To determine whether signals occurring during the early stages of undernutrition can have a suppressive effect on the central drive to the reproductive axis, the effects of 1 day of fasting on pulsatile LH and testosterone secretion were examined in adult male rhesus monkeys. Monkeys were maintained with chronic indwelling venous catheters on tether/swivel systems. One day of fasting caused a small weight loss of 0.1-0.2 kg, which represented a loss of 1-3% of the initial body weight. On a day of normal feeding monkeys showed a mean of 4.57 +/- 0.53 LH pulses/12 h (measured from 1900-0700 h). On a subsequent day of fasting LH pulse frequency was significantly reduced to 1.86 +/- 0.46 pulses/12 h (P less than or equal to 0.05). Likewise, there was a similar decrease in testosterone pulse frequency on a day of fasting. The substantial decrease in LH/testosterone pulse frequency was not caused by the intensive blood-sampling regimen, in that collection of blood samples for 12 h on 2 consecutive days of normal feeding did not result in a decrease in either LH or testosterone pulse frequency. Administration of exogenous GnRH in doses of 0.05-0.3 microgram/kg caused LH pulses of similar magnitudes on a day of normal feeding and a day of fasting, suggesting that the decrease in LH pulse frequency during the day of fasting reflects a decrease in GnRH stimulation of the pituitary rather than a loss of pituitary sensitivity to GnRH. Measurement of pulsatile LH across 3 consecutive days (e.g. a day of normal feeding, a day of fasting, and a day of refeeding) indicated that LH pulse frequency is slow before the time that the meal is missed on the second day and remains low throughout the day of fasting (normal feeding, 7 +/- 1.16 pulses/24 h; fasting, 3.33 +/- 0.33 pulses/24 h). Refeeding a normal meal at 1100 h on the third day resulted in an immediate and sustained increase in pulsatile LH secretion above normal frequency (11.07 +/- 0.33 pulses/24 h). These results indicate that very brief periods of undernutrition can significantly suppress the central drive to the reproductive axis in male rhesus monkeys, and this suppression can be rapidly reversed by refeeding. These findings argue against the hypothesis that undernutrition only suppresses central drive to the reproductive axis once a substantial amount of body weight has been lost.

To determine whether dideoxyinosine is actively transported across the placenta, four pregnant macaques (Macaca nemestrina) near term and their fetuses were infused intravenously in random order with simultaneous doses of dideoxyinosine (42.5 ,ug/min/kg of body weight) and antipyrine (41.7 ,ug/min/kg) for 30 h. The infusions took place after the dams had been chronically catheterized at 128 ± 0.8 days of gestation. In a third infusion, the dams alone received a higher dosage of dideoxyinosine (425 ,ug/min/kg) and the same dosage of antipyrine (41.7 ,ug/min/kg). Samples of maternal and fetal blood and amniotic fluid were collected at intervals for up to 30 h. The concentrations of dideoxyinosine and antipyrine were determined by high-performance liquid chromatography. The transplacental maternal-fetal drug clearances were compared by the paired Student's t test. The ratio (mean ± standard deviation) of the steady-state plasma dideoxyinosine concentration in the fetus to that in the dam was 0.49 ± 0.10 at the low dideoxyinosine infusion rate and 0.51 ± 0.00 at the high dideoxyinosine infusion rate. The clearance associated with maternal-fetal transfer of the drug, CLdf (0.38 ± 0.21 ml/min/kg), was not significantly different (P > 0.05) from the clearance associated with fetal-maternal transfer of the drug, CLfd (0.56 ± 0.27 ml/min/kg). Also, CLdf was not significantly different (P > 0.05) from CLfd when normalized with respect to the corresponding transplacental clearance of antipyrine (0.07 ± 0.04 CLdf versus 0.09 ± 0.04 CLfd). Our data indicate that passage of dideoxyinosine across the placenta in pregnant M. nemestrina near term is passive and constant over the dosage range studied.Dideoxyinosine (2',3'-dideoxyinosine; didanosine) is the second dideoxynucleoside to be approved for use in the treatment of AIDS. Although not presently approved for use during pregnancy, dideoxyinosine may be of benefit to pregnant women who cannot tolerate or have become resistant to zidovudine. In addition, data from animal models indicate that dideoxynucleoside therapy of the dam during pregnancy may delay the onset and progression of the disease in offspring infected in utero (15). Thus, information on the extent and mechanisms of transplacental transfer of dideoxynucleosides, including dideoxyinosine, is necessary in the development of therapeutic strategies for the pregnant woman and her potentially infected unborn child. As part of an ongoing series of studies on the dideoxynucleosides, we studied the extent and mechanisms of transfer of dideoxyinosine in vivo across the placenta in a representative nonhuman primate model, Macaca nemestrina.The macaque was chosen because of its anatomical and physiological similarities to humans. It is particularly suitable since it is susceptible to both the simian immunodeficiency virus (12), which produces an AIDS-like syndrome, and the human immunodeficiency virus (1). In addition, the pharmacokinetics of dideoxyinosine in M. nemestrina have been shown to be similar to those in humans (1...

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The toxicity of azidothymidine (AZT) was studied in monkey dams and fetuses that were exposed to the drug over the entire gestational period. Fourteen virus-free female macaques (Macaca nemestrina) were randomly assigned to AZT or control groups. AZT animals received the drug through a gastric catheter at a dose of 1.5 mg/kg every 4 hours, which produced plasma concentrations similar to those in humans taking 500 to 600 mg/day of AZT. Control animals received water placebo, also through gastric catheter. Some animals participated in both groups. All females were mated with the same male; 41 matings produced 20 pregnancies, of which 16 were carried to term (9 in AZT females; 7 in control females). The AZT animals developed an asymptomatic macrocytic anemia, but hematologic parameters returned to normal when AZT was discontinued. Total leukocyte count decreased during pregnancy and was further affected by AZT administration. AZT-exposed infants were mildly anemic at birth. AZT caused deficits in growth, rooting and snouting reflexes, and the ability to fixate and follow near stimuli visually, but the deficits disappeared over time. These data indicate that early exposure to AZT in utero should have no irreversible adverse effects on the fetus.

The lack of a representative animal model that permits frequent in utero fetal blood sampling is a major limiting factor for the study of maternal-fetal HIV transmission. Therefore, we have developed a maternal-fetal virus infection model using chronically catheterized macaques to simultaneously study the time-course of viral infection in the mother and the response of the fetus to maternal HIV infection. Pregnant macaques were infected with 10(3) infectious units of HIV-2(287); every 3 days blood samples from both the mother and the fetus as well as amniotic fluid samples were collected. We found a varying degree of peak and time-to-peak virus load, virus-infected PBMCs, and free virus (determined by QC-RNA-PCR method) in maternal blood. Two of the three mothers with more than 10(8) copies of viral RNA/ml of plasma at peak viremia transmitted the virus to their fetuses at about 14 days post-infection. As observed with HIV-2(287) infected mothers, virus-infected fetuses also produced a rapid rate of CD4+ cell decline in utero.