when designing clinical trials which utilize quantitative EEG to screen for central nervous system (CNS) activity of pharmaceutical agents, to control for the confounding variable of time of day at which the EEG recordings were made.
Effects of potassium channel opener KRN4884 on human conduit arteries used as coronary bypass grafts
Authors: Ren Zhen , Floten Storm , Furnary Anthony , Liu Minghui , Gately Hugh , Swanson Jeffrey , Ahmad Aftab , Yim Anthony P. C. , He Guo‐Wei 
Published: March 2003

Aims
The effects of a new potassium channel opener KRN4884 on human arteries have not been studied. This study was designed to investigate the effects of KRN4884 on the human internal mammary artery (IMA) in order to provide information on possible clinical applications of KRN4884 for preventing and relieving vasospasm of arterial grafts in coronary artery bypass grafting.
Methods
IMA segments (n = 140) taken from patients undergoing coronary surgery were studied in the organ chamber. Concentration‐relaxation curves for KRN4884 were established in the IMA precontracted with noradrenaline (NA), 5‐hydroxytryptamine (5‐HT), angiotensin II (ANG II), and endothelin‐1 (ET‐1). The effect of glibenclamide (GBC) on the KRN4884‐induced relaxation was also examined in NA or 5‐HT‐precontracted IMA. Concentration‐contraction curves for the four vasoconstrictors were constructed without/with pretreatment of KNR4884 (1 or 30 µm) for 15 min.
Results
KRN4884 induced less relaxation (P < 0.05) in the precontraction induced by ET‐1 (72.9 ± 5.5%) than by ANG II (94.2 ± 3.2%) or NA (93.7 ± 4.1%) with lower EC50 (P < 0.05) for ANG II (−8.54 ± 0.54 log m) than that for NA (−6.14 ± 0.15 log M) or ET‐1 (−6.69 ± 0.34 log m). The relaxation in the IMA pretreated with GBC was less than that in control (P < 0.05). KRN4884‐pretreatment significantly reduced the contraction (P < 0.05) induced by NA (151.3 ± 18.4% vs 82.7 ± 8.7%), 5‐HT (82.7 ± 12.2% vs 30.1 ± 7.3%), and ANG II (24.3 ± 6.3% vs 5.4 ± 1.6%), but did not significantly reduce the contraction induced by ET‐1 (P > 0.05).
Conclusion
KRN4884 has marked vasorelaxant effects on the human IMA contracted by a variety of vasoconstrictors and the effect is vasoconstrictor‐selective.
Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine
Authors: Kosoglou T. , Salfi M. , Lim J. M. , Batra V. K. , Cayen M. N. , Affrime M. B. 
Published: March 2003

Aims  To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers.Methods  Two randomized, evaluator‐blind, multiple‐dose, three‐way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. Results Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205‐428%) and DCL concentrations (73%; 62‐85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70‐142%) but not DCL concentrations (6% increase; 1‐11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (‐2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (‐1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events.Conclusions  Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.
Effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension
Authors: Minami Junichi , Kawano Yuhei , Makino Yuriko , Matsuoka Hiroaki , Takishita Shuichi 
Published: March 2003

Aims  The aim of the present study was to evaluate the effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension.Methods  Ten inpatients with mild to moderate essential hypertension (four men and six women; age: 44–64 years) underwent a drug‐free period for 7 days and a treatment period with cilnidipine 10 mg orally for another 7 days, in a randomized crossover study. On the sixth day of each period, they underwent autonomic function tests including a mental arithmetic test, a cold pressor test and a Valsalva manoeuvre. After these tests, 24 h ambulatory blood pressure, heart rate, and the electrocardiogram R‐R intervals were monitored every 30 min. A power spectral analysis of R‐R intervals was performed to obtain the low‐and high‐frequency components.Results  Cilnidipine significantly decreased the 24 h blood pressure by 6.5 ± 1.7 mm Hg systolic (mean ± s.e.mean; P < 0.01) and 5.0 ± 1.1 mmHg diastolic (P < 0.01), whereas cilnidipine did not change heart rate or any indices of power spectral components. During the cold pressor test, the maximum change in systolic blood pressure and percentage changes in both systolic and diastolic blood pressures were significantly lower during the treatment period with cilnidipine than during the drug‐free period. The baroreflex sensitivity measured from the overshoot phase of the Valsalva manoeuvre did not differ significantly between the two periods.Conclusions  Cilnidipine is effective as a once‐daily antihypertensive agent and causes little influence on heart rate and the autonomic nervous system in patients with mild to moderate essential hypertension. Moreover, it is suggested that cilnidipine has an additional clinical benefit in the inhibition of the pressor response induced by acute cold stress.
The intracellular activation of lamivudine (3TC) and determination of 2′‐deoxycytidine‐5′‐triphosphate (dCTP) pools in the presence and absence of various drugs in HepG2 cells
Authors: Kewn, Stephen , Hoggard, Patrick G. ,   Sean, Sales, D. ,   Mark, Johnson A. , Back David J. 
Published: March 2003

