147-AP-99
EMBARGOED UNTIL 2 P.M. PST, MONDAY, NOV. 29, 1999
NEW DRUGS DEVELOPED TO TREAT PAIN MAY HAVE SIDE EFFECTS THAT DAMAGE INTESTINAL LININGS, UC IRVINE STUDY FINDS
Study Challenges Assumptions About Popular "Cox-2 Inhibitor" Drugs
Irvine, Calif. -- A class of recently developed painkiller drugs that also are being used to help prevent cancer may damage linings in the stomach and intestine in people with ulcers and other gastrointestinal damage, a team of UC Irvine College of Medicine researchers has found.
The drugs, called "Cox-2 inhibitors," were developed to treat pain without causing the stomach ulcers and other gastrointestinal side effects often caused by long-term use of aspirin, ibuprofen and other drugs used to treat arthritis and pain. Cox-2 inhibitors were the most widely prescribed new drug in the country this year; so far, more than 12 million prescriptions have been written. The drugs increasingly are being used as cancer prevention agents.
But, writing in the December issue of Nature Medicine, Dr. Andrzej Tarnawski, professor and chief of gastroenterology at UCI and the Department of Veterans Affairs Medical Center in Long Beach, Calif., and his colleagues said they found in laboratory animal tissue that Cox-2 inhibitors arrested the formation of tiny blood vessels that normally induce ulcer healing and help the body recover from injury.
"Although Cox-2 inhibitors were designed as a drug that would not cause ulcers and damage seen with aspirin and related drugs, we found that they still can produce side effects by delaying healing of ulcers and other intestinal wounds," Tarnawski said. "This finding raises concerns about prescribing them to patients with existing gastrointestinal problems like gastric ulcers and erosion of the lining protecting the gastrointestinal tract."
Cox-2 inhibitors, aspirin and ibuprofen belong to a group of drugs called non-steroidal anti-inflammatory drugs (NSAIDs), which are the most commonly used drugs in the United States. In addition to treating pain, NSAIDs inhibit a cellular process called angiogenesis, the formation of tiny new blood vessels. Angiogenesis is essential for wound and ulcer healing, restoring blood flow, oxygen and nutrients to wounds. Scientists contend that blocking this process may lead to the side effects caused by long-term use of NSAIDs, especially in patients with existing ulcers and other intestinal problems. Cox-2 inhibitors were developed because aspirin and other non-Cox-2 drugs cause ulcers and other gastrointestinal damage in 60 percent of users.
In addition, angiogenesis is essential for cancerous tumors to grow and spread through the body. Recently, scientists have been exploring the role of Cox-2 inhibitors and other NSAIDs in preventing cancer. Halting angiogenesis may stop the growth of cancer, but it also can prevent the processes necessary for wound healing, causing ulcers to form.
Cox-2 inhibitors are named after one of two enzymes that help regulate wound healing and recovery from injury. The Cox-1 enzyme exists in all cells and helps maintain the protective lining in the stomach and gut. The Cox-2 enzyme also helps protect cells from injury but is seen only during inflammation. Researchers have assumed that the damaging side effects of aspirin and related drugs came from inhibiting both Cox-1 and Cox-2 enzymes and that Cox-2 inhibitors that block only Cox-2 were safe.
Tarnawski and his colleagues found that NS-398, an experimental Cox-2 inhibitor, and indomethecin, an anti-arthritis drug that blocks both Cox-1 and Cox-2, both inhibited angiogenesis, indicating that either drug could create damage and prevent wound healing.
The researchers found that the drugs inhibited angiogenesis by interfering with a molecular process that had never before been associated with the actions of NSAIDs. The drugs used another enzyme, called MAP kinase, to inhibit angiogenesis using processes that bypassed Cox-1 and Cox-2. Through MAP kinase, Tarnawski suspects, the Cox-2 inhibitors work to stop angiogenesis along a new pathway. MAP kinase acts as a messenger in many cells in the body; this study marks the first time NSAIDs have been observed regulating angiogenesis through this enzyme.
"By using the MAP kinase enzyme, Cox-2 inhibitors can therefore prevent healing of existing damage by stopping angiogenesis," Tarnawski said. "We think that this research will lead to drugs that can pinpoint the chemical activity that prevents angiogenesis without producing damage to the gastrointestinal system. We also hope that this research will lead to clinical studies that address who may be susceptible to side effects."
Tarnawski's collaborators in this study included researchers Michael K. Jones, Hongtao Wang and Rabiha Itani, Dr. James Sarfeh, professor of surgery, and Dr. Ellis Levin, professor of medicine, all with UCI and the Veterans Affairs Medical Center, and Brigitta Peskar, professor of experimental clinical medicine at Ruhr-University in Bochum, Germany. This research was supported by an award from the Department of Veterans Affairs.
###
Contact: Andrew Porterfield
(949) 824-3969
[email protected]
A complete archive of press releases is available on the World Wide Web at www.communications.uci.edu.
RSS