Abstract:
OBJECTIVE:To assess the pharmacokinetics, safety and tolerability of escalating oral doses of GW420867X, a non-nucleoside reverse transcriptase inhibitor, was investigated in healthy male volunteers in a randomized, double-blind placebo-controlled study. METHODS:Study subjects were divided into four groups of 12 subjects (10, 50, 100 and 200-mg dose groups) with eight subjects from each group receiving active treatment and the remaining four matched placebo. Subjects were initially administered a single dose of GW420867X or placebo, and following a 24- to 28-day washout period, re-exposed to the same treatment for 14 consecutive days. Safety measurements including clinical laboratory evaluations, ECG and vital signs were performed before, during and after dosing. RESULTS:Geometric mean GW420867X peak plasma concentrations (Cmax) following single oral doses of 10, 50, 100 and 200 mg were 160, 608, 1,000 and 1,662 ng/ml, respectively. Time to Cmax (tmax) increased from a median value of 1 h following the 10-mg dose, to 3 h after the 200-mg dose. Geometric mean plasma areas under the curves (AUC) were 4,325 (10 mg), 17,862 (50 mg), 35,295 (100 mg) and 62,338 ng/ml per hour (200 mg) and were proportionally less than the increase in the administered dose. Apparent terminal elimination half-life (t1/2) was approximately 50 h. Following repeat dosing, accumulation ratios based on plasma AUC were: 3.0+/-1.0 (10mg), 2.6+/-0.9 (50mg), 1.8+/-0.3 (100 mg) and 1.9+/-0.8 (200 mg) after 14 days of dosing compared to the corresponding single dose. In general, oral clearance (CL/F) was greater after 14 days and greater with higher doses except for the 10-mg dose group. Steady-state CL/F was 2.2, 3.4, 4.2, and 5.1 l/h for 10, 50, 100, and 200 mg, respectively. Steady-state was generally achieved within 7-10 days. Comparison of single and repeat dosing with GW420867X showed that Cmax increased by a factor of between 1.4 to 1.8, after 14 days of daily dosing to 288 (10 mg), 1,006 (50 mg), 1,401 (100 mg) and 2,613 (200 mg) ng/ml. These increases were proportionally less than the increase in the administered dose. GW420867X was well tolerated by subjects both after single and repeated dosing. Adverse effects reported by subjects on the active drug were similar to those receiving placebo. All episodes were rated as mild to moderate in severity and resolved spontaneously without further intervention. CONCLUSION:The pharmacokinetic findings of this study imply that systemic exposure to GW420867X decreases with increasing dose and displays time-variant pharmacokinetics, which suggests decreased absorption and/or increased clearance of GW420867X. The relatively long plasma half-life, of approximately 50 h, makes it suitable for once-daily dosing.
journal_name
Eur J Clin Pharmacoljournal_title
European journal of clinical pharmacologyauthors
Moore KH,Cass LM,Dallow N,Hardman TC,Jones A,Boyce M,Prince WTdoi
10.1007/s002280000224subject
Has Abstractpub_date
2001-01-01 00:00:00pages
805-11issue
11eissn
0031-6970issn
1432-1041journal_volume
56pub_type
临床试验,杂志文章,随机对照试验abstract::Verapamil, 0.1 mg/kg body wt, was injected i.v. over 2 minutes in 8 subjectively healthy middle-aged men, followed by a continuous infusion of 0.007 mg/kg body wt per minute. Prior to the injection several of the subjects had raised pulmonary or systemic arterial pressures. At rest, the central pressures increased sli...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00562656
更新日期:1975-06-13 00:00:00
abstract::Cyclofenil was given as a single oral dose of 200 mg, and also as 200 mg/day for eight days, to seven healthy female volunteers. Plasma was analyzed for the active metabolite and pharmacokinetic modelling was performed. A biological half life of 29 h was bound after the single dose and 18 h after the eighth day of con...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00561952
更新日期:1981-02-01 00:00:00
abstract::The pharmacokinetics of temocapril hydrochloride, a novel prodrug-type angiotensin-I converting enzyme (ACE) inhibitor, has been studied in patients with mild (Group II) to severe (Group III) renal insufficiency in comparison with subjects with normal renal function (Group I). The pharmacokinetic parameters of the act...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF02284968
更新日期:1992-01-01 00:00:00
abstract:OBJECTIVE:Use of analgesic drugs in acute renal colic varies widely in different countries. In order to assess the prescribing patterns in acute renal colic in French emergency departments (EDs), the present study compared intentions of prescription, real prescription and evidence-based data in a sample of emergency pr...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s002280100366
更新日期:2001-11-01 00:00:00
