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Biotech / Medical : Agouron Pharmaceuticals (AGPH) -- Ignore unavailable to you. Want to Upgrade?

To: margie who wrote (6075)	5/14/1999 2:24:00 AM
From: billkirn	Read Replies (2) \| Respond to of 6136

Margie and Richard: About time to close it out. What a ride, great company, great people on the thread and in the company. I will miss this. It was a valuable investment over the last 6 years. But most of all, it was special to be connected to a process that really contributed to the reduction of suffering for many people. I hope I find this combination in the future. For me, I am moving into the fuel cell area. This could dramatically reduce world pollution and help preserve our precious environment. It also appeals to my electrical engineering and computer background. Good luck to you. I will be keeping track of your reporting and opinions as they are really valuable. Bill

To: margie who wrote (6075)	9/24/1999 2:22:00 PM
From: scaram(o)uche	Read Replies (1) \| Respond to of 6136

Session: Toxicity of Antiretroviral Therapy Location: Exhibit Hall Session Date: Monday, 9/27/99 Session Time: 3:00 pm - 4:30 pm Preclinical Investigations into the Mechanism by Which HIV Protease Inhibitors May Induce Metabolic Disorders G.J. Stevens, M. Chen, R. Grecko, A. Lankford, J. Harr, C. Lee, P.W. Rose Agouron Pharmaceuticals, Inc.: San Diego, CA Background: Carr et al. (Lancet, (1998)351:1881) described several mechanisms by which HIV-1 protease inhibitors (PIs) may induce metabolic changes ("lipodystrophy"). Several of these proposed mechanisms were investigated. Methods: Preclinical investigations included: 1) The effect of cytochrome P450 3A (CYP3A) inhibition on the isomerization of all-trans-retinoic acid to the 9-cis isomer in human liver microsomes; 2) Comparison of the 3-dimensional crystal structure of the HIV-1 protease and the cellular retinoic acid binding protein-1 (CRABP1); 3) Assessment of the effects of PIs on adipocyte differentiation in 3T3 L1 cells using triglyceride accumulation and glycerol phosphate dehydrogenase activity as markers for differentiation. Results: Under the conditions utilized for the CYP3A assays, isomerization of all trans retinoic acid was not inhibited by the CYP3A inhibitor, troleandomycin. Although PIs inhibit CYP3A, our findings demonstrate that the isomerization of retinoic acid would not be affected by inhibition of this P450 isoform. Computational comparison of the crystal structure of CRABP1 and the HIV-1 protease demonstrated no three-dimensional similarities. Docking of nelfinavir to the CRABP1 binding site indicated that nelfinavir can bind to the active site, however, no hydrogen bonds are formed, suggesting little interaction between this PI and CRABP1. Thus, inhibition of CRABP1 mediated signaling of retinoic acid is unlikely to occur by direct binding of nelfinavir. At therapeutic concentrations, PIs decreased adipocyte differentiation to varying degrees (saquinavir > indinavir > ritonavir > nelfinavir = amprenavir). However, currently there is no direct evidence linking these changes in adipocyte differentiation to "lipodystrophy". Conclusion: Preclinical investigations demonstrate that PIs do not inhibit retinoic acid and are unlikely to alter CRABP1 biding of 9-cis retinoic acid as has been previously proposed. While results indicate that PIs inhibit adipocyte differentiation, the relevance of this observation is not yet known. Therefore, other mechanisms are believed responsible for the metabolic changes associated with body fat redistribution.