Download PUBLIC MEETING ON THE SAFETY OF DIETARY SUPPLEMENTS CONTAINING EPHERDINE ALKALOIDS

PUBLIC MEETING
ON
THE SAFETY OF DIETARY SUPPLEMENTS
CONTAININGEPHERDINE ALKALOIDS
VOLUME I of II
Date: August 8, 2000
Pages: 1 through 298
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1
PUBLIC
MEETING
ON
THE SAFETY OF DIETARY
CONTAINING
SUPPLEMENTS
EPHEDRINE
ALKALOIDS
VOLUME I of
Tuesday,
August
II
8,
2000
U.S. Public
Health
Service
Cohen Building
Auditorium
Washington,
D.C.
The meeting
qas convened,
pursuant
MOFFITT
in
to
the
above-entitled
notice,
at
9:00
matter
a.m.
REPORTING ASSOCIATES
(301)
390-5150
2
Public
Meeting:
Safety
Ephedrine
Alkaloids
Tuesday,
8:00
August
am
8,
AGENDA
of Dietary
Supplements
Containing
2000
Registration
9:00
am
OPENING
Wanda K. Jones,
DrPH, Director
Office
of Women's Health
9:lO
am
Ephedra-containing
Compounds:
Historical
Pharmacologic
Context
Harry
H.S. Fong,
Phased,
University
of
Illinois,
Chicago
9:50
am
BREAK
LO:05
am
-1:50
am
Adverse
Event Reports
:
Database
and Clinical
Studies
Lori
A. Love,
MD, PhD, FDA
Julie
G. Bietz,
MD, FDA
George Ricaurte,
MD, PhD, Johns Hopkins
University
School
of Medicine
Raymond L. Woosley,
MD, PhD, Georgetown
University
School
of Medicine
Cynthia
Culmo,
Texas Department
of Health
Q&A
.2:10
pm
LUNCH
1:lO
pm
2:55
pm
Adverse
Event Reports:
Ephedra
Education
Panel
of Experts
Review
Steven
E. Kimmell,
MD, MSCE, University
of
Pennsylvania
Theodore
M. Farber,
PhD, DABT, Toxichemica
International
Norbert
P. Page, DVM, MS, Toxichemica
International
Grover
M. Huchins,
MD, Johns Hopkins
University
School
of Medicine
Steven
B. Karch,
MD, City
of San Francisco
John W. Olney,
MD, Washington
University
Medical
School
Edgar H. Adams, MS, SCD, Harris
Interactive
Q&A
3:15
pm
BREAK
(on your
MOFFITT
own)
REPORTING ASSOCIATES
(301)
390-5150
and
3
Public
Meeting:
Safety
Ephedrine
Alkaloids
3:30
3:30
3:45
Abstract
Barbara
Q&A
3:50
4:05
James
Q&A
4:lO
Linda
Golodner
League
Q&A
4:25
Col.
U.S.
Q&A
4:30
4:45
of
Dietary
Session
I
J. Michael,
S.
Turner,
Esther
F.
Air
Force
Kay],
Myers,
PhD.
McGuffin,
Association
5:25
Michael
Products
Q&A
5:30
5:45
Robert
Q&A
M. Stark,
>:50
Public
Comment
5:50
5:53
5:56
1.
2.
3.
5:59
4.
5:05
5:lO
6:02
p.m.
& Turner
[Brett
Fugh-Berman,
Containing
HEAT
Swankin
Adraine
Network
Q&A
4:50
Supplements
National
RD,
FADA
MD National
President,
MD, FACP,
Session
Women's
American
Yale
Consumers
Health
Herbal
University
A
Samieh Wood, Private
Citizen
Hanna K. Zewchzer,
Private
Citizen
David Molony,
American
Association
of
Oriental
Medicine
Pablo
Francisco
Semiao,
Private
Citizen
Adjourn
MOFFITT
REPORTING ASSOCIATES
390-5150
(301)
ct
4
LISTENING
Deputy
Aaron H.
Clinical
Clinical
Building
Bethesda,
PANEL
Chair:
Wanda Jones,
Dr. P. H.
Assistant
Secretary
for Health
(Women's Health)
Director
of the Office
of Women's Health
U.S. Department
of Health
and Human Services
Burnstein,
PharmD
Pharmacokinetics
Research
Center
Pharmacy
Department
10, Room IN-257
MD
Paul Coates,
PhD
Director
3ffice
of Dietary
NIH
Supplements
Harris
Lieberrnan,
PhD
Supervisor
Research
Psychologist
US Army Research
Institute
of
42 Kansas
Street
Natik,
MA 01760-5007
Environment
Rossanne
M. Philen,
M.D.,
MS
Xealth
Studies
Branch
Yational
Center
for Environmental
Centers
for Disease
Control
and
1600 Clifton
Road, NE
vIailstop
E-23
Atlanta,
GA 30333
!4ary Ann Richardson,
Program
Officer
Yational
Center
for
\Jational
Institutes
Laboratory
Medicine
Health
Prevention
Dr.P.H.
Complementary
of Health
and Alternative
!Iarcel
Salive,
MD, MPH
?revention
Scientific
Research
Group
1ivision
of Epidemiology
and Clinical
\Jational
Heart,
Lung and Blood
Institute
dational
Institutes
of Health
3erne Schwetz,
DVM, PhD
lcting
Deputy
Commission
?ood and Drug Administration
5600 Fishers
Lane
iockville,
MD 20857
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Wanda
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Good morning,
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During
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390-5150
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individual
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14
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15
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duration
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Office
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390-5150
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390-5150
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of
And
the
him,
at
the
Starting
U.S.
and Alternative
Administration
from
the
Medicine
Richardson
Institutes
Office
the
of
Institutes
from
the
on Complementary
National
from
National
Environmental
members
on stage.
Coates
Lieberman
Center
19
r
at
the
me here
Paul
Next
Dr.
me introduce
with
Dr.
Harris
Clinical
join
let
who are
end,
17
s
now,
that
morning.
you're
Is
that
now?
my pleasure
24
now to
the
25
on Ephedra-Containing
meeting
MOFFITT
to
with
Invite
Dr.
a background
Compounds
or
their
REPORTING ASSOCIATES
(301)
390-5150
Harry
S.
presentation
Historical
Fong
ct
14
1
and
Pharmacological
2
all
of
3
questions
4
is
this
in
if
about
need
a Herculean
Jones.
8
going
to
9
Elizabeth
30 minutes
Fang , welcome
DR.
FONG:
say
not
be politically
11
try
to
stand
14
historical
15
to
this
is
the
16
University
17
Botanical
18
one
19
with
20
thanks
of
way
that
of
under
23
I will
24
expert,
25
Jones
not
but
what
do
him
So it
you.
much
public
walks
Secretary
I was
speaking
around.
and
is
But
I guess
and
being
Jones
Illinois
us getting
the
she
said
in
--
this
well,
from
Coates
some
we look
may
I'll
at
and
NIH
funds.
I would
like
place,
the
Center
I think
has
So let
come and
the
unique
Research.
up there
to
and
a very
Chicago
Supplement
Dr.
asked
pharmacology
in
for
we are
something
me make
to
do
my public
advertisement.
When Dr.
22
ask
incorrect,
for
I come
Dietary
21
very
politically
appreciate
As Dr.
out
and
we can
to
up.
perspective
two
him
presentation.
thank
you
correct
you.
point
and
Thank
I really
to
his
my inspiration
10
talk
asked
so that
be following
Dr.
Dole
13
And we've
task.
I know
12
?
Context.
impression
disagree
at
this
kind
of
MOFFITT
Jones
asked
that
with
me to
speak,
I am some kind
her
point
an expert
that
I think
that
she
of
was
an expert.
I am some kind
I should
I am.
REPORTING ASSOCIATES
(301)
390-5150
tell
And
of
Dr.
expert
by
15
definition
2
and
is
able
to
a person
say,
"Have
3
[Laughter.]
4
DR.
5
get
down
6
Good.
to
7
FONG:
dry
area
9
ephedra
of
10
names,
the
11
name.
As you
12
the
13
yellow
14
ephedra
15
what
it
16
the
plant
most
of
for
looks
In
world
20
Central
21
Americas.
we all
than
of
24
years
25
the
in
treatment
a Chinese
the
a stem
here
rlmaIr means
is
of
the
the
not
know
knows
to
Asia
there
are
give
and
you
what
has
asthma,
MOFFITT
about
been
some
in
10 species
brief
used
for
the
North
in
and
the
history.
more
China's
congestion,
there
throughout
even
a slight
as traditionally
of
distribution
distributed
in
ma huang
China
--
everyone
the
vernacular
who might
geographical
30 species
America;
know
you
is
related
"huang"
is
me
working?
ma huang,
tongue;
let
Ephedra
means
sure
willing
like.
particularly
23
mike
other
is
of
is
way,
many names,
Here
I'm
terms
Try
or
which
drug.
like.
looks
has
few
the
ephedra.
literally
the
of
this
Seneca
on the
the
Seneca
19
it
action
color
more
out
is
who
Travel."
Is
of
town
Will
what
famous
know
of
that
Ephedra
astringent
were
With
ephedra
species.
18
Slides
define
part
17
out
my presentation.
Let's
8
from
than
medicine
colds,
REPORTING ASSOCIATES
(301)
390-5150
and
As
5000
for
so on
16
ct
1
and
so forth.
And
2
ephedrine
3
guide
in
Japan
4
years
later
Merck
5
same
species
in
6
with
the
alkaloids
7
isolated
two
from
work
which
10
by Dr.
11
the
drug
into
16
ephedrine
17
to
the
18
of
ephedra
19
dietary
to
and
the
at
the
1924
as the
Kay K.
Dr.
22
detailed
23
thought
24
speaking
25
than
2 percent
or
six
from
a world
the
apart
alkaloids
Union
being
of
look
Chen
for
1927.
use
his
a pitcher
contains
alkaloids
more
and
conducted
and
back
work
Schmidt.
active
synthesized
the
as a weight
street
using
reduction
drugs.
the
giving
us a very,
with
-the
this
you.
could
major
REPORTING ASSOCIATES
(301)
390-5150
ahead
promotion
we had
in
or
we jumped
me is
work
in
particular
the
Then
to
us and
of
MOFFITT
this
a more
was
ago
was
followed
by
pioneering
College
as alternative
visiting
of
was
years
share
and
ephedrine
Peking
for
or
ephedra
of
in
recapitulation
I would
use
1930
ephedrine
Chin
classical
significant
Twenty-five
21
the
to
model
supplements
20
major
amphetamine
199Os,
and
later
got
introduction
an effort
compound
early
two
the
and
toxic
years
binding
same plant.
in
In
less
the
medicine
14
five
isolated
So you've
Western
publication
15
Europe.
Chen
20s
was
pseudoephedrine
my opinion
K.
early
and
isolated
leads
Kay
1887
the
In
8
9
in
itself
pleasure
area
of
very
so I
Chemically
be up to
alkaloids
more
are
17
ct
1
three
stereoisomeric
2
Norephedrine,
3
with
4
alkaloid.
being
Let's
5
all
in
7
differs
8
configuration
9
sci
sync
what
and
the
at
group
in
methyl
group
so one
is
the
all
18
So one
or
specific
norephedrine
look
would
example.
way
back
24
ephedra
25
of
the
note
that
is
the
expect
the
the
basic
that
effect
may be differences
species
to
I don't
expect
in
the
Seneca,
total
of
difference
lack
of
has
skeleton
the
a two
there
the
biological
are
basically
in
the
degree
And
you
I just
ephedrine
MOFFITT
different
species.
room.
alkaloids
the
to
and
and
alkaloids
this
read
want
account
a
and
methylephedrine
at
3 and
effects.
from
23
a carbon
no pseudoephedrine
norephedrine
The occurrence
vary
one
pharmacological
There
similar.
the
chemical
same.
16
activity
at
we are
as methylephedrine
and
methyl
total
Ephedrine
stereo
group
and
the
about.
by the
same difference
and
of
so that
talking
no ephedrine
ephedrine
Methylpseudoephedrine
structure
hydroxy
methylpseudoephedrine
between
the
we are
the
pseudoephedrine,
90 percent
pseudoephedrine
of
chain,
and
40 to
look
of
from
again
Ephedrine,
Methylephedrine
ephedrine
6
pairs,
this
to
for
65 percent
is
just
slide
emphasize
about
of
REPORTING ASSOCIATES
(301)
390-5150
some
from
in
60 percent
it
18
ct
1
pseudoephedrine
2
particular
3
pseudoephedrine
the
second
largest.
the
only
species
that
slide
than
Now,
4
5
and
it
6
treatment
of
7
is
is
good
8
asthma.
9
of
ephedrine
what
proven
a very
--
being
are
types
of
10
primary
11
decongestion
and
13
this
type
of
14
are
major
15
along
16
sympathomimetic
17
Alpha
18
receptors
19
release
20
it
21
then
to
at
an overview
related
1 and
and
of
act
Beta
more
one
of
for
treatment
But
the
the
pharmacology
before,
of
and
2 receptors
of
athonergic
indirect
from
neuron
release
of
they
potent
stimulating
by
of
pseudoephedrine
by
the
stimulating
the
And
stores.
norepinephrine
so
and
effect.
looks
at
23
and
norepinephrine
24
and
pseudoephedrine
one
25
and
the
being
amino
it
directly
like
some direct
If
I said
commonly
acts
treatment
and
compounds
norepinephrine
primarily
have
as
that
Beta
and
as a nasal
of
ephedrine
compound,
the
ailments
use
stress
and
dilation.
constituents,
with
decongestant
the
can
ephedra,
hypertension.
like
bronchial
Looking
22
partial
I would
use,
in
one
more
for
associated
dilator
this
intermedia.
uses
as a nasal
broncho
narcolepsy
has
ephedra
primary
And a secondarily
12
the
compared
group
MOFFITT
/
the
effective
various
is
In
structure
structures
its
sees
the
of
the
basic
same.
epinephrine
to
carbon
The
REPORTING ASSOCIATES
(301)
390-5150
ephedrine
skeleton
difference
19
ct
1
being
the
2
methyl
3
directly
4
ephedrine
5
the
hydroxy
group
So it's
group.
on the
and
release
I would
pseudoephedrine
and
8
activity
except
that
9
compound
when
it
the
13
norepinephrine
14
not
necessarily
think
I was
17
effect
the
18
used
19
professor
20
Dysmenorrhea
21
condition,
22
sorry
to
the
terms
of
do act
primarily
to
emphasize
induce
its
that
the
same
spectrum
is
a weaker
hypertensive
effect
uterine
relieve
on repeated
allowed
of
and
by you
the
can't
and
of
can
depletion
the
the
health,
reason
ephedrine
where
color
really
does
being
Every
people
to
I
does
is
dysmenorrhea.
red
of
use
consequently
slide
lessen
same effect.
health,
women's
one
unlike
the
have
women's
pain
dosing
So continuing
will
muscle
the
of
stores.
to
can
read.
emphasize
the
the
red.
