Abstract：
PURPOSE:Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. METHOD:This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. RESULTS:Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. CONCLUSION:Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.
journal_name
Eur J Clin Pharmacoljournal_title
European journal of clinical pharmacologyauthors
Langenickel TH,Jordaan P,Petruck J,Kode K,Pal P,Vaidya S,Chandra P,Rajman Idoi
10.1007/s00228-016-2062-9subject
Has Abstractpub_date
2016-08-01 00:00:00pages
917-24issue
8eissn
0031-6970issn
1432-1041pii
10.1007/s00228-016-2062-9journal_volume
72pub_type
杂志文章,随机对照试验abstract：:The effects of metolazone on the protein binding of glibenclamide were studied. It was found that increasing metolazone concentrations up to 100 ng/ml had no significant effect on the protein binding of glibenclamide studied at 10 micrograms/ml. Metolazone is unlikely to cause a clinically significant increase in the ...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00314813
更新日期：1990-01-01 00:00:00
abstract：PURPOSE:LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor, is indicated for chronic heart failure (HF) and reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization for HF. Following oral administration, LCZ696 provides systemic exposure to valsartan and ...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-016-2072-7
更新日期：2016-09-01 00:00:00
abstract：AIM:The aim of this study was to quantify the reasons and opinions of patients who reported adverse drug reactions (ADRs) in the Netherlands to a pharmacovigilance centre. METHOD:A web-based questionnaire was sent to 1370 patients who had previously reported an ADR to a pharmacovigilance centre. The data were analysed...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-010-0865-7
更新日期：2010-11-01 00:00:00
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：OBJECTIVE:Although the treatment of schizophrenia with many second generation antipsychotics is known to be associated with metabolic changes, such as hyperglycemia or hypercholesterolemia, the underlying mechanisms of these adverse reactions remain unclear. In light of the recent focus on the involvement of semicarbaz...
journal_title：European journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/s00228-007-0272-x
更新日期：2007-05-01 00:00:00
abstract：PURPOSE:Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-018-2545-y
更新日期：2018-12-01 00:00:00
abstract：:Theophylline disposition after an intravenous test dose of aminophylline was determined in 83 subjects: 7 patients with and 58 without congestive heart failure (CHF), and 18 healthy controls. Based on the pharmacokinetics of theophylline in the individual, the oral dosage of aminophylline was scheduled to attain stead...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00545964
更新日期：1982-01-01 00:00:00
abstract：PURPOSE:To investigate statin use in the elderly by age (≥ 80 vs. 65-79 years) in relation to established indications. METHODS:A population-based cohort, including data from four registers, encompassing inhabitants in Region Västra Götaland, Sweden, was used. Statin users were defined as those filling statin prescript...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-019-02645-w
更新日期：2019-07-01 00:00:00
abstract：OBJECTIVE:Theophylline is metabolized to 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine, and 1-methylxanthine by CYP1A2 and partly by CYP2E1. Because 1,3-DMU is the major metabolite of theophylline, the 1,3-DMU/theophylline ratio is viewed as a good indicator of theophylline metabolic clearance. Here, we investigate...
journal_title：European journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/s00228-006-0165-4
更新日期：2006-08-01 00:00:00
abstract：BACKGROUND:A four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype. METHODS:The cocktail consisted of the single CYP phenotyping probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (C...
journal_title：European journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/s00228-013-1561-1
更新日期：2013-12-01 00:00:00
abstract：:Atrial natriuretic factor (ANF) binding sites have been shown to be present on human platelet membranes. We investigated the effect of an infusion of ANF 5 pmol.kg-1.min-1 on platelet aggregation in whole blood ex-vivo in 8 normal volunteers. Spontaneous platelet aggregation, collagen (0.6-2 micrograms.m.-1)-induced o...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00316102
更新日期：1990-01-01 00:00:00
abstract：OBJECTIVE:The pharmacokinetics of orally and intravenously administered valsartan were determined in two studies. In a first pilot study, three i.v. doses of valsartan were given in an ascending manner (5, 10 and 20 mg) to evaluate tolerability and basic pharmacokinetics of the i.v. formulation. In a second study, the ...
