Abstract：
:Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) has gained increasing interest in the treatment of hypertension, heart failure, and renoprotection. Specifically, M100240, the thioester of the dual ACE/NEP inhibitor MDL100,173, has been evaluated in the management of hypertension. A model-based analysis, including simulations, was employed to characterize the relationship between individual M100240 drug exposure and neurohormonal response and to optimize the dose selection for future clinical studies. Sixty-two healthy subjects and 189 hypertensive patients were studied after oral once-daily administration of 2.5, 5, 10, 25, or 50 mg M100240. Pharmacokinetic-biomarker and blood pressure response models were fitted to the data with the computer program NONMEM. A direct inhibitory E(max) model adequately described the relationship between MDL100,173 concentration and ACE activity. No clear concentration or dose-dependent NEP or blood pressure responses were evident. Given a target 90% ACE inhibition, simulation reveals that (1). 50 mg M100240 once daily produces adequate ACE inhibition 24 hours postdose in only 20% of subjects, and (2). higher and/or more frequent doses on the order of 25 mg three times daily or 50 mg twice daily are required to achieve the target ACE inhibition in at least 50% of patients over 24 hours. Insufficient blood pressure-lowering effects were observed in healthy subjects and hypertensive patients due to inadequate ACE and NEP inhibition with once-daily oral doses of up to 50 mg of M100240. Divided doses might provide target ACE inhibition in more patients.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Pfister M,Martin NE,Haskell LP,Barrett JSdoi
10.1177/0091270004265365subject
Has Abstractpub_date
2004-06-01 00:00:00pages
621-31issue
6eissn
0091-2700issn
1552-4604pii
44/6/621journal_volume
44pub_type
临床试验,杂志文章abstract：:Gestational diabetes mellitus (GDM) has affected a great number of pregnant women worldwide. Artemisia extracts have been found to exhibit a potent antidiabetic effect in the treatment of type 2 diabetes mellitus. We aimed to examine the effects of Artemisia extract on insulin resistance and lipid profiles in pregnant...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.755
更新日期：2016-12-01 00:00:00
abstract：:The influence of the method of cimetidine administration on theophylline disposition was studied in nine healthy, cigarette smoking male volunteers. The treatment phases consisted of: A) theophylline alone, B) theophylline plus intermittent cimetidine therapy (300 mg IV every 6 hr), and C) theophylline in combination ...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1989.tb03398.x
更新日期：1989-07-01 00:00:00
abstract：:Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, an...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.832
更新日期：2017-04-01 00:00:00
abstract：:Renal electrolyte excretion patterns were determined in nonedematous healthy volunteers following bumetanide and furosemide in two separate clinical studies. In study 1, intravenous bumetanide was administered to 24 subjects at four dose levels. In study 2, bumetanide (1 or 2 mg) or furosemide (40 or 80 mg) was admini...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1981.tb05671.x
更新日期：1981-11-01 00:00:00
abstract：:The influence of food on the bioavailability of trimoprostil , a new antiulcer prostaglandin E2 derivative, was investigated in healthy male volunteers in four separate studies. Doses of 0.75, 1.5, and 3.0 mg were administered orally in both the presence and absence of food followed by serial blood sampling through 24...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1984.tb01830.x
更新日期：1984-04-01 00:00:00
abstract：:Although glucocorticoids and cyclosporine are frequently used to treat patients with various types of glomerulopathy, clinical responses to treatment vary considerably. Considerable interindividual heterogeneity in the suppressive effects of glucocorticoids on lymphocyte proliferation in vitro has been previously repo...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1996.tb04760.x
更新日期：1996-10-01 00:00:00
abstract：:This study aimed to investigate a food effect on the bio-availability of modified-release (MR) trimetazidine tablets in 36 healthy volunteers. Trimetazidine, an anti-ischemic drug, protects the myocardial cell from the harmful effects of ischemia. The authors investigated the effect of being under a fasting or fed sta...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1177/0091270011422813
更新日期：2012-10-01 00:00:00
abstract：:The effect of 6% hydroxyethyl starch (hetastarch) and 5% human serum albumin (albumin) infusion on coagulation in 12 patients with septic shock was evaluated. Patients were randomly assigned to receive either albumin (N = 6) or hetastarch (N = 6) infusion over a 24-hour study interval. The prothrombin time (PT), parti...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1988.tb05751.x
更新日期：1988-05-01 00:00:00
abstract：:Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm dr...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.581
更新日期：2016-01-01 00:00:00
abstract：:The principal causes of digitalis toxicity are overdose, reduced volume of distribution, reduced renal elimination, and increased myocardial sensitivity. The metabolic mechanism of digitalis toxicity is intense inhibition of sarcolemma Na-K ATPase, which leads to increases of intracellular Na+ and Ca2+ and arrhythmoge...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1177/009127008502500707
更新日期：1985-10-01 00:00:00
abstract：:In the development of a new controlled release preparation and its subsequent assessment there are a number of factors that need to be considered both related to the drug itself and to the pharmaceutical preparation. This review describes the biopharmaceutical and pharmacokinetic properties of metoprolol CR/ZOK, a rec...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1002/j.1552-4604.1990.tb03490.x
更新日期：1990-02-01 00:00:00
abstract：:The clinical pharmacist is an integral member of the Docent team at the University of Missouri--Kansas City School of Medicine with duties in both teaching and patient care. These doctoral-level clinical pharmacists have sole responsibility for providing instruction in basic pharmacology and pharmacokinetics and for t...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1981.tb05700.x
更新日期：1981-04-01 00:00:00
