A larger and more ambitious application on this topic was submitted as an ROl in response to an RFA from NIMH on """"""""Impact of HAART on HIV/CNS diseases."""""""" In response to the major criticism of the reviewers, that of lack of preliminary data, we have revised and reduced the scope of the application to meet the specifications of an R2 1 application. An R2 1 application is specifically targeted to allow generation of preliminary data. Neurological complications are the most frequent and detrimental quality of life problems experienced by people with HW-infection. The initial pathogenic step in HIV-associated neurocognitive disorders is the establishment of replicative HIV infection in the brain. Thus, lowering CNS viral burden should provide effective therapy for neurocognitive disorders. However, this goal is compromised by the fact that the exposure of the CNS to the antiretroviral drugs is restricted by active efflux of these drugs by various transporters located at the blood-brain and blood/CSF barrier. In animal studies, the efflux of the antiretroviral drugs, protease inhibitors, from the CNS has been shown to be mediated by the efflux pump, P-glycoprotein (P-gp). Therefore, we have hypothesized that inhibition of P-gp should result in enhanced concentrations of these drugs in CNS and therefore more effective therapy for prevention and treatment of HI V-associated neurocognitive disorders. Hypothesis Inhibition of P-gp increases the exposure of the CNS to protease inhibitors.
The specific aims listed below use the state of the art izoninvasive and quantitative positron emission tomography (PET) techniques to test this hypothesis in hum an subjects Specific Aims: (a) To develop a reliable, validated protocol for synthesis of l""""""""CJ-verapainil (a P-gp substrate) for IV administration to human subjects. (b) To obtain the necessary l""""""""cJ-verapamil dosimetry, imaging and pharmacokinetic data jn human subjects (n=3) to gain local regulatory approval for studies outlined under specific aim. To test our hypothesis, using PET, that inhibition of P-gp in creases the exposure of CNS to l""""""""1CJ-verapamil and, by inference, protease inhibitors.
