British scientists reported today that a low-tech, unlicensedapproach to treating sepsis effectively attacks the finalcommon pathway acted on by biotech drug candidates.
The non-biotech drugs used to treat rats with endotoxin-induced shock and two advanced cases of septic shock inhumans come off the shelf of chemical supply houses. They areanalogs of the amino acid l-arginine, and they block thearginine-dependent process of blood vessel dilation that causesblood pressure to fall and organs to fail in septic shock.
Blood vessels open wide in response to nitric oxide, or NO,which is made from l-arginine by cells lining the vessels. Abaseline amount of NO helps keep vessels at proper bore, but inseptic shock, bacterial endotoxin induces an outpouring of NO.Profound vasodilation follows. Organs that cannot get enoughblood flow fail; mortality is 50 percent to 70 percent.
Researchers at Wellcome Research Laboratories in Kent testeddifferent doses of the arginine analog L-NMMA in rats withendotoxin-induced shock. A low dose and a high dose failed toprevent death, but a midrange amount prevented a fall inblood pressure, and all five animals survived.
In two patients with septic shock who had resisted alltherapeutic efforts, doctors at St. George's Hospital in Londontried two analogs, L-NMMA and L-NAME. Although one patientdied, the other could be taken off life support. The survivingpatient had already experienced kidney failure, which mighthave prolonged the life of the analog in his circulation.
Several problems remain for introducing the NO approach toclinical testing and use. The Kent physicians noted that the twoanalogs they tested cannot be patented. "L-NMMA and L-NAMEare unlicensed drugs which have yet to undergo formaltoxicological studies and will need to be produced in a formsuitable for routine clinical use," they said.
NO blockers potentially could supplant recombinant monoclonalantibodies and cytokines in septic shock, which are beingpursued by companies in several countries. Centocor Inc.(NASDAQ:CNTO), Genentech Inc. (NYSE:GNE), Synergen Inc.(NASDAQ:SYGN) and Xoma Corp. (NASDAQ:XOMA) are amongthe many biotech players in the sepsis market.
"Unlike agents to neutralize endotoxin and individual cytokines,various combinations of which may be needed for differenttypes of shock, NO synthase inhibitors offer a single therapeuticapproach," the Wellcome group concluded.
However, as a Lancet editorial noted, NO blockers could helpcytokines in other situations, for instance as "a useful adjunctto interleukin-2, which is normally restricted because of theconcomitant hypotension" it induces through NO.
Cetus Corp., now a unit of Chiron Corp. (NASDAQ:CHIR),developed IL-2, which has yet to receive U.S. marketingapproval.
Giving gaseous NO itself may nudge aside cytokines in otherarenas, however. The editorial predicted that "therapeuticinhalation of NO will provide a new clinical strategy for themanagement of patients with adult respiratory distresssyndrome," a condition for which Genentech and Repligen Corp.(NASDAQ:RGEN) hope to develop IL-8 as therapy.
In an accompanying article, Edinburgh researchers also showedthe beneficial effect of blocking NO on the hypotension ofadvanced liver cirrhosis.
-- Roberta Friedman, Ph.D. Special to BioWorld
(c) 1997 American Health Consultants. All rights reserved.