So I'm
the
alpha
adrenergic
muscles,
and
see
that.
Ephedrine
23
they
we said,
have
because
invited
about
to
to
mean you
is
extra
a like
pseudoephedrine
from
16
and
ephedrine
effect
In
that
act
compound
biological
15
the
effect.
Either
12
and
surprising
like
comes
CNS stimulant
11
chain
norepinephrine.
Now,
the
not
pseudoephedrine
7
10
a side
same receptors
of
6
in
24
receptor
in
25
increase
the
the
also
bladder,
resistance
MOFFITT
stimulate
small
to
the
outflow
of
REPORTING ASSOCIATES
(301)
390-5150
one
urine
does
so this
20
ct
1
would
2
aneurin.
the
be good
one
category
action
the
9
epinephrine
10
mediated
11
activation
by
of
norephedrine
14
and
15
this
16
pressure
as well.
17
systemic
razor
18
from
will
produce
systolic
peripheral
a blood
pressure
and
overdose
diastolic
Most
20
ephedrine
21
because
22
receptor
23
than
epinephrine
24
both
ephedrine
25
decongestants,
its
as a very
of
The
lungs.
but
it's
and
is
one
rate
resistance
Elevate
the
both
pulse
stimulates
the
gets
hypertens
The
compounds
potent
the
so much
pseudoephedrine
and
due
to
the
branchial
Beta
effect
and
MOFFITT
cardiac
rise.
effect.
activation
the
the
ion
use.
dilation
especially
activities
vascular
and
the
receptors.
the
importantly
excessive
Broncho
beta
they
of
and
pressures
restrictions
or
that
stimulate
the
type
ephedrine
The
release
and
this
in
us
is.
than
the
alpha
of
using
but
effective.
in
us male
effects
orally
the
of
cardiovascular
longer
or
those
it
is
increase
in
as
it
output
of
from
enough
times
both
few
for
and
13
19
refrain
of
The alkaloid
that
the
as epinephrine
ten
of
and
incontinence
BPH and
tough
terms
persists
12
I
is
same action
8
of
for
should
it
In
the
management
experience
one
compounds;
have
the
unfortunately,
But,
audience
that
of
in
adrenergic
is
to
less
pronounced
sustain
longer
are
alpha
dilator
useful
as nasal
adrenergic
receptor
REPORTING ASSOCIATES
(301)
390-5150
21
ct
1
mediated
razor
constriction
3
material,
let's
4
continued
use
5
one
6
don't
know
7
call
rebound
relies
one
of
ephedrine
is
already
important
thing
stimulate
the
eccubens
area
released
it
then
us
the
the
must
binds
us the
And
effect.
use
I said
dopamine
from
As the
the
feeling
I
do not
judiciously.
system
effect
The
earlier.
related
if
aid,
that
it
and
with
days
nervous
as
brain.
of
as a medical
central
of
three
decongestants
ephedrine
release
The
adrenergic
ephedrine
compounds
the
nucleus
dopamine
Dl
and
of
a well
compound
receptors
contributes
to
and
located
our
feeling
another
Now,
product
nasal
active
of
gives
than
type
is
D2 receptors
being
and
a high.
16
weight
of
this
a rebound
So one
effect.
terms
give
have
many
then
more
of
decongestants
too
of
use
after
can
In
which
18
say
on nasal
8
9
continued
However,
2
effect.
appetite
like
in
of
also
the
also
being.
is
with
Hence
suppression.
the
CNS which
well
CNS effect
activates
anuretic
one
has
or
also
a
that.
as I said
Now,
23
ephedrine
and
24
1990s.
In
25
because
I haven't
for
ephedra
terms
of
efficacy
read
MOFFITT
earlier,
too
weight
the
loss
I have
many
promotion
was
in
of
the
a question
clinical
REPORTING ASSOCIATES
(301)
390-5150
reports.
early
mark
Of
22
1
the
ones
I could
2
is
somewhere
3
to
six
4
include
5
it
6
definitely
7
know.
between
months
and
the
or
effective
four
to
ten
pounds
effective
in
the
is
it
that
effects
suppressed
the
side
effects
of
has
the
peripheral
the
more
reason
digress
of
said
like
they
are
bit
for
23
of
the
24
compounds
25
formulas
make
and
effect
a better
MOFFITT
to
burn
that
perhaps
the
of
one
up the
is
a
the
like
to
strength
As we
amines.
dextroamphetamine
of
also
that's
relative
various
will
drug.
and
or
it
I would
at
pseudoephedrine
way
is
caffeine
and
one
which
note
is
been
central
so forth.
And methamphetamine
have
has
is
so on and
and
look
it
I don't
medication,
together.
and
CNS effect.
It
effect
is
alkaloids
appetite
agent
put
last
actions.
of
wonder,
But
type
two
also
one
it
ephedra
kind
to
methamphetamine
ephedrine
diet.
and
DCNS stimulant
synthesize
the
thermogenic
a little
the
this
thermogenic
why
from
to
triglycerides
potent
make
two
enuretic
--
so,
loss
over
studies
how long
has
used
clinical
the
it
weight
and
some effect;
I would
18
the
Theoretically
fats,
16
of
diet,
ephedrine
had
hold
some of
a restricted
8
9
get
greater
And,
coincidentally,
used
as in
then
norephedrine
weight
all
reduction
another.
REPORTING
(301)
ASSOCIATES
390-5150
the
in
of
terms
these
23
ct
I would
1
2
methamphetamine
3
in
4
primarily
5
to
6
'50s
7
was
overweight,
8
but
a lot
9
ate
just
10
the
like
and
1950s
appetite
point
out
that
amphetamine
was
really
'60s
and
as to
to
as an anoretic
appetite
'60s
and
I was
of
us
like
develop
but
very
a student
at
that
us did
take
also
not
lose
weight,
Not
as before.
12
obtained
13
1980s
14
Again,
15
opinion,
16
work
act
In
the
a lot
of
us
amphetamine
a lot
names
of
us
or
that.
from
ephedra
as weight
the
they
tolerance
the
naming
And phenylpropanolamine
11
the
time,
of
did
and
quickly.
so a lot
as well
anything
agent
suppression
suppression
prescribed
and
reduction
effectiveness
because
is
it's
been
with
or
come
after
three
in
another
used
compound
since
without
caffeine.
a question,
months
of
the
in
use
my
they
may not
anymore.
In
17
18
formulation
19
scientific
20
anoretic
21
peripheral
22
work.
23
of
24
adverse
25
system
terms
the
base
of
theoretical
because
effect,
combination
events
events
the
and
of
ephedrine
has
effect
has
so the
I would
like
to
product
also
have
of
and
CNS and
it
MOFFITT
caffeine
mechanism
caffeine
whereas,
thermogenic
However
ephedrine
other
may have
action
the
the
central
greater
combination
point
out
anemic
should
that
potentially
been
have
this
a lot
peripheral
synergistic
REPORTING ASSOCIATES
(301)
390-5150
CNS
type
of
24
1
stimulation
between
the
There's
and
various
of
within
7
product,
8
you
9
than
herbal
get
two
the
11
inclusion
what
and
also
is
the
14
index
15
adverse
16
mild,
17
one
18
though
19
have
20
flushing,
21
on and
22
of
23
ephedrine,
24
So there
is
the
this
this
I didn't
take
this
or
not,
but
profile
ephedrine
You draw
principal
times
your
like
my heart
will
idiosyncratic
own
this
and
one
and
be pumping
can
reaction
have
are
or
whatnot
now even
morning;
one
can
palpitation,
urinary
to
therapeutic
conditions
skin
retention,
I can't
I take
event
take
pseudoephedrine
a mile
is
a minute.
hypertension.
REPORTING ASSOCIATES
(301)
390-5150
so
decongestion
reactions.
severe
MOFFITT
does
I am having
Personally
If
the
dizziness,
tremors
product.
the
60 milligram
ephedrine
tingling,
adverse
adverse
30,
insomnia,
The most
the
the
even
whether
different
of
the
dosages
nervousness
are
another
available
two
of
have
of
of
still
particularly
Most
so forth.
variation
know
the
At
low.
headaches,
that
means.
particularly
can
alkaloids
things
to
different.
events
events.
product
a total
CNS stimulation
very
the
a great
contents
quite
of
of
1 don't
is
One has
Adverse
12
is
--
content
one
one
ecstasy,
other
are
us
there
from
lots.
alkaloids
13
and
same product
10
25
that
alkaloids
the
on the
products
me was
content
6
a study
diet
intrigued
two.
or
25
ct
1
That
is
2
prolonged
3
and
4
these
5
the
the
most
important
Arrhythmia
use.
in
the
case
events
in
concomitant
caffeine
dump
on and
and
of
tachycardia
our
opinion
used
the
Now,
10
drug
11
stimulant.
12
cardiacthycal
13
be taking
14
agents
15
totally
ephedrine
ephedra,
Of course
like
this
or
it
kind
among
of
amino
in
Now,
17
couple
18
are
19
sympathomimetic
20
as decongestants.
21
reduction
22
mark
23
convince
24
does
work;
people
25
loss
worth
it.
for
and
can
be very
agents
I keep
agent,
because
I have
me in
to
terms
of
have
MOFFITT
of
the
lost
to
others
make
ephedrine
a
alkaloids
short-term
in
bronchial
asthma
as a weight
that
more
not
thing.
like
effectiveness
see
should
among
sort
and
saying
this
on sympathomimetic
particularly
The
of
a CNS
patients
useful
so
coadministered
I would
Ephedra
or
event.
inhibitors
conclusion,
observations.
useful
be not
that
you
ephedrine
people
oxidase
like
then
It's
heart
stuff,
contraindicated
16
should
with
interactions
a drug.
digitalis
drugs
an adverse
drug
is
results
be associated
with
or
death
particularly
have
potential
also
other
along
One can
so forth.
to
and
dose
potentially
of
antihistamine,
by high
tachycardia
and
phenylpropanolamine
9
caused
administration
and
in
event
it's
clinical
risk
a few
to
a question
papers
benefit
pounds,
REPORTING AsSOCIATES
(301)
390-5150
to
ratio.
but
is
It
that
26
ct
In
1
2
manifested
or
terms
of
as I said
prolonged
use
from
or
the
use
6
Thank
or
very
both
of
much
this
for
product
your
8
DR.
JONES:
Thank
you
Dr.
9
Let
me turn
first
to
panel
questions
for
Dr.
11
[No response.]
12
DR.
13
have
14
you
15
question,
would
if
you
Fong
Dr.
brevity
is
the
should
of
Yes
sir.
proceed.
please
is
as street
drugs.
Fong.
members,
the
to
there
a microphone
if
you
the
If
floor.
are
microphones.
and
ask
wit
you
If
your
for
all
Identify
of
us.
yourself
record.
Jeffrey
MR. REINHART:
Pure
me turn
to
would
18
19
Let
proceed
Please
16
17
for
recommend
Fong.
JONES:
questions
be
attention.
[Applause.]
have
can
sensitivity
do not
7
10
it
individual
I absolutely
production
you
reactions
overdose.
One thing
4
5
mild/severe
Reinhart,
People
for
Foods.
Dr.
20
21
stereo
22
phenylpropanolamine
Fang , would
specificity
DR.
23
24
you
know
25
doesn't
comment
difference
and
FONG:
how to
work
you
the
way
MOFFITT
clarify
on the
between
the
This
do these
or
plan
of
high-tech
things.
I want
it
to
ephedrine?
stuff
is
good
Some of
it
just
work.
REPORTING A.SS~OCIATES
(301)
390-5150
if
27
ct
Phenylpropanolamine
The
is
and
phenylpropanolamine
stereo
Is
chemistry.
is
with
that
what
I was
has
you
are
asking
the
same
asking?
the
racemic
My understanding
used
mixture
racemic
okay.
about
phenylpropanolamine.
phenylpropanolamine
plus/minus
ephedrine,
ephedrine
that
MR. REINHART:
situation
low
in
commerce
whereas
in
is
the
plant
it
is
And you
think
that
minus.
DR.
10
a tremendous
difference
given
elucidated,
DR.
14
particular
15
able
16
norephenephrine
17
But,
18
activity
19
and
20
of
to
you
the
one
know,
in
not
23
things
cardiac
look
at
over
minus?
the
of
the
adverse
I am not
just
I have
can
MOFFITT
least
to
be
minus
that
of
CNS stimulation
and
great
in
terms
whatnot.
phenylpropanolamine
not
of
difference
that
effect
comment
the
the
be not
period
a colleague
this
answer
between
that
cautioning
you
the
at
phenylpropanolamine.
saying
a prolonged
be
can't
have
is
will
to
I really
difference
at
effect?
needs
I don't
the
is
issue.
racemic
effect
I'm
safe.
Jerry,
24
time
my conviction
terms
it
sorry,
the
or
Now,
is
25
I think
I'm
FONG:
in
pharmacological
thalidomide
differentiate
21
22
the
moment
okay.
in
MR. REINHART:
11
12
Yeah,
FONG:
to
time
on the
who used
to
use
or
those
overdose.
racemic
versus
be a professor
REPORTING ASSOCIATES
(301)
390-5150
28
ct
1
then
he decided
to
3
from
Nature
4
company.
5
So look
6
in
7
different
8
bonds
9
we call
the
are
Sunshine
See if
at
there
structure
of
erythrol,
going
that
off
in
if
different
we put
pseudoephedrine
have
different
at
makes
one
18
Nor
the
means
up with
about
the
the
doesn't
24
guys;
go one
of
methyl
just
make
of
in
those
are
the
out,
one
and
way,
of
see
T
or
they
is
the
gone
the
over
Harry
puts
here.
compounds;
It
actually
the
also
we end
talked
another
methyl
So we end
up with
and
plant
makes
structure
REPORTING ASSQCIATES
390-5150
(301)
by
here.
So,
the
so
look
structure
all
these
okay.
MOFFITT
go
other
if
Okay?
gone.
compound.
one
ephedrine
it's
which
these
So I think
what
same
a line.
three
make
substitutions
in
Remember,
ephedrine
all
these
atoms
we can
series
complicate
methylephedrines
mixture
one
isomers
servers.
of
switch
actually
going
you
off,
nor
carbon
Now,
of
we go.
Okay.
can
the
here
Okay?
carbons
we further
methyl
structure
23
them
possible
that
the
huge
25
four
Now,
that.
taking
the
directions.
Now,
that
--
all
here,
ephedrine
both
is,
an herb
asymmetric
we just
So the
Okay.
around.
two
in
McLaughl
it's
work
ephedrine.
if
Jerry
now
will
are
structures
direction
in
products,
my pointer
here,
I'm
Yes,
DR. MCLAUGHLIN:
2
16
go make money.
of
on
a
29
which
phenylpropanolamine
but
structure,
in
here
without
giving
carbon,
you
so you
right;
only
at
phenylpropanolamine
8
of
9
it's
10
the
materials
probably
plant
DR.
floor
or
to
the
14
DR.
