Abstract:
PURPOSE:Pre-clinical experiments have shown that almorexant, a dual orexin receptor antagonist, is able to inhibit cytochrome P450 3A4 (CYP3A4). Therefore, a study was conducted to investigate the effects of multiple-dose almorexant on the pharmacokinetics of midazolam and simvastatin, two CYP3A4 model substrates. METHODS:Fourteen healthy male subjects were enrolled in an open-label, randomized, two-way crossover study. Treatment period A consisted of a single oral dose of 2 mg midazolam on day 1 and 40 mg simvastatin on day 3. In treatment period B, subjects received 200 mg almorexant once daily for 9 days together with a single oral dose of midazolam on day 7 and simvastatin on day 9. RESULTS:Concomitant administration of midazolam with almorexant at steady-state levels, achieved within 4-5 days, resulted in an increase of 1.2-fold [90 % confidence interval (CI) 1.0-1.4], 1.4-fold (90 % CI 1.2-1.6), and 1.3-fold (90 % CI 1.2-1.4) in the maximum plasma concentration (C(max)), area under the concentration-time curve from time 0 to infinity (AUC(0-∞)), and terminal half-life (t(1/2)), respectively, of midazolam; the time to peak plasma concentration (t(max)) was unchanged. Whereas C(max) and t(max) were not influenced by almorexant, the AUC(0-∞) of hydroxy-midazolam increased by 1.2-fold (90 % CI 1.1-1.4) and the t(1/2) by 1.3-fold (90 % CI 1.0-1.5). Concomitant administration of simvastatin with almorexant at steady-state resulted in an increase of 2.7-fold (90 % CI 2.0-3.7) and 3.4-fold (90 % CI 2.6-4.4) in C(max) and AUC(0-∞), respectively, for simvastatin; the t(1/2) and t(max) were unchanged. The C(max) and AUC(0-∞) of hydroxyacid simvastatin both increased by 2.8-fold, with 90 % CIs of 2.3-3.5 and 2.2-3.5, respectively; the t(max) increased by 2 h and the t(1/2) was unchanged. The urinary 6-β-hydroxycortisol/cortisol ratio was unaffected by almorexant. CONCLUSIONS:Our results suggest that the observed interaction was caused by the inhibition of CYP3A4 activity, most probably at the gut level.
journal_name
Eur J Clin Pharmacoljournal_title
European journal of clinical pharmacologyauthors
Hoch M,Hoever P,Alessi F,Theodor R,Dingemanse Jdoi
10.1007/s00228-012-1403-6subject
Has Abstractpub_date
2013-03-01 00:00:00pages
523-32issue
3eissn
0031-6970issn
1432-1041journal_volume
69pub_type
杂志文章,随机对照试验abstract:OBJECTIVE:Pharmacokinetic parameters are important for dose adjustment of aminoglycosides, but they are highly variable in neonates. In this study the pharmacokinetics of a netilmicin loading dose was investigated on the first postnatal day in preterm neonates with very low gestational age (GA). METHODS:In an open pro...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-006-0153-8
更新日期:2006-09-01 00:00:00
abstract::The cellular sources or molecular mechanisms responsible for the derangement of vasoactive prostanoid levels during immunosuppressive cyclosporin (CSA) therapy have not been defined. Using cultured rat glomerular mesangial cells (MC), the cytostatic, cytotoxic and prostanoid synthesis modulating effects of CSA and FK-...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF01428385
更新日期:1993-01-01 00:00:00
abstract:PURPOSE:We assessed reported associations of CYP3A5 *1 allele with a delay in achieving target tacrolimus concentrations, and occurrence of biopsy-confirmed subclinical acute rejection (SAR) and chronic allograft nephropathy (CAN) in Japanese subjects. METHODS:Forty-one renal allograft recipients were studied. The tar...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-008-0606-3
更新日期:2009-05-01 00:00:00
abstract:OBJECTIVE:This multicenter, double-blind, placebo-controlled, parallel-group study was designed to assess the acute effects of intravenous mibefradil on the electrophysiologic characteristics of the human heart. METHODS:Seventy-one patients referred for routine electrophysiologic testing were randomized to receive one...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1007/s002280050241
更新日期:1997-01-01 00:00:00
abstract::The effect beta-adrenoceptor blockade on the pressor response to tyramine has been investigated in 6 healthy volunteers, each submitted to an i.v. tyramine pressor test before and after 7 days of propranolol 40 mg b.d. or indenolol 60 mg o.d. Tyramine was given as i.v. boluses of 1-6 mg, alternating with saline, in a ...
