A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor.

BACKGROUND: Active and safe reversibility of anticoagulation is an unmet need in clinical care. Factor IXa, required for rapid thrombin generation on platelet surfaces, is a novel target for modulating coagulation. REG1 comprises RB006 (drug) and RB007 (antidote). RB006, a ribonucleic acid aptamer, exerts its anticoagulant effect by selectively binding FIXa. RB007, the complementary oligonucleotide antidote, binds to RB006 by Watson-Crick base pairing, neutralizing its anti-FIXa activity. OBJECTIVE: To test the multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of REG1. METHODS: We randomized 39 healthy volunteers to receive either three consecutive weight-adjusted, drug-antidote treatment cycles, or double placebo. Each treatment cycle included an intravenous bolus of 0.75 mg kg(-1) RB006, followed 60 min later by a descending dose of RB007, ranging from a 2 : 1 to 0.125 : 1 antidote/drug ratio (1.5 mg kg(-1) to 0.094 mg kg(-1) RB007). Serial clinical assessments and coagulation measurements were performed through 14 days postrandomization. RESULTS: Repeat doses of RB006 achieved highly reproducible activated partial thromboplastin time (APTT) levels with low intrasubject variability (coefficient of variation 5.5%, intraclass correlation coefficient 5.8 at 15 min postdose), while repeat doses of RB007 reversed the APTT levels dose-dependently and reproducibly. There was no major bleeding and there were no other serious adverse events. CONCLUSIONS: This is the first human study demonstrating multiple repeat-dose safety, intraindividual pharmacodynamic reproducibility and graded active reversibility of an RNA aptamer-oligonucleotide antidote pair. The results lay the foundation for studying the translation of this novel anticoagulation platform to a wide variety of clinical applications.

Elemental diet and bile induced pancreatitis.

The effectiveness of an elemental diet was investigated as both a prophylactic and therapeutic agent in experimental canine pancreatitis. Pancreatitis was induced by operative injection of a bile -saline solution mixture under pressure retrograde into the main pancreatic duct. In addition to a preinjection control sample, serial biopsies were obtained at 30 minute intervals for 90 minutes after injection and fixed for light and electron microscopic examinations. In addition, preoperative and postoperative blood samples were drawn and analyzed for amylase. After operation, half of the dogs from each original group were fed Vivonex-100, the other half from each group, regular laboratory chow, yielding four ultimate groups based on preoperative and postoperative diets. Successful induction of pancreatitis was evaluated by the difference between preoperative and postoperative amylase values, all of which were significant by group at the p less than 0.01 level. No ultrastructural evidence was found for the modification of zymogen granules with the pretreatment elemental diet nor were differences evident, histologically or ultrastructurally, in the severity of pancreatitis between the pretreated and nonpretreated groups. Finally, gross mortality figures demonstrated no efficacy of elemental diet for pretreatment prophylaxis of acute pancreatitis.