JONES:
15
DR.
BRAY:
Baton
17
of
18
studies
19
would
20
clinically
21
Rouge,
that
Yes,
of
--
plant
because
either
from
there
the
a statistically
why you
23
I thought
24
executed
FONG:
MOFFITT
of
the
trial.
about
as nicely
Okay.
in
That
problem
Denmark
combination
question
for
Bray
and
so many
ask
the
from
you
could
in
published
22
was
George
has
double-blind
trial
I'm
caffeine
is
put
morning,
ephedrine
placebo,
DR.
does
the
randomized,
as you
a mixture
probably
interested
effect
25
.:i
good
Astrup,
that
that
what
have
the
in
none.
significant
comment
all
compounds
does
questions
Louisiana,
Arne
suggest
isomers
sure
mimic
one
materials.
Seeing
My reading
weight.
it
it
of
of
panel?
[No response.]
from
mixture
really
if
Other
13
16
not
somewhat
a mixture
JONES:
from
but
chemistries
potential
synthetic
going
makes
11
12
being
--
stereo
more
four
So I'm
is;
this
a racemic
least
phenylpropanolamine.
7
the
potentially
know,
have
essentially
defining
us not
but,
is
in
his
I wondered
if
marks
because
designed
a clinical
trial.
study
you're
that
and
REPORTING ASSOCIATES
(301)
390-5150
,,. ,.,
30
talking
about,
personal
yes,
a valid
4
be total
5
of
6
the
7
statistics
8
whether
9
long
10
and
11
events
weight
mark
study
that
you're
talking
question
was
loss
weight
33.5
question
My only
study.
body
the
The
thing.
3
I have
was
lost
kilo
as compared
the
is
does
five
or
six
over
prolonged
14
in
15
meeting
16
my position
17
medication
18
status.
19
professor
in
20
an agent
that
21
three,
22
index
23
the
25
the
five
and
But
at
taken
the
on the
of
just
a member
ago
ephedra
not
a low
I like
least
statistical
10 to
see
1,
JONES:
Further
of
adverse
that
for
the
those
of
are
ephedrine
from
index
of
the
with
regulatory
and
that
of
questions?
REPORTING ASSOCIATES
(301)
390-5150
as a
using
two
to
therapeutic
my question
study.
and
good
as a pharmacist
is
you
FDA ad hoc
and
an agent
in
nest
aspect
this
how
Okay?
[No response.]
MOFFITT
is
maintained;
I questioned
significance
DR.
mark
on regulatory
hand
is
isn't
a hornet's
therapeutic
to
Now in
there
into
of
pharmacochemistry
has
risk
be banned
other
and
time.
getting
years
kilogram
group
mark
is
that
placebo.
off
worth
it's
should
usually
of
I'm
even
was
seven
My question
is
I was
about
the
about
I think
be placebo
periods
But
audience,
to
weight.
pounds
So I know
24
to
weight
discussion.
or
My question
reduce
patients
five
as compared
significance.
it
this
about
that
as a
mark
not
31
ct
DR.
1
2
concluded
on time.
3
have
the
4
for
5
scheduled
6
chance
7
to
done
us
for
to
pick
the
note
Fong
Dr.
impossible
it
and
I would
day.
for
a 15-minute
get
acquainted
up the
lunch
hear
from
our
10
evening
reports
11
as they
appear
12
available.
in
Thank
13
14
will
see
15
time
at
you
panel
the
in
lo:05
send
this
that
you
background
now we're
will
lay
give
of
you
the
a
facility,
everything.
after
the
will
and
docket
that
much
break
look
the
at
FDA has
for
we will
adverse
clinical
your
We will
15 minutes.
Thank
we are
a nice
It
that
very
a.m.
out
the
that
appear
laid
database
the
you
does
with
map and
first
then
break.
When we come back
8
9
I would
JONES:
studies
made
attention.
We
be starting
on
you.
16
17
[Brief
18
DR.
JONES:
Dr.
Julie
Bietz,
Dr.
Ray Woosley,
and
Cynthia
19
Ricaurte,
20
your
21
clinical
agenda
with
studies
DR.
22
recess
this
at
discussion
and
LOVE:
guests,
24
ephedrine
alkaloid
25
including
new
of
adverse
Dr.
morning
23
9:45
Jones,
dietary
in
FDA's
Dr.
George
Culmo,
database
shown
in
and
Thank
reports.
panel
present
containing
MOFFITT
the
event
I will
information
a.m]
members,
an overview
you.
and
on the
supplements
recent
REPORTING ASSOCIATES
(301)
390-5150
assessment
of
32
ct
1
the
public
2
ephedrine
health
The
are
associated
alkaloid-containing
3
4
risk
available
5
documents
publicly
in
can
safety
of
see
from
about
the
7
long
time.
We first
became
a
we received
a report
of
9
been
10
for
purposes,
12
this
report,
13
there
were
14
with.
15
is
16
which
17
very
potent
18
just
explain
of
to
Ingredients
a Chinese
were
refer
for
to
for
all
Besides
19
in
were
21
literature
22
the
23
databases
to
24
with
same product
25
contained
this
thing
this
that
see
if
MOFFITT
among
because
man who had
significance
the
of
products
we were
for
and
unfamiliar
which
we now know
contains
alkaloids
alkaloids
means,
he took,
that
Dr.
as
are
Fong
has
us.
aware
raised
we did
there
or
ingredient
a
enhancement
that
we reviewed
also
issue
a young
the
in
products,
which
back
purposes.
as ephedrine
of
FDA concerns
this
for
ephedra
becoming
20
other
these
in
ma huang,
sympathomimetic
0091200.
goes
of
ingredients
like
name
of
assessment
slide,
aware
evaluate
that
whose
this
supplements
products
we noted
use
No.
enhancement
trying
ones
the
a death
athletic
In
11
dietary
a number
from
FDA docket
6
using
the
products.
complete
As you
with
our
was
these
the
level
to
scientific
of
look
ingredients
conce~rn;
in
and
available
were
other
adverse
events
with
other
products
that
and
we found
cases
REPORTING ASSOCIATES
(301)
390-5150
of
these.
ct
33
1
So in
1993,
I'm
2
not
1993
concerns
about
4
we held
a formal
5
examined
the
6
we had
received
7
was
the
a
which
9
hazard.
of
alkaloid
to
of
a number
12
the
data
13
public
14
working
group
of
scientific
15
working
group
to
our
16
the
17
in
ia
available
19
virtual
20
still
today
21
types
products.
are
meeting
22
public
And
at
of
that
And
it
23
working
group
that
24
dietary
supplements
25
contain
ephedrine
containing
where
we have
on these.
the
they
known
alkaloids
that
members'
to
the
that
was
the
we have
almost
safe
contain
may cause
at
of
or
and
use
feeling
of
a
I think
these
this
certain
suspected
consumers
REPORTING ASSOCIATES
(301)
390-5150
is
all
time
use
as a
which
evaluated
that
we had
served
Committee
at
agreed
discussed
ad hoc
committee
indicate
we have
1995
a special
really
information
MOFFITT
In
we really
There
was
health
meetings
Advisory
This
combination
morning,
experts
which
events.
this
time
would
adverse
1994
that
for
mentioned
information.
absence
of
advisory
this
board
a significant
Food
scientific
In
product
we convened
this.
its
evaluation
number
available
where
use
products.
a particular
represent
had
that
these
caffeine
Jones
how to
indicated
hazard
11
FDA.
of
a large
As Dr.
general
FDA first
health
felt
I know
safety
safety
ephedrine
10
if
was when
3
was
sure
to
to
a
34
experience
serious
In
2
3
new
4
adverse
5
levels
6
milligram
7
members
a
Committee
9
but
events
and
that
the
working
opinion
11
could
12
with
and
on,
attempt
these
Over
14
stated
that,
15
levels
of
16
use
17
recommended
ia
Other
19
that
20
reduce
21
establishing
22
use
23
as well
based
proposed
25
by
certain
Food
the
Advisory
reviewed
specific
public
Food
on the
all
their
ways
health
of
of
the
that
FDA
concerns
of
for
be identified
products
safes,
ephedrine
per
for
they
from
Committee
conditions
events
members
no safe
consequently
Advisory
adverse
both
as other
rule
these
Food
reasonable
Committee
data,
could
and
establish
risk
Advisory
available
alkaloid
removal
Out
24
for
supplements
agency
levels
the
they
of
that
and provided
the
the
ephedrine
members
the
full
again,
And,
address
below
The
group.
number
indicating
suggested
information
half
dietary
the
been
of
products.
13
in
had
because
an increasing
were
a rationale
to
1996,
analyses
convened.
data
in
included
alkaloids
limits
was
year,
product
ephedrine
of
events.
following
which
available
10
25
the
information
of
adverse
of
use
the
market.
suggested
that
including
serving,
alkaloids
and
and
these
public
in
1997,
June
MOFFITT
meetings
4th,
1997,
came FDA's
and
REPORTING ASSOCIATES
(301)
390-5150
daily
ephedrine
requirements.
of
would
this
35
ct
1
proposed
2
limitation
3
of
4
certain
rule
had
a number
on the
ephedrine
does
per
warning
6
information
were
7
were
in
a
information
9
alkaloids,
placed
about
the
sources
the
morning,
11
pharmacological
12
finally
the
adverse
13
derived
both
from
14
adverse
event
about
17
alkaloid-containing
ia
Fang , there
19
they
are
20
the
direct
21
both
22
and
23
heard
today?
are
24
talking
25
are
of
This
of
use.
other
meetings
and
included
ephedrine
as you
heard
and
alkaloids
ephedrine
scientific
the
and
alkaloids
literature
products
are
a wide
as
as well
primarily
use
for
about
talking
any
of
about
MOFFITT
of
as
these
that
dietary
for
use
and
under
are
drugs
but
products
supplements
cough
You have
as asthma.
of
Dr.
these,
allergy,
REPORTING ASSOCIATES
390-5150
(301)
from
there
alternative,
type
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conditions
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drug
talking
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practitioner
as well
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variety
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prescriptions
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and
alkaloids,
products.
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about
required
public
ephedrine
effects
There
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of
a milligrams
reporting.
What
15
data
these
the
a
conditions
physiological
effects
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of
it
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of
known
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and
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products
10
cold
public
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and
amounts
at
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serving
presented
our
was
statements
Considerable
5
features
which
alkaloid
label
of
we're
today.
that
not
We
contain
36
ct
n
1
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alkaloids.
These
2
3
products
Almost
States.
the
They
ingredients.
stimulants
well
all
and
9
10
for
are
include
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lung
This
11
12
variety
of
13
somewhere
14
that
15
groups
16
bodybuilding
products.
for
weight
The
17
ia
ephedra
19
botanical
20
seta
cordifolia,
21
that
extracts
22
of
23
synthetic
25
Dr.
Fong
We estimate
that
400
and
and
which
may
cetera.
are
types
again
energy
wider
there
different
and
of
or
Ma Huang
are
ephedrine
also
pinoyella;
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they
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products
fall
into
ergogenic
botanicals
and
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ephedra,
MOFFITT
as Dr.
alkaloid
Fong
alkaloids
are
can
said,
These
possible.
however,
alkaloids,
sources
are
fitness
the
market
The major
24
are
showing
et
as
products.
sources
ephedrine
energy,
category
sources
species
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a picture
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type
yohimbine
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we see
and
United
other
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3 and
now on the
with
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purposes
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et
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multiple
Sometimes
that
a general
in
combined
minerals,
weight
and
bodybuilding,
usually
uses
sold
contain
caffeine.
The primary
marketed
widely
products
are
including
as vitamins
are
it
is
listed
finally
but
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include
most
common
as the
there
be
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source
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as you
pseudoephedrine,
have
heard
norephedrine,
REPORTING ASSOCIATES
(301)
390-5150
from
37
ct
norpseudoephedrine
1
methylephedrine,
2
methylpseudoephedrine.
3
nature
4
nature.
in
you
don't
The
sources
5
6
wide
7
practice.
a
medicine
9
In
variety
of
been
11
ever-growing
12
research
13
surveillance.
14
containing
15
reporting.
see
Dr.
been
used
at
least
in
And
area
in
ephedrine
16
Along
with
types
of
the
different
ia
preclinical
19
give
20
observational,
21
And
22
standard.
23
the
24
usually
has
only
25
usually
for
a relatively
are
case
of
dietary
of
of
trials
But
have
these
are
is
and
several
hundred
short
there
in
vitro
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to
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information
usually
on
voluntary
animal
the
trials.
gold
probably
A well-controlled
infrequent.
a
supplements
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evidence
and
kind
use.
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These
epidemiological,
MOFFITT
.a
type
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based
is
sources
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traditional
is
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clinical
most
There
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and
evidence.
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in
literature
alkaloids
17
us
the
salts
centuries
now.
in
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that
five
scientific
the
or
from
state
occurs
come
ephedrine
75 years
medical
done
come
Fong
the
what
information
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mixtures
our
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there's
L forms
racemic
of
You heard
allopathic
10
The
and
are
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clinical
patients
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trial
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is
most
REPORTING ASS,OCgATES
(301)
390-5150
” _
.
__,. 1.
_. .. c. ,.
._
38
ct
information
that
occur
in
event
monitoring
case
the
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postmarketing
period
which
would
where
adverse
events
we use
adverse
be considered
a type
of
reports.
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6
detect
7
at
a
patients
to
9
clinical
trials
just
for
a relatively
1 percent
have
subjects
As Dr.
of
amphetamine-like
and
16
cardiovascular
17
depend
la
the
the
any
of
mentioned
the
nervous
alkaloid
most
part
do not
a lot
about
These
amines,
I've
The
them.
The
already
the
are
they
primarily
system.
and
500
literature
we know
they
to
that.
alkaloids.
effects,
to
occurring
three
published
for
trial
one
least
detect
sympathomimetic
and
event,
at
the
ephedrine
indirect
upon
in
Fong
characteristics
direct
in
alkaloids
many
adverse
reliably
are
a clinical
e,
require
to
that
11
this
would
be able
now on ephedrine
an examp
common
rate
10
14
on possible
have
affect
exact
the
effects
talked
about
L forms.
The pharmacology
19
spoke
about,
mechanism
20
also
21
review.
22
basal
23
increased
contractility,
increased
24
increased
stroke
central
25
stimulation,
In
the
but
and
I am just
cardiovascular
constriction
and
and
volume,
other
MOFFITT
cardiac
effects
of
action
going
to
quickly
system
it
can
stimulation,
heart
nervous
including
REPORTING ASSOCIATES
(301)
390-5150
cause
including
rate,
system
and
he
ct
39
1
bronchodilation
2
muscle
and
and
various
From
adverse
these
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and
in
angina,
and
10
we see
cardiac
cerebral
associated
and
system
and
vascular
of
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affect
nervous
we have
the
ephedrine
we see
system
hypertension,
infarction
events
most
with
that
cardiovascular
ischemia
smooth
derived
effects
cardiovascular
and
glands.
effects
adverse
the
the
and
known
that
predominantly
on skeletal
organs
effects
alkaloids.
effects
cardiomyopathy
including
hemorrhage
any
infarction.