Aims
Lamivudine (3TC, 2′‐deoxy‐3′‐thiacytidine) requires intracellular metabolism to its active 5′‐triphosphate, 3TC‐5′‐triphosphate (3TCTP), to inhibit the replication of hepatitis B virus (HBV). We have investigated the activation of 3TC, in the presence and absence of a range of compounds, in HepG2 cells. The intracellular levels of the endogenous competitor of 3TCTP, 2′‐deoxycytidine‐5′‐triphosphate (dCTP), were also determined and 3TCTP/dCTP ratios calculated.
Methods
The effects of a number of compounds on 3TC (3H; 1 µm) phosphorylation were investigated by radiometric h.p.l.c. dCTP levels were determined using a template primer extension assay. 3TCTP/dCTP ratios were calculated from these results.
Results
The phosphorylation of 3TC was significantly increased in the presence of either hydroxyurea (HU), methotrexate (MTX), or fludarabine (FLU). For example, at 100 µm HU, control 3TCTP levels were increased to 361% of control, whereas at 100 µm FLU, control 3TCTP levels were increased to 155%. dCTP pools were significantly reduced in the presence of HU and FLU, at 100 µm concentrations only. However, for all the above three compounds investigated, the ratio of 3TCTP/dCTP was favourably enhanced (e.g. at 1 µm MTX, 255% of control). Neither ganciclovir (GCV), lobucavir (LCV), penciclovir (PCV), adefovir dipivoxil (ADV), nor foscarnet (FOS) had any significant effects on 3TC phosphorylation or dCTP pools.
Conclusions
These results suggest that the activity of 3TC may be potentiated when combined with one of the modulators studied. The lack of an interaction between 3TC and the other anti‐HBV agents is reassuring. These in vitro studies can be used as an initial screen to examine potential interactions at the phosphorylation level.
Pharmacokinetics and pharmacodynamics of sibrafiban alone or in combination with ticlopidine and aspirin
Authors: Wittke, Bärbel , Ensor, Hilary , Chung, Jain , Birnböck, Herbert , Lausecker, Berthold , Ertel, Sylvie I. , Mackie Ian J. , Machin Samuel J. 
Published: March 2003

Aims
The purpose of this clinical study was to evaluate the effects of a ticlopidine/aspirin combination on the pharmacokinetics and pharmacodynamics of sibrafiban and the tolerability of the combination therapy
Methods
Thirty‐eight healthy male volunteers were randomized to receive one of the following treatments for 7 days: sibrafiban (n = 12), ticlopidine/aspirin (n = 12), or the combination treatment sibrafiban/ticlopidine/aspirin (n = 14). Concentrations of the active metabolite of sibrafiban, Ro 44–3888, in plasma and urine were determined by column‐switching liquid chromatography combined with tandem mass spectrometry. The pharmacodynamics of sibrafiban and ticlopidine/aspirin were examined by measuring the inhibition of ADP‐ or collagen‐induced platelet aggregation.
Results
The addition of ticlopidine/aspirin to sibrafiban did not significantly alter the pharmacokinetic parameters of Ro 44–3888. the geometric mean ratio for AUC(0,12h) was 110 (95% CI 0.82, 1.22). Separately, sibrafiban and ticlopidine/aspirin inhibited ADP‐and collagen‐induced platelet aggregation and the effects of the two treatments were additive. For example, the average inhibition of ADP‐induced platelet aggregation over 12 h was 42% in the sibrafiban treated group, 55% in the ticlopidine/aspirin group and 69% in the sibrafiban/ticlopidine group. The bleeding time was prolonged in the treatments with ticlopidine/aspirin (8.1 min) and sibrafiban/ticlopidine/aspirin (8.6 min) compared with sibrafiban alone (3.5 min).
Conclusions
This study shows a significant pharmacodynamic interaction between sibrafiban and ticlopidine/aspirin. Consequently, the simultaneous administration of sibrafiban and ticlopidine/aspirin should be carefully monitored to ensure the patient’s coverage with an antiplatelet drug without exposure to an excessive bleeding risk.
Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol
Authors: Shin Jae‐Gook , Kane Khadidjatou , Flockhart David A. 
Published: March 2003

