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Biotech / Medical : XOMA. Bull or Bear? -- Ignore unavailable to you. Want to Upgrade?

To: Robert K. who wrote (9556)	4/8/1999 12:01:00 AM
From: aknahow	Respond to of 17367

I agree, I would love to see XOMA develop Mycoprex with or without a partner. They don't have the financial resources to do it alone. Castello will probably try to say something new tomorrow if it is possible to do so. No hype but facts if they are available. Even revealing the mortality target would be worth something if he also revealed how close they were. The ability to do this may have been discussed with the DSMB, because at this stage in the trial whatever sense there was to this DSMB imposed blackout, no longer exist. At least I can hope. <g>

To: Robert K. who wrote (9556)	4/8/1999 12:16:00 AM
From: aknahow	Respond to of 17367

Mr. Prils friend Steven Opal on rBPI21. Just a repeat but one would think that this experts opinions would create interest in XOMA. PHARMACOKINETICS OF A RECOMBINANT AMINO TERMINAL FRAGMENT OF BACTERICIDAUPERMEABILITY-INCREASING PROTEIN (rBP'21) AFTER LIVER SURGERY IN HUMANS Steven M. Opal Infectious Disease Division, Memotial Hospital, Pawtucket, Rhode Island 02860 Received 4/22/98; accepted in the final form 6/17/98. In this issue of Shock, Wiezer and colleagues describe their experience with a recombinant form of Bactericidal/Perineability-Increasing protein (rBPI21) in animals and patients following partial hepatectomy (1). The results of this work are particularly relevant at the present time as rBPI21 is in clinical trials for several endotoxin-related disorders, including those in patients with partial hepatectomy (2, 3). The liver is critical to the clearance of both endotoxin and BPI. The metabolic effects of partial hepatectomy on the handling of both molecules need to understood before rBP,21 can be administered safely to patients following partial hepatic resection. BPI is an endogenous human endotoxin-binding and neutralizing protein found primarily in the lysosomal granules of human neutrophils. It is a 456-aniino-acid, soluble protein with a double barreled, boomerang-like three dimensional structure. There are two hydrophobic pockets on the underside of both the amino and carboxyl terminal domains of BPI that probably function as the endotoxin binding regions of the molecule (4). The protein possesses significant antibacterial properties (5), but has striking anti-endotoxin activity (6). Despite the structural similarity of BPI to lipopolysaccharide binding protein (LBP), BPI and LBP function as molecular antagonists in relationship to endotoxin activity (7). BPI binds to endotoxin and blocks its delivery to membrane-bound CD 14 molecules on neutrophils and monocytes. LBP competes with BPI for endotoxin binding as each protein has a high affinity attachment site for the lipid A portion of LPS. LBP facilitates endotoxin presentation to CD14 bearing effector cells in a manner that results in cellular activation and proinflammatory cytokine synthesis (6, 7). The opposing actions of these two competing endotoxin binding proteins largely determine the physiologic effects of endotoxin release. Very little BPI is found in the systemic circulation, but the protein is found in high concentrations (up to 24 gg/mL) in infected body fluids where abundant populations of neutrophils are found (8). LBP is a normal constituent of human plasma, and its synthesis is up-regulated as an acute phase protein. Thus, LBP levels are several orders of magnitude higher then BPI concentrations in the systemic circulation. Once endotoxin molecules are released into the blood, they are much more likely to bind to LBP than BPI. These LBP-LP'complexes then activate inflammatory cells throughout the body. An appealing anti-endotoxin strategy is to administer BPI intravenously to patients at high risk for physiologic injury from excess quantities of endotoxin in the blood. BPI has the advantage of being an endogenous human protein that naturally serves the function of endotoxin binding and neutralization (6). The protein should be non-immunogenic, and this will allow repeated administration of the protein to patients with recurrent episodes of endotoxemia. One of the potential drawbacks of BPI therapy is its short half-life in the central compartment, which is measured in minutes (9). This necessitates the use of a continuous inftlsion of the material in appropriate'clinical situations. Stability and production concerns have been addressed by the generation of an amino terminal truncated version of the protein that retains its high avidity LPS binding and neutralization characteristics (10). The current form of the protein in clinical trials is a recombinant 21 kDa molecule rBP'21 (2, 3). The study by Wiezer et al. demonstrates that the clearance of rBP,21 is considerably delayed by 80% hepatectomy in rats and modestly delayed in a series of patients undergoing partial hepatectomy (1). However, the steady state levels of rBP,21 are not significantly different from levels obtained in normal volunteers, and blood levels return rapidly to baseline in both hepatic surgery patients and normal humans. From these results, it appears that the pharmacokinetics of rBP21 are not sufficiently altered by partial hepatectomy sufficiently to adversely affect the clinical use of the anti-endotoxin protein in such patients. This is important information since patients with partial hepatic resections and other forms of liver disease tolerate endotoxemia poorly (1 1). The outcome form sepsis in patients with severe liver disease is so devastating that such patients are often specifically excluded from clinical sepsis trials. Improved strategies in the management of patients with reduced functional hepatic mass are clearly needed. The current work contributes to the promise of better treatments for these compromised patients. The clinical trials with rBP21, in partial hepatectomy should answer a number of essential questions about the role of endotoxin in this well defined group of ents (3).

To: Robert K. who wrote (9556)	4/8/1999 12:39:00 AM
From: aknahow	Respond to of 17367

univie.ac.at You have this source but just posting for others.