11
In
12
stimulant
13
seizures
14
be abuse,
myopathies,
17
effects
ia
and
nervous
effects
and
15
16
the
system
as well
I have
abuse
dependence,
and
And
there
uropathies,
on the
GI
dermatologic
19
20
do we evaluate
21
no different
22
considerations
23
pattern
24
ingredients.
25
supplements
here
psychosis
but
it
should
just
addiction.
have
including
system,
and
central
been
reports
urinary
including
of
retention,
vascular
effects
reactions.
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of
as mania
drug
finally
we have
slide
is
dietary
than
use
and
products
including
the
type
The population
includes
MOFFITT
just
supplements?
other
for
use,
a reminder
both
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in
And
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that
we look
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population,
of
products
for
these
general
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context
really
at.
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the
and
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population
REPORTING ASSOCIATES
(301)
390-5150
but
40
special
subpopulations.
2
amount,
frequency,
3
conditions
4
hard,
5
cetera,
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ingredients,
7
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and
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finally
These
known
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11
it
include
as particular
may be used,
including
restriction,
the
type
of
are
sympathomimetic
the
et
products
and
amines
that
they
are
often
which
combined
can
cause
with
other
an interactive
affect.
This
12
what
we know
13
know
in
14
ephedra
15
health-care
16
for
17
with
18
defined
19
combinations
20
use
21
supplements
22
dietary
23
they
24
previously
25
bodybuilding;
is
just
to
again
traditionally
dietary
was
only
practitioner
short
are
term.
products
The
supplements;
the
different
used,
the
the
they
the
current
use
of
is
weight
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selects
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of
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energy,
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REFORTING ASSOCIATES
(301)
390-5150
I
the
dietary
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than
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than
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manufacturer
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MOFFITT
used
are
U.S.
we
with
formulation
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It
selected
combinations
that
for
the
what
Historically
prescribed,
disorders;
contrast
to
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practitioner
herbal
and
ephedra
today.
considered
health-care
compare
about
supplements
respiratory
used
use
as well
caloric
ingredients
synergistic
very
which
of
effects.
Further
or
duration,
exercise,
and
8
9
The pattern
ingredients
41
1
and
the
2
different
3
finally
4
prolonged.
combinations
than
the
what
to
6
little
evolution
7
actually
did
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for
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9
have
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heard
10
criticisms
11
heard
data
what
that
for
its
"FDA based
and
And
proposed
events
15
contain
ephedrine
16
from
17
ephedra
alkaloids
19
FDA's
20
However,"
and
21
about
strength
22
to
23
level
the
support
and
aspects
the
duration
not
performed
this,
a causal
MOFFITT
of
There
were
many
data;
but,
what
FDA's
use
want
to
products
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impacts
types
steps
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of
to
Besides
24
and
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all
indicating
and
consideration
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sure
It
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The number
the
the
of
to
use
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analysis
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of
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evidence
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ingestion
of
individuals.
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safety
issue.
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information
proposed
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for
used
address
the
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isn't
thought
errors
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some of
of
of
data
reports
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GAO
of
quote
on numerous
alkaloids.
rule,
of
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literature
use
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on our
proposed
support
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we were
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associated
scientific
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did
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of
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undefined
said.
use
are
previously
to
And
been
the
which
evaluated
rule.
reason.
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is
us back
GAO really
adverse
25
use
used
used
safety,
has
14
18
of
a study
about
is
been
get
of
are
had
duration
Just
5
that
rule,
concerns
FDA used
the
dosing
limits.1'
also
indicated
of
individual
REPORTING ASSOCIATES
(301)
390-5150
that
we had
adverse
ct
42
1
events;
2
and
3
event
that
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many
we did
should
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of
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have
criticisms.
6
meeting
7
happened
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9
taken
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want
efforts
use;
Certain
concerning
10
for
11
scientific
literature
12
products;
FDA has
13
expert
14
questions
with
15
GAO; and,
finally,
16
evaluation
17
adverse
events.
And
18
experts
reviews
besides
there
have
In
19
20
are
many more
21
effects
of
22
frame.
And
23
some
24
pseudoephedrine
25
patterns
cases
that
been
states
and
dosage
the
deficiencies
a continuing
by
receipt
and
reported
we have
sought
outside
review.
literature
there
monographs
on the
available
information
emerging
these
outside
some of
in-house
alkaloids.
MOFFITT
of
voluntarily
of
medical
safety
a number
alkaloids
effects
the
on the
abstracts,
have
instructions
in
answer
a
industries
and
scientific
the
public
have
too
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are
of
rule.
or
articles,
injury
point
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medical
or
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which
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impact
were
time
heard
new articles
spontaneous
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about
commissioned
ephedrine
to
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reviews
the
talk
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scientific
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to
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we have
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me,
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lacked
criteria
be considered
And believe
5
cases
dietary
We are
besides
in
is
this
specific
supplements
seeing
in
or
that
cardiovascular
REPORTING ASSOCIATES
(301)
390-5150
time
other
ct
43
1
and
nervous
2
there
is
3
mechanisms.
system
information
4
these
been
of
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6
potential
7
may be direct
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system
have
of
9
last
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interest
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use
of
There
have
10
clinical
11
first
12
controlled
13
point
of
hemorrhagic
14
very
large
study
15
increased
16
weight
17
will
ia
issues
these
is
study
the
stroke
be the
subject
of
In
20
area,
21
abstract
22
randomized,
23
a ma huang
24
Sixty-seven
25
In
in
from
that
been
put
to
people
trial
of
in
MOFFITT
which
The
was
49 looking
And
a case-
at
this
was
the
was
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for
an FDA docket
to
end
any
used
dietary
and
address
the
supplement
was publication
Luke's
of
an
on a double-blind,
8-week
containing-product
indicated
there
alkaloids.
there
botanical
St.
were
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published
meeting
placebo-controlled
guarana
abuse
PPA.
FASEB there
Columbia
things
nervous
products
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ephedra
in
of
central
PPA.
in
specific
the
1999,
in
showed
has
19
18 to
particularly
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the
PPA study
persons
This
the
suggestion
a number
Yale
that
of
products.
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thought
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of
risk,
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in
investigations
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pathogenic
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neurotoxicity
from
effects.
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For
5
this
stimulant-related
efficacy
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only
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appeared
REPORTING ASSOCIATES
(301)
390-5150
of
obesity.
randomized,
there
trial
48 completed.
to
be some
ct
44
efficacy
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and
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And,
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2000
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palpitations
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trial
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synepherin
30 test
we had
caffeine
subjects
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commissioned
clinical
looked
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at
the
properties
botanical
ephedra
30
a number
reviews.
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in
in
versus
alkaloids.
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question
sources
has
16
botanical
17
problems
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the
18
Enchiosa
was
able
to
19
publications
that
have
20
pharmacokinetics
21
supplement
22
differences
23
botanical
sources
24
synthetic
products.
25
only
al,
double-blind,
pharmacodynamics
toxicities
et.
eight-week
Enchiosa,
pharmacokinetics,
15
another
that
scientific
was by Dr.
ephedrine
Calman,
an ephedrine,
but
including
seen.
a study
obesity
product,
relative
effects
recently
I mentioned
10
adverse
placebo-controlled
in
9
14
were
are
as potent
synthetic
sources
product
look,
or
was
MOFFITT
or
because
addressed
that
of
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dietary
a study
that
somehow
don't
cause
cause.
number
issue
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directly
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There
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always
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Ray,
REPORTING ASSOCIATES
(301)
390-5150
to
looking
at
ct
45
1
the
2
and,
3
health-care
4
the
use
of
ephedra
again,
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was
purposes
of
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of
7
events
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8
alkaloids.
9
that
and
the
reporting
were
rate
11
interim
14
the
15
alkaloids
containing
16
a fairly
cons istent
17
proportion
18
supplements
19
with
events.
events,
his
dietary
have
been
23
alkaloids
24
is
25
calculated
just
than
1 percent.
look
at
day,
this
the
all
We have
had
a 40 percent
events
at
are
ephedrine
supplements.
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number
you
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adverse
due
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ephedrine
time
proportion
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This
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ephedrine
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used
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review
of
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not
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cumulative
20
reporting
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of
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13
term
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medicine;
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loss
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In
22
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And
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practice,
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6
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And,
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of
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part
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MOFFITT
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year
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REPORTING ASSOCIATES
(301)
390-5150
2000.
but
this
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It
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number
ct
46
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would
be somewhere
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What's
Well,
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labeling,
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14
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colleagues
15
Research,
16
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17
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in
and
Dr.
19
What
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21
a time
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typo
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24
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25
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will
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Drug
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And
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Food
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can
in-depth
for
20
of
on these
and
in-house
cetera
that
of
about
GAO and
5
we are
events.
different
we heard
consumer
So,
time
I have
time
that
it
through
to
was March
REPORTING ASSOCIATES
(301)
390-5150
a
31st,
47
1999,
with
2
in-house
3
takes
4
be able
5
information
any
by
follow-up
the
end
us anywhere
to
investigate
reported
in
8
evaluated
9
clinical
were
this
from
10
adverse
11
using
three
to
six
these
adverse
for
least
140
on at
amount
months
events
143
longer
and
to
to
get
outcome,
events
consumers
and
product
use,
information,
of
it
or
adverse
least
diagnoses,
events,
Typically
evaluation.
demographic
course,
be received
1999.
at
time
could
December
we need
There
7
of
from
that
6
that
classification
documentation,
and
we
of
reason
for
Of the
140
product.
12
This
is
our
13
reports
14
These
were
cases
of
15
cases
where
the
event
16
an adverse
17
product
18
drug.
19
relationship
20
confounding
cut
we considered
event,
with
In
one
that
and
by
the
22
as
I stated,
23
supporting
24
that
had
25
They
were
and
of
was
was
then
in
one
MOFFITT
case
product
we did
these
information
the
signs
if
it
and
it
was
there
was
which
was
the
a
into
make
symptoms
REPORTING ASSOCIATES
(301)
390-5150
GBL.
evaluation
not
including
to
was
temporal
an in-depth
relationship
insufficient
48 where
or
tell
an incorrect
screened
a causal
patients,
we decided
supplement
cases
unevaluable.
we couldn't
co-ingested
The other
21
were
reported
where
there
there
reports.
unidentified
being
dietary
case
eight
multiple
cases
the
on these
those
assessments.
were
not
not
48
consistent
with
ephedrine
2
cases
3
impossible
to
4
alkaloids,
there
5
were
6
or
7
two.
where
too
cases
8
9
so many products
ascribe
many
of
were
other
10
attribution
11
and
12
of
13
was
we used
scheme
these
we've
difference
between
15
causality?
Well,
16
some
link
17
from
1965,
18
association
19
automatically,
20
association,
21
specificity
22
biological
23
experiment,
Cases
or
that
attributable
been
asked
was
there
there
11;
were
population.
structured
we could
into
it
factors,
our
a formal
that
where
abuse,
of
nine
ephedrine
complicating
look
and
and
I'm
is
nine
which
means
at
them
supporting
the
the
and
and
this
that's
It
the
quote
association,
is
doesn't
the
is
really
from
Dr.
Hill
whether
mean causation
of
the
association,
the
temporality,
plausibility,
the
or
as to
strength
of
what
there
viewpoints
consistency
gradient,
schemes
using
times
attribution
means
causation.
and
of
and
association
there
many
association
the
coherence,
analogy.
I should
such
used
were
relationship.
14
25
cases.
55 percent
analysis
Now,
24
effects
misuse
45 percent
a causal
the
two
intentional
we divided
been
of
or
there
had
any
confounding
So this
The
alkaloids;
mention
also
there's
MOFFITT
really
that
there
are
no consensus
or
REPORTING ASSOCIATES
390-5150
(301)
_,
“,,.,
_.
.^
/
,
i
x
_
many
no gold
ct
49
1
standards
event
on what
monitoring
voluntary
This
analysis,
if
event
and
9
attribution
temporal
use
the
adverse
had
been
care
10
evidence
of
11
when
product
12
--
13
took
there
the
the
attribution
event.
the
for
the
to
adverse
professional
there
consumer
discontinued,
and
came back
between
We wanted
whether
i.e.,
ad symptoms
clinical
for
sought
adverse
reports,
relationship
event,
dechallenge,
for
with
was health-care
adverse
was
use
spontaneous
though,
the
of
signs
we did
and
to
associated
we checked
whether
the
schema
for
that
what
medical
8
best
its
or
is
products
know
the
whether
reports,
trials.
the
is
when
if
the
was
got
the
better
symptoms
person
again
product.
How the
14
or
was
product
15
direction
16
other
17
What
18
products;
were
19
were
they
bodybuilding
20
Were
the
21
likely
22
looking
23
finally,
24
of
25
known
products
was
it
used,
used
the
at
reason
they
ephedrine
time
they
weight
of
the
were
loss,
event
physiological
MOFFITT
or
or
or
likely
event?
these
products,
they
or
others?
use
event?
This
a more
is
explanations,
the
known
extensions
pharmacological
Were
product
with
per
adverse
were
alternates
consistent
alkaloids
the
energy
or
used
abused?
using
adverse
or
Was it
or
of
products
alternatives
the
the
conditions
explanation
is
misused
that
underlying
at
was used.
effects
REPORTING ASSOCIATES
(301)
390-5150
of
and
affects
the
of
cn
1
ephedrine
alkaloids.
2
This
3
structured
4
as well
5
these
6
full
7
reported
a
of
9
energy
product.
10
events
being
11
in
previous
was
data
the
our
12
13
64 percent
14
of
age;
15
or
younger.
16
that
Although
range
of
the
injured
all
men;
that
most
19
according
of
and
most
21
majority
22
temporally
impacted
consumers
to
the
the
reported
directions
looking
of
use
first
time
MOFFITT
i
since
the
more
loss
and
adverse
than
we saw
that
_,.
‘,
at
duration
it
ranged
of
use
39 years
were
event,
they
use
label
the
and
related
of
the
of
from
19
we noted
product
labeling
practitioner
temporally
use
adults;
characteristics
on the
the
young
adverse
to
on the
.-_,.
on the
related
even
are
persons
consumer
were
25
events
under
injured
them
duration
from
percent
were
of
wide
is
more
persons
saw a health-care
24
seen
mostly
them
In
And
weight
39.8
of
23
case.
this
is
When we evaluated
ia
the
again
16 percent
may have
docket
serious.
age
that
the
be expected
we are
for
The
17
and
adverse
could
a very
in
on each
more
we see
with
available
we see
Overall
reported
and
is
that
women which
products
as I said,
results
results
series.
for
which
individual
the
case
done,
form
as the
are
all
and
the
closely
product.
use
there
under
on up to
was
one
very
a
day,
or
chronic
REPORTING ASSOCIATES
(301)
390-5150
.