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/BF00540953
更新日期:1988-01-01 00:00:00
abstract::Pharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received: 1, antipyrine 1.0 g intravenously (i.v.); 2, acetaminophen 650 mg i.v.; 3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously. Between Trials 1 and 3, antipyrine elimin...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00561374
更新日期:1988-01-01 00:00:00
abstract::The pharmacokinetics of lignocaine has been compared after epidural anaesthesia in diabetics and non-diabetic patients. Epidural lignocaine 8 mg.kg-1 was given to 8 well controlled Type II diabetic and 8 non-diabetic patients and the plasma drug concentration in serial blood samples were measured by HPLC. The plasma l...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF02333021
更新日期:1992-01-01 00:00:00
abstract:OBJECTIVE:In animal studies, it has been shown that verapamil reduces strength and endurance of the diaphragm and inhibits the beneficial effects of theophylline. We examined whether the use of verapamil in patients with severe chronic obstructive pulmonary disease (COPD) who use theophylline leads to a deterioration o...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002280050005
更新日期:2000-01-01 00:00:00
abstract::Data on forged prescriptions in Sweden in 1982-1986 were studied as an indicator in an epidemiological survey of medication abuse. The annual number of prescription forgeries doubled during the 5-year period. Psychotropic drugs accounted for 62% and analgesics for 25% of all forgeries. Benzodiazepines were the major s...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00637747
更新日期:1989-01-01 00:00:00
abstract:PURPOSE:Drug-related problems (DRPs) are common in paediatric pharmacotherapy, but few studies describe them from the parents' perspective. In the present survey, we have investigated the lifetime prevalence and type of DRPs in children in Finland. METHODS:This was a population-based survey of a random sample of 6,000...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00228-012-1426-z
更新日期:2013-04-01 00:00:00
abstract::Naftopidil exerts its antihypertensive action via alpha 1-adrenoceptor blockage and Ca2+ antagonism in vascular smooth muscle. Since the chemically similar 1-(1-naphthyl) piperazine is known to be a 5-hydroxytryptamine2 receptor antagonist, the 5-hydroxytryptamine (5-HT) antagonistic properties of naftopidil were test...
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/BF00192561
更新日期:1994-01-01 00:00:00
abstract::Accidental intoxication with tramadol of a 6-month old infant was followed by severe cerebral depression. Studies on serum, cerebrospinal fluid, and urine drug levels indicated complete penetration of the blood-cerebrospinal fluid barrier by tramadol. ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00543498
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-020-03070-0
更新日期:2021-02-01 00:00:00
abstract:OBJECTIVE:To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. METHODS:12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril...
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/s002280050209
更新日期:1996-01-01 00:00:00
abstract::Four subjects received 5 mg 14C-glipizide orally, 3 subjects 1 mg intravenously and 2 subjects 5 mg 14C-glibenclamide orally. Plasma levels of radioactivity, and urinary and faecal excretion were measured. For both drugs the disappearance of radioactivity from plasma followed complex kinetics and the apparent half-liv...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00616416
更新日期:1975-01-01 00:00:00
abstract::In a multicentre, double-blind, crossover, placebo-controlled study, the antihypertensive effect of labetalol 100 mg and chlorthalidone 10 mg, given alone or in combination, has been assessed in 32 hypertensive patients. The combination had a greater effect in reducing blood pressure than did its separate components. ...
