Investigational drug may protect cancer and AIDS patients from side effects of pain relief therapy
October 14, 2003
A drug developed to relieve one of the major side effects of pain therapy for cancer patients may offer an added benefit for AIDS patients, researchers from the University of Chicago and the Children's Hospital of Philadelphia reported Tuesday, October 14, at the 2003 Annual Meeting of the American Society of Anesthesiologists in San Francisco.
Methylnaltrexone (MNTX) was invented to reverse the constipation caused by powerful opioid-based pain relievers--such as morphine, OxyContin or Percocet--taken by patients with cancer or AIDS. Opiates also appear to increase the ability of HIV to infect certain immune system cells.
This laboratory study found that MNTX blocked increases in HIV entry and replication that occur when immune cells are exposed to therapeutic doses of morphine. In this in-vitro study, very small amounts of methylnaltrexone blocked this process.
"If our studies are borne out in future clinical trials, methylnaltrexone may improve the care of patients who take opioids for pain caused by AIDS," said Jonathan Moss, MD, PhD, professor of anesthesia and critical care at the University of Chicago and director of the study.
Many AIDS patients and more than 500,000 patients with advanced cancer depend on drugs like morphine for pain relief. One side effect of these pain relievers is severe constipation, which can be so distressing that many patients discontinue their pain medication.
Methylnaltrexone was invented to solve this problem by the late Leon Goldberg, a University of Chicago pharmacologist. To help a dying friend with morphine-induced constipation, Goldberg took naltrexone, an established drug that blocks the effects of morphine, and altered it slightly so that it could no longer cross the protective barrier that surrounds the brain.
Consequently, it did not interfere with morphine's effect on pain, which is centered in the brain, but it did block morphine's effects on gut motility, which are mediated by receptors in the gastrointestinal tract.
Goldberg's university colleagues continued to develop the compound, testing it in animals and performing the initial human safety trials and clinical studies in volunteers and patients.
Since then, the potential uses have multiplied. They now include treatments of post-operative ileus (a temporary loss of the normal contractile movements of the intestine), opioid-induced itching, and urinary retention.
In 2001, Progenics Pharmaceuticals of Tarrytown, NY, licensed the worldwide exclusive rights to develop MNTX from the UR Laboratories. Progenics Pharmaceuticals is now conducting a phase-3 clinical trial of MNTX for treatment of opioid induced constipation in patients with advanced medical illness.
The study presented at the anesthesiologists' meeting suggests an entire new indication for this promising drug.
MNTX interferes with the process the AIDS virus uses to infect specific immune system cells. HIV uses molecular structures known as CD4 and CCR5 on the surface of the cell as portals of entry. Opioids increase the expression of CR5 receptors, thereby enhancing the susceptibility of immune cells to viral infection.
In this study of monocyte-derived macrophages--a key target of HIV and a model system for testing HIV drugs--MNTX at very low doses blocked opioid-induced increases in CCR5 receptors.
"Methylnaltrexone does not represent a cure for HIV infection," emphasized Moss, "but it may offer an unexpected benefit to AIDS patients who require pain relief."
A phase-2 clinical study of MNTX is underway at the University of Chicago in opioid-treated HIV-positive individuals.
The study presented at the anesthesia meeting is scheduled to be published in the December issue of the Journal of Pharmacology and Experimental Therapeutics.
The University of Chicago Medicine
950 E. 61st Street, Third Floor
Chicago, IL 60637
Phone (773) 702-0025 Fax (773) 702-3171