/
._
<_
/
.
.
),
<.
.,
i
v.
I,
ct
51
1
use,
2
associated
3
than
4
longer-term
and
you
see
with
or
the
spread;
short-term
equal
to
one
use
week
30 percent
which
meaning
we defined
that
are
as
70 percent
less
were
use.
When we looked
5
6
documentation
7
reported
by consumers.
a
the
of
9
about
flow
that
of
them
11
predominantly
health-care
12
a third
13
36 percent
overall
14
In
at
15
over
16
including
17
of
label
are
of
18
as we've
20
serious
21
also
class
22
that
we couldn't
23
overwhelming
24
this
25
And
adverse
fact
if
the
the
you
center,
our
records
and
you
know,
So,
which
are
and
approximately
professionals.
we have
evaluated,
additional
many
just
reporting,
that
of
at
are
field
health-care
some kind
look
Medwatch
center.
cases
events
of
information
them
had
copies
labeling.
done
classified
previously
nervous
into
system,
them
new case
the
from
We clinically
19
of
professionals
to
has
and
in
of
come through
come directly
medical
a lot
come through
a third
all
amounts
come into
investigators,
50 percent
the
And
10
looking
at
we have,
how they
a third
this
approximate
and
according
tell
serious
other
to
not
as being
majority
of
adverse
series
were
four
probably
reflects
MOFFITT
the
adverse
cardiovascular,
adverse
events.
serious
or
unclear.
a bias
in
in
We
cases
The
events
serious
events
that
adverse
reporting
REPORTING ASSOCIATES
(301)
390-5150
we saw
events.
more
in
ct
1
serious
adverse
2
events
Cardiovascular
3
myocardial
infarction,
4
and
hypertension.
5
slide
6
the
7
events
8
supporting
severe
that
total
data
And
in
showing
the
slide,
what
I'm
calling
the
both
groups
would
attribution;
to
The
serious
reported
as an adverse
that
or
had
insufficient
system
effects
included
and
addiction
assess.
nervous
depression,
adverse
attributable
group
further
first
between
be attributable
the
be able
the
differences
cardiovascular
included
dysrhythmias
this
serious
i
events
stroke,
for
psychoses,
event
and
was
seen
was
also
across
all
of
groups.
Other
serious
cardiovascular
or
gastritis,
18
adverse
ischemia,
seizure,
these
serious.
group
and
to
less
system
I am just
supporting
16
than
nervous
hepatitis,
nephrogenic
factors
could
things
products
for
23
could
24
for
25
bodybuilding
evaluated
impact
on the
we noticed
is
different
loss
system
that
included
weren't
neuropathies,
and
a case
of
insipidus.
be expected,
weight
events
rebnomyallises,
diabetes
We also
first
adverse
whether
certain
product
adverse
event.
One of
that
reported
but
and
the
men and women
uses.
many more
men use
of
it
And
the
for
fitness
REPORTING ASSOCIATES
(301)
390-5150
the
the
I think
women use
purposes.
MOFFITT
use
use
this
it
ct
53
However,
1
2
of
3
a different
4
many
5
mean you
adverse
when
events
by gender
pattern
more
you
based
6
more
And
if
you
serious
adverse
a
looking
at
the
weight
9
similar
to
what
you
10
cardiovascular
11
involved.
12
high
proportion
13
It
loss
see
in
fitness
possibly
15
on a cardiovascular
adverse
16
least
of
17
events
reports
that
were
In
ia
associated
19
information,
20
cases,
looked
21
on the
product
22
contained
information
23
including
the
24
of
25
Many
them
we in
at
stated
the
the
but
it's
in
have
in
of
a very
facts.
exercise
besides
also
impacted
that
we had
at
label
and
labeling,
exercise.
all
of
and
supporting
that
and
use
the
was
all
the
of
other
available
these
product
durations.
precautionary
consumers
at
adverse
strenuous
interminable
or
at
very
cardiovascular
and
in
the
you
in
frequency
have
by use,
really
that
events
looking
that
whereas
looking
group
on how to
you
this,
this
information
MOFFITT
women
type
the
actions
In
events.
group
with
warnings
there's
predominantly
all
dose
contained
is
serious
to
that
men,
women,
with
addition
note
adverse
strenuous
14
seven
the
system
that
involved
in
what
nervous
appeared
being
in
classification
events,
category
is
the
the
subset
just
system
of
also
system
further
events
But
you
adverse
nervous
7
at
on gender.
cardiovascular
have
look
Almost
all
statements.
should
REPORTING ASSOCIATES
(301)
390-5150
take
in
ct
54
1
the
event
2
ingredient
3
these
4
them.
of
an adverse
products.
had
could
of
evaluate
a
related
9
a very
and
proportion
of
that
11
contributed
to
12
containing
the
from
15
the
16
dechallenge.
17
was
And
product
In
of
19
the
20
these
consumers
21
other
medications
22
a dietary
23
alkaloids.
of
the
in
looked
are
at
where
we
temporally
a criteria,
there
is
event
of
of
stimulants
subset
them
them
was
the
adverse
of
and
in
health-care
caused
or
ephedrine
at
alkaloid
at
supplement
health
MOFFITT
for
weight
consumers
indicating
loss
improve
when
positive
proportion
of
them
there
rechallenge.
other
you
used
were
the
smaller
positive
event,
underlying
these
all
much
Furthermore,
of
majority
course,
discontinued
Looking
24
of
of
almost
was
evidence
18
of
use
The majority
purposes.
in
adverse
the
multi-
products.
13
14
were
we specifically
all
was,
attribution
all
sources
association
that
10
25
other
that
that;
because
high
and
I said
likelihood
and
The overwhelming
caffeine
Again
the
event,
alternative
know,
other
the
a very
dietary
same time
product
many
explanations
high
containing
of
conditions.
them
proportion
supplements
that
for
of
and
they
were
using
ephedrine
had
certain
However,
REPORTING ASSOCIATES
(301)
390-5150
it
types
was
the
55
1
opinion
2
factors,
3
medication
use
4
not
a more
likely
5
And
the
6
alkaloids
7
contributed
of
the
11
extension
12
we had
the
concerning
the
previous
rate
to
of
and
alkaloids
and,
consumers
are
FDA believes
and
use
23
alkaloids
24
concern,
25
along
of
dietary
continues
in
to
in
evaluations
known
of
ephedrine
public
a listening
and
if
products.
containing
be a serious
FDA
These
be anticipated
current
of
MOFFITT
actions
that
all
our
the
these
here
current
and
events.
from
again
agreement.
alkaloids,
be using
we are
And
literature
the
the
likely
scientific
should
but
with
the
adverse
supplements
the
were
was
or
cases.
activity.
pharmacological
to
these
summarize,
be predicted
going
caused
consistent
ephedrine
therefore,
event.
whether
there
the
from
can
physiological
where
with
effects
events
all
and/or
briefly
information
adverse
have
we evaluated
were
was
ephedrine
in
pharmacological
consistent
adverse
to
alkaloids
high
condition
the
event
other
other
containing
symptoms
their
a very
are
of
adverse
ephedrine
these
health
clinically
finally,
So just
data
underlying
thought
and
of
13
the
that
supplements
supplements
signs
of
dietary
explanation
to
observed
reviewers
of
or
And,
effects
18
usr
were
10
16
clinical
dietary
8
9
the
availability
ephedrine
health
mode.
presentations
REPORTING ASSOCIATES
(301)
390-5150
All
at
ct
56
1
public
meetings
2
any
information
3
our
evaluation
hoping
we have
that
and
we hear
been
could
very
open
in
be available
assessment
some today,
of
to
safety.
thank
soliciting
impact
on
And we're
you.
[Applause.]
DR.
7
guests,
this
8
adverse
event
9
dietary
supplements.
10
11
Jones,
I will
reports
present
for
JONES:
F the
I'm
sorry?
13
DR.
JONES:
Give
your
record,
for
Risk
I'm
and
Julie,
of
containing
please
recorded
BIETZ:
with
name
--
just
for
the
record.
Oh,
certainly.
FDA CEDER,
My name
Office
of
is
Julie
Postmarketing
Drug
Assessment.
18
I will
19
events
20
postmarketing
21
and
22
available
23
1200.
the
24
25
the
DR.
17
alkaloid
record,
BIETZ:
Bietz,
members
an analysis
ephedrine
DR.
16
panel
yourself.
15
.
morning
DR.
identify
Dr.
12
14
"
BIETZ:
that
present
were
conducted
drug
complete
for
risk
review
public
for
review;
MOFFITT
of
by CEDER's
assessments
document
inspection
CFSAN provided
materials
an analysis
our
adverse
office
this
that
under
office
event
the
past
adverse
of
February
we prepared
Docket
with
reports
the
No.
is
OON
following
that
were
REPORTING ASSOCIATES
(301)
390-5150
k
ct
57
received
by CFSAN on 139
through
March
extensive
information
was made available
tabulations
8
received
9
tabulations
10
only
11
139
from
cases
18
use
attributed
to
possible
to
There
not
several
could
event.
In
ascertain
six
were
be identified.
was
35 years
with
age
a range
for
the
by the
may have
cases
it
reports
was
of
cases
disease,
named
This
MOFFITT
that
left
of
of
and
but
these
six
had
been
that
were
in
two
reports
consumer
cases.
108
days
not
events
no unique
108
focus
Thirty-one
confounded
Three
by an underlying
individuals
will
review
consumer
but
above-mentioned
an EADS product
evaluable.
The median
24
information,
cases.
nine
whether
they
These
presentation
were
products
that
1999.
139
other
summary
reports.
further
11 cases
the
were
the
review.
us with
The
the
of
from
of
readily
confounded
of
our
reports
these
additional
this
for
November
among
review
concurrent
were
25
remainder
reasons:
used.
23
The
excluded
following
us
information.
included
were
obtain
some demographic
are
clinical
to
1997
CFSAN conducted
and
event
through
clinical
12
cases,
adverse
included
cases
to
these
of
heard
CFSAN provided
1,176
1990
limited
on the
of
addition,
of
June
investigations
on many
In
from
As you've
information
7
16
1999.
follow-up
6
13
of
cases
remaining
to
cases
67 years.
REPORTING ASSOCIATES
(301)
390-5150
t
58
More
cases
involved
involved
the
system.
There
room
visits
were
8
that
sources.
Most
product
108
reports,
EADS dose
products
the
that
events.
16
with
a range
women
18
than
in
occurred
cases
the
range
23
two-thirds
24
reported
25
death,
the
report
one
In
30 cases
or
use
of
does
reduction.
from
cases
to
the
and
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Both
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REPORTING ASSOCIATES
(301)
390-5150
in
Seventeen
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contributed
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MOFFITT
for
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41 central
REPORTING ASSOCIATES
(301)
390-5150
nervous
to
ct
60
1
system
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effects
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51 years.
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ASSOCIATES
390-5150
an in-
nervous
for
system
ct
61
1
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events
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risk
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JONES:
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DR.
RICAURTE:
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George
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REPORTING ASSOCIATES
(301)
390-5150
of
the
My name
of
is
ct
62
1
neurology
at
2
Medicine
where
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the
4
laboratory
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Bayview
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I direct
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the
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and
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clinics
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Health
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Dr.
of
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disorders
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four
School
on neurotoxicology.
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10
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as the
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REPORTING ASSOCIATES
(301)
390-5150
also
ct
63
1
Structurally
is
best
Other
and
characterized
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and
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agitation,
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increased
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REPORTING ASSOCIATES
(301)
390-5150
a
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MOFFITT
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ephedrine
as a sympathomimetic
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that
pharmacologically
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64
1
myocardial
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anorexia.
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Finally,
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REPORTING ASSOCIATES
(301)
390-5150
of
for
ephedra.
a history
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65
1
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REPORTING ASSOCIATES
(301)
390-5150
the
more
CNS
ct
66
1
neuro
injury
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As indicated
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MOFFITT
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methamphetamine
9
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neurotoxicity.
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REPORTING ASSOCIATES
(301)
390-5150
colleagues
subjective
and
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67
1
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methamphetamine.
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was published
16
25
to
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ephedrine
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24
of
bring
REPORTING ASSOCIATES
(301)
390-5150
ephedrine
to
your
and
ct
68
1
attention
today
2
compounds
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Parkinson's
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ephedrine
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methamphetamine.
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presenting
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24
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slide
methamphetamine
MOFFITT
summarize
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REPORTING ASSOCIATES
(301)
390-5150
of
of
to
ct
69
1
damage
brain
dopamine
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dopamine
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with
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13
is
highly
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14
noradonergic,
15
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other
neurons
16
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17
affected
since
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of
effect
of
does
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cholinergic
in
methamphetamine
involve
neurons,
gabaergic
analyzed.
With
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neurons
neurons,
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which
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some species.
The next
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19
data
20
in
21
studies
22
methamphetamine
23
up to
2 milligrams
per
24
given
systemically
at
25
doses
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The
slides
on methamphetamine
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The
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Notably
18
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summary
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In
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given
ranging
given.
depict
various
from
animals
In
doses
These
these
per
doses
intervals,
were
ity
of
. 5 milligrams
kilogram.
two-hour
neurotoxic
then
REPORTING ASSOCIATES
(301)
390-5150
kilogram
were
a total
allowed
four
a two-
ct
70
1
week
drug-free
2
long-term
3
to
period
toxic
acute
so that
effects
of
pharmacological
4
after
number
postmortem
6
specifically
7
dopa,
a
with
9
monoamine
transporter
10
attriated
dyhydrotetabenazine.
11
these
12
see
13
that
14
axonal
15
the
16
that
dopamine
in
there
axonal
the
is
baboons
before
that's
we tested
17
you
in
19
laboratories
20
strongly
21
potential
22
shown
23
destruction
24
dopamine
25
markers.
to
that
schematically
in
the
even
MOFFITT
the
can
see
each
of
are
can
is
these
axons
And
in
lowest
an as
dose
that
I will
we and
collectively
other
which
effects.
data
terminals
--
as you
you
that
methamphetamine
here.
various
of
in
chemical,
dopamine
these
a dihydro
by methamphetamine
anatomic
damage
of
what
labeled
vesicular
we measured,
significant
collected,
indicates
the
with
you,
the
the
have
and
reduction
produced
a second,
here
Notably,
Collectively
18
transporter
produced
striatum.
a
animals;
Regardless
a dose-related
markers
these
labeled
markers
data
we measured
dopamine,
Win35428
here
drug.
we measured
dopamine
called
as opposed
the
from
tissue,
as the
a compound
here
tissue
striatae
as well
of
treatment
5
measure
methamphetamine
effects
Two weeks
using
we might
it
that
has
and
is
leads
dopaminergic
REPORTING ASSOCIATES
(301)
390-5150
other
data
the
axon
that
show
terminal
damage
to
loss
axonal
is
or
of
71
The
detected
3
are
4
studies
5
showed
the
toxicity
with
imaging
results
of
two
carried
out
in
you
6
the
In
7
for
a
important
9
middle,
because
11
quantitative
12
using
13
transporter
14
the
15
right,
16
the
17
profound
18
of
the
you
can
of
carbon
23
emits
24
positron
25
elegant
these
please
and
I think
are
the
11 labeled
positrons
studies
thus
MOFFITT
shown
is
top,
the
middle
and
we are
that
now
dopamine
on the
shown
what
left,
on the
you
there
in
on the
of
saw with
is
the
a
striatum
top
panel.
about
this
panel
is
carried
out
with
a study
As you
permits
tomographic
allow
but
animal.
