NYT Aug. 9, 1995

Impotence: More Options, More Experts, More Success

By JANE E. BRODY

Dr.Joe's Data Base

Few people relish the idea of having to go through a "clinical" procedure to
engage in sexual activity. Most would prefer sex to be a wholly spontaneous
act, which is the main reason why birth control methods that must be used at
the time of intercourse are not very popular or successful.

But when the choice is between performing a preliminary mechanical act and
being unable to enjoy sexual intercourse, a growing number of men with erectile
dysfunction are choosing to forgo spontaneity so they can maintain an active
sex life.

Compared with a decade ago, many more men are seeking help today, and there
are a growing number of ways and specialists to help them. Interestingly, the
penile implants that touched off current professional and public interest in
treating erectile problems are now among the least popular and, while still
highly effective, are mainly being used after other approaches fail. Nowadays,
when the underlying cause of erectile dysfunction permits, less risky and less
costly methods that are applied externally just before sexual activity are
preferred.

But experts caution men against self-treatment with over-the-counter
remedies that are purported to stimulate erections. A few may be hazardous and
most are ineffective.

Anatomy of Erection

Except for the spontaneous erections that occur during rapid-eye-movement,
or dream, sleep, erections start in the conscious brain with a nervous system
response to imagined or actual erotic stimulation. The penis has two
compartments that are collapsed in the flaccid state but that can expand when
filled with blood to widen and lengthen the penis. Nerves provide a chemical
signal that relaxes the smooth muscles that line feeder arteries and these
cavities. Blood then flows into the cavities, causing them to swell and
temporarily squeezing shut the escape route.

When the nerves are damaged, there is no release of the chemicals that allow
the smooth muscles to relax. When there are blockages in the arteries, the
penis cannot fill properly. And when the escape valve malfunctions, the blood
leaks out too quickly.

In the flaccid state, relatively little oxygen reaches the penile tissues,
but when the penis is erect it has a rich oxygen supply. Studies at Johns
Hopkins Medical Institutions have shown that the nerves that project into the
penis and surround its blood vessels produce nitric oxide, which triggers an
erection and maintains the health of the blood vessels and penile cavities.

A failure to have erections, even during sleep, chronically deprives penile
tissues of oxygen and nitric oxide and eventually may cause permanent damage
that makes it difficult for the penis to trap blood. Men with erectile
dysfunction should therefore not delay seeking treatment, the costs of which
are covered by most insurers.

Current Therapies

Counseling of couples, sex therapy and psychotherapy remain the best
treatment for men whose erectile dysfunction is caused by emotional factors, a
minority of sufferers. For those with organically based impotence, modern
treatments include one or more methods that can help nearly every man no matter
what the cause.

One of the newest and still experimental methods, described in June at the
annual meeting of the American Diabetes Association, involves insertion into
the urethra of one or two drugs that bypass damaged nerves. The drugs,
alprostadil and prazosin, relax smooth muscles and dilate blood vessels,
allowing the penis to fill with blood. The system, called MUSE, for medicated
urethral system for erection, was developed by Vivus Inc., a pharmaceutical
company in Menlo Park, Calif., that hopes to market it by 1997. The drug,
inserted with a tiny plunger, produces an erection within 10 minutes that lasts
up to an hour.

Meanwhile, highly effective drugs, including alprostadil, papaverine,
phentolamine and prostaglandin E1, can be injected directly into erectile
tissue.

The usually painless injections into the side of the penis use a short, fine
needle and cost $5 to $15 per dose. They are said to be successful in 75 to 85
percent of men who choose this method. Their main drawback is the possibility
that frequent use will cause a buildup of scar tissue from the needle wounds in
the penis that could eventually make an erection difficult to attain.

Another increasingly popular external method is vacuum therapy.

Just before sexual activity, a cylinder is placed over the penis and an
attached hand pump is used to create negative pressure inside the cylinder,
causing blood to flow into the penile cavities. A soft rubber ring is then
slipped over the base of the penis, which helps to maintain the erection for
about 30 minutes. Then the cylinder is removed.

The two-minute procedure, using a device called Erecaid, helps about a third
of the men who try it. Its main side effects are minor and infrequent, mainly a
reddish pinpoint rash on the penile surface and bruising if the vacuum pressure
is maintained for too long. The Erecaid device, which costs about $400, is made
by Osbon Medical Systems of Augusta, Ga., and is available by prescription
only. Another prescription vacuum device, the VED pump, at $395, is made by the
Mission Pharmacal Co., reachable at (800)531-3333.

A third external method involves oral medications that are purported to
enhance blood flow to the penis. The main drug used is yohimbine, which is
extracted from the bark of the yohimbine tree and has long used in folk
medicine to raise libido. Proponents say it helps to improve erections in about
a third of users, especially those with psychologically caused impotence, and
is most effective when combined with the antidepressant trazodone.

