By David N. Leff
Medicine and surgery have progressed a lot since the year 1859. That was when Florence Nightingale, founding mother of modern nursing, wrote:
"It may seem a strange principle to enunciate as the very first requirement in a hospital that it should do the sick no harm."
Yet today, a century and a half later, hospitals can still be hazardous, not only to health, but to life itself.
Their principal threat is sepsis — poisoning of the blood by bacterial toxins — often the side-effect of surgery. A recent study of 660 hospitalized patients indicted 21 gram-negative pathogenic organisms as perpetrators of septicemia. Topping the hit-list were Staphylococcus aureus (27 percent of the cases), Escherichia coli (19 percent) and Klebsiella (15 percent).
Within a few hours of infection, bacterial septic shock can dangerously lower a patient's blood pressure, spike body temperature, cause diarrhea and extensive blood clotting in various organs. About half a million patients a year in the U.S. alone suffer such sepsis, and more than 70,000 of them die.
Toxins in the bacterial wall apparently cause this acute mayhem by stimulating macrophages in the immune system to overproduce two key cytokines, interleukin-1 (IL-1) and interferon-gamma (INF-*).
This lethal multi-threat to patients in the very temple of modern healing — the hospital — quickly attracted funds and researchers to the burgeoning biotech companies of the mid-1980s. Their efforts focused largely on mono-clonal antibodies designed to neutralize the bacterial endotoxins that did the dirty work of septic shock, and on antagonists to the cytokines they suborned.
Today the woods are strewn with the whitened skeletons of Phase III sepsis trials that failed.
But The Quest Continues
"The initial strategies that were chosen to attempt to have a clinical impact on that disease were disappointing," recalled immunologist Vicki Sato, senior vice president of research and development, and chief scientific officer, of Vertex Pharmaceuticals Inc., Cambridge, Mass. "It remains a disappointment for all of us trying to develop novel drugs for this very important and life-threatening clinical problem."
Sato is a co-author of a paper in the latest issue of Science, dated Jan. 10, 1997." Its title: "Activation of interferon-* [INF-*] inducing factor [IGIF] mediated by interleukin-1ß converting enzyme [ICE].
"This paper reconciles two surprisingly contradictory results, Sato told BioWorld Today. "The first is that ICE knockouts were protected from a lethal dose of E. coli endotoxin, whereas the IL-1-beta knockout was not. This suggested that ICE played a larger role in mediating the response to sepsis than just control of IL-1-beta."
"Now we can see," she continued, "that ICE mediates that connection between interleukin-1-beta levels and gamma interferon levels. It's really the first indication that it's possible to regulate some of the deleterious effects of INF-gamma on its proinflammatory sepsis side, as distinct from interferon's important immunostimulatory effects on the T-cell side."
Molecular biologist Michael Su is the Science article's corresponding author. He and his co-workers at Vertex made the connection between interferon-gamma inducing factor (IGIF), a recently discovered molecule, and the regulation of those two trigger-happy cytokines, IL-1ß and INF-*.
These seminal findings validate the ICE-inhibiting compounds that Vertex and its European research partners are now grooming for clinical trials.
"It opens up the opportunity for exploring ICE inhibitors therapeutically," Sato observed, "in areas of acute inflammation caused by pathogenic bacteria." She contrasted this perspective with earlier unsuccessful attempts to tackle sepsis via IL-1 receptor antagonists.
"It also raises a number of additional therapeutic possibilities," Sato went on, "where both gamma interferon and IL-1 have been shown to participate in cellular or tissue destruction in that disease. Diabetes is one," she observed, "in which we know that the early destruction of those islet cells is mediated by both kinds of cytokines."
ICE-Stoppers Will Take On Arthritis First
Among other potential disease entities for ICE inhibition, she cited metastatic cancers, including leukemias. "IL-1 and interferon both play a role in recruiting blood cells in the vascular epithelium," Sato noted. "IL-1 has been implicated in the regulation of cell adhesion molecules that are important in the trafficking of various cell types, with respect to both metastasis and inflammation."
"Vertex now has orally active ICE inhibitors, developed jointly with our research and development partners at Hoechst-Marion-Roussel, [Frankfurt, Germany]," Sato said. "Together, we are beginning the preclinical development of one of those, preparatory to an investigational new drug application [IND] filing with the FDA. It's a combination of in vitro and mostly in vivo, work in various animal species.
"The IND," she pointed out, "is not imminent. I would expect that in the coming months of 1997, we and our partners will be able to talk about the particular compounds that are in clinical development in a little bit more detail than right now.
"This work helps us understand more precisely the complexity of the molecules involved in mediating lethal sepsis, and provides some reason for optimism about why new strategies being brought to bear continue to be worth evaluating in this clinical indication," she said.
But Sato concluded: "Sepsis is not the primary focus of our current clinical plans for the ICE inhibitors. While this work has caused us to reevaluate its potential in sepsis, the preclinical program for the ICE inhibitor is not primarily directed at sepsis. Our initial clinical indications are most likely to be targeted at the arthritides, rheumatoid and osteoarthritis." *