Abstract:
BACKGROUND:NXN-188 is a dual-action oral therapeutic being developed for the treatment of acute migraine. The mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoform and affinity for serotonin (5-hydroxytryptamine1B/D) receptors. OBJECTIVES:The aims of the initial Phase I clinical studies were to compare the pharmacokinetic (PK) properties of NXN-188 administered as a single dose or multiple twice-daily doses to healthy adult volunteers and to determine the tolerability of NXN-188 in these individuals. METHODS:Healthy adult male and female subjects were enrolled in 5 Phase I, randomized, double-blind studies, all of which (except for a fed/fasted trial) were placebo controlled. In the 4 single-dose studies, which differed with respect to feeding status and the formulation used (capsules or solution), subjects received NXN-188 at doses of 2 to 800 mg (0.027-11.2 mg/kg). In the repeat-dose study, subjects received 50-mg (0.71 mg/kg) doses twice daily for 4 days. Serum samples were analyzed for NXN-188 using validated HPLC-MS/MS methods. Standard clinical laboratory analyses (chemistry, hematology, and urinalysis) and measurements of serum creatine kinase and myoglobin levels were conducted at screening, admission, discharge, and follow-up. Baseline and postexposure values were compared to assess tolerability. Electrocardiography and physical examination were conducted at screening and at discharge and follow-up if any negative change occurred from the previous findings. Vital signs (heart rate, blood pressure, respiration), including assessment for orthostatic changes, were measured at screening, check-in, and follow-up visits (1 hour before dosing, every 30 minutes for the first 4 hours, then every hour for the next 4 hours, then every 4 hours for the remainder of the 24-hour study). Adverse events were recorded, reviewed, and monitored throughout the study. RESULTS:Two hundred three subjects (102 women, 101 men) 18 to 50 years of age were enrolled in the 5 studies; 168 subjects received NXN-188 and 35 received placebo. Most (91%) of the subjects were white; weight ranged from 69.3 to 71.8 kg (body mass index, 24.5-25.8 kg/m(2)). The initial absorption phase of orally administered NXN-188 peaked at approximately 1 hour, followed by a second absorption phase with a T(max) of approximately 4 to 5 hours. Exposure (C(max) and AUC) increased in a slightly greater than dose-proportional manner across a dose range of 2 to 800 mg (0.027-11.2 mg/kg). Elimination was multiexponential, with an initial rapid plasma drug elimination (plasma concentrations decreased approximately 70%-90% from Cmax within 24 hours after dosing), followed by a prolonged clearance phase of very low NXN-188 concentrations ( approximately 1%-5% of Cmax) that persisted for several weeks. Clearance ranged from 70 to 130 L/h, and the NXN-188 halflife ranged from 11 to 178 hours. Neither food nor gender had any measurable effect on the PK properties of NXN-188. Overall, dizziness was reported more often in the NXN-188 groups than in the placebo groups (6.3% vs 2.9%, respectively). Frequently reported adverse events that occurred more often in the placebo groups than in the NXN-188 groups were somnolence (11.4% vs 6.3%, respectively), and headache (8.6% vs 6.9%). Incidences of orthostatic hypotension (6.3% vs 5.7%) and postural (orthostatic) tachycardia syndrome (6.3% vs 5.7%) were comparable in the NXN-188 and placebo groups, respectively. No serious adverse events were reported at any dose of NXN-188 up to the current maximum dose (800 mg or 11.2 mg/kg). CONCLUSION:NXN-188 exhibited linear pharmaco-kinetics over the dose range studied and appeared to be well tolerated in these healthy volunteers.
