An old intravenous antibiotic may
have new life as a stroke treatment, researchers say.
Minocycline appears to reduce
stroke damage in multiple ways – inhibiting white
blood cells and enzymes that, at least acutely, can
destroy brain tissue and blood vessels, respectively,
says Dr. David Hess, chair of the Department of
Neurology in the Medical College of Georgia School of
Medicine. The broad-spectrum antibiotic also seems to
reduce cell suicide in the minutes and hours following
a stroke, enabling more cells to recover.
He and other researchers leading
a clinical trial that will study the drug in 60 stroke
patients in Georgia, Kentucky and Oregon say they
believe the antibiotic will be a safe, effective
adjunct therapy for tPA, the only FDA-approved drug
therapy for strokes.
“It’s a safe drug that is easy to
give and tolerate, that gets into the brain well, and
may reduce bleeding, the primary side effect of tPA,”
says Dr. Hess, principal investigator on the $1.8
million National Institute of Neurological Disorders
and Stroke-funded clinical trial. “We think it will
make strokes smaller and patient outcomes better.”
Their animal studies have shown
the drug, given within six hours of a stroke, then
every 12 hours for up to three days - the peak time of
inflammation - reduces stroke damage by up to 40
percent.
“We know it’s safe in humans and
we know the concentrations we need to see improvement
in the brains of rats can be achieved safely in
humans,” says Dr. Susan C. Fagan, professor of
pharmacy at the University of Georgia, assistant dean
for the MCG program of the UGA College of Pharmacy and
study co-investigator. “That’s an important
consideration.”
The drug’s safety and optimal
stroke dose are the primary focus of the phase-one
clinical trial in stroke patients who arrive at MCG,
University of Kentucky or Oregon Health & Science
University within six hours of symptom onset and with
measurable neurological symptoms. Every study patient
will get one of four doses, starting with 200
milligrams, the most common dose already used, and
increasing incrementally up to 700 milligrams. They’ll
get half their first dose at subsequent 12-hour
intervals for a three-day period then be followed for
90 days.
“We are going to be drawing
samples from patients to make sure we achieve the
concentrations that we want in the blood, plus we want
to define the half-life in stroke patients to see if
it’s different than in the younger patients who take
it for other reasons,’ says Dr. Fagan. Newer
intravenous antibiotics have replaced minocycline in
the United States, but an oral version is used to
treat conditions such as acne and rheumatoid
arthritis. “If the half-life is longer, we can give it
less frequently. We are really fine-tuning the dose,”
she says. They’ll do this by looking in the blood for
biomarkers, indicators of inflammation, to see if
inflammatory factors go up after three days. “It may
give us a clue we should treat patients longer,” says
Dr. Fagan, a co-investigator on the studies leading to
minocycline’s use in rheumatoid arthritis.
One way minocycline fights
inflammation is by inhibiting microglial cells, white
blood cells activated by a stroke, says Dr. Hess.
“When they get activated, they get angry and produce
materials that damage the brain. The inflammatory
cascade is bad and good. Early on it’s bad, later on
it may actually do some good things,” he says.
Typically these microglial cells are sentinel immune
cells for the brain, helping eliminate infections and
secreting factors that support neurons. However,
acutely in a stroke, brain tissue can become their
target. “They are basically cleaning house at first,
then later, they are supportive, releasing growth
factors and promoting the growth of new blood
vessels,” adds Dr. Fagan.
Minocycline also blocks matrix
metallo-proteinases, also released during stroke,
which destroy the basement membrane of blood vessels.
The presence of these enzymes also is a mixed bag. “If
you want angiogenesis – you want to make new blood
vessels – you need MMPs around to get rid of the old
ones, like tearing down an old building to build a new
one,” says Dr. Hess. However, in patients lucky enough
to get the clot buster tPA, the enzyme increases the
major risk factor: bleeding. Dr. Hess notes that while
this initial clinical trial is in ischemic strokes, he
thinks minocycline also may be useful in hemorrhagic
strokes, which account for about 12 percent of
strokes, where clearly blocking MMPs would come in
handy.
Minocycline also works by
blocking apoptosis, or cell suicide, an observation
originally made by MCG Cell Biologist Zheng Dong. “It
does this by increasing a protein called bcl-2, which
helps cells survive,” says Dr. Hess.
The antibiotic’s potential
usefulness in protecting brain cells began surfacing
in scientific literature within the last few years.
“It was so interesting to us because we knew that a
lot of the limitations of other drugs that had been
tried in rodents but didn’t work in stroke patients
were that they didn’t cross into the brain,” Dr. Fagan
says. “We knew that minocycline did based on previous
experiments and the fact that many people who take it
for acne or rheumatoid arthritis get dizzy. So we were
encouraged by this.
“We wanted something we could
give at least three hours after stroke or later. In
our studies in animal models, we found at delayed time
intervals it was profoundly neuroprotective,” says Dr.
Fagan. “We studied it at multiple time points at
multiple doses and, in fact, some of the most
important work we did was finding out how the rodent
dose really could be translated to humans,” she says,
referencing work published in Experimental
Neurology in 2004.
For the clinical trial, Wyeth
Pharmaceuticals will make the sterile powder used for
injection available from Japan, where it’s still in
use.
