By Dean A. Haycock

BioWorld International Correspondent

It now takes more than the reattachment of a finger or a hand to make a headline. But there was a time when operations that successfully reattached severed fingers and limbs received front page coverage. As surgical techniques evolved and as surgeons' skills grew, these remarkable operations became more "routine" and no longer caught the media's eye.

The early news accounts that highlighted reattached limbs rarely mentioned a problem that still complicates such operations, reperfusion injury. As blood flows back into a limb or organ that had been cut off from circulation, a cascade of events occurs that leads to cellular injury. These events include the production of free radicals and release of chemicals that mediate inflammation. The resulting damage affects tissue and can cause local blood circulation to fail. Reperfusion injury also threatens patients undergoing operations which require surgeons to tie off blood supply to an organ.

"Reperfusion injury is a major clinical problem. If you look at the literature, you will see that many different approaches have been tried and have failed in their attempts to stop, inhibit or reverse reperfusion injury. It is a very difficult field but it is a very significant clinical need," Martin McGlynn, president and CEO of Pharmadigm Inc., in Salt Lake City, told BioWorld Today.

And it represents a multi-billion dollar market opportunity in the U.S., according to McGlynn. This includes preventing reperfusion injury occurring after hemorrhaging.

Now new research reported in the January issue of The Journal of Trauma, Injury, Infection, and Critical Care suggests that there is a promising new candidate for treating or preventing reperfusion injury. The work is described in a report by Robert Lohman, a plastic surgeon at the University of Utah Medical School, and his co-authors entitled "Dehydroepiandrosterone protects muscle flap microcirculatory hemodynamics from ischemia/reperfusion injury: an experiment in vivo study."

In the study, researchers isolated a body wall muscle in the groin of male rats. Using microsurgical techniques, the plastic surgeons clamped off the main vessels supplying blood to the flap of muscle in the delicate operations. Other smaller blood vessels were cauterized.

Six hours later, the clamps were removed and reperfusion initiated. The researchers monitored the effects of reperfusion on the flow of blood and on blood vessels in the previously deprived tissue using video cameras connected to microscopes and other techniques.

The rats received one of three treatments: no pretreatment; a pretreatment consisting of dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone dissolved in propylene glycol; or propylene glycol by itself.

The flow of red blood cells and capillary density were reduced by approximately two-thirds in both the control and propylene glycol-treated rats. And both groups experienced total cessation of blood flow after one day. All of the rats that received DHEA, by contrast, showed complete reflow after the clamps were removed and all muscle flaps were viable after 24 hours.

"The thing that excites us is that a naturally occurring steroid has these kinds of properties. To our knowledge, this is the first demonstration in the literature that an endogenous steroid hormone has a dramatic role to play in this kind of ischemia reperfusion injury," McGlynn said.

Bill Wardell, senior scientific officer at Covance Inc. saw the video tape of the reperfusion experiments.

"I was impressed because this seemed to just about shut off the deleterious effects of ischemia. I was very impressed by the tape and the graphs," Wardell said, "It looks like a good candidate for post-ischemia injuries."

All this is good news for Pharmadigm, which owns use patents on DHEA.

"We have seven issued U. S. patents and 16 patent applications in the U.S. They relate to a broad method of use claims on a whole series of clinical conditions, McGlynn said.

Pharmadigm may also benefit from a lack of competitors.

"To our knowledge, Pharmadigm is unique in this regard. We have not come across any other company that is developing these steroid hormones for application in the acute care arena," McGlynn said.

The company is working with synthetic versions of the natural steroid hormone and developing proprietary intravenous formulations for it and its derivatives.

Barbara Araneo, vice president of basic and preclinical research at Pharmadigm and a co-author of the paper said "We have taken DHEA out of context, out of its normal routine, given it in a different way, in a different dose, and have revealed these very special properties. We don't know precisely its mode of action but it is not an anti-inflammatory."

A major focus of current research at Pharmadigm is the mechanism of action during reperfusion injury, according to McGlynn. Araneo and the other authors are now writing a paper which describes the role played by neutrophils in reperfusion injury.

Pharmadigm also plans to pursue market opportunities in cardiovascular reperfusion, ischemia and stroke.

"We are also targeting patients populations where we can benefit from protection under the Orphan Drug Act in the U.S. and their equivalent in Japan and Europe," McGlynn.

Pharmadigm is looking for partnerships with major pharmaceutical companies which can help it design and fund broader clinical trials. *

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