journal_name
Clin Therjournal_title
Clinical therapeuticsauthors
Vaughan D,Speed J,Medve R,Andrews JSdoi
10.1016/j.clinthera.2010.01.006subject
Has Abstractpub_date
2010-01-01 00:00:00pages
146-60issue
1eissn
0149-2918issn
1879-114Xpii
S0149-2918(10)00007-Xjournal_volume
32pub_type
杂志文章,随机对照试验abstract:OBJECTIVES:The aims of this study were to assess how closely cardiologists in Pakistan followed published recommendations for lipid management and to identify the factors associated with such behavior. METHODS:A cross-sectional survey was delivered in person between September and December 2007 to all cardiologists pra...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2009.07.020
更新日期:2009-07-01 00:00:00
abstract:BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) has a substantial negative impact; however, within long-term follow-up studies, a proportion of patients do very well, both symptomatically and functionally, suggesting that the lower the symptom burden, the greater the functional improvements. Studies in major...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2006.11.006
更新日期:2006-11-01 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:OBJECTIVES:The aims of this study were to determine the prevalence of prescribing potentially inappropriate medications (PIMs) based on the 2002 Beers criteria among ambulatory patients aged > or =65 years, to compare PIM prevalence rates based on the 1997 Beers criteria and Zhan criteria with the rate obtained using t...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2005.01.009
更新日期:2005-01-01 00:00:00
abstract::Congestive heart failure (CHF) afflicts more than 4.6 million people in the United States and increases at a rate of 400,000 newly diagnosed patients per year. With more than 1.5 million hospital admissions per year attributed to CHF, it is the number one cause of hospitalization. Hospital length of stay (LOS) is one ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/s0149-2918(96)80223-2
更新日期:1996-07-01 00:00:00
abstract::Patient counseling is an important aspect of family planning. Patient choice, compliance, and satisfaction with a contraceptive method depend heavily on the counseling experience. This is especially true in the United Kingdom where contraceptives are provided to patients at no direct cost to them. Women are therefore ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/s0149-2918(96)80187-1
更新日期:1996-01-01 00:00:00
abstract:BACKGROUND:Trials of monotherapy with alpha(1)-adrenergic-receptor antagonists (alpha(1)ARAs) and 5 alpha-reductase inhibitors (5ARIs) have found that the former drug class is effective in managing benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and improving the maximal urinary flow rate...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/s0149-2918(07)80077-4
更新日期:2007-03-01 00:00:00
abstract:PURPOSE:Despite modern reperfusion and pharmacologic therapies, myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Therefore, the development of further therapeutics affecting post-MI recovery poses significant benefits. This review focuses on the post-MI immune response and immuno...
journal_title:Clinical therapeutics
pub_type: 杂志文章,评审
doi:10.1016/j.clinthera.2020.09.006
更新日期:2020-10-01 00:00:00
abstract::Six hundred forty-eight patients (50.5% men; 49.5% women) with diabetes mellitus on animal-source insulin therapy for at least five years were studied. In this patient population, approximately 68.7% had Type I insulin-dependent diabetes mellitus and 31.3% had Type II noninsulin-dependent diabetes mellitus, nonetheles...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1991-09-01 00:00:00
abstract:PURPOSE:The effect of peripheral arterial disease (PAD) among young and middle-aged adults can be significant, but no previous study has examined the prognosis and the associated health care cost of the disease in this population. We evaluated the clinical and economic burden of PAD in patients from a large claims data...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2014.06.013
更新日期:2014-08-01 00:00:00
abstract::The added hypotensive effect of bevantolol, a new cardioselective beta-blocker, was studied in 244 patients with mild to moderate essential hypertension following prior treatment with hydrochlorothiazide or placebo. After four weeks of monotherapy with 50 mg/day or 100 mg/day of hydrochlorothiazide or placebo, the mea...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract:OBJECTIVE:This study assessed the cost-effectiveness of escitalopram for the treatment of depression in the Netherlands from a societal perspective. METHODS:A decision tree model was constructed using decision analytical techniques. Data sources included published literature, clinical trials, official price/tariff lis...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2012.04.006
更新日期:2012-06-01 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:BACKGROUND:Aspirin is a widely used NSAID that has been extensively studied in numerous conditions. Nonprescription analgesics, such as aspirin, are frequently used for a wide variety of common ailments, including conditions such as dental pain and tension-type headache. OBJECTIVE:We sought to compare the efficacy and...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2011.11.018
更新日期:2012-01-01 00:00:00
abstract::In a double-blind factorial clinical trial in 300 patients (150 primiparae and 150 multiparae), the effects of amniotomy, rociverine, and butylscopolamine bromide administration on the course of labor were investigated. Rociverine significantly reduced the dilatation time and had no effect on the delivery time. Butyls...