Win35428.
that
the
transporters
results
me here
a postmortem
label
is,
interesting
and
emission
that
focus
with
just
the
where
is
treated
Now,
I
complicated
study
animal
dopamine
that
on the
essentially
And
imaging
panels,
focus
animal
see
bear
three
treated
data.
loss
19
22
--
to
here
from.
represents
when
control
of
a somewhat
are
methamphetamine
that
is
simply
label
chemical
21
after
autoradiographic
and
important
data
Just
The middle
methamphetamine
20
types
be
Shown
same baboons
this
bottom.
tritiated
the
the
can
as well.
different
There
an the
top.
techniques
words,
slide.
the
methamphetamine
neurochemical
other
a minute
10
of
for
the
What's
may know
carbon
execution
of
studies.
These
direct
visualization
REPORTING ASSOCIATES
(301)
390-5150
11
are
of
ct
72
1
dopamine
terminals
2
DR.
3
seconds.
4
conclusion.
JONES:
So if
5
you
the
levels
Dr.
Ricaurte,
would
simply
here
7
of
8
postmortem
9
PET imaging,
is
dopamine
that
during
10
human
11
and
to
12
see
that
13
methamphetamine
14
transporters.
we've
methamphetamine
patients
the
15
What
directly
17
with
that
18
some
studies
19
given
20
for
21
simply
22
produces
23
and
does
compare
of
24
you
a loss
to
is
of
that
them
loss
dopamine
to
of
do with
controls,
you
can
to
dopamine
of
done
monkeys
to
To
ephedrine
recently
And what
like
of
ephedra?
ephedrine
ephedrine
with
and
where
potency.
loss
a study
potential
of
shows
exposed
we have
doses
see
are
accommodate
this
slide
methamphetamine
transporters
--
of
dopamine
transporters.
In
discussed
have
you
in
disease
of
30
and
information
compared
monkeys,
and
animal
conducted
neurotoxic
higher
a summary
previously
this
squirrel
difference
dopamine
is
about
And what
that
evidence
the
in
shows
done
methamphetamine,
fivefold
the
with
subjects
shows
have
confirmed
Parkinson's
human
you
this
is
users,
with
striatum.
good.
life
Armed
the
towards
that
studies.
16
Very
transporters
what
of
move
DR. RICAURTE:
6
25
at
the
summary,
what
cardiovascular
MOFFITT
I've
and
covered
today
neuropsychiatric
REPORTING ASSOCIATES
(301)
390-5150
are,
I've
ct
73
1
complications
of
2
abuse
3
discussed
4
limitations
of
5
limitations
that
6
But
7
highlight
for
you
the
8
ephedrine
has
for
dopamine
9
you.
DR.
JONES:
liability,
the
would
12
into
I've
the
time,
invite
the
13
for
neurotoxicity.
are
presenting
to
record.
in
our
today
neurons
you,
the
full
We would
in
Dr.
is
studies.
to
simply
that
the
brain.
R.icaurte.
text
welcome
the
animal
potential
Thank
put
also
some of
them
neurotoxic
I've
Due to
address
I recognize
you
and
their
of
full
Thank
We
your
remarks
text.
[Applause.]
14
DR. RICAURTE:
record
of
16
DR.
JONES:
17
Dr.
Woosley.
18
DR. WOOLSEY:
15
upon,
I cannot
for
products,
touched
potential
reason
10
11
ephedrine-containing
complete
19
committee,
20
Woosley,
21
Georgetown
22
pharmacology
23
pharmacology.
24
board
25
president
and
I will.
the
written
Very
of
University
Pharmacology
department.
I am also
certified
of
clinical
the
MOFFITT
of
a Ph.D.
certified
Society
for
at
the
in
internist
pharmacologist,
American
Raymond
Medicine
I am chair
board
you.
the
here,
and
I have
a
you.
members
as shown
submit
thank
thank
Jones,
I am,
where
then
remarks,
good,
Dr.
guests,
Professor
I will
and
Clinical
REPORTING ASSOCIATES
(301)
390-5150
currently
and
ct
74
1
Pharmacology
and
2
Therapeutics.
I am a consultant
for
3
government
employee,
working
4
few
years,
but
I appear
5
for
presenting
6
today
to
you
I have
this
products
i nvolved
and
8
objective
analysis
of
9
to
a year
10
12
also
13
came to
the
same results.
14
watched
the
other
15
is
16
it's
17
approaches
18
my approach
based
19
however
want
Neil
20
pharmacologist
22
factors
in
23
trying
24
variability.
25
studying,
to
any
other
I can
give
you
that
were
are
an
presented
take.
on the
look
to
those
Often
unfortunately,
MOFFITT
ago
drug
very
the
different
today
give
background
but
studying
or
the
response
which
drug
variable
of
would
action,
toxicity.
REPORTING ASSOCIATES
(301)
390-5150
drugs
explain
many
you
biases
my experiences.
the
it
complex
as a clinical
factors
studying
were
I will
them;
began
contributed
identify
at
I have
same cases,
between
following
and
as
those
that
And
those
analysis
though,
of
cases
of
pharmacologist
a similar
differences
people
to
my opinion
a clinical
140
25 years
that
volunteer
to
I think
My experience
21
you
presentations
there
you
last
today.
cases
performed
that
that
that
140
Benowitz,
co llleague
always
the
as an unpaid
ties
be giving
cases.
interesting
hope
a special
CFSAN for
information
the
11
and
FDA,
so ago.
I will
Dr.
with
no financial
7
me about
the
times
ct
75
1
2
suppression
3
1988.
It
lives,
but
the
I was
co-director
trial.
This
was
the
the
was
study
study
of
was
antiarrhythmic
taking
of
And
cardiac
a trial
that
drugs
began
ended
to
study
ia
in
save
prematurely
under
that
arrhythm
intended
stopped
drugs
lives.
the
because
actually
were
my interest
in
cardiac
toxicity.
It
of
was heightened
seldane-induced
10
series
studies
11
FDA to
study
rare
in
cardiac
1995,
14
products
15
cages
16
heavily
17
drugs
18
actions
19
drugs
cardiac
arrest
with
funding
from
factors
responsible
complication.
So in
had
been
reported
to
I have
more
recently
reviewed,
of
over
this
period
So I guess
21
the
medwatch
22
we often
23
it.
24
looking
25
pharmacology
reports
knew
And
at
in
the
the
of
in
some of
this
the
case,
it
been
MOFFITT
known
fairly
actually
ephedrine
FDA,
and
it
the
the
140
was
the
other
cases
cardiac
cardiac
classes
of
we were
prescription
pharmacology,
pharmacology
has
many
the
of
time.
those
often
and
a
and
--
with
trials
and
NIH
that
of
by my experiences
antihistamines
began
reviewing
reports
antiarrhythmic
and
for
that
the
medwatch
I saw a case
the
of
influenced
20
when
95 cases
that
in
1990
sudden
often
the
in
is
or
for
very
cases
looking
drugs
but
not
different.
where
centuries.
REPORTING ASSOCIATES
(301)
390-5150
at
where
all
of
We are
the
And we are
ct
76
1
looking
2
prescription
3
people
4
different
at
the
come at
said
7
of
8
reported
9
of
is
with
use
the
I used
I went
one
to
five.
is
the
through
a different
following
scoring
five
cases
sympathomimetic
amines,
resolution
related
the
to
report
of
the
discontinuation
information
necessary,
15
contained
the
information
necessary
16
evaluation
of
17
So that
would
18
similar
to
19
temporally
20
dechallenge
21
reasonable
the
related,
or
some of
So it
included
of
or
the
the
it
the
with
five,
the
report
a reasonable
likely
causes.
would
be very
expected,
report
it
may have
information
was
lacked
necessary
for
a
amount
of
evaluation.
22
25
for
generally
but
consequence
product
and
other
reactions
reaction
of
the
excluding
a score
a score
with
and
the
I
as ephedrine,
associated
contained
get
the
a dechallenge
product,
causation
when
them
administration
included
the
system.
gave
such
14
said
and
and
as a medical
the
symptoms
of
and
was used
accepted
or
24
usual
situation
backgrounds
generally
product
evidence
its
different
the
And
temporally
23
than
approaches.
--
was
a different
So it
this
But
6
in
use.
5
10
drug
that
earlier,
was
was
a slight
available
unlike
intensive
the
in
reports
evaluation,
MOFFITT
reduction
the
in
report.
in
1995,
affidavits
REPORTING ASSOCIATES
(301)
390-5150
the
And
these
from
as was
ct
77
witnesses,
family
people
injured
members,
in
the
A score
accepted
great
evaluation
8
causes
9
one,
10
one
to
causation.
13
patients
14
reports
15
fluids
16
reports.
there
report
and
their
which
in
17
by many
of
19
and
20
this
already.
21
that
in
22
take
into
23
pharmacology
24
structural
25
amphetamine
I will
too
the
report.
go quickly
analyzing
account
of
shown
it
MOFFITT
of
I was
you
is
reports
that
cases
to
of
by view
the
biological
and
postmortem
heavily
influenced
already
because
have
learned
seen,
you've
to
to
--
And
I had
to
the
the
and
difference
REPORTING ASSOCIATES
(301)
390-5150
seen
repeat
about
ephedrine
simple
other
chemistry
the
have
a
allow
of
amines.
the
or
a score
important
you
I had
between
here;
complete
analytical
these
sympathomimetic
similarities
is
that
I think
all
for
affidavits
this,
through
these
lacked
assessed
products
structures
there
And
was
available
doing
But
or
generally
incomplete
my case
ephedrine-containing
the
it.
members,
often
was
other
records,
family
in
been
just
in
medical
were
Well,
18
was
causation
the
it
but
explained
assess
of
victims
necessary
may have
have
reasonably
copies
that
information
might
And
was
consequence,
of
the
11
of
three
the
that
that
12
of
of
Two,
sometimes
report.
as a medical
deal
and
of
a
ct
78
1
methyl
group
2
and
group
Methamphetamine
ago.
The very
that
was
similar
It's
similar
but
isomer
that
is
is
11
thing
12
sensitivities,
13
course
they
14
because
it
15
phenelylamine
16
alpha
17
nervous
18
like
19
vessels
all
at
the
were
is
backbone
the
20
heart
22
increase
23
have
24
the
25
reports
And
there
have
which
medical
Well,
these
blood
vessels,
cardiac
work
and
been
looked
centuries,
those
at
and
stimulant
has
it
the
to
of
same
of
does
same
interact
the
with
sympathetic
on the
constrict
amines
increase
and
more
sympathomimetic
MOFFITT
all
market
blood
use.
when
will
blood
any
including,
in
at
And
often
products
can
an
a different
do the
sorry.
stimulate
are
pick
different
allows
and
phenylephrine
and
can
which
which
receptors
to
looking
as adrenaline
a catecholamine
beta
from
and
very
curve.
potencies,
acting
of
but
compounds
doses
fact
chemically
response
I got
these
different
system.
21
that
of
the
stereochemistry
dose
different
and
is
same properties
all
a second
a metabolite
has
that
but
also
the
The message
this
about
structure,
pseudoephedrine
a different
10
talked
by changing
sensitivity,
9
here.
chemical
phenylpropanolamine
ephedrine.
8
hydroxyl
of
pressure,
these
ephedrine
recent
years
amines
affect
are
REPORTING ASSOCIATES
(301)
390-5150
and
compounds
carefully
in
the
over
clinical
known
to
be
ct
79
associated
sudden
with
stroke,
heart
attack,
arrhythmias
I and
death.
3
So this
4
analyzing
the
5
104
cases
of
6
find
that
the
7
here,
8
very
9
by or
was
under
the
there
that
fives
associated
shown
that
with
the
11
Arrhythmia
such
12
tachycardia,
13
awareness,
syncope,
dizziness,
14
myocardial
infarction
were
15
effects
16
amine
Three
that
you
given
17
to
for
would
the
this
and
21
cases
22
to
23
personality
change
one
24
that
I gave
a score
of
25
four
was
to
cases
of
given
four
MOFFITT
any
of
that
the
was
caused
and
are
would
the
cause
I reviewed
frequent
cases
here.
and
REPORTING ASSOCIATES
(301)
390-5150
anxiety
the
a score
occurred
24 cases,
be
lower
and
five,
the
people.
to
I gave
most
cardiac
sympathomimetic
affect
tremors
of
and
These
psychoses
--
seizures,
to
with
And when
five
was
pain,
compounds
cause
there
as a four.
seen.
expect
CNS symptoms.
that
all
of
20
threshold,
chest
class
seizure
death
arrhythmias
stimulate
19
ten
that
ventricular
brain
expected
I found
I felt
rated
population
18
other
shown
an ephedrine-
were
to
a large
And
are
as atrofibulation,
palpitations
the
fours
of
product.
at
the
use
as
look
you
sudden
containing
you
in
five
the
10
fact
four
here,
that
that
if
scored
cases
evidence
I used
And
I've
are
seven
and
cases.
140
140
were
strong
known,
in
140
of
five
seven,
reports
a score
of
ct
80
1
Severely
2
given
3
felt
4
the
a five,
were
use
and
of
of
9
what
to
but
that
drugs
are
earlier
almost
11
drug
dosage
12
the
labeling.
13
And
I think
14
terfenadine
15
receptor
diversity.
16
channels
in
17
change
18
sensitivity
19
polymorphism
20
responsible
21
to
--
over
for
and
of
one
for
kind
so,
receptor
diversity
24
existed,
beta
25
explain
the
heart,
acid
was
the
result
I
of
that
that
in
the
And
that
or
can
fact
all
Fong
and
the
as recommended
all
of
there
are
that
on
this.
learned
there
with
is
ion
a simple
protein
can
mutation
response
dosage
a factor.
drugs
that
an ion
these
in
we've
is
caused
as Harry
explain
example,
a receptor
that
not
are
now,
for
alter
or
channel
the
that
can
be
supersensitivity
drug.
I believe
23
was
"drugs11
things
an untoward
of
cases,
the
can't
a drug.
in
all
We know
amino
to
clearly
these
drugs
strokes
which
I think
compounds
and many
the
factors
over,
the
were
product.
