What RU-486 means for animals

From ANIMAL PEOPLE, November 2000

WASHINGTON D.C.––The pharmacological
race to be first to market a safe,
affordable, easily administered contraceptive
drug for dogs, cats, and nuisance wildlife may
have heated up with the September 28, 2000
decision of the U.S. Food and Drug Administration
to allow Danco Laboratories, of New
York City, to market the RU-486 abortion pill.
The Danco formulation, called
Mifeprex, includes five separate tablets, to be
taken in a two-step sequence. The first three
tablets, taken at once, contain mifepristone.
Better known by the chemical index number
RU-486, mifepristone is an androgen steroid
which blocks the production of progesterone, a
hormone required to sustain pregnancy. Two
days after taking the mifepristone tablets, the
user takes two more tablets containing misoprostol,
another hormonal drug which causes
her body to expell the aborted fetal tissue.

Mifepristone is a close chemical relative
of mibolerone, an androgen steroid developed
and manufactured by the Upjohn
Company. Mibolerone has been used by prescription
for more than 20 years to suppress
estrus in racing greyhounds, sled dogs, some
show dogs, and many species of animals kept
in zoos, but has not been marketed to the general
public.
Mibolerone has never been available
for use in controlling populations of street dogs,
partly because of the difficulty involved in providing
the necessary regular doses, but mostly
because of political opposition.
In theory, mibolerone could be
mixed with food and fed as necessary to street
dogs recognized by a neighborhood caretaker.
Proper precautions, such as feeding only one
dog at a time, could minimize the risk of overdose
or underdose.
In present formulations, mibolerone
is not cost-competitive with surgical spaying. It
also doesn’t offer the advantages of surgical
spaying in modifying animal behavior to
increase compatibility in human households. In
addition, unlike immunocontraception drugs,
which have been developed more recently,
mibolerone cannot be given in stronger dosage
to induce permanent sterility. Indeed, one
advantage of mibolerone for temporary use by
zookeepers and owners of racing dog or show
dog kennels is that the animals can readily
breed if regular doses are discontinued.
If manufactured in sufficient volume
and in appropriate formulations, however,
mlbolerone could become much less expensive––
and could become an efficient humane
means of controlling street dog or feral cat
reproduction temporarily while rescuers catch
and spay the females. Stabilizing numbers of
street dogs or cats and beginning to achieve a
reduction typically requires sterilizing approximately
70%. Getting to 70% by catch-and-spay
process often seems painfully slow to communities
eager to rid themselves of animals perceived
as public health threats, even when the
dogs or cats are also part of those communities’
first line of defense against vermin.
Meanwhile, until the rescuers reach
70%, sterilizing part of the population can
actually increase the numbers of dogs or cats
because there is less competition for food
among pregnant females, who then bear more
live young, and nurse longer, and because
more puppies or kittens from each litter survive

The use of mibolerone could accordingly
save millions of animals per year from
being poisoned, shot, drowned, electrocuted,
or gassed with car exhaust, which are the typical
fates of street dogs, especially, and sometimes
feral cats too in parts of Asia, Africa,
and Latin America. In those places, rabies
continues to kill thousands of humans each
year, the majority of them young children who
play with street dogs, while the barbituates
used to dispatch animals by needle are either
not affordable, not legally sold, or are simply
not available.
Anti-rabies innoculation and surgical
neutering have been introduced throughout the
world in recent years, but have just begun to
become affordable in many underdeveloped
nations, where the amount of sterilization
surgery needed to reduce the numbers of street
animals continues to far exceed the amount
that veterinarians can quickly accomplish.
By preventing births in advance of
surgery, mibolerone could markedly reduce
the numbers of dogs to be vaccinated and sterilized
eventually. Seventy percent of the
females could be taken out of the breeding
population almost overnight, pending sterilization
surgery.
A similar product for cats could prevent
the growth of an immense feral cat population
to take over the food sources and shelter
vacated by falling numbers of dogs––a phenomenon
retrospectively evident but not recognized
in U.S. animal control pickup data
from the 1970s and 1980s.
Scarcely even considered a serious
animal control problem by most public health
authorities circa 1960, U.S. animal shelter
feral cat intake soared throughout the next
three decades in almost inverse proportion to
dog intake, which has fallen steadily since the
mid-1960s.
Feral cat intake has, however, fallen
rapidly since the advent of neuter/return in
the early 1990s, especially in cities like San
Francisco and San Diego, which have long
had very large and aggressive donor-funded
feral cat sterilization programs.

