From: sbharris@ix.netcom.com(Steven B. Harris)
Subject: Re: My Two Cents
Date: Sun, 21 Sep 1997
Newsgroups: alt.support.menopause

In <60250f$d1c$1@samba.rahul.net> Karen Kay <karen@wordwrite.com>
writes:

>I don't know. What do you think about all those doctors who prescribed
>Redux and fen-phen? Do you think they were acting in the spirit of the
>Hippocratic oath?


    If these were prescribed for life-threatening and intractable
obesity, yes.  "First, do no harm" means don't do anything where the
risks outweight the benefits.  It doesn't mean that doctors and
patients should never do any treatment with risks.

    It's hard to tell what risks are, sometimes, of course.  Fen-phen
hasn't been big for that long, and the numbers of people on it have
been small up to about 2 years ago.  That's not much time.  One should
be careful of things that are relatively new.

    Sometimes a little judgement can keep you from getting into big
problems.  By the time the dexfen and fenfluramine drugs were pulled
off the market, I had only a couple of people still on them (they had
absolutely insisted).  All of the others had been switched to
phentermine alone-- a drug still thought to be pretty safe at the
present time.  I've a long-standing interest in serotonin syndromes,
and (actually) the idea of heart valve damage from serotonin and
serotonin active drugs is not that new.  Serotinin in green bananas
(Matuki) is thought to cause the valve damage seen in Matuki eaters in
West Africa.  Serotonin is thought to be behind the valve damage seen
in serotinin secreting tumors (carcinoids).  When I heard about the
Mayo results with fen-phen last year, I guessed immediately that the
serotonin-active half of the combo was the offender.  And it looks like
it was.

                                    Steve Harris, M.D.

From: sbharris@ix.netcom.com(Steven B. Harris)
Newsgroups: sci.med
Subject: Re: Diet drugs heart damage suit.
Date: 16 Feb 2000 07:37:12 GMT

guido@bbs.cpcn.com (guidonospamMD) in Message 88c35p$pnv@net-
axs.com managed to out-do herself by writing:

   >>Some of the producers of phentermine no longer produce the
drug. There was no proof offered that phentermine was safe.<<

   Comment: Actually, there's no proof offered that a Sunday
drive is safe. Or that any drug that seems to do fine in a
million people, won't up and kill the million-and-first guy who
takes it. That's what makes risk risky, don't you know.

   The inductive problem of uncertainty and risk may be
approached via the evidence of the past. Phentermine has been
used as a diet drug for decades, and the heart problems did not
surface in all of that time. Now that fenfluramine is off the
market and we know what to look for in hearts, nobody has yet
seen any evidence that valve problems are over-prevalent in
phentermine-takers who have never taken fenfluramine. At least
two companies continue to produce phentermine. If some companies
have quit making this long-generic product, it only means that
they do not have much at stake, and that given the $3.5 billion
risk (the fenfluramine-maker's hit so far), they do not trust
THAT much in the ability of juries to understand fine differences
between one diet drug and another. Nor can one hardly blame them,
when one sees J. Guidotti flailing away at this, despite having a
medical degree. It's a scary world we live in. Can you see Guido
as a paid expert witness?

  The intelligent layman may still take heart, even if Guido is
lost at sea. There is good evidence, for those who wish to look,
that the heart valve damage and pulmonary hypertension which
resulted from fen/phen (and from fenfluramine taken alone) is due
to the direct serotonergic properties of d-fenfluramine. This
drug is not just a serotonin re-uptake inhibitor (SSRI) in the
CNS: it causes immediate serotonin agonist effects everywhere,
also, probably by causing serotonin release from platelets. For
example, if a mouse is given an overdose of fenfluramine, it dies
immediately of pulmonary hypertension. This is not something that
happens with an overdose of (say) Prozac.  Or even with phente-
rmine, which in overdose doesn't give isolated pulmonary hyperte-
nsion, but ordinary garden-variety systemic hypertension, with
pulmonary pressure-rises lagging far behind.

  The isolated long-term pulmonary hypertension of serotonergics
is a very specific effect due to vascular constriction and
proliferative obliteration. It is much like that observed
with long-term use of certain ergot-derived vasoconstrictors, and
also as part of the pathology of people who have serotonin-
producing carcinoid tumors. Vessels long-constricted by serotonin
fibrose and disappear (e.g., the retroperitoneal fibrosis of
methylsergide).  If this happens in the lung, the remaining
vascular bed develops high perfusion pressures as a result of
blood having nowhere else to go.

