Effects of a State- and Use-Dependent Nav1.7 Channel Blocker on Ambulatory Blood Pressure: A Randomized, Controlled Crossover Study.

Vixotrigine is a state- and use-dependent Nav1.7 channel blocker being investigated for the treatment of neuropathic pain conditions. This randomized, double-blind, placebo-controlled crossover trial was designed to evaluate changes in blood pressure with the administration of vixotrigine using ambulatory blood pressure monitoring (ABPM).

Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation.

The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.

Clinical assessment of potential drug interactions of faldaprevir, a hepatitis C virus protease inhibitor, with darunavir/ritonavir, efavirenz, and tenofovir.

Background: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. Studies were performed to investigate potential drug interactions between faldaprevir and the commonly used antiretrovirals darunavir/ritonavir, efavirenz, and tenofovir to guide the coadministration of faldaprevir with these agents in human immunodeficiency virus/HCV-coinfected patients.

Methods: In 3 open-label, phase 1 pharmacokinetic (PK) studies, healthy adult volunteers received (1) darunavir/ritonavir (800 mg/100 mg once daily) with and without faldaprevir (240 mg once daily); (2) faldaprevir (240 mg twice daily) with and without efavirenz (600 mg once daily); or (3) faldaprevir (240 mg twice daily) or tenofovir (300 mg once daily) alone and in combination.

Safety, pharmacokinetic, immunogenicity, and pharmacodynamic responses in healthy volunteers following a single intravenous injection of purified staphylococcal protein A.

A single-dose study was conducted to characterize the safety, pharmacokinetic, immunogenicity, and pharmacodynamic activity of highly purified Staphylococcal protein A (SPA), a native bacterial protein with immune-modulatory activity. Twenty healthy adults received a single intravenous dose of either 0.3 µg/kg (n = 8) or 0.

Efficacy of a methylphenidate transdermal system versus t.i.d. methylphenidate in a laboratory setting.

Objective: To test the efficacy and tolerability of the methylphenidate transdermal formulation (MTS) against immediate-release methylphenidate (IR MPH) and placebo in a 12-hr analog classroom setting.

Method: A total of nine boys ages 6 to 9 years, medicated with MPH for ADHD, complete a within-subject, double-blind study. For the purpose of the study, the boys are administered a dose of 20 cm(2) MTS, a matched dose of IR MPH 10 mg TID, and placebo.

Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects.

Study Objective: To examine the effect of telavancin, a lipoglycopeptide antibiotic with potent gram-positive activity, on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A probe substrate. Design. Phase I, randomized, double-blind, placebo-controlled, crossover study.

Pharmacokinetics of BILR 355 after multiple oral doses coadministered with a low dose of ritonavir.

The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID.

Pharmacokinetics of Oral Azithromycin in Serum, Urine, Polymorphonuclear Leucocytes and Inflammatory vs Non-Inflammatory Skin Blisters in Healthy Volunteers.

Two open-label studies were conducted to assess the serum, urine, polymorphonuclear (PMN) and red blood cell (RBC) pharmacokinetics of a 5-day course (1500mg total) of oral azithromycin. Inflammatory and non-inflammatory blisters were also induced to study the propensity of azithromycin to preferentially concentrate at a model infection site. 14 subjects participated in the two studies and tolerated azithromycin and the study methods well.

Multiple-dose pharmacokinetics and safety of bevirimat, a novel inhibitor of HIV maturation, in healthy volunteers.

Background And Objective: Bevirimat [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] is a novel inhibitor of HIV-1 maturation. This study was performed to investigate the pharmacokinetics and safety of bevirimat during repeated dosing in healthy volunteers.

Subjects And Methods: The study was a 10-day, randomised, double-blind, placebo-controlled, dose escalation study.

Safety and pharmacokinetics of Bevirimat (PA-457), a novel inhibitor of human immunodeficiency virus maturation, in healthy volunteers.

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV) maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n = 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n = 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters.

Fosamprenavir plus ritonavir increases plasma ketoconazole and ritonavir exposure, while amprenavir exposure remains unchanged.

Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV.

Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers.