Culture clash
Despite the potential benefits to be
had from introducing mibolerone into the animal
care-and-control chemical arsenal, the
cultural obstacles to making it more widely
available have proved immense.
Upjohn and the Carnation Company
began developing a contraceptive dog food
with mibolerone as the active ingredient in
1975. In August 1980, the same year that
RU-486 was first synthesized by French chemical
researcher Emile Baulieu, Carnation pet
food division director L.G. Miller, Ph.D.,
wrote to Long Island animal rescuer Severa
Aguero that the contraceptive dog food was
almost ready to sell.
“We are currently involved with the
FDA to get clearance on our birth control dog
food,” Miller confirmed. “We may receive a
marketing permit on our product this year,”
Miller continued. “We would then be able to
market the product through veterinarians.
Hopefully in a couple of years we could market
the product through retail stores.”
Approval for distribution of
mibolerone as an Upjohn product called
Cheque Drops was obtained, after testing at
racing greyhound kennels. Cheque Drops
caught on with greyhound racers, and use
soon spread to sled dogs. The Iditarod and
other major dog sled races prohibit giving the
dogs steroids or other drugs with similar
effects, but mibolerone is exempted.
But all did not go well for Carnation
––not because of any problems associated with
giving mibolerone to dogs, but because of
fallout from mifepristone testing in France by
the original manufacturer, Rousel Ucalf, a
subsidiary of the German firm Hoescht A.G.
As well as having contraceptive
properties, mifepristone was in 1982 discovered
to be an abortificant. That projected the
entire mibolerone chemical family into the
middle of the international controversy over
human abortion.
Opposition to human abortion was
just reaching peak momentum, worldwide.
Then-U.S. President Ronald Reagan had been
swept into office in 1980 partly for his opposition
to the 1973 Roe-vs.-Wade U.S. Supreme
Court decision legalizing abortion. Reagan
received his strongest voting support from religious
Catholics and Christian fundamentalists.
Also in 1980, Islamic fundamentalists
overthrew the Shah of Iran, bringing the
late Ayahtolah Khomeini to power.
Khomeini’s anti-abortion views reinforced the
position of most of Islam.
In India, Hindu fundamentalism
rose with opposition to abortion-as-birth-control
promoted by then-prime minister Indira
Gandhi as a rallying focus. Ironically, the
Blue Cross of India and Beauty Without
Cruelty-India were actively investigating
chemosterilants for street dogs, and might
have eagerly promoted mibolerone had it
become available to them.
Politically, it was a bad time to try
to market anything with potential for causing
human abortion––even if a pregnant woman
would have to eat enough hard-to-stomach dog
food in one meal to feed a Great Dane for a
week in order to achieve abortion.
Coincidentally, advocates for the
poor were just then opposing federal budget
cuts proposed by the Reagan administration by
amplifying stories of homeless people, senior
citizens, and large low-income families who
were purportedly forced to eat dog food to
make ends meet.
The RU-486 issue heated up in 1983,
with fallout for mibolerone, when the FDA
authorized a nonprofit organization called the
Population Council to begin sponsoring clinical
trials of mifepristone on human volunteers
at the University of Southern California.
Abortion opponents swiftly linked
RU-486 and mibolerone, using the images of
humans eating dog food to squelch the
Upjohn/Carnation contraceptive product.

