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These studies are designed to test a wide range of neurotoxicity effects including CNS stimulation or depression, re ex perturbation, peripheral nerve damage, cognitive effects on learning and memory, motor activity effects and neuropathology The tests are conducted using rats or sometimes mice In the acute neurotoxicity study, approximately 10 to 15 animals per sex per dose group are administered a single gavage (bolus) dose of the test material There are usually three dose groups and a control Behavioral assessments are made on the day of dosing, and at 1 and 2 weeks post dose The assessments include tests on motor activity, a functional observation battery (FOB), and neuropathology (at termination) The FOB screens for sensorimotor, neuromuscular, autonomic and general physiological effects of a test compound Table 2110 depicts component tests of the FOB.

Suppose that the levels are labeled so that the initial level is 1. Note that all ^ transitions from level 1 are to level 2. Hence, when considering the matrix h sjx in ^ 12 sjx . Since Eq. (17.10), it suf ces to consider only the element h

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90 Malinoski, F J; Hasty, S E; Ussery, M A; Dalrymple, J M Prophylactic ribavirin treatment of dengue type 1 infection in rhesus monkeys Antiviral Res 1990, 13, 139 149 91 Jordan, I; Briese, T; Fischer, N; Lau, J Y N; Lipkin, W I Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells J Infect Dis 2000, 182, 1214 1217 92 Baker, R; Bray, M; Huggins, J W Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections Antiviral Res 2003, 57, 13 23 93 Jahrling, P B; Zaucha, G M; Huggins, J W Countermeasures to the reemergence of smallpox virus as an agent of bioterrorism In Emerging Infections 4, Scheld, W M; Craig, W A; Hughes, J M (Eds) ASM Press, Washington, DC, 2000, pp 187 200 94 Kern, E R.

These functional tests have the advantage over biochemical measures that they permit repeated evaluation of individual animals over time to determine the onset, progression, duration, and reversibility of neurotoxic effects Motor activity is also measured over time and can be evaluated by a variety of devices One such device that has been frequently used is the gure 8 maze, which consists of a series of interconnected alleys (in the shape of the numeral 8) converging on a central open area and covered with transparent acrylic plastic Motor activity is detected by photobeams, and an activity count is registered each time a photobeam is interrupted by the animal Motor activity sessions are generally 60 minutes in length and each session is divided into 5- to 10-minute reporting intervals (epochs).

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Habituation is an end point evaluated in the motor activity test, and this is de ned as a decrement in activity during the test session Activity is expected to decrease toward the end of the test as the animal s exploratory activity normally lessens as the time in the maze increases Neuropathological examinations are the same as those described below for the subchronic neurotoxicity test Before the acute neurotoxicity study is conducted, it is necessary to conduct a preliminary test to determine the time of peak effect after dosing of the test material Preliminary tests may evaluate a selected group of end points in the FOB or other sensitive end points, if known, for a particular test material Results of this preliminary test will determine the time when observations are performed on the day of dosing in the acute neurotoxicity study..

In vitro activity of potential anti-poxvirus agents Antiviral Res 2003, 57, 35 40 95 Smee, D F; Wong, M H; Bailey, K W; Beadle, J R; Hostetler, K Y; Sidwell, R W Effects of four antiviral substances on lethal vaccinia virus (IHD strain) respiratory infections in mice Int J Antimicrob Agents 2004, 23, 430 437 96 Borio, L; Inglesby, T; Peters, C J; Schmaljohn, A L; Hughes, J M; Jahrling, P B; Ksiazek, T; Johnson, K M; Meyerhoff, A; Toole, T; Ascher, M S; Bartlett, J; Breman, J G; Eitzen, E M; Hamburg, M; Hauer, J; Henderson, D A; Johnson, R T; Kwik, G; Layton, M; Lillibridge, S; Nabel, G J; Osterholm, M T; Perl, T M; Russell, P.

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Table 21.10 Example of Evaluations Made in a Functional Observation Battery Home Cage and Open Field Arousal Gait Posture Vocalizations Piloerection Lacrimation Salivation Urination/defecation Grooming behavior Rearing Abnormal movements Tremors, convulsions Manipulative Ease of removal Ease of handling Touch response Righting response Hindlimb foot splay Forelimb grip strength Hindlimb grip strength Finger-snap response Catalepsy Palpebral closure Pupil function Physiological Body temperature Body weight

; Tonat, K Hemorrhagic fever viruses as biological weapons: medical and public health management JAMA 2002, 287, 2391 2405 97 Fisher-Hoch, S P; Gborie, S; Parker, L; Huggins, J Unexpected adverse reactions during a clinical trial in rural West Africa Antiviral Res 1992, 19, 139 147 98 Kilgore, P E; Ksiazek, T G; Rollin, P E; Mills, J N; Villagra, M R; Montenegro, M J; Costales, M A; Paredes, L C; Peters, C J Treatment of Bolivian hemorrhagic fever with intravenous ribavirin Clin Infect Dis 1997, 24, 718 722 99 Enria, D A; Briggiler, A M; Levis, S; Vallejos, D; Maiztegui, I; Canonico, P G Tolerance and antiviral effect of ribavirin in patients with Argentine hemorrhagic fever Antiviral Res 1987, 7, 353 359 100 Mardani, M; Jahromi, M K; Naieni, K H.

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