Objective: To evaluate the safety and pharmacokinetic interaction between GW433908, ritonavir (RTV), and efavirenz (EFV).

Methods: In period 1, subjects received either a once daily (QD) regimen of GW433908 1395 mg + RTV 200 mg (Study 1) or a twice daily (bid) regimen of GW433908 700 mg + RTV 100 mg (Study 2) for 14 days. In period 2, subjects received EFV 600 mg QD with either the same GW433908 + RTV regimen as in period 1 (arm 1) or with a GW433908 + RTV regimen that included an additional 100 mg of RTV (arm 2) for 14 days.

Multicentre evaluation of the in vitro activity of linezolid in the Western Pacific.

Multiresistance to antimicrobial agents is common in staphylococci and pneumococci isolates in the Western Pacific region. The activity of linezolid, a new oxazolidinone, was evaluated against a spectrum of Gram-positive species collected in the region. Eighteen laboratories from six countries in the Western Pacific examined the linezolid susceptibility of 2143 clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci (CoNS) and Enterococcus spp.

Multicentre assessment of linezolid antimicrobial activity and spectrum in Europe: report from the Zyvox antimicrobial potency study (ZAPS-Europe).

Objective: To evaluate the in vitro spectrum and activity of linezolid, a recent oxazolidinone, according to well-controlled surveillance data from 42 medical centers in 13 countries throughout Europe.

Methods: Participants tested the susceptibility of 125 clinical strains of enterococcal and staphylococcal species against 13 drugs using reference broth microdilution trays or the standardized disk diffusion method of the National Committee for Clinical Laboratory Standards (NCCLS). Streptococcal species (n = 25 at each center) were tested against six drugs using E test (AB BIODISK, Solna, Sweden).

Multicenter assessment of the linezolid spectrum and activity using the disk diffusion and Etest methods: report of the Zyvox(R) antimicrobial potency study in Latin America (LA-ZAPS).

Linezolid was the first clinically applied member of the new antimicrobial class called the oxazolidinones. These agents have a powerful spectrum of activity focussed against Gram-positive organisms including strains with documented resistances to other antimicrobial classes. We conducted a multicenter surveillance (Zyvox Antimicrobial Potency Study; ZAPS) trial of qualifying Gram-positive isolates from 24 medical centers in eight countries in Latin America.

A multicenter evaluation of linezolid antimicrobial activity in North America.

Overall, 141 centers in North America enrolled in this international surveillance study designed to evaluate the in vitro antimicrobial activity and spectrum of linezolid, a new oxazolidinone. Each participant tested the susceptibility of clinical isolates of staphylococcal species (n = 85) against 12 drugs, and enterococcal species (n = 40) against 6 drugs using reference broth microdilution trays; and of streptococcal species (n = 25) against 6 drugs using Etests (AB BIODISK, Solna, Sweden). Quality control testing was conducted using recommended strains, and verification of resistance to linezolid and select other agents was performed by a regional monitor.

Effect of food on the pharmacokinetics of (-) and (+) dOTC when administered as an oral racemate.

The objective of this study was to evaluate the effect of food on the pharmacokinetics of racemic dOTC, a nucleoside analogue reverse transcriptase inhibitor, in adult male volunteers. Twelve healthy adult male subjects were enrolled in a randomized, open-label, single-dose crossover study. All were nonsmoking, within 15% of ideal body weight, and between 18 and 50 years of age.

Pharmacokinetics and pharmacodynamics of aztreonam and tobramycin in hospitalized patients.

Background: Pharmacokinetic/pharmacodynamic (PK/PD) optimization of antibiotic therapy has been shown to improve outcomes in several antibiotic classes. Despite the frequent use of beta-lactams, clinical data in humans remain limited.

Objective: This study evaluated the relationship between serum pharmacokinetics, pharmacodynamics, pathogen susceptibility, and clinical outcomes in patients receiving aztreonam or tobramycin monotherapy.

Multi-laboratory assessment of the linezolid spectrum of activity using the Kirby-Bauer disk diffusion method: Report of the Zyvox Antimicrobial Potency Study (ZAPS) in the United States.

