Douglas H. Taylor

Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women

Vaginal Gel Versus HIV HIV prevention technologies for women are urgently needed, especially in sub-Saharan Africa where young women bear the greatest burden of the HIV epidemic. Abdool Karim et al. (p. 1168; published online 19 July) present the results of the CAPRISA 004 randomized control trial. The nearly 3-year-long trial, conducted in urban and rural South African women, tested the efficacy of a vaginal gel containing the antiretroviral drug tenofovir in preventing HIV infection. The dosing strategy required application of the gel both before and after coitus, and with this regime HIV infection was reduced by approximately 39% overall, by 54% in women with high adherence to the protocol, and with no increase in overall adverse event rates. Tenofovir in a vaginal gel formulation shows significant protection against HIV infection in a randomized control trial. The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.

Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid

A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the pregnant rat exposed to TCE by inhalation, by bolus gavage, or by oral ingestion in drinking water. The kinetics of trichloroacetic acid (TCA), an oxidative metabolite of TCE, were described by a classical one-compartment pharmacokinetic model. Among the required model parameters for TCE, partition coefficients (PCs) and kinetic constants for oxidation were determined by vial equilibration and gas uptake methods, respectively. The fat:blood PC was 33.9; the blood:air PC was 13.2; and the fetal tissue:fetal blood PC was 0.51. TCE was readily metabolized with high substrate affinity. In naive and pregnant female rats the maximum velocities of oxidative metabolism were 10.98 +/- 0.155 and 9.18 +/- 0.078 mg/kg/hr, while the estimated Michaelis constant for the two groups of rats was very low, 0.25 mg/liter. The first-order rate constant for oral absorption of TCE from water was 5.4 +/- 0.42/hr-1 in naive rats. With TCA, the volume of distribution (0.618 liter/kg) and the plasma elimination rate constant (0.045 +/- 0.0024/hour) were estimated both from intravenous dosing studies with TCA and from an inhalation study with TCE. By comparison of the two routes of administration, the stoichiometric yield of TCA from TCE was estimated to be 0.12 in pregnant rats. To develop a data base for testing the fidelity of the PB-PK model, inhalation and bolus gavage exposures were conducted from Day 3 to Day 21 of pregnancy and a drinking water exposure from Day 3 to Day 22 of pregnancy. Inhalation exposures with TCE vapor were 4 hr/day at 618 ppm. The TCE concentration in drinking water was 350 micrograms/ml and the gavaged rats received single daily doses of 2.3 mg TCE/kg. Time varying physiological parameters for compartment volumes and blood flows during pregnancy were obtained from the published literature. Using the kinetic parameters determined by experimentation, TCE concentrations in maternal and fetal blood and TCA concentrations in maternal and fetal plasma were predicted from the PB-PK model by computer simulation and compared favorably with limited data obtained at restricted time points during pregnancy for all three routes of exposure. On the basis of the PB-PK model, fetal exposure to TCE, as area-under-the-curve, ranged from 67 to 76% of maternal exposure. For TCA the fetal exposure was 63 to 64% of the maternal exposure. The fetus is clearly at risk both to parent TCE and its TCA metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of Caudal Autotomy on Locomotor Performance of Wall Lizards (Podarcis muralis)

We examined the effects of caudal autotomy on terrestrial and arboreal locomotory perfor- mance using European wall lizards (Podarcis muralis) from an established population in Cincinnati, Ohio. Tail loss significantly increased running speed and distance travelled but markedly decreased arboreal locomotor performance (speed and distance). The effects of tail type (original, unbroken vs. regenerated, previously broken) seldomly were significant before autotomy but became more markedly apparent fol- lowing tail removal. Significant interactions between tail type and autotomy indicated that individuals possessing original or regenerated tails responded differently to tail loss. Whereas original tails were associated with superior locomotor performance before tail loss, individuals that had possessed regenerated tails before autotomy ran fastest and farthest and traversed an arboreal substrate fastest after their tails were removed. These results suggest that lizards that have been previously subjected to caudal autotomy are able to learn by experience how to compensate for the absence of a tail and, accordingly, traverse an arboreal substrate faster - even after their tail has regenerated and is subsequently autotomized again. The importance of these trends is discussed in light of foraging and escape mode postulates.

