These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition.

Toxicology studies were performed in rats and rhesus macaques to establish a safe starting dose for intratumoral injection of an oncolytic vesicular stomatitis virus expressing human interferon-b (VSV-hIFNb) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59Â10 9 TCID 50 (50% tissue culture infective dose) of VSV-hIFNb into the left lateral hepatic lobe of Harlan Sprague Dawley rats. Plasma alanine aminotransferase and alkaline phosphatase levels increased and platelet counts decreased in the virus-treated animals on days 1 and 2 but returned to pretreatment levels by day 4. VSV-hIFNb was also injected into normal livers or an intrahepatic McA-RH7777 HCC xenograft established in Buffalo rats. Buffalo rats were more sensitive to neurotoxic effects of VSV; the no observable adverse event level (NOAEL) of VSV-hIFNb in Buffalo rats was 10 7 TCID 50 . Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared with VSV-hIFNb, toxicity of VSV-rIFNb (recombinant VSV expressing rat IFN-b) was greatly diminished in Buffalo rats (NOAEL, >10 10 TCID 50 ). Two groups of two adult male rhesus macaques received 10 9 or 10 10 TCID 50 of VSV-hIFNb injected directly into the left hepatic lobe under computed tomographic guidance. No neurological signs were observed at any time point. No abnormalities (hematology, clinical chemistry, body weights, behavior) were seen and all macaques developed neutralizing anti-VSV antibodies. Plasma interleukin-6, tumor necrosis factor-a, and hIFN-b remained below detection levels by ELISA. On the basis of these studies, we will be proposing a cautious approach to dose escalation in a phase I clinical trial among patients with HCC.

Summary Focal cortical epilepsy is currently most effectively studied in humans. However, improvement in cortical monitoring and investigational device development is limited by lack of an animal model mimicking human acute focal cortical epileptiform activity under epilepsy surgery conditions. Therefore, we assessed the swine model for translational epilepsy research. Swine were used due to their cost effectiveness, convoluted cortex, and comparative anatomy similar to humans. Focal subcortical injection of benzyl-penicillin produced clinical seizures correlating with epileptiform activity demonstrating temporal and spatial progression. Swine were evaluated under 5 different anesthesia regimens. Of the 5 regimens, conditions similar to human intraoperative anesthesia, including continuous fentanyl with low dose isoflorane, was the most effective for eliciting complex, epileptiform activity after benzyl-penicillin injection. The most complex epileptiform activity (spikes, and high frequency activity) was then repeated reliably in 9 animals, utilizing 14 swine total. There were 20.1 ± 10.8 (95% CI: 11.8–28.4) epileptiform events with greater than 3.5 hertz activity occurring per animal. Average duration of each event was 46.3 ± 15.6 (95% CI: 44.0 to 48.6) seconds, ranging from 20 to 100 seconds. In conclusion, the acute swine model of focal cortical epilepsy surgery provides an animal model mimicking human surgical conditions with a large brain, gyrated cortex, and is relatively cheap among animal models. Therefore, we feel this model provides a valuable, reliable, and novel platform for translational studies of implantable hardware for intracranial monitoring.

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P-selectin inhibition has been evaluated as a therapeutic for prevention and treatment of venous thrombosis. In this study, a novel oral small-molecule inhibitor of P-selectin, PSI-421, was evaluated in a baboon model of stasis induced deep vein thrombosis (DVT). Experimental groups included i) primates receiving a single oral dose of 1 mg/kg PSI-421 two days prior and continued six days after thrombosis (n = 3); ii) primates receiving a single daily subcutaneous dose of 0.57 mg/kg enoxaparin sodium two days prior and continued six days post thrombosis (n = 3); and iii) primates receiving no treatment (n = 3). PSI-421 treated primates had greater percent vein reopening and less vein wall inflammation than the enoxaparin and controls at day 6. Microparticle tissue factor activity (MPTFA) was significantly lower in the animals receiving PSI-421 immediately after thrombosis (T+6 hours day 0) suggesting lower potential for thrombogenesis in these animals. PSI-421 also reduced soluble P-selectin levels versus controls at T+6 hours day 0, day 2 and 6. Experimental animals in any group showed no adverse effects on coagulation. This study is the first to demonstrate a reduction in MPTFA associated with vein reopening and reduced vein inflammation due to oral P-selectin inhibition in a baboon model of DVT.