Abstract:
BACKGROUND:PHX1149 is a dipeptidyl peptidase-4 (DPP4) inhibitor that is currently in clinical development for the treatment of type 2 diabetes mellitus. PHX1149 is a small (molecular weight = 241.16 Da), highly water-soluble (>2 g/mL), orally active molecule with a selectivity index of 15- to 319-fold relative to those of other members of the DPP family. The biochemical median inhibitory concentration of DPP4 is 2.5 nmol/L. OBJECTIVE:The aim of these 2 double-blind, randomized, placebo-controlled studies was to examine the pharmacokinetic (PK) parameters and pharmacodynamic (PD) properties and tolerability of single and multiple ascending doses of PHX1149 in healthy human subjects. METHODS:Healthy men and women aged 18 to 60 years were recruited to participate in a single- or a multiple-dose study in which sequential dose escalation paradigm was used. In the single-dose study, subjects were given a single oral dose of PHX1149 50 to 500 mg or placebo; in the multiple-dose study, subjects were given PHX1149 at doses from 50 to 400 mg or placebo QD for 13 days. There was no intrasubject dose escalation. Blood samples were collected from each subject at a series of time points ranging from 1 hour before to 24 hours after dosing on day 1 in the single- dose study and on days 1, 7, and 13 in the multiple-dose study. PK and PD analyses were performed in plasma samples to determine Cmax, Tmax, AUC0-t, AUC0-infinity, and DPP4 enzymatic activity. The drug accumulation index was also calculated for each dose of PHX1149 in the multiple-dose study. Adverse events (AEs) were monitored in both studies through physical examinations, including measurement of vital signs, and clinical laboratory testing. In both studies, electrocardiography was performed. RESULTS:The single- and multiple-dose studies enrolled 30 and 28 subjects, respectively, for a total enrollment in the 2 studies of 58 healthy adult subjects. The distribution of male and female subjects was 14 (47%) and 16 (53%), respectively, in the single- dose study and 16 (57%) and 12 (43%) in the multiple- dose study. In the single-dose study, 28 (93%) subjects were white; in the multidose study, all subjects were white. The mean (SD) ages in the 2 studies were 51 (10) and 51 (12) years, respectively; and mean (SD) body weights were 89.0 (10.8) and 81.1 (10.9) kg, respectively. PHX1149 exhibited dose-proportional increases in mean Cmax AUC0-t, and AUC0-infinity across the evaluated dose ranges. Tmax ranged from 2 to 4 hours, and t1/2 ranged from approximately 10 to 13 hours. No drug accumulation was observed. Plasma DPP4 inhibition at 24 hours was >or=50% in the multiple-dose study for doses of >or=100 mg. PHX1149 400 mg achieved approximately 90% 24-hour plasma DPP4 inhibition in the multiple-dose study. All AEs were characterized as mild, with the exception of 1 case of moderate edema, which occurred 17 days after the end of dosing in the multiple-dose study (50-mg dose group) and was considered unrelated to the study drug. Adverse events were experienced by 47% of all subjects studied in the single-dose study and 93% of subjects in the multiple-dose study. The rates of AEs were comparable between the study and placebo groups. CONCLUSIONS:The PK parameters and PD properties of PHX1149 were suitable (eg, tl/2, DPP4 inhibition) for once-daily dosing in this group of 58 healthy subjects. All doses were well tolerated.