The in vitro activity of linezolid against common Gram-positive pathogens was compared to that of penicillin or ampicillin or oxacillin (depending upon genus), cefazolin, erythromycin, clindamycin, quinupristin/dalfopristin, levofloxacin, nitrofurantoin and vancomycin by disk diffusion methods. One hundred and six centers (31 states in US) tested recent clinical isolates of Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecium, E. faecalis, Streptococcus pneumoniae, and other streptococci.

Antimicrobial susceptibility of quinupristin/dalfopristin tested against gram-positive cocci from Latin America: results from the global SMART (GSMART) surveillance study.

Gram-positive cocci are important causes of both nosocomial and community-acquired infections, and antimicrobial resistance among these pathogens has become an important problem worldwide. Since resistance among these organisms can vary substantially by geographic location, we conducted a multicenter surveillance study with isolates from five Latin American countries (15 medical centers). Quinupristin/dalfopristin (formerly RP-59500) is a novel streptogramin combination with focused activity against Gram-positive cocci, many exhibiting emerging resistance.

New agents for Gram-positive bacteria.

Infections caused by multiple-resistant Gram-positive organisms continue to occur at an alarming rate worldwide. Two new and unique antimicrobial agents targeted specifically against such organisms, quinupristin/dalfopristin and linezolid, have been approved for use in the USA in the past year and will play an important role in the treatment of life-threatening infections. In addition, several new fluoroquinolones have been approved recently or will be available in the near future to aid in the treatment of infections caused by resistant strains of Streptococcus pneumoniae.

Safety, tolerability, and pharmacokinetics of single oral doses of BCH-10652 in healthy adult males.

Racemic dOTC (BCH-10652) is a novel nucleoside reverse transcriptase inhibitor consisting of two enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine, (-)dOTC and (+)dOTC, that have both shown activity against human immunodeficiency virus type 1. The objectives of this study were to characterize the safety, tolerability, and stereospecific pharmacokinetics of single oral doses of racemic dOTC in healthy, nonsmoking adult male volunteers. Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (-)dOTC were determined.

Absolute bioavailability and disposition of (-) and (+) 2'-deoxy- 3'-oxa-4'-thiocytidine (dOTC) following single intravenous and oral doses of racemic dOTC in humans.

The purpose of this study was to characterize the pharmacokinetics and determine the absolute bioavailability of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) (BCH-10652), a novel nucleoside analogue reverse transcriptase inhibitor, in humans. dOTC belongs to the 4'-thio heterosubstituted class of compounds and is a 1:1 mixture of its two enantiomers, (-) and (+) dOTC. Twelve healthy adult male volunteers each received oral (800-mg) and intravenous (100-mg) doses of dOTC in two study periods separated by at least 7 days.

A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia.

National Nosocomial Resistance Surveillance Group participants from 22 hospitals across the United States reviewed medical records for hospitalized patients with vancomycin-resistant enterococcal (VRE) or vancomycin-susceptible enterococcal (VSE) bacteremia to identify risk factors associated with the acquisition of VRE bacteremia, describe genetic traits of VRE strains, and identify factors predictive of clinical outcome. VRE cases were matched to VSE controls within each institution. Multiple logistic regression (LR) and classification and regression tree (CART) analysis were used to probe for factors associated with VRE bacteremia and clinical outcome.

Comparison of the abilities of grepafloxacin and clarithromycin to eradicate potential bacterial pathogens from the sputa of patients with chronic bronchitis: influence of pharmacokinetic and pharmacodynamic variables.

A randomized open-label study was conducted to compare the pharmacokinetics and pharmacodynamics of grepafloxacin with those of clarithromycin in patients with chronic bronchitis whose sputa were colonized with potential bacterial pathogens. Patients received oral grepafloxacin 400 mg od for 10 days (n = 15) or oral clarithromycin 500 mg bd for 10 days (n = 10). Sputum samples were collected before the first dose, 1, 4 and 8 h after a dose on day 1 and then before a dose on days 2, 3, 5, 7 and 10 to determine the time to eradication (T(erad)) of the potential bacterial pathogens.