Life term for selling
Upjohn and Carnation did not give
up easily. In early February 1985, Carnation
pet food division new products manager Hugh
Chamberlin released to media the then-current
national animal shelter killing statistics and
announced that Carnation would soon seek
FDA approval to sell a contraceptive dog food
called Extra Care in grocery stores.
“We have requested FDA clearance
for over-the-counter sales of this birth control
dog food. If we obtain this clearance, the
product would be available in late 1985,” L.G.
Miller confirmed to Severa Aguero on
February 25, 1985.
By 1988, RU-486 was already in
general use in France and China. China, in
fact, reportedly made compulsory abortion by
means of forced ingestion of RU-486 a central
part of a one-child-per-family policy. The violations
of human rights inherent in the policy
and that it was advanced by a Communist
nation which was actively repressing religion
made RU-486 an even larger target for the
U.S. religious right.
Roussel Ucalf withdrew plans to sell
RU-486 in the U.S.
The FDA then banned importation of
RU-486 into the U.S.
Carnation quietly withdrew from the
fight. The Extra Care brand name was trademarked
but forgotten. Upjohn equally quietly
continued to sell Cheque Drops, in low-key
competition with a canine formulation of the
human birth control drug Ovaban.
Ovaban, available for dogs since
circa 1983, also has some following among
sled dog racers and show dog fanciers, but
apparently has unpopular side effects in some
dogs, and never been successfully incorporated
into dog food.
The controversy over RU-486, and
by extension mibolerone, raged on. Leading
scientists told Congress in 1990 that RU-486
should be legalized for use in cancer treatment.
Austria, Belgium, Britain, Denmark, Finland,
Germany, Greece, Israel, the Netherlands,
Russia, Spain, Sweden, and Switzerland
joied France and China in approving it.
The U.S. Supreme Court in 1992
upheld the FDA ban on RU-486, but President
Bill Clinton lifted the ban upon taking office in
January 1993, and directed the Department of
Health and Human Services to investigate
ways to test, license, and manufacture it.
In May 1994 Roussel Ucalf donated
its patent on RU-486 to the nonprofit
Population Council. Clinical trials on 2,100
women began in October 1994 at the
University of California-San Francisco.
Private investors formed Danco
Laboratories in 1995, specifically to market
RU-486. The FDA conditionally approved
RU-486 in September 1996, but required
another three years of research before issuing
the recent notice of final approval.
Mibolerone meanwhile came into
use for treating uterine cancer in dogs––and
became the canine birth control method of
choice throughout northern Europe, where
many nations restrict use of surgical spaying.
Mibolerone became relatively familiar
to athletic officials and law enforcement
during the 1990s for wholly unrelated reasons,
as result of largely illegal use by bodybuilders––almost
all of them male. Arizona
eventually included mibolerone by name on a
list of drugs which if given or sold to juveniles
can cost the source a life term in prison.

Questions
To date, formulations using mibolerone
seem to have been commercially manufactured
only for use in canids. However,
there seem to be no technical obstacles to making
doses suitable for cats, deer, beavers, and
other mammal species whose numbers may be
considered problematic. The major questions
about whether Upjohn and Carnation or perhaps
another pet food maker will try again to
introduce a contraceptive pet food containing
mibolerone center on three other issues:
• Will the U.S. religious right reimpose
a ban on RU-486 and related chemicals
through an Act of Congress? Republicans
including Presidential candidate George W.
Bush, U.S. Senator Sam Brownback of
Kansas, and U.S. Representative Tom Coburn
of Oklahoma indicated almost immediately
that they would favor banning RU-486 et al by
law. Upjohn is unlikely to do anything that
might again catch mibolerone in the crossfire.
• Will the U.S. FDA action significantly
influence acceptance of RU-486 and
related drugs in Africa, Asia, and Latin
America? In general, once a drug is widely
distributed in the U.S., it becomes available
worldwide, including in unauthorized “knockoffs”––as
with the penile stimulant Viagra–
–whether or not other nations’ regulatory bodies
approve. However, animal care-and-control
is a sufficiently public function, even
when done mostly by private nonprofit organizations,
that animal rescuers are unlikely to be
able to use mibolerone or locally made knockoffs
without at least tacit official approval.
• Will a market still exist for
mibolerone after the advent of immunocontraceptives,
which might be as easily deployed
and less expensive? Even more to the point
for animal rescuers, will mibolerone still be of
value after immunosterilants reach the market?

Vaccines
Immunocontraceptives and immunosterilants
work by activating the natural bodily
defenses against foreign cell tissue––from
which sperm cells of the same species as the
female receptor are normally exempt. The
immunocontraceptives and immunosterilants
closest to becoming generally available, at
least by prescription, must be given by injection.
However, the dose may be combined
with anti-rabies vaccination and vaccinations
against other common dog and cat diseases.
The effect of immunosterilization is
not quite the same as that of sterilization
surgery because the animal’s behavior does
not change, except in not becoming pregnant.
Therefore immunosterilization may never
replace spaying as the contraceptive treatment
most popular with petkeepers
At the 2000 Spay-USA conference
held in July at Bentley College in Waltham,
Massachusetts, six leading immunocontraceptive
and immunosterilant researchers agreed
that final FDA approval of several promising
methods may be only two to five years away.
[See “Introducing a different needle,” A N IMAL
PEOPLE editorial, September 2000.] Although some controversy may
attend immunocontraceptives and immunosterilants
because they are genetically engineered,
even the most adamant opponents of genetic
engineering tend to exempt vaccines from their
criticism because of the potential vaccines
have to reduce human and animal suffering.
As the uproar over RU-486 is
unlikely to simmer down at any time soon,
Upjohn may decide that trying again to sell a
mibolerone-based contraceptive dog food isn’t
worth the bother. But, during the next two to
five years and perhaps for longer, animal rescuers
around the world will continue to wish
they had it––by the truckload.