for each data point was equal to or less than 9% of the mean for the data point. AZD-7648 == Animals. was the amount of time needed for fractional redistribution of a neuroparalytic quantum of toxin from your extraneuronal space to the intraneuronal space. This redistribution event was a dose-dependent phenomenon. It is likely that the approach used to identify the factors that govern postchallenge efficacy of antibodies against botulinum toxin can be used to assess the factors that govern postchallenge efficacy of medical countermeasures against any agent of bioterrorism or biological warfare. == Introduction == The potential use of botulinum toxin as a weapon in functions of bioterrorism or biological warfare has prompted vigorous efforts to develop medical countermeasures (Arnon et al., 2001;Lane et al., 2001; NIAID Blue Ribbon Panel on Bioterrorism and Its Implications on Biomedical Research, 2002 [http://www.nti.org/e_research/source_docs/us/congress/house_representatives/129.pdf]). The three categories of brokers that are receiving the greatest attention are vaccines, therapeutic antibodies, and pharmacologic antagonists (Casadevall, 2002;Dickerson and Janda, 2006;Simpson, 2009). Of these three, the only ones for which there is a reasonably clear understanding of the temporal relationship between efficacious administration of the countermeasure and challenge with toxin are vaccines. Vaccines must be administered to patients before challenge with toxin, and the temporal relationship that governs efficacy is the amount of time needed for any particular antigen and vaccination protocol to evoke a protective immune response. The issues surrounding the use of therapeutic antibodies and pharmacologic antagonists are more complex. For AZD-7648 example, each of these classes of brokers can be used in either preincident or postincident scenarios. In a preincident scenario, the goal would be to protect individuals against subsequent exposure to pathologic levels of botulinum toxin. In a postincident scenario, the goal would be to block, or perhaps more realistically diminish, the full impact of prior exposure to toxin. The temporal factors that govern efficacy of preincident and postincident administration of therapeutic antibodies and pharmacologic antagonists are not well understood. To date, no pharmacologic antagonist of botulinum toxin has been described that is 1) notably effective in blocking the onset of toxin action in vivo, and 2) approved for human use or close to entry into human clinical trials. The situation with therapeutic antibodies is more encouraging. A polyclonal preparation of antibotulinum toxin antibodies has already been approved by the Food and Drug Administration for human use (Arnon et al., 2006,2007). In addition, prospects are good that an oligoclonal preparation of therapeutic antibodies will soon enter clinical trials (Amersdorfer et al., 1997;Chen et al., 1997;Nowakowski et al., 2002). This suggests that it would be worthwhile to undertake experiments that can accomplish two things. First, it would be helpful to know the interval of time before or after exposure to any given dose of toxin that administration of therapeutic antibodies can provide protection. Second, it would be useful to identify the factors that govern these temporal associations. In this article, a series of experiments are offered that focus on the use of therapeutic antibodies in a postincident scenario. The factors that determine an efficacious end result are described, and the underlying mechanisms that govern these factors are identified. In addition, a conceptual framework is presented that could ultimately be applied to pharmacologic antagonists if and when brokers are discovered that are likely to have clinical power in a postincident scenario. == Materials and Methods == == == == Toxin. == Botulinum toxin type A (complex and real) was purchased from Metabiologics (Madison, WI). All of the experiments, with Rabbit Polyclonal to Notch 2 (Cleaved-Asp1733) the exception of those AZD-7648 shown inFig. 4, were done with.