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/s002280050259
更新日期：1997-01-01 00:00:00
abstract：OBJECTIVE:To evaluate the effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. METHODS:A single 5-mg capsule of tropisetron was administered orally to 13 healthy subjects. Plasma concentrations were determined by validated HPLC procedures and data were analyzed by using nonc...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-003-0595-1
更新日期：2003-06-01 00:00:00
abstract：:The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 2...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00314864
更新日期：1992-01-01 00:00:00
abstract：:Factors influencing the disposition of clotiazepam in man were evaluated in a series of pharmacokinetic studies in healthy volunteers given a single 5 mg dose. Old age caused an increased volume of distribution of clotiazepam in women, and its clearance tended to be reduced in elderly men. Use of oral contraceptives, ...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00546709
更新日期：1984-01-01 00:00:00
abstract：OBJECTIVE:To analyse the contribution of adverse drug reactions (ADR) to hospital readmissions. METHODS:This was a case-control study in which unscheduled admissions of patients who had been admitted to the hospital during the two previous months were assessed during a 21-month period. The patient was considered a cas...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-008-0473-y
更新日期：2008-07-01 00:00:00
abstract：OBJECTIVES:Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-007-0269-5
更新日期：2007-05-01 00:00:00
abstract：:The hypocholesterolemic cation resins, cholestyramine and colestipol, have variable effects on the absorption parameters of a number of lipophillic, anion drugs. Because of the unpredictable nature of this interaction, we have assessed in human volunteers the effect of these resins on the rate and total absorption of ...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00542221
更新日期：1983-01-01 00:00:00
abstract：PURPOSE:The aim of this study is to validate medication proxies for the identification of children diagnosed with atopic disorders that can be applied in various types of epidemiological research. METHODS:Records of 7439 children, aged between 0 and 10 years, in the period 2001 until 2010, were retrieved from the Regi...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-015-1940-x
更新日期：2016-01-01 00:00:00
abstract：:We have evaluated the pharmacokinetics of high doses of clonidine, as used in the prophylactic treatment of alcohol withdrawal syndrome, in 11 alcohol-dependent patients undergoing surgery for oesophagogastrectomy. Clonidine was given in a bolus of 150 micrograms followed by a continuous infusion. After a mean period ...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00315500
更新日期：1993-01-01 00:00:00
abstract：PURPOSE:To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital. METHODS:We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and regist...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-020-03043-3
更新日期：2020-11-13 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：:The peripheral histamine-inhibiting and central sedative effects of single oral doses (SOD) and of repeated administration for one week (steady state, SS), of 20 mg hydroxyzine HCL and 10 mg cetirizine have been assessed in 12 healthy volunteers, in a double-blind placebo-controlled cross-over study. Peripheral H1-rec...
journal_title：European journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/BF00626365
更新日期：1991-01-01 00:00:00
abstract：:In order to assess whether dinnertime administration of a once daily dose of famotidine is more advantageous than a bedtime dose in suppressing evening and nocturnal gastric acidity, we gave nine patients with a past history of duodenal ulcer in double-blind, randomized fashion either (1) placebo at 6 p.m. and 10 p.m....
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/BF00609254
更新日期：1988-01-01 00:00:00
abstract：:In 8 social drinkers, the effect of a single dose of Liv.52 or placebo on ethanol absorption has been studied after ingestion of 30 ml whisky in 5 min. The t1/2 absorption with Liv.52 was 3.62 min, significantly less than after placebo, 6.29 min. The peak concentration after Liv.52 (49.9 mg.100 ml-1) was significantly...
journal_title：European journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/BF00280076
更新日期：1991-01-01 00:00:00
abstract：OBJECTIVES:The study was conducted to investigate whether oral co-administration with citrus juices significantly affects the pharmacokinetics and/or pharmacodynamics of pranidipine, a new 1,4-dihydropyridine calcium antagonist, in healthy male subjects. Grapefruit juice and orange juice, which were both commercially a...
journal_title：European journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/s002280050547
更新日期：1998-11-01 00:00:00
abstract：PURPOSE:In the past few years, several fracture-related events have been reported with chronic use of selective serotonin reuptake inhibitors (SSRIs) throughout the globe. Hence, an updated systematic review and meta-analysis was necessary to ascertain the risk involved. The present work evaluated the association of SS...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/s00228-020-02893-1
更新日期：2020-10-01 00:00:00
abstract：:The haemodynamic effects of prenalterol, a new beta-1 agonist, were studied in 10 patients with chronic heart failure. Following intravenous prenalterol infusions of 1 mg, 2.5 mg and 5 mg at 15 min intervals, oral slow release prenalterol 20 mg, 30 mg and 50 mg was given at 2 h intervals and then 50-100 mg bid for one...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00542125
更新日期：1983-01-01 00:00:00
abstract：:The disposition of paracetamol following an oral dose of 1.0 g was compared in 10 healthy volunteers, 7 patients with moderate chronic renal failure and 6 patients with end stage renal failure on maintenance haemodialysis. Paracetamol absorption was normal in the patients with renal failure. The mean plasma half-life ...
journal_title：European journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1007/BF00558162
更新日期：1989-01-01 00:00:00
abstract：OBJECTIVE:As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated. METHODS:The study was carried out in ten healthy volunteers using a randomis...
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/s002280050646
更新日期：1999-07-01 00:00:00