Physiologically Based Pharmacokinetic Modeling of the Lactating Rat and Nursing Pup: a Multiroute Exposure Model for Trichloroethylene and its Metabolite, Trichloroacetic Acid

A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the lactating rat and nursing pup. The lactating dam was exposed to TCE either by inhalation or by ingestion in drinking water. The nursing pups exposure to TCE was by ingestion of maternal milk containing TCE. The kinetics of trichloroacetic acid (TCA), a metabolite of TCE, were described in the lactating dam and developing pup by a hybrid one-compartment model. The lactating dams exposure to TCA was from metabolism of TCE to TCA. The pups exposure to TCA was from metabolism of TCE ingested in suckled milk and from direct ingestion of TCA in maternal milk. For the PB-PK model, partition coefficients (PCs) were determined by vial equilibration, and metabolic constants for TCE oxidation, by gas uptake methods. The blood/air and the fat/blood PCs for the dam were 13.1 and 34.2, and for the pup, 10.6 and 42.3, respectively. The milk/blood PC for the dam was 7.1. In lactating rats and rat pups (19-21 days old) the maximum velocities of oxidative metabolism were 9.26 +/- 0.073 and 12.94 +/- 0.107 mg/kg/hr. The plasma elimination rate constant (K = 0.063 +/- 0.004 hr-1) and apparent volume of distribution (Vd = 0.568 liter/kg) for TCA in the lactating dam were estimated from both intravenous dosing studies and an inhalation study with TCE. For the pup, K (0.014 +/- hr-1) and Vd (0.511 liter/kg) were estimated from a single 4-hr inhalation exposure with TCE. The dose-rate-dependent stoichiometric yield of TCA from oxidative metabolism of TCE in the lactating rat is 0.17 for a low-concentration inhalation exposure (27 ppm TCE) and 0.27 for an exposure above metabolic saturation (about 600 ppm TCE). For the pup, the stoichiometric yield of TCA is 0.12. With changing physiological values during lactation for compartmental volumes, blood flows, and milk yields obtained from the published literature and kinetic parameters and PCs determined by experimentation, a PB-PK model was constructed to predict maternal and pup concentrations of TCE and TCA. To test the fidelity of the PB-PK lactation model, a multiday inhalation exposure study was conducted from Days 3 to 14 of lactation and a drinking water study, from Days 3 to 21 of lactation. The inhalation exposure was 4 hr/day, 5 days/week, at 610 ppm. The TCE concentration in the drinking water was 333 micrograms/ml. Prediction compared favorably with limited data obtained at restricted time points during the period of lactation.

An ultrastructural examination of the mode of UV-induced toxic action of fluoranthene in the fathead minnow, Pimephales promelas

Juvenile fathead minnows (Pimephales promelas) were exposed to fluoranthene (< 0.2, 6.1, and 12.5 μg l−1) in the presence of solar ultraviolet radiation (SUVR) for 6, 12, 24, 48, and 96 h. Ultrastructural pathology of the secondary gill lamellae was examined using transmission electron microscopy. Following 12 h of exposure to 12.5 μg l−1 fluoranthene and SUVR (UV-A = 49.5 μW cm−2, UV-B = 4.2 μW cm−2), the outer mucosal layer of epithelial cells exhibited cellular swelling and dilation of endoplasmic reticulum and mitochondria. At 48 h, additional morphological alterations in mucosal cells included hypertrophy, blebbing of the plasma membrane, and the presence of cytolysosomes, myelinoid bodies, and lipid droplets. The staining characteristics of these droplets were consistent with that of neutral unsaturated lipids, which suggested that their formation was the result of rapid lipid peroxidation reactions. In addition, a second physiologically distinct reaction occurred within the secondary lamellae following 24 h of exposure. This reaction was inflammatory in nature, and as the exposure progressed, was characterized by edema, leukocyte infiltration, and vasoconstriction. In those fish exposed to 6.1 μg l−1 fluoranthene and SUVR, a similar progression compared to 12.5 μg l−1 exposure of mucosal cell damage and inflammatory-type reaction was evident beginning at 24 h of exposure. The net result of mucosal cell hypertrophy and the inflammatory-type reaction was a significant increase in the water-blood diffusion distance of 294% and 285% for those fish exposed to SUVR and the 12.5 and 6.1 μg l−1 fluoranthene treatments, respectively, suggesting that lethality was a consequence of respiratory stress due to the decreased oxygen diffusion capacity of the gills. These observations demonstrate that the mode of action of photo-induced fluoranthene toxicity in fish is a disruption of mucosal cell membrane function and integrity.

Spatial Orientation by Salamanders Using Plane-Polarized Light

Tiger salamanders (Ambystoma tigrinum) can perceive the plane of polarization in linearly polarized light and can learn to use that e-vector direction for spatial orientation in indoor orientation tests.

