By David N. Leff
Topping the news these days is successful implantation of the first artificial heart into a cardiac patient near death. Although the same strangulation of arterial blood flow causes cerebral stroke, don¿t expect development of an artificial brain.
Cerebral ischemia is the third commonest cause of death in Western countries. An estimated 600,000 Americans suffer strokes every year. Approximately 158,000 of these will die of that cerebral blood starvation annually, and 1 million survivors are permanently disabled.
Rescuing stroke victims from death is somewhat comparable to coronary artery bypass for heart attack. But in stroke, time is more urgent ¿ it¿s measured in hours. Currently approved stroke therapy must be administered to qualified patients within three hours of the brain attack¿s onset. Most patients don¿t get to the hospital that soon. Of victims hospitalized with stroke, 20 percent do not leave alive. Some of those lucky enough to do so undergo reperfusion ¿ reopening the clogged blood vessels to restore the flow of oxygen and nutrients to the stricken brain cells.
But there¿s a cruel irony to this reperfusion procedure. It can cause further insult on top of the initial injury. The perpetrators of this additional damage are thought to be free oxygen radicals ¿ another irony, if true. That is, the very act of restoring free flow of oxygen-freighted blood gives rise to loose-cannon oxygen radicals.
The antidote: catalytic antioxidants, which can destroy free radicals without being consumed in the reaction. And each catalytic antioxidant molecule can lay low many free radicals.
A paper in the July 2001 Journal of Neuroscience reports, ¿Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant.¿ Its senior author is neuroanesthesiologist David Warner, at Duke University Medical Center in Durham, N.C.
Antioxidant Did Well¿ In Stroke-Stricken Rats
The catalytic antioxidant that he and his co-authors tested in rats was supplied by Incara Pharmaceutical Corp., of Research Triangle Park, N.C. The firm¿s senior vice president for antioxidant therapy, clinical pharmacologist Richard Gammans, told BioWorld Today: ¿The Incara technology that we¿re developing we actually licensed originally from inventors at Duke University. In this particular journal paper,¿ he added, ¿we supplied Prof. Warner with those compounds, and unrestricted financial support, for him to conduct experiments in the areas of stroke.¿
Warner presented preliminary data last fall at the annual meetings of the American Societies of Anesthesiologists in San Francisco, and Neuroscience, in New Orleans. He reported that Incara¿s catalytic antioxidant had shown activity in the animal models comparable or superior to agents currently in development for blockage of a brain-supplying artery.
The rats that served as animal models of cerebral ischemia acquired the attacks by having their middle cerebral arteries tied off for varying periods of time. Animals treated 7.5 hours later ¿ over twice the approved three-hour window of opportunity ¿ did well. They received Incara¿s proprietary catalytic antioxidant, which inactivates reactive oxygen species such as superoxide, hydrogen peroxide and peroxynitrate in a manner similar to natural enzymes.
Rodents subjected to focal ischemia for 90 minutes, and given the drug by injection into the brain 60 minutes before the occlusion, showed 70 percent reduction of the total brain infarct. Those that received the treatment a few minutes after reperfusion had infarct diminution of 70 percent to 77 percent. Rats treated six hours after ischemia and reperfusion reduced total infarct volume by 54 percent.
Incara¿s president and CEO, Clayton Duncan, stated, ¿Our strategy is to seek a pharmaceutical or biotechnology industry partner for treatment of stroke. Assuming we can enter into a corporate partnership and satisfactorily complete the preclinical studies, we intend to initiate Phase I clinical trials in the first half of 2002.¿
Gammans pointed out, ¿A Phase I clinical trial would be strictly assessment of safety and doses ¿ at or above those we would expect to give stroke patients. Three dozen healthy volunteers at most would receive intravenous infusions of the test compound at varying doses. A subsequent Phase II study,¿ he continued, ¿would enroll 100 to 150 patients at multiple stroke-specialty investigative centers capable of using the newer magnetic resonance imaging techniques. These would measure the amount of brain that has lost its blood flow very early in the stroke, then look at the ability of our catalytic antioxidant to salvage the area of brain that¿s at risk. We would actually look in human stroke patients at the analogous effect that we saw in the rodent studies.
¿In the process of doing the development work,¿ Gammans observed, ¿Incara has selected a compound as a candidate ¿ AEOL 10150. It¿s a more suitable analogue than the one the paper is about. And we¿re conducting the toxicology, chemistry formulation and related research that goes into providing the document to open an IND and initiate the Phase I studies.¿
Typical Ischemia Paralyzes One Side Of Brain
Duke¿s Warner told BioWorld Today, ¿The cortex and the caudaputamen ¿ which coordinates motor function, as in Parkinson¿s disease ¿ are involved in motor function. Strokes in a similar region in a human are hemiplegic ¿ paralysis on one half of the body, opposite the side of the brain that has the stroke. Similar behavior was observed in these rats. They tried to walk straight,¿ he recalled, ¿but walked in circles, because one side was defaulting toward the weak side. The severity of the paralysis was reduced in the drug-treated animals.
¿A human patient with the same stroke,¿ Warner pointed out, ¿would have a problem with both the leg and the arm. They would be potentially paralyzed on the side opposite the brain infarct. Also, speech deficits, and things like that, which we don¿t test in rats. Speech,¿ he went on, ¿would be in the cortex and temporal lobe, which are commonly associated with stroke. The cortex controls speech, and without blood flow it dies.¿
Warner and his co-authors are now ¿working with a new generation of the compound, which has substantially fewer side effects. Any drug that we use to treat brain disease,¿ he observed, ¿if you give enough of it, is going to have neurotoxic side effects. In rats, these are mainly ataxia and heightened sensitivity to sound. The metalloporphyrins we¿re working with,¿ he concluded, ¿have 1/15th the toxicity of the drug used in our paper.¿