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:1981-01-01 00:00:00
abstract::Flecainide, a new antiarrhythmic agent, was given to eight healthy men to ascertain plasma drug levels and to assess tolerance for the drug. Each subject received a single intravenous (IV) dose (0.5, 1, 1.5, or 2 mg/kg) of flecainide, and plasma levels of unchanged flecainide were measured by gas-liquid chromatography...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1984-01-01 00:00:00
abstract:BACKGROUND:Several studies have reported increased health care resource use among hypertensive patients with uncontrolled blood pressure (BP). OBJECTIVE:The purpose of this study was to investigate the relationship between BP control and health care resource use. METHODS:Data were obtained from the Caring for Hyperte...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1016/s0149-2918(01)80143-0
更新日期:2001-10-01 00:00:00
abstract:BACKGROUND:Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. OBJECTIVE:The aim of this study was to assess the pharmacokinet...
journal_title:Clinical therapeutics
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.clinthera.2006.01.015
更新日期:2006-01-01 00:00:00
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::Exposure of the eye to airborne particles in patients predisposed to allergy often results in the signs and symptoms of allergic conjunctivitis such as red, itchy eyes and ocular discharge. The mediators of these allergic symptoms include histamine, inflammatory substances such as prostaglandins, and other products of...
journal_title:Clinical therapeutics
pub_type: 杂志文章,多中心研究
doi:10.1016/0149-2918(95)80066-2
更新日期:1995-09-01 00:00:00
abstract:BACKGROUND:Besifloxacin is a topical fluoroquinolone with potent in vitro activity against a broad spectrum of ocular pathogens, including drug-resistant strains. Besifloxacin ophthalmic suspension 0.6% given 3 times daily for 5 days has been reported to be more effective than its vehicle in the treatment of bacterial ...
journal_title:Clinical therapeutics
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.clinthera.2010.12.004
更新日期:2011-01-01 00:00:00
abstract:BACKGROUND:Use of cholesterol-lowering regimens has been shown to reduce the risk of coronary heart disease (CHD), both in primary and secondary prevention. However, there have been few studies of the relative benefits and risks of the various cholesterol-lowering agents in patient groups with specific risk factors for...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1016/s0149-2918(01)80050-3
更新日期:2001-03-01 00:00:00
abstract::In trying to identify the therapeutic impact of a drug, clinical trials eliminate potentially confounding factors such as comorbidities, poor compliance and treatment errors in diagnosis, dosing, and drug interactions. Elimination of these variables means that attempts to use clinical data as the basis for predicting ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/0149-2918(95)80098-0
更新日期:1995-11-01 00:00:00
abstract::Coexisting diseases may have unforeseen yet clinically significant effects on patients' well-being. Both generic and disease-specific measures are frequently used to assess health-related quality of life (QOL). The present study assessed the effects of comorbidity on the results of QOL measures through an analysis of ...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/S0149-2918(00)88295-8
更新日期:1999-02-01 00:00:00
abstract::The pharmacokinetics of cimetidine were studied in three newborn infants with reflux esophagitis or stress ulcer. One infant was given 5 mg/kg intravenously (IV), one was given 10 mg/kg IV, and one was given 10 mg orally. Serum concentrations 30 minutes after administration were 1.2 micrograms/ml, 5 micrograms/ml, and...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract::Nonadherence to recommended pneumococcal conjugate vaccine (PCV) schedules may have implications for protection against pneumococcal disease. In this commentary, we have assessed adherence to the recommended dosing schedules (the completion of the primary PCV and booster series) in different European countries. We fou...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2014.03.001
更新日期:2014-05-01 00:00:00
abstract::The total cost of administering calcium polycarbophil per unit dose (two tablets) was compared with that of administering psyllium mucilloid (one packet dissolved in 8 oz of water) in 20 elderly nursing-home residents. Times for printing labels, checking and initialing labels, gathering materials needed, and preparing...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:
更新日期:1990-01-01 00:00:00
abstract::A total of 804 pediatric patients (572 neonates and 232 infants and children) with suspected or documented serious infections were enrolled in a multicenter open study of netilmicin, a new semisynthetic aminoglycoside. All patients were evaluable for safety; 161 (20%) had bacteriologically documented infections and we...
journal_title:Clinical therapeutics
pub_type: 临床试验,杂志文章
doi:
更新日期:1983-01-01 00:00:00
abstract:PURPOSE:The Enhancing Quality of Prescribing Practices for Older Veterans Discharged From the Emergency Department (EQUIPPED) program is a quality improvement initiative that combines education, clinical decision support (ie, geriatric pharmacy order sets), and in-person academic detailing coupled with audit and feedba...
journal_title:Clinical therapeutics
pub_type: 杂志文章
doi:10.1016/j.clinthera.2020.02.013
更新日期:2020-04-01 00:00:00
abstract:PURPOSE:The goal of this study was to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on lipid profiles in patients with type 2 diabetes. METHODS:The MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched from inception through October 31, 2013. Randomized controll...
journal_title:Clinical therapeutics
pub_type: 杂志文章,meta分析,评审
doi:10.1016/j.clinthera.2014.11.008
更新日期:2015-01-01 00:00:00