george,
I read the slides (but not yet the KPMG report). I very much agree with the concept of biting off a small chunk of the sepsis problem and demonstrating first that it works for something. I also see that theoretically meningo was a logical choice - clearly defined and homogeneous, easy to see if your drug works and good theoretical evidence that it should work. I still worry about a trial in a fast moving, rare disease though - you can't get big numbers of patients and you can comparatively easily be simply unlucky. It's all so much easier in something undramatic like periodontal disease or the like.
BTW, I came across the following (probably only tangentially relevant) new item:
HMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Haichao Wang, 13* Ona Bloom, 3 Minghuang Zhang, 3 Jaideep M. Vishnubhakat, 3 Michael Ombrellino, 23 Jiantu Che, 3 Asia Frazier, 23 Huan Yang, 3 Svetlana Ivanova, 3 Lyudmila Borovikova, 3 Kirk R. Manogue, 3 Eugen Faist, 4 Edward Abraham, 5 Jan Andersson, 6 Ulf Andersson, 7 Patricia E. Molina, 2 Naji N. Abumrad, 2 Andrew Sama, 1 Kevin J. Tracey 23
Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
1 Department of Emergency Medicine and
2 Department of Surgery, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA.
3 The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
4 Department of Surgery, Klinicum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
5 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
6 Department of Infectious Disease, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
7 Department of Rheumatology, Astrid Lindgren's Children's Hospital, Karolinska Institute, Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: hwang@picower.edu
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Volume 285, Number 5425 Issue of 9 Jul 1999, pp. 248 - 251
©1999 by The American Association for the Advancement of Science.
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Peter |
