Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study.

BACKGROUND: Inhibitors of factor (F) IXa show potent antithrombotic activity with a low risk of bleeding in preclinical models. We investigated the anticoagulant potential of oral TTP889, a small molecule that inhibits up to 90% of FIXa activity at therapeutic doses, using a clinical model of extended prophylaxis in hip fracture surgery (HFS). METHODS: In this multicenter, randomized, double-blind study, 261 patients received oral TTP889 (300 mg once daily) or placebo starting 6-10 days after HFS, and standard thromboprophylaxis for 5-9 days. Treatment was continued for 3 weeks and all patients then underwent mandatory bilateral venography. The primary efficacy outcome was venous thromboembolism (VTE; venographic or symptomatic deep vein thrombosis or pulmonary embolism) during treatment, and it was evaluated centrally by an independent adjudication panel. The main safety outcome was bleeding (major, clinically relevant non-major, and minor events). RESULTS: Two hundred and twelve patients with an evaluable venogram were included in the efficacy analysis. The primary efficacy outcome occurred in 32.1% (35/109) of patients who had been allocated TTP889, and 28.2% (29/103) of patients on placebo (P = 0.58). There were no major bleeding events, and only two clinically relevant non-major bleeding events with TTP889. CONCLUSION: Partial FIXa inhibition with TTP889 300 mg daily was not effective for extended prevention of VTE after standard prophylaxis for up to 9 days. Coupled with the low incidence of bleeding episodes, this suggests a lack of antithrombotic potential. Further investigation of TTP889 in different clinical settings is needed. (Clinical trial registration information URL: http://www.clinicaltrials.gov. Unique identifier: NCT00119457).

Evaluation of the systemic toxicity of coal liquefaction-derived materials following repeated dermal exposure in the rabbit.

The subchronic toxicity of two materials produced by the EDS direct coal liquefaction process was investigated using adult New Zealand white rabbits as the test species. Recycle solvent (RS: 204-427 degrees C) and fuel oil (FO: 204-538 degrees C) were applied to the intact dorsal surface of rabbits, 5 days per week for 4 weeks. Materials were applied as suspensions (2.5 and 10.0 g 100 ml-1) in white oil. White oil alone was administered to concurrent control groups. Both RS and FO elicited gross signs of toxicity including severe dermal irritation, loss of body weight (16-25%) and mortality (4/20 in the high-dose group treated with RS). Systemic effects included liver enlargement as evidenced by histologic findings of diffuse hepatocytomegaly, cytoplasmic degeneration and hepatocellular vacuolation as well as elevated serum cholesterol. There was also evidence of testicular, seminal vesicle and thymic atrophy. More pronounced effects were apparent in the high-dose groups. Testes and epididymides from four of the five FO-treated male rabbits were unremarkable at the microscopic level. The testes, epididymides and seminal vesicles of the fifth animal were atrophic. Three of ten RS treated rabbits showed testicular atrophy associated with hypospermatogenesis in the testes, aspermia in the epididymides and vesiculitis in the seminal vesicles. Four additional animals showed evidence of seminal vesicle atrophy. The liver enlargement was probably due to compensatory metabolism; however, exposure to similar materials at higher levels has resulted in liver toxicity. Thymic and testicular atrophy may have been a secondary response to dermal irritation, stress or body weight loss.

Metabolism of phencyclidine. The role of iminium ion formation in covalent binding to rabbit microsomal protein.

Incubation of phencyclidine (PCP) with rabbit liver microsomes and Na14CN resulted in the metabolically dependent formation of a 14C-labeled cyano adduct of the drug. After isolation by HPLC, this compound was identified as the alpha-aminonitrile [1-(1-phenylcyclohexyl)-2-cyanopiperidine] derivative of PCP by use of chemical-ionization and gas-chromatographic coupled electron-impact mass spectrometry. Synthetic alpha-aminonitrile exhibited identical chemical properties and comigrated in HPLC and GLC with the metabolism derived cyano adduct. Molecular identification of the adduct formed by cyanide trapping provided evidence for the formation of an iminium ion during PCP metabolism. Quantitative estimation by HPLC demonstrated that the alpha-aminonitrile accounted for over 50% of the PCP metabolized in 30 min by hepatic microsomes in vitro. Metabolism-dependent covalent binding of [3H]PCP to rabbit liver microsomal proteins was inhibited by cyanide ion in a concentration-dependent manner with an IC50 value of 57 microM. The concentrations of cyanide ion used in these experiments did not significantly inhibit the metabolism of PCP. These results support our suggestions that iminium ion formation may represent an important intermediary step in the metabolism of PCP and that such a reactive electrophilic species may be capable of covalent interactions with nucleophilic groupings on microsomal macromolecules.