I said
So dosage
six
probably
dosage
and
these
one
22
12 severe
the
occur?
in
were
said
this
pressure,
and
I reviewed,
10
of
were
associated
events
cases
These
blood
an ephedrine-containing
be involved,
the
there
clearly
Well,
kinds
increased
that
and
the
receptors
exaggerated
MOFFITT
and
what
we know
receptor
ion
REPORTING
(301)
polymorphism
channels
cardiovascular
are
response
ASSOCIATES
390-5150
about
the
that
enough
that
to
81
are
occurring
in
At
these
is
5
responsible
6
tolerate
7
occasional
this
and
for
this
person
Why is
10
that
are
11
drug,
12
therapeutic
13
products
14
can
15
supersensitive
never
have
ephedrine
index
with
more
said
of
only
for
18
seizures,
19
effects
20
giving
healthy
some
sudden
in
and
21
22
effective
23
because
24
she
25
until
is
in
the
people,
use
in
and
effective
has
moved
and
attack.
medicine
drugs
past
a two
of
cause
is
20 which
there
heart
less
serious
or
the
today.
although
individuals,
other
in
stroke,
other
a
many
reactions
out
a
--
10 and
ephedrine,
causes
death,
the
warning
preventing
the
individuals
susceptible
they
that
heart
an
safe
attack,
adverse
a normal
people
dosages.
think
I
not
can
but
We now have
that
susceptible
excessive
or
tendencies
clinically
people
problem,
only
two.
therapeutic
So I conclude
17
safe
earlier,
population
16
in
And medicine
Fong
some
a stroke
It
is
where
any
take
reaction.
I believe
not
are
available.
be used
that
without
will
can
a serious
disconnect,
there
as Harry
individuals
have
products
Well,
many
diversity
these
today?
individuals.
same time
receptor
8
9
the
compounds
4
many
take
their
MOPFITT
the
first
will
harmful
often
to
labels
effect
do not
adverse
few
not
know
effects
doses.
of
ephedrine
that
he or
of
And
REPORTING ASSOCIATES
(301)
390-5150
be
ephedrine
for
me
ct
82
1
there
2
used
3
nutritional
4
standards
5
effects,
adverse
6
people.
So to
7
unacceptable.
is
no acceptably
as a dietary
even
evidence
to
value
offset
effects,
me the
ephedrine
using
its
expected
risk
it
benefit
has
no proven
current
known
to
when
harmful
occur
ratio
in
is
some
just
you.
[Applause.]
9
MS.
10
employed
11
here
12
Officials
13
meeting.
by
CULMO:
the
today
Texas
who has
In
to
My name
of
paid
light
speak
the
for
of
the
1%
impressive
credentials,
but
19
unsolicited
long-term
on-the-job
20
experience
of
Food
23
I am pleased
24
Drug
issue.
a state's
I don't
now
category
you
offer
AFDO is
represents
present
Officials,
to
MOFFITT
to
comments
state,
and
a lot
I'm
plenty
of
a the
knowledge
and
products.
a background
herein
in
this
regulatory
have
I have
of
a 104-year-old
federal,
expenses
Drug
through
on this
22
Food
get
to
give
of
I am
so I should
perspective
I'll
but
my nervousness,
17
21
Health,
I am
and
of
this
Culmo.
time,
16
with
of
my travel
going
I am here
Cynthia
Association
15
time.
fast
is
Department
on behalf
14
25
of
because,
medical
Thank
8
dosage
supplement,
or
of
safe
on the
referred
on this
to
Association
as AFDO,
important
organization
local
government,
REPORTING ASSOCIATES
(301)
390-5150
and
issue.
that
ct
83
regulatory
officials,
2
whom are
3
dietary
4
and
Drug
5
for
achieving
6
supplements.
and
involved
in
food
supplements.
more
9
consistently,
specifically
through
placed
11
provision
of
12
the
13
supplements.
adequate
consumers
14
15
often
equated
16
concentrated
17
physiological
18
in
19
foods
added
extracts
of
and
the
20
risk
specific
22
those
23
related
24
and
25
dietary
good
dosage.
to
that
This
particularly
is
educate
dietary
is
contained
affects
that
profound
result
conventional
fast
purity
tracking
of
particularly
critical
of
safety
the
important
supplements.
MOFFITT
and
botanical.
address
and
of
have
practices,
consistency
written
help
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to
We had
supplements
many
support
manufacturing
requirements
to
compared
and
safety
to
use
botanicals
unextracted
AFDO continues
numerous
foods,
when
whole
in
dietary
and pharmacological
health
these
on product
of
conventional
of
docket.
appropriate
safety
strategies
this
and
Food
dietary
information
and
the
to
of
priority
label
on safe
Although
issues
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on
the
develop
on a few
testimony
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focusing
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comment
on the
comments,
to
regulation
to
Many
supports
desire
effective
10
efforts
AFDO strongly
AFDO wishes
8
associates.
safety
Administration's
7
21
industry
REPORTING ASSOCIATES
(301)
390-5150
areas
ingredients
for
all
ct
84
1
On several
2
concern
regarding
3
information
4
regarding
5
product
interactions,
6
has
been
7
historical
8
people.
deficiencies
for
safe
9
The
12
of
13
weight
14
physiologic
15
alkaloids,
16
other
use;
in
traditional
the
information
drug
restrictions
for
by clinical
addresses
containing
medical
use
products
as dietary
loss
and
exercise
and
pharmacological
including
safety
ephedrine
of
these
the
labeled
and
actions
in
of
products,
enhancement,
use
as young
alkaloids.
supplements
their
safety
or
such
the
or
which
studies
preparations
docket
its
labeling
problematic
at-risk
supplements
expressed
the
including
established
Today's
11
and
and
uses
dietary
AFDO has
contraindications,
not
10
occasions
the
of
use
for
known
ephedrine
combination
with
stimulants.
17
The
18
questions
19
additional
20
public
21
first
22
questions
23
actions
24
heard
25
actions
following
posed
for
this
AERs and
by the
of
the
-the
previous
include
and
are
speakers
bronchial
MOFiITT
with
that
going
expected
dilation
specific
to
was made
In
regards
to
read
to
the
the
physiological
well-documented,
allude
the
regard
spring.
I am not
known
ephedrine
to
information
past
and
responses
forum
the
FDA this
question
--
are
as you
to.
and
have
The beneficia
decongestant
REPORTING ASSOCIATES
(301)
390-5150
1
85
effects.
Another
2
and
3
suppression
overweight
or
and
4
also
6
including
7
serious
8
blood
9
seizures,
expected
action
obese
persons
adverse
and
adverse
known
for
pressure,
events
12
and
13
reports
14
events
15
clearly
16
supplements
17
adverse
is
psychosis
in
states.
Since
are
other
included
each
of
types
attacks,
these
adverse
AERs,
reported
to
the
all
the
products
in
the
and
since
with
all
ephedrine
association
between
containing
ephedrine
the
use
of
alkaloids
FDA
adverse
toxicity,
the
of
elevated
heart
death.
are
stimulant
and
and
the
ephedrine
consistent
and
potent
have
surprisingly,
contain
loss
appetite
actions
arrhythmias,
represented
several
this
that
cardiac
stroke,
11
to
neurologic
events
Not
due
be weight
physiological
cardiovascular
10
might
thermogenesis.
Serious
5
there
is
dietary
and
the
events.
And
18
19
reported
20
over
21
ephedrine-containing
22
recommended,
23
the
just
by FDA in
90 percent
of
or
Not
as well
as in
the
1997,
this
new series
injured
consumers
the
dietary
manufacturer
24
25
positive
to
at
lesser
first
supplement
amounts,
on the
labeling.
go over
each
as CFSAN and
MOFFITT
serious
of
CEDER there
of
AERs
documents
took
the
products
than
that
as
as directed
the
external
was
an evaluation
REPORTING ASSOCIATES
(301)
390-5150
reviewers
by
ct
86
performed
by mention
mispronounce
3
a PharmD
4
and
5
possibly
6
containing
names
within
Center
if
the
use
Drug
the
of
I
Claudia
for
who describe
division
conservative
Kowalski,
Evaluation
adverse
ephedrine
reactions
11
clinical
12
effectiveness,
13
adverse
14
that
15
history
16
events
from
of
events
as
alkaloid-
Drug
reference
have
in
drugs
established
It
physicians
familiar
prescribed
through
Janet
18
as follows,
and
19
most
that
20
supplements,
21
The primary
22
one,
23
between
the
24
dynamic
properties
likely
reflects
drugs
reason
two.
I'll
adverse
Additionally
MOFFITT
for
the
most
likely
expectations
patient's
report
medical
the
summarized
adverse
CEDER's
these
belief
three:
events
and
ephedrine
although
--
'Ithe
the
it
is
dietary
adverse
is"
report
believe
alkaloid-containing
causing
our
tbe
system.
quote
of
safety
"we nonetheless
ephedrine
EADSs are
well-controlled
their
and
Woodcock
I quote:
adverse
drug
and
with
the
its
evaluating
the
a well-established
Dr.
17
also
Evaluations'
where
contraindications,
effects.
Risk
may reflect
prescription
trials
and
of
evaluation
frame
10
25
FDA's
to
CEDER's
traditional
I apologize
products.
7
9
and
an RPH and MS,
CEDER,
related
more
--
the
Research,
8
--
effects.
she
lists,
similarity
known
pharmaco
alkaloids."
many
EADes
REPORTING ASSOCIATES
(301)
390-5150
may conta
in
ct
87
other
ingredients
these
data
the
focuses
of
ephedrine
4
the
adverse
5
alkaloids
6
taken
7
of
8
constituents
on the
9
relationship
between
In
are
containing
the
adverse
adverse
fact
that
we are
with
EADes,
it
question
Supplement
Health
supplements
or
14
stricter
15
are
16
maintain
normal
17
produced
general
and
more
to
The
two,
the
same
level
other
the
causal
and
the
the
diet
and
rather
than
drugs.
to
function
And
they
affect
or
of
body
the
the
or
well-being.
central
nervous
alkaloids
20
appetite
21
increased
22
in
combination
with
caffeine,
23
of
weight
for
individuals
and
of
Dietary
dietary
as foods
supplement
structure
the
Act,
requirements
ephedrine
may play
increasing
loss
risks
produced
effects
are
associated
MOFFITT
system
a role
perceived
metabolism
These
significant
the
DSHEA,
Education
19
25
at
alkaloids
regulated
regulatory
intended
24
that
constituents,
supports
ephedrine
fact
ephedrine
other
not
presence
the
with
of
associated
the
words,
associated
of
events.
Under
18
element,
other
a variety
events
11
12
events
interpretation
common
alkaloids.
with
cogent
on the
3
10
most
stimulation
in
suppressing
energy
levels.
by ephedrine
it
on a low-calorie
with
effects,
taking
REPORTING ASSOCIATES
(301)
390-5150
An
particularly
may increase
drug
of
and
the
the
rate
diet.
there
products
are
ct
88
1
for
2
long
3
cardiovascular
4
alkaloids
had
5
function,
or
energy
or
periods
6
weight
of
time.
that
8
medicine,
9
conditions
such
10
emphysema,
and
11
diseases
12
supplements
13
cure,
14
TCM to
ephedra
is
from
for
17
taking
18
with
19
months
20
women
are
weight,
of
obese
doses
of
23
characterizing
24
use
25
bodybuilding.
for
women
of
expressed
Chinese
of
medical
congestion,
asthma,
conditions
diseases
to
or
and
are
in
is
treat,
not
fight
duration
used
have
on a low-calorie
of
diet
times
caffeine
weight
in
fatigue.
studies
three
either
dietary
diagnose,
to
ephedra,
increased
We are
22
iron,
the
structure,
Medicine
Ephedra
200 milligrams
the
of
intended
disease.
for
individuals.
treatment
dose
experienced
normal
These
pump
and
traditional
nasal
not
any
without
21
its
characteristics
that
taking
School
short-term
20 milligrams
or
the
in
Considering
demonstrated
healthy
bronchitis.
prevent
16
in
use
by ephedrine
maintaining
as cough,
and
15
in
used
TCM,
or
produced
well-being
Wei
when
The bronchodilation
no role
7
lose
particularly
stimulation
Dr.
or
loss,
a day,
for
loss
six
compared
with
placebo.
not
ephedrine
for
the
ephedrine
aware
of
weight
effective
for
The
MOFFITT
data
evaluating
loss
or
data
and
the
dose
increasing
question
addresses
REPORTING
(301)
energy
duration
of
or
efficacy
ASSOCIATES
390-5150
lower
and
not
ct
89
1
safety.
2
The
3
agricultural
4
been
5
alkaloid-containing
6
programs
7
During
8
representatives
9
in
health
concerned
with
comment
periods
of
review
11
ephedrine-containing
12
safe.
eleventh
15
passage
16
regulatory
of
any
Six
still
19
The
20
to
determine
21
manufacturers
22
ephedrine-containing
23
studies
24
the
25
subjects
short
in
hearings,
public
the
have
of
that
will
were
sometimes
been
instrumental
to
on more
have
haven't
financial
claim
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to
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the
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studies,
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delaying
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touted
the
happened?
a burden
numbers
the
trial
for
in
alone.
or
safety
clinical
dollars
products
were
occasion.
What
pose
that
safety
a large
billion
diet
show
delivered
one
and
publish
products
produced.
cost
should
that
than
to
on going,
improve
passed
been
safety
promised
results
state
concern.
supplement
restrictions
years
this
have
long
ephedrine
Both
to
studies
agencies
17
studies
and
of
and
have
FDA,
supplements.
dietary
hour
as the
testified
journals
The promises
pharmacies
aspect
industries
placebo
13
safety
dietary
AFDO have
double-blind,
as well
the
and
peer
14
departments,
departments,
10
18
states
sales
Have
of
for
the
subjects,
number
of
L
that
dropped
MOFFITT
were
eliminated
REPORTING ASSOCIATES
(301)
390-5150
due
to
ct
90
1
significant
2
were
3
individuals
side
subjects
effects?
that
to
were
be part
for
7
that
8
adverse
9
stimulant
they
clinical
appears
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10
of
of
that
even
among
the
adverse
events
and
13
ephedrine
14
assumes
that
15
ephedra
as a dietary
16
medical
benefit
17
ephedrine
18
supplements
deliberation
has
in
is
safe
The occurrence
21
supplement
22
pressure
23
unacceptable
of
and
and
heart
--
persons.
in
his
discussion
a safe
dose
value
a safe
to
lack
of
dose
taking
of
proven
containing
benefit
ratio
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in
can
in
these
events
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effects
series
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as a dietary
increase
the
susceptible
medical
adverse
side
products
they
rates
MOFFITT
-
of
dosages
without
The
series
of
of
However,
risk
ephedrine-containing
at
24
25
types
unfavorable.
