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

To: Robert K. who wrote (16688)	2/28/2004 10:43:55 PM
From: dwight martin	Read Replies (1) \| Respond to of 17367

medscape.com and Introduction Severe Sepsis: Results of a Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled, Clinical Trial Posted 02/17/2004 Abstract Objective: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. Design: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. Setting: One hundred forty-six intensive care units from nine countries. Patients: Approximately 2,522 patients were planned to be enrolled </=12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. Measurements and Main Results: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p = .80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. Conclusions: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis. Administration of the Nitric Oxide Synthase Inhibitor NG-methyl-L-arginine hydrochloride (546C88) by Intravenous Infusion for Up to 72 Hours Can Promote the Resolution of Shock in Patients With Severe Sepsis Results of a Randomized, Double-Blind, Placebo-Controlled Multicenter Study (Study No. 144-002) Posted 02/13/2004 Abstract and Introduction Abstract Objective: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure >/=70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. Design: Multicentered, randomized, placebo-controlled, safety and efficacy study. Setting: Forty-eight intensive care units in Europe, North America, and Australia. Patients: A total of 312 patients with septic shock diagnosed within 24 hr before randomization. Interventions: Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). Measurements and Main Results: Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p = .004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. Conclusions: In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.