One hypothesis for persisting HIV-associated neurocognitive disorders (HAND) in effectively treated individuals is the limited permeation of antiretroviral agents (ARV) across the blood-brain barrier (BBB). However, the physicochemical factors limiting the brain entry of a given ARV and the mutual interactions of combined drugs on their brain entry have not been properly characterized. Using transporter kinetic measurements, we show that large lipophilic drugs such as protease inhibitors (PI) have strong binding affinities to drug efflux transporters expressed at the BBB and thus are prevented from entering the brain. However, when combined, the PI with the highest binding affinity (i.e., boosting ritonavir) will occupy a large proportion of the transporter binding sites and thus slow down the efflux rate of the coadministered PI thereby facilitating its brain entry. Furthermore, using thermodynamic measurements and computational modeling, we show that ARV with small cross-sectional areas (AD < 70 Å(2)) and octanol-water distribution coefficients (-1 < log D <5) such as most nucleoside analogues have a high passive influx and cross the BBB despite interactions with drug transporters. These data indicate that HIV therapies combining small diffusing molecules with large lipophilic molecules are better suited for brain entry and should be preferred for HAND. This work highlights the role of PI as modulators of drugs' brain entry.

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Poultry litter was evaluated as a fertilizer in a young (three-year-old) and an old (35-yearold) black walnut (Juglans nigra L.) plantation in southwest Missouri. The older planting had a fescue (Festuca arundinaceae Schreb.) ground cover that is grazed by cattle. In the young plantation, weeds were mowed and sprayed with herbicides once annually in the spring. Litter was applied at rates of 6.72 Mg ha −1 and 13.44 Mg ha −1 for one year in the spring in the young plantation and at 8.96 Mg ha −1 for two years in the spring and once in late summer in the older plantation. Height growth and leaf nitrogen (N) concentrations were improved during the summer following litter applications in the young plantation, but neither diameter growth nor nut production increased in the older plantation. Second-year height growth treatment differences for the young plantation were not significant. The number of nuts increased in the second year, but differences between treatments were not significant.