Drug, New Hope Used in WWII, immune-system booster is now tested in AIDS
by Jamie Talan, Staff Writer
AN EXPERIMENTAL MEDICINE injected into U.S. military men during World War II fell into obscurity for decades and now has re-emerged in the battle against AIDS.
The drug-Substance R or Reticulose- stimulates the immune system and also interferes with viral replication, making it an important advance in pharmacology, doctors say. After more than 60 years of use, the drug is finally undergoing testing to move it through the Food and Drug Administration process.
Meanwhile, people such as Octavio A. Perez, a 32-year-old AIDS patient in Manhattan, report substantial benefit through the current drug trials. Perez spent years on a mix of AIDS drugs that caused such troublesome side effects-distressing nightmares and neuropathies of the hands and legs-that they kept him housebound. Two months ago, he began taking injections of Reticulose.
"It's really been unbelievable," said Perez. "I can walk without pain. I can sleep again." It is too early to tell whether Substance R will become a mainstream, federally approved drug for AIDS, or for any of the other conditions that might benefit from enhancing the immune system. But a small pharmaceutical company called Advanced Viral Research Corp. is betting on the drug's 67-year-old anecdotal history and has begun testing it in AIDS patients overseas. The company is planning to file several applications for its use with the Food and Drug Administration, which means that testing could move forward.
Whether the drug proves as powerful as the developers' claim, the substance stands as a lesson in endurance. Substance R was created in 1933 by a doctor who wanted to develop a medicine for his patients that would mimic the body's immune system. What Dr. Vincent Lapenta didn't know-and what no one would know for more than 60 years-is that the compound fits into a relatively new class of drugs called protein nucleic acids.
"I had never known anything to do this," said Dr. Shalom Z. Hirschman, former director of infectious diseases at Mount Sinai School of Medicine, who has left his tenured position to develop and test Reticulose.
"The lure of opening up an entire new field of therapeutics was too much," Hirschman said.
It will take years of testing before the FDA has enough data to rule on a drug's effectiveness and grant approval for use in the United States.
Ironically, Reticulose had a place in medicine for decades, listed in the Physician's Desk Reference from 1940 to 1960. At the time, Phillips Roxanne Pharmaceutical Co. was manufacturing the drug for Lapenta. In the early '60s, the company sold rights of the drug to Key Pharmaceuticals. Then, it disappeared from the PDR.
Scientists at Key Pharmaceuticals were having difficulty figuring out the chemistry of the drug-how it works-in an attempt to comply with new FDA guidelines on drug regulation passed in 1962. Scientists at Phillips Roxanne had made a slight change in the formula in 1959-bovine serum replaced horse serum as a stabilizing compound-and the newly created FDA would not allow the drug to bypass the regulation process as it had done with thousands of other drugs developed before the federal law went into effect. (The change was necessary because horse serum was linked to serum sickness.) Reticulose, now owned by Key, would have to be tested as a new drug.
Perplexed by its chemistry, the company abandoned the drug, selling rights to the substance to a Singapore firm. Within a few years, the overseas company began bankruptcy proceedings, and chances that Substance R would ever see the light of day seemed bleak.
But Bernard Friedland, a chemist at Key, would not give up on the drug.
He'd heard about the bankruptcy proceedings that began in 1972 and ended in 1985. He decided to buy the drug around 1985, and a manufacturing plant in the Bahamas that had been sitting in moth balls for more than a decade.
"I felt the drug was too important to lose," said Friedland, now 74. "I couldn't let it die." The mixture created by Lapenta in 1933 was a brew of genetic RNA material and proteins grown at certain temperatures. He used the substance on his own patients for viral infections. Others also talked about its benefits. But like all drugs of its time, the clinical success was anecdotal. There was never a serious drug trial.
When the FDA threatened its availability in the early '60s, doctors began to hoard the injectable drug for their patients. Hundreds of thousands of patients were treated for influenza A, encephalitis and other viruses during the pre-FDA decades, Friedland said.
Col. Ralph Thompson, a physician of the U.S. Medical Corps and deputy director of the Armed Forces Institute of Pathology in Washington, D.C., witnessed the same benefits in some of his charges during World War II and later: "I shall never forget the miraculous course that followed the treatment with this drug," he told colleagues at a 1960 meeting. " ... and will remember those others of my command who became ill and stricken with influenza who did not receive Reticulose therapy." He said he had also recommended its use in children with virulent encephalitis.
The substance was still a chemical mystery to Friedland when he bought the drug from the bankruptcy courts. In 1995, Hirschman was asked to take a look at the drug. Hirschman had studied nucleic acids at the National Institutes of Health in the '60s, and he had just been reading a study on nucleic acids in Science when it hit him.
"I was looking at a peptide nucleic acid, a relatively new class of substances that have powerful effects on the inflammatory process," Hirschman said. Peptide nucleic acids were first described in the early '90s. "No one would have appreciated this chemistry," Hirschman said of the early developers of the drug.
The first person he called was Friedland, who had set up a company to work on Substance R.
Hirschman's wife, Frances E. Newmann-Hirschman, a geneticist and AIDS crisis worker in Westchester, had been given samples of the drug to test. She'd been trying to find substances to fight AIDS, and she learned about Reticulose.
Her husband took the formula back to his lab. "I immediately began experimenting with it," he said. He discovered that the drug had potent interactions with the immune system, stimulating cytokines, interferon, tumor necrosis factor and other immune substances.
In addition to AIDS, the researchers believe it can also be a treatment for genital warts, human papillomavirus, herpes C virus and certain forms of arthritis. Hirschman said it could even help boost the immune system in cancer patients, a possibility that was first described by Thompson in 1960.
There are probably thousands of drugs in development that never make it into the hands of patients. But the protein nucleic acids are a new entity, opening up the possibilities of strengthening the immune system in its fight against infections, said Howard Young, section head of cellular and molecular immunology at the National Cancer Institute. He's done some genetic laboratory work with Reticulose. "There's a reasonable basis for it to work. A lot of people are studying this new class of drugs for their potential to modulate the immune system." In 1996, Hirschman's company launched the first rigorous double-blind control trials of Reticulose.
In the study, 43 AIDS patients in Barbados were randomized to receive Reticulose or a placebo injection for 60 days. This was the only treatment these patients received. At the end of the study, patients who received the drug had no signs of opportunistic infections and reported feeling more energetic, Hirschman said. Those on placebo did not report similar benefits.
Nine of the patients are still on the drug, which is taken by injection every day.
Hirschman hopes that Reticulose might be used in conjunction with conventional AIDS cocktails to strengthen the immune system.
"The more we learn about this class of drugs, the better we will be able to tailor them to treat specific diseases," Hirschman said.
July 11, 2000, Newsday