In this turbulent time of multi-trillion-dollar budgets, debts anddeficits, mere billions aren't what they used to be.
Still, the number of people on earth add up to 6 billion-plus. Of thisnumber, one in six _ over 1 billion men, women and mainly childrenin the Third World _ are living prey to a tiny predatory parasite,whose numbers are numberless.
This blood-sucking, iron-depleting, anemia-inflicting nematode bearsthe scientific name, Ancylostoma caninum. (See BioWorld Today,June 21, 1995, p. 1.) Paradoxically, that unwelcome lodger in thebowels of humans and canines secretes proteins that bid fare toprevent a class of diseases that cause approximately half of all deathsin the U.S. These range from cerebral stroke to pulmonarythrombosis to heart attack and beyond.
In a sense, the body has only itself to blame _ not a parasite _ forthese diverse lethal ailments, all arising from the over-eager action ofthe life-saving coagulation cascade. Wherever blood is spilled, froma pin-prick to a slashing knife wound to an internal hemorrhage, thebleeding itself signals the coagulation machinery to switch on.
The dozen or more blood-clotting factors serially activate one afterthe other, like the domino effect, with the terminal factor, the enzymethrombin, forming fibrin. This filamentous protein creates ameshwork, something like sandbags shoring up a flood-threatenedlevee, to seal off the wound with blood clots.
When the cascade over-does its wound-healing coagulation by pilingon clots (thromboses) which block coronary arteries, damaged byatherosclerosis, the result is chronic and fatal cardiovascular diseases.
For hookworms to make a living by feeding on human blood, theyhave to defeat the complex coagulation cascade. They do so bydeploying equally subtle blood-thinning inhibitors against specificclotting factors.
Industrial and academic researchers are busy tracking down andcloning these proteins as preventive treatment for the range ofdevastating thrombotic illnesses.
Today's issue of the Proceedings of the National Academy ofSciences (PNAS) carries a report by Corvas International Inc., of SanDiego, titled: "Anticoagulant repertoire of the hookwormAncylostoma caninum." Its senior author is George Vlasuk, vicepresident of biological research at Corvas.
He and his associates have isolated blood-thinning proteins inparticular from A. caninum, and created recombinant cDNA clonesfrom three of them, named nematode anticoagulant proteins (NAP)for clinical development.
One of these, NAPc2, is being groomed for Phase I/II clinical trials inthe U.S. "early in 1997," Vlasuk told BioWorld Today. "We'vealready begun manufacture of clinical supplies for this study, undercontract," he said. "And we're starting to put together the necessarydocumentation to file an investigational new drug application by theend of the year for the Phase I safety study, and take it through to aPhase II efficacy endpoint as well."
An earlier Corvas thrombin inhibitor, CVS-1123, a synthetic smallmolecule underwent a Phase I clinical trial in the U.K.; it ended latelast year. We're getting ready to present some of the data at a meetingin mid-April, Vlasuk observed. "The bottom-line results," he added,"are very positive. The orally delivered drug was well-absorbed in adose-dependent manner, with no adverse reactions."
At present, the leading anticoagulant drug on the market is low-molecular-weight heparin, marketed under the trade-name Lovenoxby Rhone-Poulenc Rorer Inc., of Collegeville, Pa. Heparin is anorganic acid derived from slaughterhouse livers and lungs. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.