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

To: Robert S. who wrote (7330)	9/25/1998 10:05:00 PM
From: aknahow	Respond to of 17367

Robert S, I see your still at it. You may like this even more as it is even more apt to scare the bulls. <g> Other Formats: Links: Order this document J Antimicrob Chemother 1997 Jan;39(1):13-18 No increase in endotoxin release during antibiotic killing of meningococci. Prins JM, Speelman P, Kuijper EJ, Dankert J, van Deventer SJ Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. Endotoxin is liberated following antibiotic killing of Gram-negative rods, and antibiotics may differ in this respect. Although the amount of filterable endotoxin has also been reported to increase following antibiotic killing of meningococci, it is unknown how this influences the host response. We investigated the influence of three antibiotics on levels of free endotoxin in culture medium and cytokine production in whole blood ex vivo during killing of four strains of meningococci. Bacterial killing was significantly more efficient with penicillin or ceftriaxone than with chloramphenicol, and free endotoxin levels were lower after exposure to antibiotics as compared with no treatment (ANOVA, P < 0.001). Endotoxin levels were lowest after exposure to chloramphenicol. In three of the four strains exposure to antibiotics resulted in considerably lower cytokine levels (ANOVA, P < 0.001), and TNF-alpha levels were significantly lower after exposure to penicillin or ceftriaxone than after chloramphenicol treatment. Only in the strain that induced the lowest levels of TNF-alpha were cytokine levels comparable for untreated and treated samples. We conclude that fear of excessive endotoxin release or cytokine production caused by effective antibiotics is not justified in the treatment of meningococcal infections. PMID: 9044022, UI: 97196933 the above report in format documents on this page through Loansome Doc

To: Robert S. who wrote (7330)	9/26/1998 8:47:00 AM
From: Robert K.	Read Replies (2) \| Respond to of 17367

Dear Robert S.>Since you ARE perplexed about endotoxins I thought I would give you a opinion from a Dr Opal. If you do a medline search on him you will find his previous activities to cover a broad swath of sepsis research. Please pay particular attention to how he describes bpi antiendotoxin potential. (VBG) Now for the abstract>>>>>>>>> > >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 S. who wrote (7330)	9/27/1998 10:45:00 PM
From: Cacaito	Read Replies (3) \| Respond to of 17367

Robert S, the abstract you post is a review (check the end), not an original research, full of hypothesis and the work of others (most of the time the reviewer is one of the top researchers in the subject, or a young fellow starting a career). This is important to start reading about a subject, but it will be better to have the full article ( I will try, but it takes time to find it, sometimes weeks). It deals mainly on traditional antibiotics and their role in the release of endotoxin. General idea: some antibiotics kill the bacteria and release the endotoxins, others do not. The author is not sure what is better, if endotoxins are not release then some defense mechanisms are not started, but if they are a lot of inflammation comes by. BPI goes further, it helps in the killing, it helps regulate the immune defense response, and it regulates it with little if any inflammatory damage, plus other positive actions, like decreasing problems with intravascular coagulation and/or bleeding disorders. A very superior model, with very good basic sciences and animal experiments supporting it, and mounting evidence from several phase I, and II human subjects studies. To wait for the phase III results is the clue. The article post by Robert K does give you some answer to this question, is a review of some of the experience on BPI actions and pharmacokinetics, indeed a very good choice as a reply. The stock is very low price, maybe extremely cheap. If one believe in all the previous evidence then one is a holder and of course a nervous one waiting to make it or break it, like me. If one does not believe, I suspect like you, is better to wait on the sidelines, see the price go up slowly toward the end of the year and when the results comes out lose some of the upside, and pick it less cheap, but still cheap, or even wait a little bit after the initial hoopla and pick it after the profit taking. Not a bad strategy either. Best luck and jump at the right time. cacaito