abstract:OBJECTIVES:To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE). METHODS:A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM)...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-009-0760-2
更新日期:2010-03-01 00:00:00
abstract::The interaction between the main components of the new glycopeptide antibiotic teicoplanin, A2-2, A2-3, A2-4, A2-5 and A3-1, and human serum albumin has been studied in vitro by equilibrium dialysis (pH 7.4, 37 degrees C). From Scatchard analysis of the data, the calculated association constants (Ka) were: A2-2, 2.47 ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00544566
更新日期:1987-01-01 00:00:00
abstract::The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of h...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00198307
更新日期:1995-01-01 00:00:00
abstract:PURPOSE:Few data on the efficacy and safety of drugs in children are available as in the past, these children were not included in randomized controlled trials (RCTs). Data on the efficacy and safety of drugs in children are extrapolated from adults. The EMA recognizes the need for long-term safety studies on various d...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00228-010-0930-2
更新日期:2011-05-01 00:00:00
abstract:OBJECTIVE:To describe and compare the distribution of prescribed drugs in diabetic patients between 1992 and 1995. METHODS:Two cross-sectional surveys of a random selection of medical records of diabetic patients, from three community health centres (CHCs) in the Stockholm metropolitan area, were carried out. The age ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s002280050285
更新日期:1997-01-01 00:00:00
abstract:OBJECTIVE:To investigate the CYP1A2 phenotype distribution in a population with an increased exposure to polychlorinated biphenyls (PCBs) that would likely induce an increased activity of this enzyme. Further, to investigate the effect of sex, smoking, and oral contraceptive use on the CYP1A2 activity. METHODS:In 305 ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-006-0205-0
更新日期:2006-12-01 00:00:00
abstract:OBJECTIVE:Iloprost is a potent PGI2 mimetic, which has been shown to be therapeutically effective in several vascular disorders. Due to its rapid clearance from the central compartment, iloprost is administered mainly by i.v. infusion, which limits its use to hospitalized patients. In order to improve pharmacotherapeut...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1007/s002280050336
更新日期:1997-01-01 00:00:00
abstract::We have studied the pharmacokinetics of tulobuterol given transdermally or by aerosol inhalation in healthy male volunteers. Tulobuterol was rapidly absorbed after inhalation, with a tmax of 0.8-1.5 h. The Cmax and the AUC increased linearly with dose. Tulobuterol was well absorbed after transdermal administration, wi...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00316473
更新日期:1993-01-01 00:00:00
abstract:OBJECTIVES:To assess (1) whether the utilisation of codeine or propoxyphene differs among the three major Swedish cities (Stockholm, Göteborg and Malmö) and between urban and semirural areas; (2) if so, whether it co-varies with the utilisation of other potentially dependence-promoting drugs, benzodiazepines; (3) what ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s002280050680
更新日期:1999-10-01 00:00:00
abstract:PURPOSE:To evaluate the clinical relevance of the Janus Web Application (JWA) in screening for potential drug-drug interactions (DDIs). METHODS:One hundred and fifty patients taking two drugs or more were studied. Potential DDIs were identified by the JWA. Interviewing the patient and looking into his/her medical reco...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-008-0547-x
更新日期:2008-12-01 00:00:00
abstract::The presence of a possible correlation between changes in left ventricular mass of hypertensive patients and the degree of blood pressure reduction with different antihypertensive drugs has been investigated in 40 outpatients by M-mode echocardiography. Ten of these, with blood pressure in normal limits with different...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF00556886
更新日期:1984-01-01 00:00:00
abstract::We have previously shown that inhaled salbutamol further increases the bronchodilator response after the maximum effect of theophylline has been obtained in patients with severe chronic bronchitis. We now report the results of adding maximally effective doses of theophylline to the maximum response obtainable from sal...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00542540
更新日期:1982-01-01 00:00:00
abstract::Acute studies of clonidine suggest that it lowers blood pressure by central enhancement of baroreflex sensitivity coupled with diminished evidence of sympathetic outflow, but longterm clonidine data have not been conclusive. We examined effects of one month of low dose clonidine (0.4 +/- 0.15 mg/day) alone in 13 essen...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF00558378
