Drugs of the Deep

[FDA]

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[U.S. Food and Drug Administration]

Drugs of the Deep

Treasures of the Sea Yield Some Medical Answers and Hint at Others

by John Henkel

Don Hochstein raises a thin glass tube up to his eye level and flicks
it with a fingernail. Inside the pencil-width vessel, a substance with
the texture of gelatin shimmies and wobbles but doesn't move from the
tube's bottom.

"There's endotoxin in there, you can bet on it," he says, slipping the
tube back into a rack.

Hochstein, former deputy director of product quality control (he
retired last Sept. 3) in the Food and Drug Administration's Center for
Biologics Evaluation and Research, is demonstrating a simple
analytical test. It's one that medical professionals, drug companies,
pharmacies, and others use worldwide to detect the presence of
endotoxins--dangerous toxic byproducts of "gram-negative" bacteria
such as Salmonella and E. coli.

The test is the limulus amebocyte lysate assay and is, Hochstein says,
"remarkable" for its origin: the horseshoe crab. The limulus test,
along with an osteoporosis treatment derived from salmon and a bone
filler made from coral, are approved medical products that come from
the sea.

Until recently, virtually all medical products had terrestrial
sources. For example, organisms found in soil have yielded products
such as penicillin, amoxicillin, and other antibiotic compounds
responsible for saving millions of Americans from suffering and death.

Sea-based products are rare, but some experts say the world's oceans
and waterways may harbor the next generation of drugs, biologics, and
even a few medical devices. Dozens of promising products, including a
cancer therapy made from algae and a painkiller taken from snails, are
in development at research laboratories right now. Other products,
such as an anti-inflammatory drug extracted from an organism called
the Caribbean sea whip, are under FDA review. Three approved products
already have brought the healing power of the sea successfully into
the world of public health.

_A Lucky Horseshoe_

Along the Eastern Seaboard of the United States, it's not unusual when
strolling on the shore to find horseshoe crabs that have "beached" or
shed their shells. These crabs, the limulus species, are important
players in the ecology and marine life of shore areas from Maine to
Florida. Their importance increased when, more than two decades ago,
researchers discovered that, due to some unique properties, the crabs'
blood could be used to detect dangerous endotoxins in drugs, medical
devices, and even water.

Endotoxins are produced when E. coli and other gram-negative bacteria
break down. The effect on humans exposed to the toxins ranges from
fever to hemorrhagic stroke. "This underscores the importance of the
test in finding these toxins before they can do any damage," says
Hochstein.

Before the limulus amebocyte lysate (LAL) test was marketed, medical
professionals gauged endotoxin presence by injecting the substance
being analyzed into a rabbit's ear. If the animal developed a fever,
endotoxins were present. Rabbit tests still are done but are "falling
out of favor," says Hochstein, because "they are just too
complicated." The tests take four to five hours, and labs must keep
caged rabbits on hand.

By contrast, the LAL test uses a glass tube and takes only one hour.
Drawing blood from horseshoe crabs causes the animals no harm, and
they can be returned to their habitat within 48 hours.

By many accounts, the discovery of the LAL test was serendipitous. In
1971, National Institutes of Health researcher Jack Levin was studying
various marine animals when he discovered that blood in horseshoe
crabs exposed to E. coli bacteria had clotted. He then drew fresh
blood from some horseshoe crabs and exposed it to E. coli in the
laboratory. The blood clotted to a gel-like consistency. Further
experiments in the NIH Bureau of Biologics, which later became part of
FDA, confirmed that if any endotoxins are present, the blood will
clot.

Hochstein was a major participant in those early tests, and he recalls
setting up shop at a NASA facility on the Eastern Shore of Virginia to
catch and draw blood from 1,000 horseshoe crabs at a time. He and his
colleagues also kept as many as 200 crabs in tanks filled with ocean
water in labs outside Washington, D.C., to ensure an available blood
supply.

The team ultimately developed a method for separating amebocytes,
which are similar to human white blood cells, from the rest of the
crab's blood. These cells then were spun in a centrifuge to
intentionally rupture them and create a "lysate," the essence of the
LAL test, which is freeze-dried and looks like grains of salt.

In 1973, FDA published regulatory guidelines for producing the LAL
test, and in 1977, the agency licensed the first LAL product to
Massachusetts-based Associates of Cape Cod. Five other companies have
developed their own LAL products since then. Hochstein says FDA's LAL
work is an excellent example of transferring technology from the
public to the private sectors.

The test has a large market in drug companies that use LAL to detect
endotoxin contamination in injectable products, says Melissa Juntunen,
marketing coordinator for Associates of Cape Cod. "Probably every
major pharmaceutical company uses it," she says. Medical device firms
also use the test to ensure that catheters, pacemakers, and other
invasive devices are endotoxin-free.

_From Fish to Pharmacies_

Osteoporosis, a crippling disease marked by a wasting away of bone
mass, affects as many as 25 million Americans, 90 percent of them
women, at an expense of $10 billion a year, according to the National
Osteoporosis Foundation. The disease may be responsible for 1.5
million fractures of the hip, wrist and spine in people over 50, the
foundation says, and may cause 50,000 deaths. Given the pervasiveness
of osteoporosis and its cost to society, experts say it is crucial to
have therapy alternatives if, for example, a patient can't tolerate
estrogen, the first-line treatment.