journal_name
Clin Therjournal_title
Clinical therapeuticsauthors
O'Farrell AM,van Vliet A,Abou Farha K,Cherrington JM,Campbell DA,Li X,Hanway D,Li J,Guler HPdoi
10.1016/j.clinthera.2007.08.005subject
Has Abstractpub_date
2007-08-01 00:00:00pages
1692-705issue
8eissn
0149-2918issn
1879-114Xpii
S0149-2918(07)00240-8journal_volume
29pub_type
杂志文章,随机对照试验abstract::This study evaluated the efficacy, safety, and most suitable dose of omeprazole in short-term acute treatment (4 weeks) and maintenance treatment (6 months) of patients older than 60 years of age with endoscopically diagnosed gastric ulcer (GU) or duodenal ulcer (DU). This randomized, prospective study included 156 pa...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1994-11-01 00:00:00
abstract:BACKGROUND:Respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) in early life has been associated with sustained airway hyperreactivity during childhood; however, corresponding data in premature infants are sparse. OBJECTIVE:The objective of this study was to determine whether RSV-LRI during early...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2011.01.007
更新日期:2010-12-01 00:00:00
abstract:BACKGROUND:Recombinant activated factor VII (rFVIIa) is indicated to treat bleeding episodes or prevent bleeding related to surgery in patients with hemophilia A or B who have antibodies to coagulation factors VIII or IX. The first-generation rFVIIa formulation is stable when stored under refrigeration. A new formulati...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/s0149-2918(08)80055-0
更新日期:2008-07-01 00:00:00
abstract:PURPOSE:Glucosamine is widely used by patients with osteoarthritis (OA) to provide symptomatic relief and to delay disease progression. However, clinical studies have reported inconsistent clinical outcomes. The current study hypothesized that the reported inconsistent clinical results could be, in part, due to variabl...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章
doi:10.1016/j.clinthera.2020.06.009
更新日期:2020-08-01 00:00:00
abstract:BACKGROUND:The utilization pattern of dronedarone was unknown, especially regarding prescribers' compliance with the product's prescribing information (PI) following its availability and the implementation of the Food and Drug Administration-approved risk evaluation and mitigation strategy for the drug in the United St...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2011.08.013
更新日期:2011-10-01 00:00:00
abstract:BACKGROUND:Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2011.04.015
更新日期:2011-05-01 00:00:00
abstract:BACKGROUND:Patients with mild intermittent or mild persistent asthma represent 70% of asthma sufferers. Inhaled corticosteroids (ICSs) are the mainstay of treatment for persistent asthma, although many of the early clinical studies of these drugs included only patients with moderate to severe asthma. OBJECTIVE:This ar...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/s0149-2918(02)80017-0
更新日期:2002-07-01 00:00:00
abstract:PURPOSE:Restless legs syndrome (RLS) is a commonly occurring neurologic disorder that affects up to one third of women during pregnancy. RLS has been associated with increased sympathetic tone in the nonpregnant population. We examined whether a RLS surrogate is associated with a higher prevalence of pregnancy and neon...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2015.11.021
更新日期:2016-02-01 00:00:00
abstract::In a previous report of a multicenter study (Kannel et al, 1990), the results of 6 months' treatment with lovastatin in 489 adults with primary hypercholesterolemia were presented. The present report contains the results from the 236 women patients. The intial dose of lovastatin was 20 mg daily and could be increased ...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,多中心研究
doi:
更新日期:1992-05-01 00:00:00
abstract:BACKGROUND:Pitavastatin, a fully synthetic β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject v...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2014.06.021
更新日期:2014-09-01 00:00:00
abstract::Ketoprofen is a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid family with demonstrated efficacy in the treatment of rheumatoid arthritis and osteoarthritis; a distinguished safety profile; and good tolerability. This report describes a new extended-release formulation that maintains therapeutic pla...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:
更新日期:1994-03-01 00:00:00
abstract:BACKGROUND:Therapeutic proteins have revolutionized the treatment of many diseases. In the near future, many more therapeutic proteins are likely to become available for an increasingly wide range of indications. OBJECTIVES:This article reviews the incidence, causes, and consequences of formation of antibodies to ther...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/s0149-2918(02)80075-3
更新日期:2002-11-01 00:00:00
abstract::The increasing worldwide recognition of the deleterious sequelae of Chlamydia trachomatis urogenital tract infections makes rapid, inexpensive diagnostic tests a high priority. Cell culture, still the standard for all other methods, is only 90% sensitive. Direct fluorescent antibody (FA) tests use highly specific mono...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1986-01-01 00:00:00
abstract:PURPOSE:Surgery, radiotherapy, and chemotherapy are the mainstays of cervical cancer treatment. Many patients receive multiple treatment modalities, each with its own long-term effects. Given the high 5-year survival rate for cervical cancer patients, evaluation and improvement of long-term quality of life are essentia...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2014.11.013
更新日期:2015-01-01 00:00:00
abstract:OBJECTIVE:This study was conducted to evaluate data on chemotherapy-associated anemia and thrombocytopenia, and cycle delays in patients with cancer in a community oncology practice. METHODS:Data on adult patients (age > or =18 years) with cancer treated in outpatient oncology clinics throughout the United States betw...