19
use
deal
The
the
the
healthy
supplements
makes
extent
summarized
medical
dietary
the
sympathomimetic
identify
supplement.
alkaloids
the
for
supplements.
there
of
to
the
and
a great
sought
dietary
to
apparently
so adequately
were
studies?
known
Woosley
12
what
pattern
Dr.
review
controlled
studies,
the
and
participants
as healthy
those
the
reported
11
20
in
study,
document
agents
studies
a carefully
noncompletion
It
the
screened
of
physician-monitored,
reasons
If
blood
individuals
supervision.
reported
to
on dietary
REPORTING ASSOCIATES
(301)
390-5150
FDA in
a
supplements
91
containing
2
of
the
3
occurring
ephedrine
iceberg
4
5
Harvard
6
one
7
dietary
8
proportion
9
or
of
alkaloids,
the
number
from
these
The
evaluation
School
percent
of
of
only
of
adverse
events
by Dr.
Walker,
M.D.
the
tip
products.
Public
the
represent
Health,
serious
supplements
is
may well
concluded
adverse
reported
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to
be smaller
the
PhD of
less
than
caused
by
FDA.
The
by an order
of
true
magnitude
more.
10
In
11
31,
12
60 of
13
containing
14
ephedrine
1999,
the
20 months
FDA received
which
could
15
producing
16
disabilities
from
17
arrest,
heart
18
Walkers
estimates
19
to
20
serious,
21
events
22
alkaloids.
23
ephedrine
24
are
25
families.
or
and
from
attacks,
of
some cases,
for
MOFFITT
to
ephedrine-
supported
a role
some affected
of
events.
are
permanent
cardiac
If
correct,
Dr.
300
may be suffering
disabling
serious,
March
events;
disruption,
a month
dietary
are
to
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deaths,
rates
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from
1997,
and psychosis.
reporting
in
alkaloids
devastating
adverse
seizures
individuals
Risk
or
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included
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June
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supplements,
Adverse
3,000
140
be clearly
dietary
in
from
or
containing
fatal
adverse
ephedrine
supplements
containing
and
consequence
the
individuals
REPORTING ASSOCIATES
(301)
390-5150
and
is
their
ct
92
1
Are
2
these
3
affected
4
the
5
loss
6
significant
7
But
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outcomes
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of
products
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advisory
Food
Advisory
11
available
12
could
indicate
over
be identified
use
The growing
associated
15
ephedrine
alkaloids
16
data
lead
must
17
Mario
18
stated
19
that
20
to
21
for
in
his
these
to
the
can
are
identify
1996,
that
based
upon
dietary
an
the
the
alkaloids
supplements.
the
consistency
of
the
safety
today.
Medical
his
review,
of
importance
dose
of
containing
lack
Newark
a safe
of
FDA in
continued
in
dose.
the
ephedrine
and
from
conclusions
events.
members
same conclusion
Enchioso,
one
the
a
safe
supplements
the
relationships
whether
in
dietary
and
one
of
number
with
AERS
by
level
for
14
of
weight
propose
an expected
half
of
indicates
for
energy
concluded
no safe
use
may be
adverse
convened
Committee
data,
13
enhancing
do not
panel
Outcomes
marketed
life-threatening
addition,
the
available
currently
of
expert
with
currently
and
risk
In
10
Data
bodybuilding
these
associated
by dosage?
by dosage.
8
9
the
College
"1 believe
in
of
relation
ephedrine
supplements.
In
22
23
would
provide
24
consideration,
25
safe
dose
the
absence
some basis
it
of
would
ephedrine
MOFFITT
of
clinical
for
risk
not
indication
to
benefit
be possible
considering
that
to
user
REPORTING ASSOCIATES
(301)
390-5150
recommend
a
ct
93
1
characteristics.
2
appears
3
from
4
in
Strenuous
to
increase
dietary
both
men and
f-)
Dr.
in
our
7
Exercise
8
system
9
Ephedrine
view
11
another
12
susceptibility."
in
adverse
15
consistent
caffeine
16
ephedrine
and
17
In
18
combination
19
increased
addition,
of
it
stimulants
for
21
potentially
22
also
account
23
with
a combination
in
that
and
rate.
the
heart
the
could
the
stimulant
be
individual's
three
types
a AERs he reviewed
of
the
were
properties
for
is
well-established
has
a synergistic
adverse
Love
positive
Another
taking
nervous
which
difference
in
sympathic
augment
exercise
known
the
exercise.
of
caffeine.
As Dr.
24
alkaloids
individuals
during
pressure
concluded
the
risk
20
of
for
"several
could
reported
with
effects
ephedr ,ine
of
blood
stress
events
adverse
events
activation
increases
He also
14
25
adverse
mechanism
13
serious
of
commented,
suffered
and/or
cardiovascular
exercise
containing
Benowitz
which
moderate
women."
results
10
risk
supplements
5
6
the
to
of
noted,
it
negative
ephedrine-containing
MOFFITT
effect
could
have
with
a
on thermogenesis
increased
these
the
events.
impact
the
that
adverse
effects
that
may
seen
agents.
result
dietary
documented
supplement
REPORTING ASSOCIATES
(301)
390-5150
with
products
ct
94
1.
is
a positive
urine
2
could
3
military
4
professional
5
ephedrine-containing
screen
be particularly
Most
adverse
7
supplements
containing
8
last
of
9
states
occurred
from
months
or
of
years
11
Safety
12
limiting
use
13
adverse
events
14
identified,
15
warnings
16
because
of
17
protect
these
to
why
these
20
performance
21
easily
22
other
23
the
these
days
or
24
these
products
25
during
Texas
day
these
of
products
weeks.
occurred
in
AERs,
the
to
the
use
to
after
cannot
young
individuals
with
conditions.
individuals
or
be assured
by
Life-threatening
medical
to
at
medical
no
Label
increased
risk
conditions
would
not
individuals.
states
products
and
are
enhancers,
demonstrated
marketing
states.
dietary
AERs reported
first
of
medication
19
the
of
athletes.
from
and
use
use.
directed
The
the
being
and
advertising
An example
is
ample
consumed
for
of
of
the
of
the
labeling
consumers'
in
Health's
evidence
weight
boosters.
review
and
exemplified
Department
FDA have
energy
by FDA's
MOFFITT
-
the
preexisting
18
effects
and
the
by their
AERs and
and
collegiate,
ephedrine
the
This
athletes
now prohibit
products
Serious
for
amateur
organizations
series
amphetamines.
problematic
personnel.
6
10
for
petitions
This
is
products
received
perception
received
rule-making
REPORTING ASSOCIATES
(301)
390-5150
loss,
and
by
of
95
1
procedures
2
speed,
that
and
said
please
3
It's
4
state
5
or
6
many
7
are
expecting
8
and
finally
to
sign
states
delayed
and
act
for
Could
Chinese
speed.
an individual
on sales
products.
action
FDA to
And
because
provide
they
leadership
restrictions.
you
please
wrap
up or
get
wrap
up here.
a conclusion?
In
Okay.
conclusion,
I need
being
or
regulatory
oversight,
address
the
regulation
of
encourages
16
committee
ephedrine
of
the
There
have
present
It's
aside
25
relied
of
AFDO
advisory
external
have
dietary
illness
to
been
utilized,
supplements
significant
under
reports,
and
containing
or
conditions
unreasonable
recommended
manufacturers.
23
24
included
specialties
alkaloids
or
two
series
that
injury
products.
many
expeditiously.
been
concluded
of
I am compelled
these
act
two
medical
have
risk
FDA to
reports,
scientific
most
the
to
a representative
involved
by
for
individual
meaningful
MS. CULMO:
18
Chinese
distributed
waiting
with
the
restrictions
nationally
have
the
meaningful
DR. JONES:
to
keep
save
impossible
about
these
up today,
to
virtually
bring
labeling
sign
and
upon
time
act
to
place
responsibly
by
the
general
MOFFITT
to
politics
and
as the
public
health
public
to
protect
REPORTING ASSOCIATES
(301)
390-5150
the
money
agency
their
96
safety.
2
high
3
doing
Recent
regard
polls
by
a good
4
the
demonstrates
general
5
needless
injuries.
6
for
opportunity
7
working
8
important
with
to
all
DR.
that
and
trust
We would
held
viewed
as
is
FDA must
like
to
comment,
interested
public
9
public
FDA is
in
job.
To continue
this
that
and
issue.
JONES:
thank
Thank
the
to
you.
Ms.
Culmo.
these
USPHS
forward
address
Thank
you,
in
we look
parties
health
act
to
this
[Applause.]
DR.
members
for
couple
JONES:
staying
18
first
from
since
I have
the
panel,
the
role
since
of
the
of
women
24
and
25
you
even
that
to
if
all
panel
I needed
the
other
might
take
of
you
have
thyroid
to
the
asking
any
some say
midlife
to
condition
effects.
prod
a
first
Any
suggestions
with
compounds?
these
DR. WOOSLEY:
I think
on
as 40 percent
have
obviously
as the
of
condition
might
which
just
whatsoever
as many
later
answers
prerogative,
the
data
contribute
MOFFITT
and
as an underlying
20 --
about
questions
I will
of
thyroid
interaction
for
a microphone,
from
and
open
panel.
an estimated
cardiac
that
on time
to
do any
undiagnosed
23
thank
times.
We want
16
And
clearly
REPORTING ASSOCIATES
(301)
390-5150
can
of
underlying
the
an
the
have
role
conditions
hypothyroid
ct
97
1
individuals
2
sympathomimetic
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in
4
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140
are
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based
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11
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unaware
13
risk.
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amine
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were
in
of
I think
But
group
disease
be another
their
condition
15
these
cases
16
that
dosage
17
took
the
18
risk
factor.
that
wasn't
DR.
JONES:
20
DR.
COATES:
21
DR.
JONES:
22
state
your
24
of
25
brief
Dietary
the
are
at
hyperthyroid.
data
that
I'm
we have
aware
any
pharmacology,
illness,
I would
that
often
increased
of
there
were
is,
thyroid
Thank
Thanks
the
at
that
you.
some of
supplements
perfectly
the
could
Dr.
very
and
time
if
they
be another
Coates.
much.
record,
say
are
be at
it
also
I have
Paul,
--
would
you
the
Office
name?
DR.
23
is
on the
the
amine
For
that
who might
adjusted
19
call
people
than
group
taking
sympathomimetic
more
or
aspect
were
have
based
itself
would
these
as are
we would,
recall
hypothyroidism
that
any
for
I don't
but
we don't
that
risk
I seem to
arrhythmias
The other
14
increased
any.
complication
quantify
group.
be at
knows,
risk
other
9
to
made Lori
so,
of
known
COATES:
I'm
Supplements
at
Paul
Coates,
NIH.
I have
from
two
questions
I
questions
for
MOFFITT
Dr.
Love,
REPORTING
(301)
and
one
brief
ASSOCIATES
390-5150
question
--
ct
98
for
Dr.
Ricaurte.
Dr.
3
would
4
Luke's
5
you
6
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7
know
you
10
you
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DR.
published.
was
references
for
Calman
study
the
in
it
abstract
that
but
the
which
the
form,
St.
St.
do you
since?
I have
not
was published
heard
in
that
abstract
it's
form
been
in
FASEB
1999.
11
DR.
COATES:
12
DR.
LOVE:
The
just
recently
13
I missed
You noted
published
LOVE:
It
for
slide?
study
been
maybe
the
and
on your
Roosevelt
--
provide
study
referenced
in
to
Roosevelt
if
would
be able
8
9
Love
journal
it
was
14
DR.
were
COATES:
15
number
16
to
17
reporting
la
between
19
those
who were
using
20
loss
as opposed
to
21
primarily
be
sure
going
23
appeared
24
purposes.
25
classification
by
And
fast
system
represented,
bodybuilding
DR.
LOVE:
to
be using
An in
of
that
me.
the
that
for
our
data
the
population
events
2000.
concerned
adverse
event
occurred
among
for
the
more
men,
term?
of
bodybuilding
looking
at
were
REPORTING ASSOCIATES
(301)
390-5150
weight
products
a better
there
the
a difference
of
fitness
--
I was
primarily
want
the
whether
there
who was using
From
it
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for
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MOFFITT
then
products
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published
reports
the
study?
study,
was
event
for
Calman
before
I understood
adverse
the
Calman
that
the
22
And
the
more
course,
ct
99
1
central
2
if
you
in
some of
nervous
looked
exercise
that
at
did
you
could
see
COATES:
of
10
you
that
11
dopaminergic
12
in
13
the
tantalizing
brief
14
and
monkeys.
Can you
15
into
16
monkeys
17
had
18
human?
about
remarks
21
apologize.
22
potential
in
23
methamphetamine
24
there
you
events
what
do not
Dr.
the
remark
about
the
ephedrine
data
MOFFITT
be reflected
ended
ephedrine
bit
baboon
it
is
to
at
with
studies
more
that
on the
when
on
you
as you
compared
of
end
were
and
know,
insight
done
in
that
you
in
the
be so tantalizing
data
although
a paucity
the
Well,
to
you
same conclusion
in
the
then
me a little
to
meant
the
could
studies
I will
Ricaurte,
studies
baboon
the
mind
towards
and
give
you
I think
That
seizures
strenuous
of
humans
RICAURTE:
not
if
the
that
draw
of
of
cardiovascular
Ricaurte.
in
think
were
is
And
methamphetamine
20
also
methamphetamine
studies
DR.
the
approach
neurons
could
19
25
the
how you
but
cases
irrespective
Dr.
a tantalizing
similar
more
Particularly
for.
question
said
effects.
were
on just
provided
9
of
individuals,
was used
one
type
there
impact
DR.
ask
it
these
that
product
system
brief
the
closing
and
neurotoxic
that
of
a very
the
early
stage;
studies.
clearly
indicates
to
REPORTING ASSOCIATES
(301)
390-5150
me that
like
I
ct
methamphetamine,
2
of
3
damage
4
system.
ephedrine
ephedrine,
that
dopamine
studies.
are
lowest
the
8
neurotoxicity
neurons
9
whether
10
humans.
or
11
12
that
when
13
produce
14
orders
of
15
that's
also
questions
18
Lieberman.
19
have
21
adjustment
22
tolerance
23
more
24
would
25
we don't
of
the
ephedrine
primate
look
at
those
the
from
is
or
the
in
we are
of
SCHWETZ:
Dr.
dosage,
primates
I can
tell
doses
that
are
We don't
two
Dr.
Schwetz
and
Berne
Schwetz
from
Woosley.
develops?
MOFFITT
the
questions,
made to
And
likely
DR. WOOSLEY:
the
on the
know
if
ephedrine.
I have
receptor
what
produce
subjects
nonhuman
panel,
less
is,
to
for
normally
as yet
the
extrapolates
case
for
with
monkeys
by some humans.
the
nervous
know
used
JONES:
to
central
that
isomer
We don't
issues
toxicity
minus
brain.
methamphetamine
you
in
the
potential
know
the
that
have
What
the
where
With
a question
likely
that's
is
primate
data
DR.
20
the
the
DR.
17
in
not
the
16
has
that
doses
in
this
ephedrine
I think
current
--
to
How much
account
are
for
these
more
then
the
of
polymorphism?
It
is
an excellent
REPORTING ASSOCIATES
(301)
390-5150
FDA.
I
an
the
adjustments
be made by people
to
Dr.
who
question
and