   Ergot vasoconstrictors are associated with gangrenous tissue
loss (the old St. Anthony's fire from rye mold = ergot) from
vessel constriction, and (as in carcinoid) with a very charact-
eristic proliferative heart-valve disease. An additional odd fact
I've mentioned here before is that West African natives who
subsist on "matoki," a green banana staple rich in natural
serotonin, also get a rare heart valve disease. This is
histologically identical to that seen in carcinoid, and from
ergot serotonergics, and (as it just so-happens) is the same odd
valve pathology associated with fen/phen and fenfluramine alone.
It is evidently a result of the serotonin-receptor-induced
proliferation of cardiac myofibrocytes (see below). Outside the
CNS, serotonin functions as a growth factor: one which is taken
up, stored, and delivered by platelets, as a small part of the
normal healing stimulus in vessel wounds. The distinctive
proliferative heart valve disease caused by serotonin and certain
serotonin-active diet drugs, characterized by myocytes growing
where they should not, is this normal process gone wrong from
being over-driven and in appropriately activated.

   When the fenfluramine/valve damage and pulmonary hypertension
connection was first announced, many will remember that I pieced
the above mechanism together from sketchy evidence, and posted it
as working hypothesis for the benefit of this usenet group and
others.  Where was Guido, then? (I know... billing Medicare in
Pennsylvania). Earlier this year, I'm pleased to see that the
molecular biologists have published work which is well on the way
to confirming many of these ideas. Gosh, they figured it all out
for themselves, apparently, and have many new details besides.
Ain't science wunerful?  My input wasn't used or needed, but
that's not to say that the main conclusions being reached aren't
the same as you all heard here on sci.med first, from Yours
Truly, in 1997.

   Alas, however, it seems that it is Janice Guidotti still
doesn't get any of it, even yet. She remains (figuratively or
not) in the back room of the courthouse with the litigators who
are looking to make a buck off anything that sounds strange and
scary. Guilt by association-- that's our legal system. And all
this crap from a supposedly educated person with the gall to
write about some other doctor's "lack of knowledge and insight,"
when it comes to fen/phen pathology.

  Hey, Guido: Glass Houses. It is you yourself who are a medical
benchmark against which paranoid, mendacious, and biology-
clueless shrinks should be compared. In fact, I propose that all
physician witlessness regarding basic physiology, should
henceforth be expressed in milliguidos (mG). In your honor.

   (Note that this proposed new SI unit has the virtue that if
Gastaldo ever goes to medical school, we can switch over to a new
standard without having to change the abbreviation).

                            S. Harris, M.D.
============================================================


Mol Pharmacol 2000 Jan;57(1):75-81

Possible role of valvular serotonin 5-HT(2B) receptors in the
cardiopathy associated with fenfluramine.

Fitzgerald LW, et al

CNS Diseases Research, The DuPont Pharmaceuticals Research
Laboratories,Experimental Station, Wilmington, Delaware, USA.
lawrence.w.fitzgerald@dupontpharma.com

Dexfenfluramine was approved in the United States for long-term
use as an appetite suppressant until it was reported to be
associated with valvular heart disease. The valvular changes
(myofibroblast proliferation) are histopathologically indistin-
guishable from those observed in carcinoid disease or after
long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring
ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimul-
ation is known to cause fibroblast mitogenesis, which could
contribute to this lesion. To elucidate the mechanism of "fen--
phen"-associated valvular lesions, we examined the interaction of
fenfluramine and its metabolite norfenfluramine with 5-HT(2)
receptor subtypes and examined the expression of these receptors
in human and porcine heart valves. Fenfluramine binds weakly to
5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfe-
nfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C)
receptors and more moderate affinity for 5-HT(2A) receptors. In
cells expressing recombinant 5-HT(2B) receptors, norfenfluramine
potently stimulated the hydrolysis of inositol phosphates,
increased intracellular Ca(2+), and activated the mitogen-activa-
ted protein kinase cascade, the latter of which has been linked
to mitogenic actions of the 5-HT(2B) receptor. The level of
5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at
least 300-fold higher than the levels of 5-HT(2C) receptor
transcript, which were barely detectable. We propose that
preferential stimulation of valvular 5-HT(2B) receptors by
norfenfluramine, ergot drugs, or 5-HT released from carcinoid
tumors (with or without accompanying 5-HT(2A) receptor activati-
on) may contribute to valvular fibroplasia in humans.

PMID: 10617681, UI: 20085428

----------


Trends Pharmacol Sci 1999 Dec;20(12):490-5

Pulmonary hypertension, anorexigens and 5-HT: pharmacological
synergism in action?

