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Background: The REG2 anticoagulation system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous control agent, anivamersen., Objectives: To assess the safety, tolerability and pharmacokinetic and pharmacodynamic responses of REG2., Patients/methods: In this phase 1a study, 36 healthy volunteers were enrolled into five cohorts and given one dose of pegnivacogin. Cohorts 1 (n = 6) and 1A (n = 4) received 0.5 mg kg(-1); cohort 2 (n = 6) received 1.0 mg kg(-1); cohort 3 (n = 6) received 3.0 mg kg(-1); and cohort 4 (n = 8) received 2.0 mg kg(-1) . In cohorts 1-3, two subjects were randomized to placebo. Cohort 4 subjects were subsequently randomized to single-dose (n = 4) or multidose (n = 4) anivamersen., Results: The mean maximum observed concentrations of pegnivacogin in cohorts 1, 1A, 2 and 3 at median time were 5.16 μg mL(-1) at 84 h, 5.19 μg mL(-1) at 72 h, 9.32 μg mL(-1) at 90 h, and 32.5 μg mL(-1) at 84 h, respectively. The maximum relative activated partial thromboplastin time and time needed to achieve this were 1.18 at 2 days, 1.16 at 2 days, 1.27 at 3 days, and 1.85 at 2 days, respectively. The calculated mean half-life and mean residence times of pegnivacogin were 6.12 days and 9.6 days, respectively. There was rapid reversal with intravenous anivamersen, although subsequent reaccumulation of pegnivacogin was observed., Conclusions: In our first-in-human study, REG2 was well tolerated and provided dose-proportional anticoagulation for several days after a single subcutaneous dose, with complete, although transient, reversal by its control agent. This study demonstrates the first application of a subcutaneously administered aptamer, and represents a potential advance in aptamer therapeutics., (© 2012 International Society on Thrombosis and Haemostasis.)

The objectives of this study were to evaluate the safety and tolerability of RheothRx (poloxamer 188) injection administered as an intravenous (i.v.) infusion to healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. Thirty-six healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation trial for RheothRx injection. The volunteers were randomized to three treatment groups (12 per treatment group, with eight receiving active therapy and four receiving placebo). In each treatment group, volunteers received RheothRx injection or placebo as an i.v. infusion on two occasions at least 3 weeks apart to make a total of six doses being studied (10, 30, and 45 mg/kg/h for 72 h, 60 mg/kg/h for 43.3 to 72 h, 60 and 90 mg/kg/h for 24 h). Serial plasma samples were collected during and up to 36 h after the end of the infusions; urine was collected over intervals from the start of the infusion until 36 h after the infusions were terminated. Plasma and urine samples were assayed for poloxamer 188 by gel-permeation chromatography. Pharmacokinetic parameter values were calculated by noncompartmental and compartmental methods. Poloxamer 188 was eliminated primarily by renal excretion. Estimates of clearance, elimination rate constant, and apparent volume of distribution at steady state values were independent of infusion rate. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

An automated high-pressure liquid chromatographic (HPLC) system compatible with any standard tablet dissolution apparatus was developed. This system allowed the individual drug concentrations within a product to be determined simultaneously, even when the drugs had similar structures and UV spectra. This automated system permitted unattended sampling and concentration determination at predetermined time intervals. The dissolution medium was pumped continuously through a fixed-volume, microprocessor-controlled injector and returned to the USP rotating-basket dissolution apparatus. No corrections for the changing dissolution medium volume were necessary since each injection onto a reversed-phase HPLC column consumed just 10 microliter of medium. Dissolution tests were performed on three brands of trisulfapyrimidines tablets. Sample injections were made automatically at 5.1-min intervals for approximately 2 hr. Dissolution profiles were determined for each drug in each product. Statistically significant differences were found in the mean concentration-time values between drugs within a drug product and between the drug products.

A simple and sensitive method for the simultaneous analysis of carbaryl and 1-naphthol in whole blood by reversed-phase high-performance liquid chromatography and fluorescence detection is described. Spiked blood (heparinized) containing an internal standard was hemolyzed and extracted with ethyl acetate. After centrifugation the extractant was removed and taken to dryness. Reconstitution and subsequent high-performance liquid chromatography-fluorescence analysis yielded linear standard curves for carbaryl and 1-naphthol. Linear response vs. concentration profiles were obtained for carbaryl and 1-naphthol extracted from buffer solutions as well. A simple chemical hydrolysis study of carbaryl is included to illustrate the effectiveness of the extraction procedure and assay.

A high-pressure liquid chromatographic method for the sensitive and rapid determination of chloramphenicol, chloramphenicol-3-monosuccinate, and chloramphenicol-1-monosuccinate is presented. The procedure utilizes a reversed-phase chromatographic column with UV absorption detection. The assay is useful for monitoring patients receiving chloramphenicol, determining the pharmacokinetics of parenteral chloramphenicol sodium succinate, and certifying sterile chloramphenicol sodium succinate.