Researchers at the University of Cincinnati (UC) have found a
combination drug therapy that increases diuresis, or the enhancing of urine output
from the body. This could aid in the treatment of patients who have conditions
where fluid retention is an issue, in particular congestive heart failure,
chronic kidney disease and liver disease. The study was recently published in Frontiers in Physiology.
"Nephrologists and cardiologists have
used thiazide derivatives either alone for the treatment of mild to moderate
hypertension, or in conjunction with loop diuretics for the treatment of fluid
overloaded conditions, says Manoocher Soleimani, MD, professor and associate
chair for research in the Department of Internal Medicine at the UC College of
Medicine. "When used alone, thiazides are very mild diuretics. This research
shows that when used in conjunction with the uricosuric drug probenecid,
thiazides can exhibit robust diuretic effect.
Soleimani says a problem physicians have been trying to solve
for years is finding the best diuretic regimens for patients with conditions
where fluid retention is a major problem.
Researchers in the Soleimani Lab at the UC College of
Medicine found a molecule in close proximity to where thiazide was working in
the kidney was being activated and blunting the diuretic effect of thiazide.
That protein is called pendrin for which there was no known inhibitor.
Probenecid has historically been used to lower blood uric
acid in people with gout. Soleimani says recent research shows probenecid unexpectedly
has an impact in the area of the kidney where pendrin blunts the effect of
"In order to further investigate that, we treated the animal
models with probenecid for six days, says Soleimani. "After six days,
hydrochlorothiazide was added to the probenecid regimen, and suddenly a huge
diuresis was seen.
Soleimani says urine output increased by 20 percent in experimental
animals treated with only thiazide, and a similar increase was seen in patients
treated with probenecid alone. But when used as a combination therapy,
probenecid and thiazide increased the urine output by 400 percent. Even at
lower, more physiologic doses closer to what humans would be taking, the
combination therapy increased urine output by 250 percent.
According to Soleimani, in addition to downregulating
pendrin, probenecid also helps eliminate uric acid, which is one of the side
effects of thiazides.
This is probably the first study
where a medication with no diuretic effect (probenecid) significantly enhances
the diuretic effect of thiazides, says Soleimani. "Future studies are planned
to test the effect of this regimen in patients with chronic kidney disease or
congestive heart failure.
The research was supported by a Merit Review Award from the
U.S. Department of Veterans Affairs and funds from the UC Center on Genetics of
Transport and Epithelial Biology. Collaborators with Soleimani include Sharon Barone,
and Kamyar Zahedi, PhD, both senior research assistants and Marybeth Brooks,
research assistant, all in the Department of Internal Medicine; and Jie Xu, MD,
PhD, research scientist in the Department of Pathology and Laboratory Medicine
at the UC College of Medicine.