CONTACT: L. E. OHMAN
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Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Finding may lead to new drugs to treat autoimmune disorders
IOWA CITY, Iowa -- There is no cure for the autoimmune disease rheumatoid
arthritis, but treatment with certain anti-malarial drugs often causes
the disease to go into remission, in some cases permanently.
Unfortunately, the therapeutic dose of the anti-malarials is close to
the toxic dose, so care must be taken when using them. It should be possible
to design more effective and safer drugs to treat rheumatoid arthritis
and other autoimmune disorders, but until now scientists haven't known
how the drugs work to cause remission in rheumatoid arthritis.
A key advance in this area may have been found by Dr. Donald Macfarlane,
professor of internal medicine at the University of Iowa and staff physician
at the Iowa City Veterans Affairs Medical Center. Working with human and
animal cells in the laboratory, Macfarlane and his colleague Lori Manzel,
have shown that the anti-rheumatic anti-malarial drugs inhibit an activity
of the defense system that may cause the body to attack itself. Understanding
why a drug works clears the path for designing safer, more potent drugs.
Macfarlane and Manzel's work is published in the current issue of The Journal
This is how it works: When bacteria invade the body, their DNA may be
released when they are engulfed and killed by disease-fighting cells. Research
by Dr. Arthur Krieg, UI associate professor of internal medicine, has shown
that this bacterial DNA activates the body's defense system. Little pieces
of the bacterial DNA, called CpG-oligodeoxynucleotides, activate the immune
system in a manner similar to that of the whole DNA.
Macfarlane found that very small amounts of the anti-malarial drugs
chloroquine, hydroxychloroquine and quinacrine completely inhibit the immune
activity stimulated by CpG-oligodeoxynucleotides. Suspecting that this
effect accounts for the useful anti-rheumatic action, he started looking
for other chemical compounds that block this type of immune system activation.
"We have already tested over 230 chemicals in the test tube, and
50 or so are very interesting -- one is 150 fold more potent than Plaquenil,
the most commonly prescribed drug of this type," Macfarlane says.
"After we have identified the best test tube drugs, they can be tested
in animals and eventually in humans."
Drugs discovered in this way could be useful in treating a wide range
of disorders, including septic shock, inflammatory bowel disease and respiratory
infections in addition to rheumatoid arthritis and lupus erythematosus.
Macfarlane is starting to talk to drug companies with the resources to
move the research into a preclinical phase.
This research was funded by the Iowa City Veterans Affairs Medical Center.