The overall aim of these studies is to design and utilize a fetal/neonatal macaque model for the evaluation of the potential toxicities of various anti-HIV drug treatment(s) proposed for use in the human pediatric patient. Our long-term objectives will be (1) to devise methods for assessing potential pre- and postnatal toxicities during exposure to anti-HIV drug therapies, (2) to evaluate various drug treatment and administration periods for testing the potential toxicities of various anti-HIV drugs, (3) to determine the effects of pre- and postnatal anti-HIV treatment strategies on normative growth and development, specifically related to neurobehavioral, hematologic, and physiologic parameters, and (4) to correlate adverse effects with drug levels achieved in the maternal, fetal, and neonatal/infant compartments. One of the greatest challenges with new anti-HIV therapies will be to determine the route of administration and dosages to be used. Within Specific Aim 1, we will establish methods for treating the drug(s) under scrutiny. Drug administration via the maternal (oral or intravenous [IV]), fetal (""""""""oral"""""""" via amniotic fluid, intraperitoneal, or IV), and neonatal/infant (oral, IV) routes will be evaluated using AZT as a prototype drug. In addition to monitoring for toxicity, these studies will provide information on drug levels achieved in various maternal (serum, urine), fetal (amniotic fluid, serum, cerebrospinal fluid [CSF]), and neonatal (serum, urine, CSF) compartments. The information gained from these studies will be applied to further evaluations of the potential toxic and adverse effects of prenatal and pre- and postnatal treatment of various anti-HIV drugs by monitoring growth and neurobehavioral development (Specific Aim 2) and hematologic effects while monitoring drug levels achieved in various maternal, fetal, and neonatal/infant compartments (Specific Aim 3). Both treatment periods (prenatal [gestational day (GD) 60-160] and pre-and postnatal [GD 60-160 and daily for 6 months]) will be pursued since it is currently unknown if pre- and postnatal treatment alone will prove sufficient to alter transmission of the virus or the course of infection. It will be important to identify the spectrum of adverse effects that may be related to this lengthy exposure period. With the studies outlined above we will be able to compare the differing routes of drug administration (maternal versus fetal) in addition to a varying length of drug exposure (prenatal versus pre- and postnatal). It is our goal to evaluate the optimal methods for drug delivery while minimizing toxic or adverse effects, and to determine the potential ramifications or various drug treatment strategies on pre-and postnatal individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032299-03
Application #
3147283
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1991-09-30
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Veterinary Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Castillo, Alesha B; Tarantal, Alice F; Watnik, Mitchell R et al. (2002) Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta). J Orthop Res 20:1185-9
Tarantal, Alice F; Castillo, Alesha; Ekert, Jason E et al. (2002) Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). J Acquir Immune Defic Syndr 29:207-20
Tarantal, A F; Goldstein, O; Barley, F et al. (2000) Transplantation of human peripheral blood stem cells into fetal rhesus monkeys (Macaca mulatta). Transplantation 69:1818-23
Tarantal, A F; Marthas, M L; Shaw, J P et al. (1999) Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety and efficacy studies. J Acquir Immune Defic Syndr Hum Retrovirol 20:323-33
Tarantal, A F; Gargosky, S E (1995) Characterization of the insulin-like growth factor (IGF) axis in the serum of maternal and fetal macaques (Macaca mulatta and Macaca fascicularis). Growth Regul 5:190-8