Originally created 12/30/00

Researchers test Viagra alternative



Targeting a new pathway for how erections occur, researchers at Medical College of Georgia may have found an alternative impotence treatment for those not helped by Viagra.

But the experimental compound has been tested only in rats and needs further safety studies before it could be tried on humans, and that will be up to the Japanese company that owns it, the researchers said. And because it is injected - not a method well-received by men - the researchers are trying to find a way to apply the drug topically.

Still, the initial results met with great acclaim. The study will be published in the January issue of the journal Nature Medicine and last month won the Jean Francois Ginestie Prize for best basic research paper presented at the 9th World Meeting on Impotence Research of the International Society of Impotence Research.

The mechanics of an erection might seem a little backward. It is when the smooth muscle of the penis relaxes that the blood flow increases six to 10 times into the penis, swelling the spongy tissue beneath the muscle that then collapses the surrounding veins and traps the blood inside. The gas nitric oxide is essential to this muscle relaxation. Viagra (sildenafil citrate) works by blocking an enzyme called phosphodiesterase, which breaks down cyclic GMP, which is essential to the relaxation process and allows it to continue, said MCG physiologist Thomas M. Mills, one of the investigators in the study. For Viagra to work, those chemicals must first be made, said Dr. Ronald Lewis, chief of urology at MCG and a consultant on the study, who has conducted other Viagra studies.

"Therefore, if somebody doesn't have those initial (chemical) messengers, then Viagra will not work for them," Dr. Lewis said. "The other thing about Viagra is it does have some effect on other enzymes (particularly involving the heart) that make it risky for people who are on products like nitroglycerine."

Overall, Viagra works for about 60 percent of the men who take it, "and that's phenomenal," Dr. Lewis said. "Still you have in that situation 40 percent where we'd like to find another alternative."

The MCG team decided to look at the other end of the process. The smooth muscle of the penis is normally in a contracted state and the arteries nearly closed, Dr. Mills said.

"It's a low-blood-flow organ," Dr. Mills said. Although the contraction cycle is not fully understood, powerful vasoconstrictors such as norepinephrine and endothelin-1 are probably involved and may work to increase an enzyme called Rho-kinase. At the very heart of the constriction process is a protein called myosin light chain, which can either have a phosphate attached or not. An enzyme called myosin light chain kinase adds that phosphate and, when it is attached, the myosin protein can combine with another protein called actin and lead to contraction. A different enzyme, called myosin light chain phosphatase, removes the phosphate and can lead to muscle relaxation. Rho-kinase, the MCG researchers say, suppresses the amount of the phosphatase enzyme and prevents relaxation. The MCG researchers used the experimental compound Y-27632 to block Rho-kinase in rats and achieved a response every time, Dr. Mills said.

"We have here a system that may be a new strategy for treating erectile dysfunction," Dr. Mills said. "Because we're not attempting to alter the relaxation method, rather we're inhibiting constriction and that's not been done before."

And it may be easier to circumvent the constriction than to try and overpower the system, Dr. Lewis said.

"By actually blocking the constriction, we feel that is a more efficient way to get into the system," Dr. Lewis said.

Such as Viagra, Y-27632 was originally formulated as a potential hypertension drug. The compound came along with hypertension researcher Dr. R. Clinton Webb when he became the new chairman of the Department of Physiologyin January, and other researchers convinced him to let them try it on rats as an impotence treatment, Dr. Mills said. The response was tremendous in the first animal, "and I thought, `Boy, we're on to something here,"' Dr. Mills said.

Between 20 million and 30 million men suffer from some form of impotence in the United States, and Viagra and similar products under development have revolutionized how they are treated, Dr. Lewis said. It would be nice to have something that worked on a different pathway, he said. One such product, Uprima (apomorphine) works as a dopamine agonist in the sex centers of the brain and showed promise, Dr. Lewis said. But because of safety concerns from the Food and Drug Administration, the company that makes it will now try for licensing in Europe and gather more data before bringing it back to the United States, which may delay it a few years, Dr. Lewis said.

What happens next to Y-27632 is up to its manufacturer, Welfide Corp. in Osaka, Japan, Dr. Mills said. He e-mailed company officials this week urging them to pursue further testing of the compound for impotence.

"So they fired back and said, yes, they're very excited about it and they'd get back to us," Dr. Mills said. "But it's their drug and they get to decide what to do with it."

Even at this early stage, the results have attracted international attention, Dr. Mills said.

"There's a whole lot of excitement about this drug. It really is something that is of great interest to the medical community," Dr. Mills said.

Reach Tom Corwin at (706) 823-3213.