Aims   We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol.Methods   The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data.Results  Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O‐demethylation with estimated Ki values (0.24 µm and 0.09 µm, respectively) that were substantially lower than that of haloperidol (0.89 µm). The inhibitory effect of S(–)‐reduced haloperidol was more potent than the R(+)‐enantiomer, with estimated Ki values of 0.11 µm and 1.1 µm, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 µm. The N‐dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 µm.Conclusions  The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(–) enantiomer being more potent.
Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation
Authors: Cremers Serge , Schoemaker Rik , Bredius Robbert , Den Hartigh Jan , Ball Lynne , Twiss Irene , Vermeij Pieter , Vossen Jaak 
Published: March 2003

Aims  Intravenous formulations of busulfan have recently become available. Although busulfan is used frequently in children as part of a myeloablative regimen prior to bone marrow transplantation, pharmacokinetic data on intravenous busulfan in children are scarce. The aim was to investigate intravenous busulfan pharmacokinetics in children and to suggest a limited sampling strategy in order to determine busulfan systemic exposure with the minimum of inconvenience and risk for the patient.Methods  Plasma pharmacokinetics after the first administration was investigated in six children using nonlinear mixed effect modelling.Results  Pharmacokinetics showed little variability and were described adequately with a one‐compartment model (population estimates CL,av=0.29 l h−1 kg−1; V,av=0.84 l kg−1; t1/2=1.7–2.8 h). Combined with limited sampling and a Bayesian fitting procedure, the model can adequately estimate the systemic exposure to intravenous busulfan, which in children appears to be at the lower end of the adult range.Conclusions  Busulfan systemic exposure in children during intravenous administration can be estimated adequately with limited sampling and a Bayesian fitting procedure from a one‐compartment model. Intravenous busulfan pharmacokinetics in children should be the subject of more research.
Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population
Authors: Hamdy Samar Ismail , Hiratsuka Masahiro , Narahara Kaori , El‐Enany Mervat , Moursi Nadia , Ahmed Mohammed Salah‐Eldin , Mizugaki Michinao 
Published: March 2003

Aims  The goal of this study was to determine the frequencies of important allelic variants of CYP2C9, CYP2C19, CYP2E1 and DPYD in the Egyptian population and compare them with the frequencies in other ethnic populations.Methods  Genotyping of CYP2C9 (*2 and *3), CYP2C19 (*2 and *3), c2 variant of CYP2E1 and DPYD alleles (*2 A‐*6 ) was carried out in a total of 247 unrelated Egyptian subjects. An allele‐specific fluorogenic 5′ nuclease chain reaction assay was applied for detection of CYP2C9 and CYP2C19 variants. Other variants of the CYP2E1 and DPYD genes were determined using polymerase chain reaction (PCR)‐restriction fragment length polymorphism and allele‐specific PCR based assays.Results  CYP2C9 allele frequencies in 247 Egyptian subjects were 0.820 for CYP2C9*1, 0.120 for CYP2C9*2 and 0.060 for CYP2C9*3. For CYP2C19, the frequencies of the wild type (CYP2C19*1) and the nonfunctional (*2 and *3) alleles were 0.888, 0.110 and 0.002, respectively. CYP2C19*3, which is considered an Asian mutation, was detected in one subject (0.40%) who was heterozygous (*1/*3). Two subjects (0.80%) were homozygous for *2/*2, while no compound heterozygotes (*2/*3) or homozygotes for *3 were detected. For CYP2E1, only four subjects (1.70%) had the rare c2 variant, expressed heterozygously, giving an allele frequency of 0.009. Five variants of DPYD were analysed, with no splice sites (*2 A) or ΔC1897 (*3) found in this population. The frequencies of other variants were 0.028, 0.115 and 0.090 for *4, *5 and *6, respectively.Conclusions  Comparing our data with that obtained in several Caucasian, African‐American and Asian populations, we found that Egyptians resemble Caucasians with regard to allelic frequencies of the tested variants of CYP2C9, CYP2C19, CYP2E1 and DPYD. Our results may help in better understanding the molecular basis underlying ethnic differences in drug response, and contribute to improved individualization of drug therapy in the Egyptian population.
A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice
Authors: Cutts Christopher , LaCaze Adam , Tett Susan 
Published: March 2003

Aims  The new cyclooxygenase‐2 (COX‐2) selective inhibitors, celecoxib (Celebrex®) and rofecoxib (Vioxx®), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self‐audit of the clinical use of selective COX‐2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia.Methods  A structured audit form was developed and distributed to interested GPs. The form was self‐administered and focused on issues about COX‐2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions.Results  A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti‐inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment.Conclusions  These results show that COX‐2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX‐2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self‐reporting.