journal_title:Clinical therapeutics
pub_type: 杂志文章,多中心研究
doi:10.1016/j.clinthera.2009.11.020
更新日期:2009-01-01 00:00:00
abstract::Healing rates were examined retrospectively in 124 outpatients with peptic ulcer who had received cimetidine for at least four weeks. Treatment was unsuccessful in 73 patients. A statistical analysis of the factors involved in treatment failure revealed that in patients with duodenal ulcers 60.6% of the treatment succ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:The contribution of intestinal bacterial strains (gut microbiota) in human metabolism and obesity is being increasingly recognized. The goal of this article was to provide a commentary on the clinical usefulness of these data. METHODS:We performed a review of the currently available articles on PubMed. FINDIN...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2015.03.008
更新日期:2015-06-01 00:00:00
abstract:OBJECTIVES:The primary study objective was to assess the time course and intensity of sedation after administration of immediate-release (IR) and extended-release (XR) quetiapine fumarate in healthy subjects during dose initiation. The tolerability of the 2 formulations was also evaluated. METHODS:This was a randomize...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2009.03.002
更新日期:2009-03-01 00:00:00
abstract:BACKGROUND:Anemia is a common complication of chronic kidney disease (CKD). The approved dosing interval for currently available erythropoiesis-stimulating agents (ESAs) is 2 to 3 times weekly for epoetin alfa (EPO) and every 1 to 2 weeks for darbepoetin alfa (DARB). However, clinicians sometimes use less frequent dosi...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2007.09.012
更新日期:2007-09-01 00:00:00
abstract::This paper reviews the issues that are critical for the valuation of medical resources in the context of health economic studies. There are several points to consider when undertaking the valuation of medical resources. The perspective of the analysis should be established before determining the valuation process. Fut...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:
更新日期:1994-05-01 00:00:00
abstract::One hundred children with peritonitis resulting from a perforated appendix were treated with ceftazidime or netilmicin. Metronidazole was added to both groups to treat the anaerobic organisms commonly associated with the infecting aerobic organisms in peritonitis. Escherichia coli was the most common aerobe found in p...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1990-01-01 00:00:00
abstract::The pharmacodynamic parameter that appears to correlate best with a successful therapeutic outcome with beta-lactam antibiotics is the length of time the serum antibiotic concentration remains above the minimum inhibitory concentration (MIC) for the infecting pathogen. By maximizing this parameter, continuous administ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/S0149-2918(00)86736-3
更新日期:1999-11-01 00:00:00
abstract:BACKGROUND:It has been reported that the efficacy of acute forms of nicotine replacement therapy, such as nicotine gum and lozenges, improves when sufficient quantities of medication are used. OBJECTIVE:This analysis examined whether adherence with daily nicotine patch wear was associated with improved rates of smokin...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2008.09.016
更新日期:2008-10-01 00:00:00
abstract:BACKGROUND:The need for an approach to measuring health results that incorporates patients' and payers' perspectives has generated a wide range of health care outcomes (HCOs), but it is yet unknown whether these HCOs are appropriate or valid for the health care decision-making process. OBJECTIVE:The goal of this study...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2011.07.013
更新日期:2011-09-01 00:00:00
abstract:PURPOSE:External electric muscle stimulation (EMS) of the thigh muscles was found to reduce pain resulting from diabetic neuropathy (DN), a vascular complication of diabetes. This study investigated circulating hematopoietic stem cells (HSCs) after EMS treatment. Impaired function of HSCs and the subpopulation endothel...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2017.05.340
更新日期:2017-06-01 00:00:00
abstract::In this double-masked, double-dummy, randomized, single crossover study, we compared single doses of a fast-dissolving wafer formulation of famotidine with a conventional tablet formulation of ranitidine in patients with gastroesophageal reflux disease (GERD). Patient preference time until symptomatic relief, and pred...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/s0149-2918(97)80074-4
更新日期:1997-01-01 00:00:00
abstract::A benzothiazepine derivative, CRD-401, was administered orally in a dosage of 60 to 120 mg/day to 14 patients with various renal diseases. The systolic pressure was lowered slightly in some cases after administration of CRD-401. Urine volume and urinary excretion of electrolytes were increased by the drug in most pati...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1981-01-01 00:00:00
abstract:BACKGROUND:Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM has become more refined with the development of new monitoring techniques and more specific assays. OBJECTIVE:This article summarizes current data on TDM of the follow...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/s0149-2918(02)85038-x
更新日期:2002-03-01 00:00:00
abstract:PURPOSE:The formulary inclusion of proton pump inhibitors (PPIs) in the government hospital health services in Qatar is not comparative or restricted. Requests to include a PPI in the formulary are typically accepted if evidence of efficacy and tolerability is presented. There are no literature reports of a PPI scoring...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2016.03.004
更新日期:2016-05-01 00:00:00
abstract:BACKGROUND:Impaired mineral homeostasis affecting calcium, phosphate, and magnesium is a result of parathyroid hormone (PTH) deficiency in hypoparathyroidism. The current standard of treatment with active vitamin D and oral calcium does not control levels of these major minerals. Recombinant full-length human PTH 1-84 ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2014.04.001
更新日期:2014-05-01 00:00:00