Enter the salmon, which, like humans, produces a hormone called
calcitonin that helps regulate calcium and decreases bone loss. For
osteoporosis patients, taking salmon calcitonin, which is 30 times
more potent than that secreted by the human thyroid gland, inhibits
the activity of specialized bone cells called osteoclasts that absorb
bone tissue. This enables bone to retain more bone mass.

Though the calcitonin in drugs is based chemically on salmon
calcitonin, it is now made synthetically in the lab in a form that
copies the molecular structure of the fish gland extract. Synthetic
calcitonin offers a simpler, more economical way to create large
quantities of the product.

FDA approved the first drug based on salmon calcitonin, Calcimar, an
injectable form marketed by Rhone-Poulenc Rorer, in 1975. Since then,
two drugs made by Novartis and marketed under the trade name
Miacalcin--one injectable form and one administered through a nasal
spray--were approved. An oral version of salmon calcitonin is in
clinical trials now. Salmon calcitonin is approved only for
postmenopausal women who cannot tolerate estrogen, or for whom
estrogen is not an option.

_A Coral Performance_

Scuba divers and snorklers have long marveled at the intricate
patterns of coral reefs in the Pacific, Caribbean, and other exotic
locations. These patterns are now a marvel for people with certain
kinds of bone injuries. A product made from the rigid exoskeletons of
marine coral can fill voids caused by fractures or other trauma in the
upper, flared-out portions of long bones.

Called hydroxyapatite (HA), the material is similar in structure to
human bone. FDA approved the HA product Pro Osteon Implant 500, made
by Interpore International, in 1992. When HA is implanted into a bone
void, its web-like structure allows surrounding bone and fibrous
tissue to infiltrate the implant and make it biologically part of the
body.

The implants, which are either blocks in pre-cut sizes or granules
used to fill in the spaces not covered by the blocks, must be used
with reinforcement devices such as steel rods to ensure that the
fracture remains stable until it heals. "Otherwise," says Nadine
Sloan, biomedical engineer in FDA's restorative devices branch, "the
implant may crack when you walk or put any weight on it. It wouldn't
have sufficient strength to support the weight until bone grows into
it or the fracture heals."

Although it is possible for patients to donate bone from other sites
on their body to repair a fracture, this causes extra trauma, says
Sloan. "One of the real advantages of using [coral-based] implants is
that they avoid a second surgery that would be necessary if a donor
site is used."

FDA also has approved coral-derived implants for applications such as
bone loss around the root of a tooth and in certain areas of the
skull.

_On the Horizon_

Research into new products from the sea, including medical products,
is in "high gear" in labs across the United States, says Linda Kupfer,
program officer for the National Sea Grant College Program. A unit of
the Commerce Department's National Oceanic and Atmospheric
Administration, Sea Grant is a network of 29 university-based programs
in coastal and Great Lakes areas that involves more than 300
institutions. Though research into medical products is only part of
the program's focus, some "very promising work" with medical potential
is under way in Sea Grant-supported labs, Kupfer says.

For example, researchers at the University of Hawaii have created what
may be a novel cancer treatment from blue-green algae. Using compounds
called cryptophycins extracted from the algae, researchers have
treated mice implanted with cells that cause prostate and breast
cancer. The compounds appear to affect the cancer cells' internal
structure, possibly keeping the disease from spreading. Much work
remains before a drug treatment could be created, but at least one
major pharmaceutical company has shown interest in developing the
compounds as an anti-cancer therapy.

At the University of Rhode Island, professor Yuzuru Shimizu is
developing a culturing system that will ensure an adequate supply of
sea-based organisms that show anti-tumor properties. Shimizu is
examining metabolites of single-celled plankton called
dinoflagellates, which National Cancer Institute tests have shown to
have cancer-fighting potential.

Scientists at the University of California's Santa Barbara and San
Diego campuses are researching compounds called pseudopterosins.
Extracted from the Caribbean sea whip, a type of coral that resembles
shrubbery on the sea floor, the compounds are being investigated for
use in skin-care products. They also appear to have anti-inflammatory
properties and could see use someday as treatment for skin irritations
resulting from injury or infection. One pseudopterosin-based product,
licensed from the university, is in clinical trials now. The
researchers hope to take their work even further: "Our next attempt
will be to develop drugs for inflammatory diseases such as arthritis
and asthma, among others," says William Fenical, an organic chemist at
UC San Diego.

Other important sea-based medical product work is in progress outside
the Sea Grant program. For instance, the National Cancer Institute is
sponsoring clinical trials of five substances derived from marine
invertebrates such as sea hares and bryozoans that may have use in the
future as cancer treatments. Elsewhere, one drug company is testing a
neurotoxin obtained from a seagoing snail common in the Pacific as a
potent painkiller. Early clinical trials have shown that the substance
relieves some of the worst kind of chronic pain and could someday be
an alternative to morphine.

For the time being, the sea's potential as a medicine cabinet remains
largely in the realm of experimentation. But science is moving
quickly, and many experts say the world's waterways may soon yield
some effective medical treatments, if not some miracle cures.

John Henkel is a staff writer for FDA Consumer.

FDA Consumer magazine (January-February 1998)
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References

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