Many experts question its biological activity and consider it a placebo,
working in some men who are physically able to have erections because the men
believe it will. Side effects may include mild dizziness, nausea, nervousness
and headaches.

In addition, there are penile implants, used mainly when other approaches
are unacceptable or ineffective. Although they are expensive to install (the
device, surgeon's fee and hospital costs run well into the thousands of
dollars), the procedures are not experimental and the costs are usually covered
by insurance.

One type consists of two semirigid but bendable rods that are inserted into
the penile cavities, making the penis firm enough for penetration but still
flexible enough for concealment. Another type involves implantation of two
penile cylinders, a pump and a fluid-filled reservoir. When the pump is
squeezed, fluid fills the cylinders, creating an erection, which can be
deflated by activating a release bar on the pump.

A third type of implant involves a series of interlocking plastic blocks
that can be "erected" or deflated by a spring-loaded cable that passes through
them. Inflatable implants can sometimes malfunction but can be replaced if
necessary. Their main disadvantage is that the surgery permanently alters the
penis and makes it impossible to recover unaided erections or to use other
techniques.
_________________________________

New Treatments for Impotence in testing stage NYT 08/09/95

By SANDRA BLAKESLEE

c.1995 N.Y. Times News Service

Many men who suffer from impotence balk at jabbing a needle - even a very tiny
one - into the penis, even if it results in a good erection. Such injections
deliver what is currently one of the safest and most effective treatments
available for erectile dysfunction.

But now two less invasive treatments for impotence are being tested in clinical
trials. And while manufacturers are careful not to make claims about their new
products, doctors familiar with the treatments are optimistic.

One method involves a tiny plunger that places a drug into the urethral
opening. Within minutes, an erection occurs. The other method is everyman's
first choice: a simple pill to swallow.

The plunger method, which is farther along in testing, ``is ideal for men who
can't deal with injections,'' said Dr. Fran Kaiser, associate director of the
division of geriatric medicine at the St. Louis University School of Medicine
and a principle investigator in a clinical trial of the method.

It not only restored erections, she said, but led to full ``sexual intercourse
in more than 70 percent of men with long-standing erectile dysfunction caused
by a variety of problems, including diabetes.''

The pill is in very early stages of testing by Pfizer Inc., said Dr. Irwin
Goldstein, a professor of urology at Boston University Medical Center. It
exploits the fact that the penis produces an enzyme found nowhere else in the
body and that this enzyme can be manipulated, through an inhibitor, to promote
erections. The biochemical pathway underlying the erection process was only
recently described, Goldstein said, and can potentially be altered with a
variety of oral drug therapies.

The plunger approach is being developed by Vivus Inc., a small pharmaceutical
company in Menlo Park Calif. They call their delivery system the MUSE, short
for medicated urethral system for erection.

The MUSE is ``like a Pez dispenser,'' Kaiser said. ``It's a thin plastic tube
with a button on top.'' The tube, which is the width of a vermicelli noodle,
carries inside it a little pellet containing the drug alprostadil.

In June, the Food and Drug Administration gave the Upjohn Co. approval to use
alprostadil for treating impotence through needle injections, called Caverject.
Alprostodil relaxes smooth muscle, allowing blood to flow into the penis and
promote an erection.

The dispenser delivers the same drug differently, Kaiser said. After urinating,
the man inserts the tube into his wet urethral opening, she said. ``He presses
the button on top to release the drug and then rolls his penis between his
hands for 10 to 30 seconds to facilitate distribution of the drug,'' Kaiser
said. ``Ten minutes later, he has an erection that lasts about 60 minutes.''

Diabetic men responded ``quite nicely'' to the MUSE, Kaiser said. Results of
the clinical trial were first described at the American Diabetes Association's
national meeting, which was held in Atlanta in June. Sixty percent of diabetic
men experience impotence, according to the association.

The MUSE was tested in 247 men at 8 medical centers, said Dr. Neil Gesundheit,
vice president of clinical and regulatory affairs at Vivus. Men with severe,
moderate and mild impotence were included in the study, he said, which tested
various doses of two drugs, alprostadil and prazosin. Some men received a
placebo, an inert compound with no medical value.

The most effective treatment was a 500-milligram dose of alprostadil,
Gesundheit said. More than half the men under that regimen achieved erections
that were adequate for intercourse, he said, whereas fewer than 3 percent of
men who received the placebo had erections.

Men with severe damage to their circulatory systems or with extensive nerve
damage did not respond to the MUSE, Gesundheit said. But for those with milder
forms of impotence - men who get partial erections or who can achieve them only
sporadically - the MUSE worked extremely well, he said. The main side effect is
a sense of pain and burning in the urethra that can last five to fifteen
minutes, Gesundheit said, but it happened in only 20 to 30 percent of the men
tested.