MacLean MR
Division of Neuroscience and Biomedical Systems, Institute of
Biomedical and Life Sciences, Glasgow University, Glasgow, UK G12
8QQ. M.MacLean@bio.gla.ac.uk

In pulmonary hypertension (PHT), pulmonary vascular resistance is
elevated as a result of increased pulmonary vascular tone and
pulmonary vascular remodelling. Certain diet pills, such as the
fenfluramines, have been associated with the development of PHT.
This class of drugs act as indirect 5-HT receptor agonists
and can inhibit 5-HT reuptake and cause the release of 5-HT from
platelets. Many pulmonary vasoconstrictors, including 5-HT,
activate both Gi- and Gq-linked receptors. Increasing evidence
suggests that Gq activation might amplify Gi-linked intracellular
pathways to 'uncover' or potentiate vasoconstrictor responses - a
phenomenon known as pharmacological synergism, which occurs in
the pulmonary circulation. In this review the evidence that
5-HT plays a role in PHT and that pharmacological synergism might
contribute to its pathology is discussed.

PMID: 10603491, UI: 20072946

----------


Am J Cardiol 1999 Aug 1;84(3):304-8

Detailed examination of fenfluramine-phentermine users with valve
abnormalities identified in Fargo, North Dakota.

Kimmel SE, et al
Department of Medicine, Hospital of the University of Pennsylvan-
ia, and Center for Clinical Epidemiology, and Biostatistics,
University of Pennsylvania School of Medicine, Philadelphia
19104, USA. skimmel@cceb.med.upenn.edu

Although several studies have reported on valve abnormalities
among users of fenfluramine or dexfenfluramine, detailed infor-
mation on these subjects has not been provided, limiting the
ability to understand who may be at risk for valve abnormalities
and to generate hypotheses about the etiology and pathogenesis of
these abnormalities. This study was a detailed medical record
review of 18 previously reported users of fenfluramine and
phentermine, all with valve abnormalities on echocardiogram and 2
with surgical pathology. Both clinical characteristics and
medication use were recorded by trained abstracters using a
standardized data collection form. Two subjects (11%) had other
possible etiologies of valve disease: a history of rheumatic
fever and prescribed ergotamine. Three subjects (17%) had a
history of migraine headaches and 4 (22%) had murmurs noted
before using fenfluramine. Use of medications that may
affect serotonin receptors was common: ergotamine (1 subject,
5%), selective serotonin reuptake inhibitors (6, 33%), sumatript-
an (2, 11%), and mirtazapine (1, 5%). Prior medication and
nonmedication allergies were recorded in 6 (33%)
and 3 (17%) subjects, respectively. All subjects had symptoms
possibly due to fenfluramine or phentermine side effects. This
study raises the hypotheses that valvular heart disease among
fenfluramine users may be less common than previously estimated,
that serotonin excess may play a role in valve pathology,
and that a patient's response to anorexigens and other medicati-
ons may serve as a marker for increased risk. Further study is
needed to test these hypotheses.

Comments:
  Comment in: Am J Cardiol 1999 Aug 1;84(3):324-6, A8
PMID: 10496440, UI: 99424759


----------
Int J Obes Relat Metab Disord 1999 Sep;23(9):926-8

Dose-effect of fenfluramine use on the severity of valvular heart
disease among fen-phen patients with valvulopathy.

Li R, Serdula MK, Williamson DF, Bowman BA, Graham DJ, Green L
Epidemic Intelligence Service, Epidemiology Program Office and
Division of Nutrition and Physical Activity, Centers for Disease
Control and Prevention, Atlanta, GA 30341-3717, USA. RIL6@CDC.GOV

OBJECTIVE: To determine whether the severity of valvulopathy was
associated with the dosage of fenfluramine taken by fenflurami-
ne-phentermine users with valvulopathy. DESIGN: Out of 105
suspected valvulopathy case reports received by the US Food and
Drug Administration (FDA) among fenfluramine-phentermine
users, 74 patients meeting FDA case definition for valvulopathy
were included in this study. Patients with severe valvulopathy
were classified as those either undergoing valve replacement
surgery or having severe aortic or mitral regurgitation; all
other patients were considered to have less severe valvulopathy.
RESULTS: The proportion with severe valvulopathy increased from
20-66% with increasing fenfluramine dosage from </=40 mg/d to
>/=60 mg/d. Compared with patients taking<40 mg/d fenfluramine,
patients taking >/=60 mg/d had an adjusted odds ratio of 9.2 (95%
confidence interval=2.1-40.8) for severe valvulopathy. CONCLUSI-
ON: Compared to patients with less severe valvulopathy, those
with severe valvulopathy were substantially more likely to have
taken >/=60 mg/d fenfluramine.

PMID: 10490797, UI: 99421616