Posted by Mike Mullen MD

In Reply to: pulmonary hypertension and Redux - any common link between them? posted by barrydoc

I read in a doctor's periodical that 18 in 1 million patients can develop
the condition yearly. They claim that is about the same as in the general
population. Here's what Dr. Myers had to say about it:

Dexfenfluramine - Miracle Drug or Pandora's Box?

Dexfenfluramine, an anorexic (appetite suppressant) drug used for years in
Europe for treatment of obesity, has just been approved (April 29, 1996) by
the FDA for use in the United States. Dexfenfluramine causes release of
serotonin, a neurotransmitter (or messenger) in the brain from the
pre-synaptic neurons (brain cells). The exact mechanism of action of
serotonin is uncertain; however, increased levels of serotonin appear to
stimulate an area in the brain (hypothalamus) that controls satiation, mood,
sleep, body temperature, and other vital functions.

Obesity is a chronic illness requiring long-term treatment to achieve
long-term results. In recent years, this has become the standard for
treatment and has resulted in the concept that prescribed medication should
be thought of as a part of the puzzle for ongoing treatment. This is the
rationale developed in the studies by Weintraub (Clin Pharmacol Ther 1992
May;51(5):619-33) combining phentermine with fenfluramine (two different
appetite suppressants) to assist in the treatment of obesity.

Some clinicians are now proposing to prescribe dexfenfluramine on a
long-term basis to help control obesity. Dexfenfluramine can assist with
losing weight. Patients placed on dexfenfluramine generally lose 5 - 10 kg.
(approx. 11 - 22 lbs.), a weight loss that can lead to significant
improvement in hypertension and diabetic control. There, however, is a major
cloud hanging over this drug. Dexfenfluramine appears to cause a serious
medical condition called Pulmonary Hypertension that affects an (estimated)
1 in 40,000 patients. The symptoms of this complication may be vague chest
discomfort or development of an insidious feeling of shortness of breath. If
one develops pulmonary hypertension, stopping the medication may or may not
stop the disease process; a lung or a heart-lung transplant may be required.
Interestingly, the incidence of this serious complication was not
significantly higher than in the general population unless the individual
took the medication for more than 3 months. Another potentially serious
concern is that dexfenfluramine (in high doses) has been shown to cause
significant damage to brain serotonin neurons. Dexfenfluramine appears to
initially stimulate neurons to release serotonin resulting in higher
serotonin levels. However with high doses (in rodents), these neurons appear
to be damaged resulting in depletion of serotonin. Low levels of serotonin
are associated with sleep and mood disorders, especially depression.

In a well controlled study performed by Una McCann, et al in The Journal of
Pharmacology and Experimental Therapeutics (vol 269, no. 1, 1994: 792-798),
squirrel monkeys (a primate) given only four (4) days of dexfenfluramine
showed significant reductions of serotonin activity when their brains were
examined 17 months later! The doses used were approximately three to five
fold higher than the doses that have been used in Europe but these doses are
substantially higher than what the manufacturer is recommending for use in
the United States. This study would seem to imply possible permanent brain
changes (serotonergic neural injury) resulting from the short term use of
dexfenfluramine at high levels. At this time it is unknown whether similar
changes can occur in humans treated with long-term, high dose
dexfenfluramine, despite the fact that large numbers of people in Europe
have used this medication.

On a more positive note, a recent article (Una McCann, Jie Yuan, George
Ricaurte, European Journal of Pharm 283 (1995) R5-R7) concluded that the
neurotoxic effects of fenfluramine (the mixture of dexfenfluramine with its
optical, non-active isomer L-fenfluramine) can be prevented when
administered with fluoxetine, a serotonin re-uptake inhibitor. In this
study, mice given fenfluramine for 6 days at a dosage known to cause
neurotoxicity did not show any evidence of depletion of regional brain
serotonin activity when their brains were examined two weeks later.
Admittedly, this was a short-term study and mice are not the ideal model for
studying neurotoxicity (primates are closer to humans). However, this
preliminary data seems to indicate that there may be ways to deal with the
possible neurotoxicity of dexfenfluramine that may occur with long-term use.

EDITORIAL NOTE: We already know that dexfenfluramine can result in pulmonary
hypertension in a small percentage of individuals but if taken by millions
of people for prolonged periods of time, we may see hundreds of people
affected by this serious complication. Additionally, it would seem prudent
that a study be undertaken in Europe to assess what behavioral and where
possible, neuropathologic changes have occurred in people previously treated
long-term with dexfenfluramine. It would be a shame to attempt to improve
our weight and subsequently our health by causing significantly more
depression and other mood disorders in an already at-risk population.

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