Firm seeks to control Jekyll and Hyde molecule.

Nitric Oxide: Too Much In Body Causes Disease

Nitric oxide - the human body needs it in small doses, but too much can cause debilitating diseases.

The small molecule is so complex, it's called the "Jekyll and Hyde" molecule by the head of UCSD's nephrology department.

However, a local pharmaceutical company believes its arsenal of "neutralizing sponges" will provide the answer to combating some of the inflammatory diseases caused by excessive nitric oxide production in the body.

At Medinox, Inc., a San Diego-based company, scientists are working to reverse the negative effects of the pernicious gas in the human body. It's a tricky task.

In small amounts, nitric oxide "polices the body to fight against infection and regulates blood pressure," said Ching-San "Monte" Lai, founder, president, chief executive and chairman of Medinox.

In large amounts, triggered by inflammations, nitric oxide can cause a myriad of diseases, Lai said.

Roland C. Blantz, a professor of medicine and head of UCSD's nephrology department, has labeled it Jekyll and Hyde, after author Robert Louis Stevenson's 19th - century novel about good and evil.

"With acute conditions, it's generally good to get rid of it," Blantz explained. "In more chronic conditions, if you eliminate nitric oxide, one might fear the cells would proliferate more rapidly."

Acute and chronic diseases make up Medinox's list of targeted diseases - hemodialysis-induced and IL-2 cancer therapy-associated hypotension (low blood pressure), acute lung distress syndrome, hemorrhagic shock, allograft (transplant) rejection, stroke, diabetes and arthritis, Lai said.

He said Medinox's approach is unique in that while traditional pharmaceutical firms make drugs that block the production of nitric oxide at the enzyme level inside the cell, Medinox's compounds target excessive nitric oxide outside the cell.

These compounds act like sponges that "mop up excessive nitric oxide," he said.

So far, Medinox has tested three compounds on animals, targeting different diseases.

NOX-100, a potential treatment for hemodialysis-induced hypotension, is first in line to be tested in humans - pending regulatory approval in early 1999.

Medinox plans to test the compound's safety on 25 to 30 patients afflicted with the disease. The tests will take place at UCSD's Medical Center.

The compound is given intravenously during dialysis to restore the blood pressure, Lai explained. Hypotension occurs in almost 25 percent of 200,000 dialysis treatments, he added.

The company also hopes to obtain regulatory approval to test NOX-100, combined with the widely used anti-rejection drug cyclosporine A, in patients with organ transplants to prevent inflammatory responses, Lai said.

"Animal studies have shown using less cyclosporine can prolong organ survival and reduce side effects, including cardiac toxicity," Lai said.

But UCSD's Blantz remains skeptical. What works in animals doesn't always translate to humans, he said.

"The transplantation process extends over several weeks, I am not sure you can be confident eliminating nitric oxide would have a beneficial effect," he explained.

Nevertheless, Blantz said, the company's technology may have some advantages over enzyme inhibitors.

"The problem with enzyme blockers is they are not totally selective," he said. "They might block some other enzymes that control blood flow. If they are artificial, you are not sure how fast the body can dispose of them."

Pfizer Inc.'s wonder drug Viagra has had some of the same problems, Lai said.

Viagra works by boosting the reduced levels of nitric oxide that cause impotence, In doing so, the drug causes the positive effect of "dilated vessels," but at the same time induces a dangerous drop in blood pressure, Lai explained.

Other companies, including North Carolina-based Apex Bioscience and Canadian-based AnorMed, are also seeking a way of "neutralizing nitric oxide," but Lai is optimistic that his company's technology will capture the market.

"Our compounds are relatively nontoxic and bind to nitric oxide three times tighter than nitric oxide binds to hemoglobin (the technology used by Apex)," Lai said.

The Taiwanese native and former professor first discovered, then licensed, the technology while doing research at the Medical College of Wisconsin. As a tenured professor, Lai spent 15 years climbing the academic ladder at the university.

A sabbatical leave in 1995 at the San Diego-based biomedical research firm Pharmingen (now part of New Jersey-based Becton Dickinson & Co.) prompted Lai's move into entrepreneurship.

"I decided I didn't want to do one thing for the rest of my life," Lai said.

Pharmingen invested $1 million seed money to pave the way for Medinox to open its doors three years ago. JAFCO, a Japanese venture capital firm, invested another $2.9 million in Lai's emerging company.

Lai is hoping to soon add another $6 million to the company's portfolio in a second round of private financing.

Considering Medinox's monthly burn rate of $150,000 and cash reserves of $2.3 million, additional financing will be a necessity to keep the company afloat, Lai said.

He said he wants to sell Medinox shares on the stock exchange in the new millennium by seeking to join forces with large pharmaceutical firms.

Lai, whose first name "San" means mountain - thus the nickname Monte - feels right at home in Sorrento Valley's biotech circle.

"San Diego offers a unique conducive environment," he said. "It promotes small companies and offer a good mix of academic and industrial institutions."