Antiretroviral agents are currently the only approved therapy for treatment of HIV dementia, but treatment response is frequently unsatisfactory or short-lived, or agents poorly tolerated in doses adequate for CNS penetration. The reason for the incomplete response may be that the pathophysiology of HIV-related cognitive impairment is initiated by the virus, but involves a complicated inflammatory cascade within the brain. Therefore, effective therapy needs to focus on these indirect mechanisms in addition to viral suppression. One hypothesis for the pathophysiology of dementia is that neurotoxic substances are produced by specific interactions between infected macrophages and astrocytes to damage and destroy neurons. In this schema, we are interested in the role of the lipid inflammatory mediator, platelet activating factor (PAF). This is a potent biological mediator that exerts its effects in as variety of cells and tissues and has been detected at high levels in the CSF of immune-suppressed HIV-1 infected patients with CNS dysfunction. Lexipafant is a PAF antagonist with high affinity for the PAF receptor with an excellent safety profile. Currently, controlled clinical trials of Lexipafant are under way in treatment of asthma, pancreatitis, ulcerative colitis and pre-operative ischemia. It has shown to be active via oral route and is well- tolerated in human volunteers using doses up to 750 mg bid. No prior clinical research has been reported with Lexipafant in HIV-infected individuals.
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