Seasonal and daily plasma corticosterone rhythms in American toads, Bufo americanus

Concentrations of corticosterone were measured in the plasma of American toads, Bufo americanus, on a seasonal basis using a radioimmunoassay technique. Two populations of toads, maintained under different light conditions, were monitored to observe the effects of photoperiod on the seasonal rhythm of plasma corticosterone. Under a natural photoperiod toads demonstrated a rhythm consisting of a spring peak and a fall peak in corticosterone concentration. Toads maintained under a 12L:12D photoperiod all year round demonstrated a similar rhythm with peaks in the spring and fall. This suggests that an endogenous (circannual) rhythm of corticosterone may be playing an important role in the seasonal change of overt behavior and physiology of Bufo americanus. A daily rhythm of corticosterone was also detected in toads when blood samples were taken every 4 hr. When compared to a previously published circadian rhythm study of locomotor activity, the surge in corticosterone concentration for the day occurred at 1730 just prior to the peak in locomotor activity.

Extraocular perception of polarized light by orienting salamanders

SummarySpatial orientation corresponding to the bearing of thee-vector of linearly polarized light can be demonstrated in sighted and eyeless salamanders (Ambystoma tigrinum) trained under linearly polarized light. However, if opaque polyethylene plastic is inserted over the skull of these animals, whether they are sighted or eyeless, orientation is uniform within the test arena. Bidirectional oriented movement is restored in both groups, however, when transparent plastic is substituted in the same animals. A discussion of the possible mechanism for perception of polarized light by extraocular photoreceptors (EOPs) is given.ZusammenfassungDurch Dressur unter linear polarisiertem Licht wird beiAmbystoma tigrinum sowohl mit als auch ohne Augen eine Orientierung nach deme-Vektor linear polarisierten Lichtes nachgewiesen. Wird jedoch über dem Schädel (unter der Haut) eine opake Polyäthylen-Scheibe eingeschoben, so findet sich weder bei geblendeten noch bei Tieren mit Augen eine Orientierung nach deme-Vektor. Wird die opake Plastikscheibe durch eine transparente ersetzt, so tritt in jedem Fall die Orientierung (± 180 °) wieder auf. Die möglichen Mechanismen der Wahrnehmung polarisierten Lichtes durch extraokulare Rezeptoren werden diskutiert.

Circadian Modulation of the Rat Acoustic Startle Response

The acoustic startle response (ASR) of male rats was measured during several sessions over a 24-hr period in both a light-dark cycle and a constant-dark condition. Each session consisted of 10 trials each at 80, 90, 100, 110, and 120 dB white noise. The results indicate robust daily and circadian modulation of ASR amplitude that consist of an approximately twofold nocturnal increase at eliciting-stimuli intensities above 80 dB. Similar results were observed in female rats in constant-dark conditions. To determine whether daily changes in auditory thresholds were responsible for the observed modulation, ASR reflex modification procedures were used. These procedures were designed to measure auditory thresholds at frequencies of 10 and 40 kHz at several times of day. The results suggest a lack of significant circadian differences in auditory thresholds at these frequencies. This study demonstrates a novel role of the rat circadian system in the modulation of ASR amplitude.

Developmental neurotoxicity following premating maternal exposure to hexachlorobenzene in rats

The maternal transfer of hexachlorobenzene (HCB) may place the developing organism at risk. The present study assessed the developmental neurotoxicity of HCB using a battery of behavioral tests. Two weeks prior to breeding, maternal rats were exposed via gavage to either 10 or 100 mg HCB/kg body weight. Behaviors evaluated in pups exposed maternally to HCB included the negative geotaxic reflex on postnatal day (PND) 6, 8, and 10, olfactory discrimination (PND 9-11), and the development of exploratory behavior (PND 15-20). Significant effects in these three tests indicated hyperactivity in HCB-exposed pups. No significant effects on learning (swim T-maze) or motor activity were detected in older offspring (PND 40 and 50 respectively). The acoustic startle response (ASR) revealed apparent age-related effects of maternal HCB exposure. On PND 23 pups from the high treatment group demonstrated significantly reduced ASR amplitude, whereas these same animals, tested on PND 90 (using a reflex modification design), showed elevated ASR amplitude relative to the controls. This work demonstrates that HCB is a behavioral teratogen, and suggests that human fetuses and suckling infants may be at risk from the neurotoxic effects of HCB.