By David N. Leff
High blood pressure - primary hypertension - is a prime risk factor in coronary artery disease (CAD) and cerebral stroke. Nearly 1 million Americans a year die of CAD, which tops cancer 2-to-1 as the main cause of death in the U.S. And 50 million people have high blood pressure.
Low blood pressure - hypotension - is a paradoxical hallmark of another disease, septic shock, which hospitalizes some 700,000 Americans annually in intensive care. Sepsis, brought on by bacterial infection, is fatal in 30 percent to 50 percent of that six-digit number diagnosed. Annual septic shock deaths are in the 150,000 mortality ballpark.
"In septic shock," explained research pharmacologist Daniela Salvemini, "the over-taxed immune system goes into overdrive, and counterattacks an overwhelming infection with every means it has - especially an outpouring of neutrophils and macrophages. In the process, the body's system for maintaining vascular pressure is damaged."
This low-pressure syndrome causes the blood vessels to dilate and become leaky, thus denying oxygen and nutrients to the body's vital organs - notably, lungs and kidneys. To reverse this cutoff of perfusion, physicians take three tacks: prompt antibiotic therapy, intravenous fluid replacement and vasoconstrictors. Shrinking the diameter of arteries, veins and capillaries forces the blood through narrowed channels, thereby raising blood pressure again.
In current septic shock therapy, Salvemini recounted, "physicians seek to achieve vasoconstriction by using first, the catecholamine dopamine, then another one, norepinephrin - their goal being to maintain blood pressure. But a highly unwanted side effect of that immune reaction," she continued, "is the upsurge of oxygen free radicals, superoxide anions, which destroy those potent vasoconstrictors - the catecholamines."
"These anions," elaborated Denis Forster, MetaPhore Pharmaceutical Inc.'s executive vice president, "are given off by activated immune cells, neutrophils, and get converted to hydrogen peroxide, H2O2, such as is used to kill bacteria. It's an enzyme in your cell, vinyl peroxidase, that takes hydrogen peroxide - with chloride ion present in your blood - and in effect makes Clorox bleach, to kill those infectious pathogens. The analogy," he went on, "is that basically the septic shock patient is on fire. It's a free radical burning - oxidation - that he or she is undergoing."
But as Isaac Newton propounded, "To every action there is always opposed an equal reaction." Thus, to the all-consuming superoxide anion, the body opposes an inflammation-quenching enzyme - superoxide dismutase - SOD. In advanced disease states, the anion overcomes the SOD, with frequent fatal outcome.
From New Insight, New Drug
Salvemini is director of biology at MetaPhore, in St. Louis. As such, she is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated August 15, 2000. Its title: "Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock."
One major insight is the development, led by MetaPhore's Forster, of a small molecule that takes on the heavy protective lifting of the body's native SOD. "It selectively mimics the SOD family of enzymes," Forster told BioWorld Today, "but instead of having a molecular weight of 30,000, our mimetic weighs in at 483 MW, and has all the functions and selectivity of the natural SOD enzyme.
"My co-workers and I at the company," Forster observed, "published the compound in Science last October" (see BioWorld Today, Oct. 8, 1999, p. 1). They designated it M40403, and put it to work in laboratory rats." Salvemini described their in vivo experiment:
"The first question in our hypothesis was: Are catecholamines destroyed by oxygen free radicals in vivo? If so, then we should be able to prevent the fall in blood pressure. To answer it we used the animal model of septic shock in rats. To induce the sepsis, we injected the lipopolysaccharide (LPS) endotoxin from E. coli intravenously, and saline into control rats.
"That IV LPS bolus in 10 rats," Salvemini recalled, "led within nine hours to a profound fall in blood pressure associated with 90 percent mortality. But when we injected 10 other animals with our M40403 SOD mimetic, as an IV infusion one hour after the LPS, it prevented the development of hypotension, and greatly reduced mortality - to 90 percent survival.
"So we showed that when we gave the mimetic after the onset of septic shock, that compound, by removing the superoxide generated in vivo by the endotoxin, completely prevented hypotension - and those rats did not die."
Despite that preclinical success, human trials of MetaPhore's SOD mimetic are far over the horizon.
Forster explained why: "We are bringing several drugs forward to Phase I clinical trials, but none of the trials we are headed toward includes septic shock at this point. We definitely have plans to use it for that indication, but the question is finding an appropriate corporate partner. The reason is that there have probably been, I would guess, at least 24 or 25 clinical trials reported in septic shock. Therefore it's very hard to convince your investors or management that you should go out and spend multimillion dollars for clinical trials."
Mimetic - Sidelined, Not Pipelined
He continued: "The difficulty with doing such clinical trials is that septic shock has a number of different etiologies. The cause of death basically is lack of perfusion - multiorgan failure. But even if you can restore perfusion and blood pressure, you haven't necessarily removed the underlying etiology of the disease. Obviously, sepsis means that these patients are infected with an infectious agent.
"If for example," he went on, "this is a drug-resistant microorganism, the fact that you can maintain the patient's blood pressure for a while - unless you have the right antibiotic on board - is not going to do you any good, because the disease is so multifactorial. For a small company like ours, septic shock is not the first place you go."
But what about Parkinson's disease (PD), as Salvemini's PNAS paper hinted in passing?
"In Parkinson's disease," she observed," dopamine is a catecholamine, which free radicals will break down. In the brain's substantia nigra, dopamine gets destroyed by superoxide and other radicals, which leads to PD. She went on: "We don't know yet whether our SOD mimetic drug has a potential use in PD. We're studying that question right now."