If all goes well, Vivus hopes to get approval for the MUSE from the drug agency
in 1997. The pill therapy being developed by Pfizer might be ready to be
marketed in 1998, Goldstein said.

Women with diabetes and other diseases that affect blood circulation also
suffer from sexual dysfunction, he said.

``They can't have orgasms for exactly the same reasons that men can't have
erections and orgasms,'' Goldstein said. ``Women can use these same drugs, oral
and suppository, to increase vaginal and clitoral blood flow,'' he said, which
should allow them to have normal orgasms.
__________________________________

Diabetes and Obesity may have a Genetic Link NYT 8/9/95
Copyright 1995 The New York Times

By GINA KOLATA

c.1995 N.Y. Times News Service

Scientists have found the first human gene that is associated with adult onset
diabetes, a disorder that is closely tied to obesity. The gene is also
associated with increased body weight among the obese.

But researchers cautioned that the findings were preliminary. Mutations of the
gene do not by themselves cause either obesity or diabetes and the discovery
does not immediately lead to treatments or genetic testing that would show
whether a person was at risk of developing either condition.

``It's important to keep this in perspective,'' said Dr. Philip Gordon,
director of the National Institute of Diabetes and Digestive and Kidney
Diseases in Bethesda, Md.

So far, he said, the findings are provocative but do not constitute proof that
the mutations in the gene cause the diseases.

Others agreed, but said that if the gene mutations do turn out to alter a
person's risk of developing diabetes or obesity, the discovery might be a first
step toward identifying and treating people before they develop these
disorders.

``Right now, there's no way of identifying who's susceptible'' to diabetes or
obesity, said Dr. James O. Hill, an obesity researcher at the Center for Human
Nutrition at the University of Colorado Health Science Center in Denver.

Instead, doctors wait until a person has diabetes and then try to treat it, by
which time much of the damage is done.

Only about 25 percent of fat people develop diabetes, said Dr. Xavier
Pi-Sunyer, who directs the obesity research center at St. Luke's-Roosevelt
Hospital in New York.

The idea would be to find out who was most at risk and to attempt to delay the
disease's onset by overcoming the genetic mutation. Although the ideal would be
to prevent diabetes altogether, Pi-Sunyer cautioned that the new gene's effects
``are not strong enough for that.''

The research was begun because the gene in question, the beta 3 adrenergic
receptor gene, seemed perfectly situated to cause both obesity and diabetes. If
so, the scientists hypothesized, mutations in the gene might be more common in
people with these disorders.

The gene was theoretically linked to obesity because it directs fat cells to
make a protein that increases the metabolic rate. So cells with defective beta
3 adrenergic receptors might, in theory, burn calories too slowly.

The diabetes connection arises because only a certain group of fat cells have
the beta 3 receptor. They are visceral fat cells, the fat cells that are spread
through body organs.

These cells release fatty acids directly into the liver, where they are
converted into very low density lipoproteins. The lipoproteins in turn stymie
muscle cells in their attempts to use blood sugar, thereby raising blood sugar
levels and setting the stage for diabetes.

In three papers being published today in The New England Journal of Medicine,
investigators linked the gene to an earlier age of onset of diabetes and to an
increased weight among fat people.

One paper, by Dr. Alan R. Shuldiner and his colleagues at the Johns Hopkins
University School of Medicine in Baltimore, examined Pima Indians of Arizona,
who have an extraordinarily high incidence of diabetes and obesity. About
two-thirds are obese and half are diabetic by age 40.

Shuldiner found that Pima Indians who inherit two copies of the mutated gene
burned about 82 fewer calories a day and developed diabetes five years earlier
on average than Indians without the mutation.

A second paper, by Dr. Leif C. Groop and his colleagues at the University of
Lund in Sweden, examined 335 people in Finland, 128 of whom had diabetes. They
found that people with a single copy of the mutated gene developed diabetes
five years earlier on average than those without it but that diabetes was not
more common in those with the mutated gene.

The third paper, by Dr. Philippe Froguel of the Centre National de la Recherche
Scientifique in Lille, France, and his colleagues, examined 185 people who were
extremely obese.

They found that the 14 subjects in the group with a mutated gene were fatter,
weighing an average of 308 pounds. Those without the gene weighed an average of
277 pounds.

Gordon cautioned, however, that the studies do not prove that the mutated gene
caused diabetes to occur earlier in adults who would have ordinarily gotten it.
Nor did they prove that the gene makes fat people grow even fatter.

``What's been shown here is an association between an early onset diabetes and
a certain type of mutation in this receptor gene,'' he said. ``That does not
mean that there is a causal relationship. The idea that the loop's been closed
here is premature.''

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