http://allafrica.com/stories/200612060603.html
South Africa: Scientists Warn State-Supplied Aids Drug Poses Diabetes Threat
December 6, 2006
Posted to the web December 6, 2006
Tamar Kahn
Johannesburg
Widely used HIV drug stavudine increases the risk of diabetes, scientists warned
yesterday at the 19th World Diabetes Congress, as they urged government to
speed up registration of an alternative antiretroviral medicine called tenofovir. Their
call has added weight to an AIDS activists' campaign to expand access to cheap
generic copies of tenofovir, which is believed to have fewer side-effects than other
treatments. "Antiretroviral medicines are HIV patients' best hope, but they are not
without their problems," said Linda Gail Bekker, co-director at Desmond Tutu
HIV/AIDS Centre at the University of Cape Town.
SA has one of the world's worst HIV epidemics, with about 5,5-million people
living with the disease, according to government figures. About 310000 of them
are receiving antiretroviral therapy, says the health department. Most of these
patients are taking stavudine, also called d4T. The drug is one of three provided
to patients in SA as "first-line therapy", along with lamivudine (3TC) and nevirapine
or efavirenz. If patients develop severe side-effects or resistance, they switch to
"second-line therapy", based on zidovudine (AZT), didanosine (ddI), and
ritonavir-boosted lopinavir (Kaletra).
Yesterday, scientists highlighted a growing body of published studies showing
an association between stavudine and the onset of diabetes, which in turn raises
the risks of heart attack and stroke. For example, results from the DAD (data
collection on adverse events of antiretroviral drugs) study presented at the eighth
International Congress on Drug Therapy in HIV Infection in Glasgow last month
showed three drugs in a class called nucleosides -- stavudine, didanosine and
zidovudine -- were associated with increased risk of diabetes. The risk was
highest with stavudine. The study showed patients had an increased risk of 19%
of developing diabetes each year they were on stavudine.
The drugs were also associated with other metabolic changes, including increased
cholesterol levels and the development of lipodistrophy, in which the body's fat
distribution changes. Prof Peter Reis from Amsterdam's Academic Medicine Centre
said the problems associated with stavudine were "not a reason to withhold these
life- saving drugs" in SA. He said while stavudine was the best affordable choice
for many developing countries, they should move away from it as quickly as possible.
Although manufacturer Gilead has licensed production of tenofovir to local drug
manufacturer Aspen Pharmacare, it is waiting for Medicines Control Council
approval, having submitted its dossier on tenofovir 10 months ago. "Our best-case
scenario is to have the drug registered by the end of March 2007," said Aspen
head of strategic trade Stavros Nicolau.
"GMCarter" <fiar@verizon.net> wrote in message
Contact: Marjorie Dwyer
marjorie.dwyer@joslin.harvard.edu
617-732-2415
Joslin Diabetes Center
Mechanism discovered for muscle wasting seen in diabetes, AIDS and other diseases
Discovery could one day lead to new drug therapies
BOSTON -- Muscle wasting is associated with aging and a serious consequence of different
diseases, including cancer and diabetes. Researchers at Joslin Diabetes Center, with the
assistance of other collaborating researchers, have discovered an important biochemical pathway
for muscle wasting--as well as a potential target for drug therapy. The study will be published
in the Oct. 15 issue of the journal Cell.
Muscle wasting is a hallmark of a number of diseases, including cancer, bacterial sepsis, AIDS,
diabetes, and end-stage heart, kidney and obstructive pulmonary disease. Muscle wasting can
cause generalized weakness and debilitation and in its extreme, when respiratory muscles are
involved, asphyxia and even death.
Dongsheng Cai, M.D., Ph.D., a postdoctoral Fellow at Joslin Diabetes Center and Steven
Shoelson, M.D., Ph.D., Helen and Morton Adler Chair and Associate Research Director at Joslin
Diabetes Center, and Professor of Medicine at Harvard Medical School in Boston, along with
their colleagues at Joslin, Beth Israel Deaconess Medical Center, The Children's Hospital
Boston, Spaulding Rehabilitation Hospital, and Regeneron Pharmaceuticals in Tarrytown, NY, used
transgenic (genetically altered) mice to study the biochemical pathways underlying muscle
wasting. Their studies zeroed in on a transcription factor called NF-kB, which is well known
for its importance in immune cells but was previously not known to be a critical mediator of
muscle wasting.
