The fact that many kinases share a highly conserved catalytic domain complicate

In the first case , the patient was a young child who had been infected with TWS119 vaccinia virus after coming in close contact with his father, who had received the smallpox vaccine. The child developed severe eczema vaccinatum, and after RO5185426 unsuccessful treatment with Vaccinia Immune Globulin Intravenous , was administered ST-246. Based on the child��s inability to swallow a pill and the need to use a very low dose due to his low body weight, the ST-246 was administered via a nasogastric tube. In the second instance, a 20-year old male had developed progressive vaccinia after receiving cancer chemotherapy subsequent to having received the smallpox vaccine. The patient was taking ST-246 with little to no food, significantly decreasing absorption. In both of these cases, an IV formulation would have facilitated dose administration and simplified any required dose adjustment. A new formulation has been developed for IV administration of ST-246. The tolerability and pharmacokinetics of this formulation have been evaluated in mice, rabbits and NHP in order to determine the optimal administration strategy. The results are compared with the pharmacokinetics observed after oral administration. The in-life portions of the experiments were conducted at several different laboratories, all of which conducted studies according to all Federal, State, and local guidelines for the use of animals in research and were reviewed and approved by their respective Institutional Animal Care and Use Committees prior to conduct of the studies. Oral studies were conducted at MPI Research in Mattawan, MI. The protocols for these studies at MPI were reviewed and approved by MPI Research IACUC before each study. The IACUC approval ID numbers were as follows: 1151-021 ; 1151-023 ; and 1151-065. Those studies were conducted in compliance with the Testing Facility Animal Welfare Assurance filed with NIH. The study in NHP did not require any procedures that were anticipated to cause more than slight or momentary pain or distress to animals, such as the collection of blood samples. NHP were observed cageside at least twice daily for any signs of morbidity, mortality, injury, and availability of food and water. Any animals found in poor health were to be monitored further for possible treatment and/or euthanasia. The IV studies in mice and rabbits were conducted at Oregon State University and the protocol approved by their IACUC for those studies was Number 3871. The IV infusion studies in NHP were conducted at Charles River Laboratories under approved protocol numbers MDA00051; 20002163; and 20002757.

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