abstract：:The purpose of this study was to characterize the effect of potent CYP2D6 inhibition byparoxetine on atomoxetine disposition in extensive metabolizers. This was a single-blind, two-period, sequential studyin 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1177/009127002762491307
更新日期：2002-11-01 00:00:00
abstract：:This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1177/0091270009339187
更新日期：2009-09-01 00:00:00
abstract：:The therapeutic and biochemical effects of two commonly employed diuretic preparations were compared in a double-blind fashion in 32 patients with congestive heart failure. At the doses employed, furosemide and a fixed combination of spironolactone and hydrochlothiazide maintained control of the clinical manifestation...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1002/j.1552-4604.1977.tb04625.x
更新日期：1977-07-01 00:00:00
abstract：:The pharmacokinetics of dexketoprofen trometamol were evaluated in two studies using healthy volunteers. In the first study, the relative bioavailability of a single oral capsule of dexketoprofen free acid 25 mg or dexketoprofen trometamol 25 mg (given as 37 mg of the trometamol salt) was compared to ketoprofen 50 mg ...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1998-12-01 00:00:00
abstract：:The effect of desipramine on chronic ventricular ectopic depolarizations (VEDs) was studied in 10 patients with at least 30 VEDs per hour. A single-blind, placebo-controlled, dose-ranging protocol was followed. Efficacy was defined as a decrease in VED frequency of at least 75%, base on three 24 hour ambulatory ECGs o...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章
doi：10.1002/j.1552-4604.1989.tb03297.x
更新日期：1989-02-01 00:00:00
abstract：:Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; ≤12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged fir...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.147
更新日期：2013-10-01 00:00:00
abstract：:The antipyretic activity of ibuprofen (Brufen) and paracetamol (Crocin) was compared in 22 children with pyrexia who received either ibuprofen or paracetamol in syrup form. Both axillary and rectal temperatures were recorded prior to drug administration and 1/2, 1, 2, 3, 4, 5, 6, 8, and 12 hours after dosing. Analysis...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1980.tb01685.x
更新日期：1980-11-01 00:00:00
abstract：:An equation is derived to estimate mean steady state serum concentration (Css) from trough steady state serum concentration (Cmin) which can be used for drugs with either linear or nonlinear pharmacokinetic properties. In 15 subjects receiving phenytoin monotherapy, estimated Css did not differ significantly from meas...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1990.tb03612.x
更新日期：1990-06-01 00:00:00
abstract：:The aim of this study was to apply individualized, physiologically-based pharmacokinetic (iPBPK-R) modeling of 14 CO2 production rates measured by the erythromycin breath test (ERMBT) to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease (ESR...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.1818
更新日期：2021-01-18 00:00:00
abstract：:Monitoring drug levels in patients is standard practice in presentday critical care medicine. Clinical laboratories, however, are often unable to assay drug levels immediately following phlebotomy. This may result in blood samples being kept under a variety of storage conditions for nonuniform periods of time. The cur...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1988.tb03212.x
更新日期：1988-08-01 00:00:00
abstract：:The objective of this randomized clinical trial was to compare steady-state gestational RBC and plasma folate concentrations in pregnant women supplementing daily with 1.1 mg (regular dose) vs. 5 mg (high dose) folic acid. Thirty-seven pregnant women, who were not previously taking folic acid, were enrolled in this op...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.387
更新日期：2015-02-01 00:00:00
abstract：:Aliskiren is the first in a new class of orally active, direct renin inhibitors for the treatment of hypertension. This open-label, nonrandomized, single-center, parallel-group study compared the pharmacokinetics and safety of a single 300-mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic im...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1177/0091270006294404
更新日期：2007-02-01 00:00:00
abstract：:In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2-receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to pa...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,多中心研究
doi：10.1002/jcph.880
更新日期：2017-07-01 00:00:00
abstract：:Microgravity is produced for 20 to 30 seconds in NASA's KC-135 aircraft at the end of a 2 G pullup for each of 40 parabolas per flight. Continuous transcranial Doppler ultrasound, arterial blood pressure, and acceleration levels were recorded for 12 male and 8 female healthy subjects without known cardiovascular or ce...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1991.tb03648.x
更新日期：1991-10-01 00:00:00
abstract：:Piragliatin is a CYP3A substrate; its inactive metabolite M4, formed through cytosolic reductase, is reversibly metabolized back to piragliatin through CYP3A. The impact of concomitant CYP3A modifiers thus cannot be predicted. Drinking alcohol under fasting conditions is associated with a recognized glucose-lowering e...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1002/jcph.617
更新日期：2016-05-01 00:00:00
abstract：:Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanis...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.867
更新日期：2017-07-01 00:00:00
abstract：:Cannabinoids, including smoked marijuana and delta9-tetrahydrocannabinol (THC) (dronabinol, Marinol), have been used to treat human immunodeficiency virus-1 (HIV)-associated anorexia and weight loss. Concerns have been raised, however, that these compounds might have adverse effects on the immune system of subjects wi...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.2002.tb06007.x
更新日期：2002-11-01 00:00:00
abstract：:Neutropenia is the most commonly reported hematologic toxicity following treatment with palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for metastatic breast cancer. Using data from 185 advanced cancer patients receiving palbociclib in 3 clinical trials, a pharmacokinetic-pharmacodynamic model was develo...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.902
更新日期：2017-09-01 00:00:00
