Since the first reports of acquired immune deficiency syndrome (AIDS) emerged in 1981, considerable scientific progress has been made in understanding its pathogenesis and treatment. The virus that causes it, human immunodeficiency virus (HIV), has been conclusively identified and tests developed to detect its presence in body fluids. A number of antiretroviral drugs have been approved in the United States for the treatment of AIDS, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors. Although such agents are beneficial, AIDS continues to be a significant health problem globally, and remains a leading cause of death among U.S. males 22-45 years of age. By 1995, results of studies had demonstrated that combination therapy was superior to monotherapy in extending symptom-free survival. In late 1995, results of trials studying combinations of inhibitors of HIV protease (PIs) with either one or two nucleoside analogs demonstrated that the protease inhibitors saquinavir (Invirase), ritonavir (Norvir), and indinavir (Crixivan) would be the most potent weapons thus far in the antiretroviral arsenal. In 1996, three protease inhibitors were approved by the FDA. In early 1997 a fourth PI, nelfinavir (Viracept), was approved. In 1996, studies demonstrated that combining NRTIs with non-nucleoside reverse transcriptase inhibitors (NNRTIs) was useful as antiretroviral chemotherapy, resulting in reduced or undetectable viral loads. The most common adverse effect of this class of drugs is rash. Three NNRTIs have been FDA-approved: nevirapine (Viramune) in mid 1996, delavirdine (Rescriptor) in early 1997, and DMP 266 (Sustiva) in mid-September of 1998. In many patients, appropriate combinations of antiretroviral drugs appear to circumvent the ability of HIV-1 to generate drug-resistant viruses. Viral load has been validated as a surrogate marker of disease progression. Additionally, an individuals risk of disease progression can be assessed early in the course of the clinical evaluation with the use of HIV RNA PCR and bDNA assays. At that time appropriate combination therapy can be instituted. Treatment has radically extended the length and quality of life of HIV-infected individuals. However, viral resistance remains the primary reason for failure of anti-HIV drug therapies. As the number of recognized mutant strains of HIV has increased, so has the need for new therapies which can be successfully incorporated into our drug armamentarium. The compound being evaluated in this study, (+)-calanolide A, was extracted from the tree Calophyllum lanigerum, which is found in the rainforest of Sarawak, Malaysia, and was tested as part of the National Cancer Institute's (NCIs) anti-HIV screening program. MediChem Research, Inc., has the exclusive license to the NCI use patent on this compound, as well as a process patent for the total synthesis of (+)-calanolide A. All compound administered to humans is manufactured synthetically, preserving the environmental value of forest lands.
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