The investigators created two different strains of transgenic mice--MIKK mice, in which NF-kB
was activated selectively in muscle tissue, and MISR mice, in which NF-kB activation was
inhibited in muscle. The MIKK mice were viable and appeared normal at birth, but as they
matured, their body weight was reduced due to decreases in skeletal muscle mass. Their muscle
fibers were also smaller than those of their non-genetically altered littermates. On the other
hand, the MISR mice were normal in terms of appearance, body weight, and individual muscle
weight and histology (the appearance of cells under the microscope) throughout life.
High doses of drugs called salicylates have been shown to inhibit NF-kB activity, so the
researchers studied the impact of these drugs on MIKK mice. In one protocol, they initiated
treatment with salicylates after weaning in 4-week-old MIKK mice already affected by muscle
wasting. The mice's body weights increased with salicylate treatment and, after six months of
therapy, their body weight, muscle mass and muscle fiber size were nearly normal. In a
prevention protocol, salicylate treatment was begun during gestation. In these latter mice,
body weights and muscle mass were essentially normal throughout life.
The researchers also studied the effects of blocking NF-kB activation in mouse models of muscle
wasting, including immobilization/denervation and cancer. The former is a model for the muscle
wasting that occurs during disuse, such as when a limb is casted, or in spinal cord injuries.
Inhibition of NF-kB in MISR mice was accompanied by a partial remission of denervation-induced
muscle atrophy, including increased muscle mass and fiber size. Muscle wasting is a significant
problem for patients with certain forms of cancer, where it seriously diminishes their quality
of life. They found that the MISR mice with cancer were protected from loosing muscle mass, and
the MISR mice had much better survival rates than did normal mice with cancer. Thus, selective
NF-kB blockade in muscle decreased muscle wasting and prolonged survival in this mouse model of
cancer.
"The discovery that NF-kB activation is sufficient to cause skeletal muscle atrophy in vivo and
that blockage of the NF-kB pathway can ameliorate atrophy suggests a new set of drug targets
for chemical intervention during cachexia, cancer, AIDS and other settings of atrophy," the
authors conclude. "This is critically important because unfortunately there are currently no
drugs approved for the treatment of skeletal muscle atrophy."
###
Other authors of the study included J. Daniel Frantz, Ph.D., Nicholas E. Tawa Jr., M.D., Ph.D.,
Peter A. Melendez, Ph.D., Byung-Chul Oh, Ph.D., Hart G.W. Lidov, M.D., Ph.D., Per-Olof
Hasselgren, M.D., Ph.D., Walter R. Frontera, M.D., Ph.D., Jongsoon Lee, Ph.D., and David J.
Glass, M.D. The study was funded by the National Institutes of Health and the American Diabetes
Association.
For more information, contact: Marge Dwyer or Jenny Eriksen 617-732-2415
About Joslin Diabetes Center
Joslin Diabetes Center, dedicated to conquering diabetes in all of its forms, is the global
leader in diabetes research, care and education. Founded in 1898, Joslin is affiliated with
Harvard Medical School. Joslin research is a team of over 300 people at the forefront of
discovery aimed at preventing and curing diabetes. Joslin Clinic, affiliated with Beth Israel
Deaconess Medical Center in Boston, the nationwide network of Joslin Affiliated Programs, and
the hundreds of Joslin educational programs offered each year for clinicians, researchers and
patients, enable Joslin to develop, implement and share innovations that immeasurably improve
the lives of people with diabetes. As a nonprofit, Joslin benefits from the generosity of
donors in advancing its mission. For more information on Joslin, call 1-800-JOSLIN-1 or visit
www.joslin.org.