更新日期:1981-01-01 00:00:00
abstract:OBJECTIVE:The goal of this study was to determine the frequencies of important allelic variants of two drug targets, dipeptidyl carboxypeptidase ( DCP1) and cholesteryl ester transfer protein ( CETP), and two other drug receptors, beta-2 adrenergic receptor ( ADRB2) and 5-hydroxy tryptamine 2A receptor ( HTR2A), in the...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-002-0423-z
更新日期:2002-04-01 00:00:00
abstract::The blood level versus time curve for unchanged cimetidine after a 200 mg oral dose has been determined in 20 apparently healthy subjects, ranging from 22 to 84 years of age. A significant relationship between the area under the curve (AUC) and age was found (r = 0.81; P less than 0.001). The peak concentrations of ci...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00618514
更新日期:1979-05-21 00:00:00
abstract::In a model of mental stress the influence of nifedipine and hydrochlorothiazide on stress-induced changes in blood pressure, heart rate, and plasma catecholamines was studied in normal persons. The drugs were used to investigate whether substances with antihypertensive but no particular sympatholytic properties were c...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00544008
更新日期:1983-01-01 00:00:00
abstract::We have evaluated the effects of repaglinide, a new non-sulphonylurea oral hypoglycaemic agent that has a stimulatory effect on insulin secretion. Forty-four patients with NIDDM, already treated with a sulphonylurea, took part in an open, randomised, group comparison study of 12 weeks duration, during which they recei...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF00315490
更新日期:1993-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Dosing of vancomycin in pediatric patients undergoing continuous venous-venous hemodiafiltration (CVVHDF) is challenging. Characterization of vancomycin pharmacokinetics can assist with dosing and attainment of goal serum concentrations. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS:Patient...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-019-02664-7
更新日期:2019-08-01 00:00:00
abstract::The present study was designed to investigate the effects of raised intragastric pH on the absorption of theophylline from a sustained-release formulation. Six healthy male volunteers participated in the cross-over randomised study and on one of two occasions were pretreated with 240 mg omeprazole, administered in thr...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF01740660
更新日期:1992-01-01 00:00:00
abstract:PURPOSE:The objective of this study was to appraise the safety profiles of HES preparations and to find out which HES preparation was the most acceptable in cardiovascular surgery through a comparison with control solutions. METHODS:Pertinent randomized controlled trials were selected through a search of Pubmed, Embas...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,meta分析,评审
doi:10.1007/s00228-011-1008-5
更新日期:2011-08-01 00:00:00
abstract:OBJECTIVE:The aim of the present study was to develop a real-time reverse-transcription polymerase chain reaction (RT-PCR) methodology for the quantification of thiopurine methyltransferase (TPMT) gene expression in whole blood and compare it with the TPMT enzyme activity measured in red blood cells. METHODS:TPMT gene...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-003-0617-z
更新日期:2003-07-01 00:00:00
abstract:PURPOSE:This study investigated the effects of clotrimazole troche on the risk of transplant rejection and the pharmacokinetics of tacrolimus. METHODS:The data mining approach was used to investigate whether the use of clotrimazole increased the risk of transplant rejection in patients receiving tacrolimus therapy. Pa...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-019-02770-6
更新日期:2020-01-01 00:00:00
abstract::The effect of acute and long-term treatment with propranolol on cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2) has been studied in 8 young healthy volunteers. CBF was measured by 133Xe-inhalation and single photon emission computer tomography, and CMRO2 was calculated from the arterio-veno...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00315115
更新日期:1990-01-01 00:00:00
abstract::A four-period, two-panel, single-rising-dose study (0.1-100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5 alpha-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00199874
更新日期:1994-01-01 00:00:00
abstract:PURPOSE:The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multic...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00228-012-1357-8
更新日期:2013-03-01 00:00:00
abstract::The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thu...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00870989
更新日期:1986-01-01 00:00:00