Brooklyn, N.Y. - Nonsteroidal anti-inflammatory drugs, or NSAIDs,
as they are more commonly called, are widely prescribed by doctors
for pain control and inflammation. An extraordinary number of prescriptions
(more than 100 million) are written every year for these drugs. Although
they are potent and popular drugs of choice, they do have the potential
for causing multi-organ toxicity. For example, in 1998, more than
54,000 NSAID poisoning cases were reported to poison control centers.
Professor Sidhartha Ray of Long Island University's Arnold & Marie
Schwartz College of Pharmacy and Health Sciences, an international
authority on mechanistic toxicology in the field of drug and chemically
induced programmed cell death (apoptosis) and unprogrammed cell death
(necrosis), has recently investigated the mechanisms of action of
Diclofenac (DCLF), the most common NSAID used in clinical practice
for the treatment of osteoarthritis, rheumatoid arthritis and acute
muscle pain conditions.
For the first time, Ray, an Indian-born resident of East Brunswick,
NJ, has shown in vivo that DCLF's potential to cause kidney
toxicity may be DNA damage-dependent. Collectively, his data suggest
that DCLF-induced kidney toxicity may involve production of dangerous
free oxygen radicals leading to oxidative stress and massive genomic
DNA fragmentation. Past studies have shown cell death by necrosis
whereas Dr. Ray's studies reveal that DCLF can cause massive programmed
cell death or apoptosis in kidneys. "This opens up a whole new
dimension in basic science research at the molecular level,"
says Ray. "We don't want to have indiscriminate use of DCLF in
clinical practice. Since we know now it can potentially cause DNA
damage, we want to reexamine it and the whole family of NSAIDs."
In his investigation, Ray and his collaborators (Eamon Hickey, Stephen Gross,
Ravindra Raje and Vincent Reid) exposed mice to low, medium and
highly toxic doses of DCLF. Kidney tissues were analyzed to determine
the degree and type of DNA damage and evaluated for the presence
of apoptotic characteristics in kidney cells. Results showed massive
kidney injury at the cellular level. Now Ray is investigating synthetic
as well as natural products that can serve as antidotes to DCLF-caused
kidney damage. "Pharmaceutical companies may now address these
concerns and may consider reformulating this medication in such
a way that it will be less harmful to consumers," he says.
(This study was published in the prestigious journal, Free Radical
Biology & Medicine (Vol. 31, No. 2, pp.139-152, 2001).)
A professor at Long Island University since 1994, Ray's previous
research showed how long-term grape seed extract exposure retards
progression of chemically induced liver cancer in animals, and also
how it is beneficial in Tylenol-induced liver injury. He recently
received a U.S. patent on his research, "Beneficial effects
of grape seed extract pre-exposure on acetaminophen-caused liver
injury." He is the first to show how acetaminophen modulates
expression of cell death-regulating genes, such as bcl-2 and bcl-XL,
in the liver (published in the journals, Archives of Biochemistry
& Biophysics, 1999; Archives of Toxicology, 2000;
and Free Radical Biology & Medicine, 2001).
Ray recently chaired a Continuing Education symposium at the world's
largest toxicology meeting (Society of Toxicology, held at Nashville,
Tennessee in March 2002). The focus of the symposium was "Regulation
of drug and chemically induced apoptotic cell death: New in
vivo perspectives." Ray has editorial appointments on
such notable international journals as Archives of Toxicology
and Toxicology Letters, and was named a Fellow of the American
College of Nutrition. He serves as a grant reviewer for several
international organizations, and reviews manuscripts for 15 international
scientific journals. He has received peer-reviewed grants totaling
$220,000 from pharmaceutical companies in the past five years,
and is compiling a research monograph series for two prestigious
publishing companies. |
