Hello Dew. Use your wayback machine and do some DD on rBPI21 and Protein C and you just may find that rBPI21 would have been the perfect adjuvant for Lilly's Xigris because it turbo boosted the effects of Xigris, yet Lilly and Xoma could never get together to create a "possible" dynamic agent to combat gram negative sepsis and sepsis in general...there is much research out on this yet due to "unknown" reasons that had us "so called" highly informed investors in Xoma shaking our heads and being perturbed with Xoma mgt to the point of calling for investigations into payoffs for keeping rBPI21 out of the Xigris mix, so that Lilly could go after the Sepsis market solo....
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1191640 Protective effect of bactericidal/permeability-increasing protein (rBPI21) in baboon sepsis is related to its antibacterial, not antiendotoxin, properties. G Schlag, H Redl, J Davies, and P Scannon
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria.
Abstract OBJECTIVE AND SUMMARY BACKGROUND DATA: The recombinant fragment of bactericidal/permeability-increasing protein, rBPI21, has potent bactericidal activity against gram-negative bacteria as well as antiendotoxin (lipopolysaccharide [LPS]) action. On the basis of these activities, the authors sought to discover whether rBPI21 would be protective in baboons with live Escherichia coli-induced sepsis and whether the potential protective effects of rBPI21 (together with antibiotics) would be more closely related to its antibacterial or LPS-neutralizing effects. METHODS: In a prospective, randomized, placebo-controlled subchronic laboratory study, the efficacy of rBPI21 or placebo was studied over 72 hours in chronically instrumented male baboons infused with live E. coli under antibiotic therapy. RESULTS: Intravenous rBPI21 attenuated sepsis-related organ failure and increased survival significantly. Bacteremia was significantly reduced in the rBPI21 group at 2 hours after the start of the E. coli infusion, whereas circulating LPS was less affected. The in vivo formation of tumor necrosis factor was significantly suppressed by the rBPI21 treatment regimen. Microcirculation and organ function were improved. CONCLUSIONS: In baboon live E. coli sepsis, the salutary effect of rBPI21 results from a more prevalent antibacterial than antiendotoxin activity.
Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis.
Methods We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0·2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat.
Findings Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8·7%) of 393 patients died during the study: 14 (7·4%) in the rBPI21 group and 20 (9·9%) in the placebo group (odds ratio 1·31 [95% Cl 0·62–2·74], p=0·48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3·2%] vs 15 of 203 [7·4%], odds ratio 2·47 [0·94–6·51], p=0·067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77·3%] vs 126 of 190 [66·3%], p=0·019).
Interpretation
Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.
also: The anti-endotoxin agent, rBPI21, significantly attenuates surgically induced tumour growth in an experimental metatases murine model of breast cancer Authors: O'Donoghue G.T.; Pidgeon G.; Harmey J.; Dedrick R.; Redmond P.H.; Bouchier-Hayes D.J. Source: Journal of Surgical Research, Volume 114, Number 2, October 2003, pp. 300-300(1)
Wiezer MJ, Boelens PG, Vuylsteke RJ, Nijveldt RJ, Meijer C, Cuesta MA, Meijer S, van Leeuwen PA Department of Surgery, Vrije Universiteit Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
INTRODUCTION: Major hepatic resections are still associated with considerable morbidity. Gut-derived bacteria and bacterial endotoxin are considered to play a central role in the pathophysiology of complications. Experimental studies suggest that bactericidal/permeability-increasing protein (BPI), which has both antibacterial and endotoxin-neutralising properties, can reduce postoperative complications. MATERIAL AND METHODS: A phase II, double-blind, placebo-controlled, multicentre, dose escalation trial was conducted in patients undergoing major liver resection, and clinical outcome, infectious complications, plasma amino acid patterns, coagulation and fibrinolytic cascade systems and neutrophil functions were compared between the two treatment groups and an extra group of patients undergoing major abdominal non-hepatic surgery. RESULTS: Drug administration in this patient group was safe, and resulted in a significant reduction of infectious complications. Furthermore, beneficial effects were found in the postoperative amino acid ratio and fibrinolytic cascades, and rBPI21 preserved leukocyte functions. CONCLUSION: Administration of rBPI21 in patients undergoing major liver resection is well tolerated and results in improvement of both clinical and biochemical parameters.
http://www.future-drugs.com/doi/abs/10.1586/1744666X.2.5.787 Expert Review of Clinical Immunology September 2006, Vol. 2, No. 5, Pages 787-799 (doi:10.1586/1744666X.2.5.787) Innate recognition of bacteria: potential therapeutic targets for bacterial sepsis..
A new era for sepsis treatment? Understanding sepsis as a consequence of host immune response Deborah T Hung, Lindsey R Baden Division of Infectious Disease, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. dhung@partners.org Division of Infectious Disease, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Sepsis is a syndrome of increasing prevalence and accounts for high mortality in the intensive care unit. The search for sepsis therapies in the past decades have been marked by disappointment and failure. More recently however, new insights have been gained in the process of sepsis which have broadened the field of therapeutic approaches. Elucidation of the signal transduction pathways that are involved in innate immunity have begun to link the pathogen-host interaction to the resulting broad host response. Insights into the host response have resulted in a greater understanding of its complexity as an intricate web involving inflammation, haemostasis and the endothelium. This recent explosion in understanding coincides with the first success in sepsis therapy with the advent of activated protein C and may herald a new era for sepsis treatment. http://www.expertopin.com/doi/pdf/10.1517/13543776.12.2.181?cookieSet=1
So much information on why rBPI21 and Xigris should have been partnered together to fight this oncoming wave of sepsis, that was indicated way back in the 90's, and yet nothing ever came of it...kinda like keeping Jordan and Pippen apart and the Championship run of the Bulls may never of happened?????
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