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/BF00548395
更新日期:1982-01-01 00:00:00
abstract:OBJECTIVE:Intragastric pH-metry is widely used to evaluate the efficacy of antisecretory drugs, but statistical interpretation of the measurements has not yet been standardised. METHODS:The effects of single morning (N = 9) or evening (N = 7) doses of the H2-receptor antagonist famotidine, 20 mg (QUAMATELR. Gedeon Ric...
journal_title:European journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002280050139
更新日期:1996-01-01 00:00:00
abstract::Total beta-adrenoceptor density and beta 1- and beta 2-subtype distribution in right and left atria and in different ventricular regions from 14 failing and seven nonfailing human hearts have been compared. End-stage heart failure was due to idiopathic dilated cardiomyopathy (n = 8) or ischaemic cardiomyopathy (n = 6)...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00265923
更新日期:1992-01-01 00:00:00
abstract::Clorazepate 20 mg was given i.m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. "Total nordiazepam", i.e. the sum of clorazepate and...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00563103
更新日期:1979-04-17 00:00:00
abstract:PURPOSE:This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600 mg) in 20...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-020-03046-0
更新日期:2020-11-17 00:00:00
abstract::The disposition of oral metoprolol was studied in 5 women during the last trimester of pregnancy and 3 to 5 months after delivery. After a single oral dose of 100 mg the individual peak plasma concentration in the pregnant state was only 20-40% of that after pregnancy. The plasma half-lives of metoprolol were about th...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00613820
更新日期:1983-01-01 00:00:00
abstract::The effect of procainamide (P) on left ventricular function as measured by the systolic time intervals (STI) was studied in 14 patients with primary myocardial disease. P, 7.5 mg/kg body weight, was given intravenously at a rate of 100 mg per minute. Administration of P produced a decrease in left ventricular performa...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00561387
更新日期:1980-10-01 00:00:00
abstract::A placebo-controlled, single blind, crossover study was done to evaluate the inotropic effects of single oral doses of mexiletine and disopyramide assessed by the measurement of Systolic Time Intervals (STI). Each of 8 healthy volunteers received five treatments in random order: 200 and 400 mg mexiletine, 100 and 200 ...
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/BF00541525
更新日期:1986-01-01 00:00:00
abstract::The effects of the ingestion of food and digoxin on the cardiovascular system alone and in combination have been observed in eight healthy subjects. A positive inotropic response was seen following food (2.5 MJ) and intravenous digoxin (0.01 mg/kg) with significant decreases in QS2Index (QS2I) pre-ejection period (PEP...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00615959
更新日期:1986-01-01 00:00:00
abstract:PURPOSE:Tacrolimus is a commonly used immunosuppressant in solid organ transplantation recipients, but it is characterized by a narrow therapeutic range and large inter-individual variability. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of ...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/s00228-012-1296-4
更新日期:2013-01-01 00:00:00
abstract::Guidelines presented previously for the analysis of plasma concentration versus time data for a drug exhibiting concentration-dependent plasma protein binding were successfully applied to the distributional parameters of a new cephalosporin, ceftriaxone. This approach provided several striking observations when the ph...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF01037956
更新日期:1983-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Opicapone is a novel third generation catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to compare the levodopa pharmacokinetic profile throughout a day driven by the COMT inhibition either following repeated doses of opicapone or concomitant administration with enta...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00228-014-1701-2
更新日期:2014-09-01 00:00:00
abstract::A cross-over study of kinetics has been undertaken in 12 healthy adults volunteers using two sustained-release theophylline products that allow once a day dosing (Theo-Dur tablets and Dilatrane A.P. bead filled capsules) to compare the i.v. pharmacokinetic profiles when taken with an hyperlipidic meal and a balanced s...
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/BF00609431
更新日期:1989-01-01 00:00:00
abstract::Changes in venous haemodynamics were studied after administration of a single dose of 3 g Heptaminol Adenosine Phosphate (HAP) to 30 subjects with primary varicose veins. Strain gauge plethysmography was used to observe changes in venous volume and in maximal venous outflow, 1, 2, 3 and 4 h after dosing. A significant...
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/BF00609421
更新日期:1989-01-01 00:00:00
abstract::Pharmacokinetic and metabolic studies with 3H-etilefrine were performed to assess the importance of a first-pass effect on the pharmacodynamic action of this sympathomimetic amine. Identical amounts of 3H-activity, ca. 80% of the dose, were excreted in the urine after intravenous or oral administration, which indicate...
journal_title:European journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1007/BF00614015
更新日期:1975-12-19 00:00:00