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WASHINGTON, D.C. -- Duke University Medical Center
researchers report that an important step has been achieved in
the development of a blood substitute for use during
surgery.

The phase II trial tested a genetically modified version of
hemoglobin, the oxygen-carrying protein in human red blood
cells.

According to the Duke researcher who led the clinical trial,
such a blood substitute could lead to lowered medical costs for
patients and hospitals, and reduced demand for banked human
blood. A viable oxygen carrier would not only eliminate the
possibility, however slight, of disease transmission, but also
a common side effect of donated blood -- immunosuppression in
the recipient.

"The potential benefits to patients of a viable blood
substitute are enormous," said Dr. Bruce Leone, associate
professor of anesthesiology at Duke. "Anything we can do to
decrease the external sources of blood is significant. We could
now have something else to offer patients other than donated
human blood.

"While routine use of such a product is three to five years
off, this is an important and exciting first step," he said.
"This is the first time a recombinant form of hemoglobin has
been used as a pre-surgical volume replacement."

Leone prepared the results of the Duke trial for
presentation Sunday (March 10) at the 70th Clinical and
Scientific Congress of the International Anesthesia Research
Society.

The phase II clinical trial suggested the safety of
administration of large doses of the recombinant hemoglobin
during surgery. Previous phase I studies conducted elsewhere
demonstrated that the small doses of the product were safe in
healthy, non-surgical patients. Future larger-scale clinical
trials are needed to fully document the effectiveness of the
recombinant hemoglobin, Leone said.

The blood substitute used in the trial was developed by
Somatogen Inc., a biotechnology company based in Boulder, Colo.
The product, rHb 1.1, is trademarked under the name Optro.

Somatogen creates rHb 1.1 by inserting the gene for the
altered hemoglobin into the common bacteria E. coli., which
then produces large quantities of the recombinant hemoglobin
through the fermentation process, much like recombinant insulin
is produced today.

The trial, which was conducted at Duke Hospital, involved 10
patients who underwent total hip replacements, a surgical
procedure that usually entails blood transfusions either during
or after surgery.

In the trial, physicians removed two units of blood from
each patient immediately before surgery and replaced it with a
mixture of saline solution and rHb 1.1 (up to 50 grams),
creating a solution the color of a "red zinfandel wine," Leone
said. The rHb 1.1 is designed to fulfill the oxygen-carrying
responsibilities of the red blood cells for the duration of the
procedure, which normally lasts about six to eight hours. If
patients needed additional blood after surgery, they received
their own.

"None of the patients experienced any significant side
effects or adverse reactions from the product, and all of the
procedures went without problems," Leone said. "Patients
couldn't tell the difference, the surgeons couldn't tell the
difference. Based on this small population of patients, the
recombinant hemoglobin appeared to be safe and effective.
Furthermore, none of the patients required donor blood."

In the pursuit of a viable blood substitute, companies and
researchers have pursued two general strategies -- one that
makes use of the oxygen-carrying capability of the hemoglobin
molecule, and another that creates emulsions of
perflourocarbons.

Scientists have been able to isolate the hemoglobin molecule
for more than 50 years. However, efforts to use the molecule --
either human or animal -- have largely been unsuccessful for
two main reasons -- kidney toxicity and inefficient oxygen
carrying capability.

When administered directly into humans, free hemoglobin
molecules quickly break down into two components that cause
renal failure when they interact with kidney tissue, Leone
said. Also, hemoglobin isolated from its natural environment
within red blood cells loses its effectiveness in carrying
oxygen through the blood and "off-loading" it to tissues.

Attempts to overcome these problems using strategies that
chemically alter cow hemoglobin or extract the hemoglobin
molecule from banked human blood that has passed its expiration
date have met with limited success, Leone said.

In addition, the yields from both sources are considered to
be too low to provide a reliable and practical blood source of
hemoglobin, Leone said. He added that it is not certain that
the processes used to retrieve and sterilize the hemoglobin
from the "expired" human blood will completely remove the
threat of disease transmission.

"Somatogen has taken a novel approach to this problem,"
Leone said. "The genetic modification in essence 'glues' the
hemoglobin protein together so it doesn't break into its toxic
parts once inside the body. This recombinant form of hemoglobin
also carries oxygen efficiently outside the environment of the
red blood cell.

"The method can create large quantities of recombinant
hemoglobin without the threats of any disease, so it appears to
be viable blood substitute," Leone added.

In 1978, the Green Cross Corp. developed an oxygen-carrying
substance based on an emulsion of perflourocarbons. While the
substance received FDA approval 11 years later, it was quickly
removed from the market for lack of effectiveness.

Since then, researchers have developed newer and more
efficient emulsions that are showing promise in various
clinical trials being conducted in the United States and
abroad.

While Leone said it is too early to calculate specific
dollar savings from the recombinant hemoglobin, there are
definite clinical benefits to the recombinant hemoglobin as
another tool to help surgical patients avoid exposure to donor
blood.

"Although the risks of infection are exceedingly rare (1 in
3,000 for hepatitis or 1 in 500,000 for HIV), there are other
consequences," Leone continued. "Transfused blood can cause
immunosuppression in the recipient. Many studies have
demonstrated an increased rate of infections in people who have
received transfusions. Until now, we have had no
alternatives."

For example, about half of all Duke's hip replacement
patients pre-donate their own blood before surgery, mainly out
of fear of contracting a blood-borne disease. This process
usually involves numerous visits over a period of weeks to a
blood bank, which is inconvenient for the patient and adds the
blood processing and storage expenses.