Download Nixon, Haqpave, Devans 23~ Doyle Attorneys

Nixon, Haqpave,
AOCHESTER,NEW
,718,
YORK
14‘303
546-8000
CA8LE:NIXONHARG
ROCHESTER
TELEX: 978450
Devans
SUITE
1200,
1090
VERMONT
WASHINGTON,
ONE ROCKEFELLER
PLAZA
N E W YORK,NEW
YORK 10020
1212)
23~Doyle
Attorneys
ancl Counselors
at Law
* PARTNERSHlP
lNCL”DlNG
PROFESSION*L
CORPOAATlONS
(202)
D.C.
AVENUE,
N.W.
247
ROYAL
POST
OFFICE
PALM
BEACH,
TELEX:
FLORIDA
SUITE
810
U.S. HIGHWAY
,001
842-3600
JUPITER,
YORK
66521
February
18, 1983
Dockets Management Branch
Food and Drug Administration
Department of Health and
Human Services
Room 4-62
5600 F ishers Lane
Rockville,
Maryland 20857
CITIZEN PETITION
The undersigned submits this petition
under 21
CFR 10.30 to request the Commissioner of Food and Drugs to
open the administrative
record in the Over-the-Counter
Drug Review of Drug Products (Docket No. 76N-0052N) to
accept the enclosed materials
relating
to the
recently-completed
study conducted at Johns Hopkins
University
Medical School.
A. Action
Requested
The undersigned respectfully
requests that the
administrative
record be opened to permit the enclosed
materials
to be considered in the referenced O T C Drug
Review.
B. Statement
1027
33480
20005
1305,
NEW
WAY
BOX
,3051859-6255
586-4100
CABLE:NIXONHARG
PALM
of G rounds
The grounds on which petitioner
relies
are that
phenylpropanolamine
hydrochloride
(PPA) is one of the
ingredients
of nasal decongestants
which are the subject
of the above-referenced
Proposed OTC Cold, Cough, Allergy,
Bronchodilator
and Antiasthmatic
Products Monograph. (41
The Panel
Fed. Reg. 38312, 38400, September 9, 1976.)
Monograph concluded that PPA and its salts are safe and
effective
as oral nasal decongestants
for O T C use in the
The Tentative
F inal Cough/Cold
specified
dosages.
Monograph has not yet been published.
FLORtDA
746-1002
ONE
33458
Dockets
February
Page 2
Management
18, 1983
Branch
The enclosed
materials
summarize
a study
demonstrating
the safety
of PPA in weight
cont.rol
products.
Since the same ingredient
is involved
in the
two products,
the enclosed
materials
are highly
significant
to the agency’s
OTC Drug Review of cough/cold
drug products
as well as to its OTC Drug Review of weight
control
products.
(47 Fed. Reg. 8466 et seq.,
February
26, 1982. ) Therefore,
these materials
should
be
considered
in both reviews
at the earliest
possible
time.
Please note that a parallel
Citizen
Petition
dated January
11, 1983, was filed
by the undersigned
requesting
that the
administrative
record
in the Weight Control
OTC Drug
Review be opened to permit
the enclosed
materials
to be
considered
in that review.
C. Certification
The undersigned
certifies
that,
to the best
knowledge
and belief
of the undersigned,
this petition
includes
all information
and views on which the petition
and that it includes
representative
data and
relies,
information
known to the petitioner
which are unfavorable
to the petition.
& Doyle
Suite 1200
1090 Vermont Avenue,
N.W.
Washington,
D. C. 20005
(202) 842-3600
MEDICAL
6, ,
919 THIRD
AVENUE
* NEW
YORK,
COMPANY, It&.‘
N.Y. 10022
l
(212)
h
688-4420
January
3, 1983
Dr. Mark Novitch
FOOD AND DRUG ADMINISTRATION
5600 Fishers Lane
Rockville,
MD 20857
Dear Dr. Novitch:
Enclosed please find a just completed clinical
study conducted at
Johns Hopkins University
Medical School by Ira Liebson, M.D.
evaluating
possible
adverse symptoms attributable
to phenylpropanolamine
including
but not limited
to blood pressure,
pulse, psychological
and
mood changes.
This study is in three parts a, b and c and has been completely
evaluated using the most modern statistical
methods.
The results
a.
3.
C.
d.
e.
study
Phenylpropanolanine
Phenylpropanolamine
Phenylpropanolamine
Phenylpropanolamine
Phenylpropanolamine
Following
is a quick
clearly
indicate
does not
does not
does not
does not
is not a
summary of this
that:
affect blood pressure.
raise pulse rate.
have abuse or addictive
affect mood.
stimulant.
three
part
potential.
study:
A.
A parallel
group design study of 150 healthy normotensive
volunteers
who participated
in a double-blind,
placebo
controlled
comparison of the effects
of phenylpropanolamine
HCl on biood pressure,
pulse and mood. Two dosage forms of
phenylpropanolamine
were studied
(75 mg sustained-release
and 25 mg t.i.d.)
in comparison with placebo.
Subjects
were studied for a 12-hour testing
session in which measurements of blood pressure,
pulse and subjective
drug effect
(mood) were obtained nine times during the session.
B.
A crossover
design involving
59 healthy,
normotensive
patients
in the evaluation
of the effects
of phenylpropanolamine
HCl
in normal volunteers.
This study also measured blood pressure
(sitting,
standing
and supine),
pulse and subjective
drug
This
effect
(mood) nine times during the 12-hour session.
study compared 75 mg sustained-release
phenylpropanolamine
with placebo.
After one washout day the subjects
returned
to complete the second leg of the crossover.
During this
second session they received
the alternate
medication
which
was not administered
on the first
day.
Overall,
the results
of this present study are quite compatable
with the results
of Study A. No clinically
relevant
adverse
state
effects
were noted on pulse, blood pressure or subjective
-*
*,i
of this
h.t--.
‘4
4’
B
1
dh
’
a = Dr. Mark Novi'
ljanuary
3, 1983‘
Page 2
(mood),
C.
in
phenylpropanolamine
subjects
compared
to placebo
subjects.
An additional
analysis
was undertaken
on the data collected
as
part of Parts A 6 B as indicated
above.
These analyses
focused
on a comparison
of possible
subjective
effects
of phenylpropanolamine
on affective
state
("mood“),
compared with those of
potent
CNS-active
drugs.
'
These analyses
clearly
indicated
that phenylpropanolamine
in
doses of 25 mg t.i.d.
or 75 mg sustained-release,
were not
associated
with euphoria,
amphetamine-like
reactions,
sedation
or stimulation
in data derived
from the 150 patients
parallel
group design study and the 59 patient
crossover
study.
This study
supporting
Hull Hayes
reconfirms
the numerous previously
submitted
clinical
studies
the safety
of phenylpropanolzmine
delivered
to Dr. Arthur
by the Proprietary
Association
Task Force on Phenylpropanolamine.
The overwhelming
conclusion
of all of
the wide safety
of phenylpropanolamine
confidence
of the Agency in maintaining
drug.
this data clearly
substantiates
and definitely
supports
the continued
phenylpropanolamine
as a Category
1
In view of all of this accumulation
of scientific
data and vast consumer
usage over the past 40 years it would be highly
detrimental
to the consumer,
the Agency and industry
to consider
changing
the status
of phenylpropanolamine
at this
time.
Considering
the fact that more than five billion
doses of phenylpropanolamine
are consumed each year in cough and cold and diet aid products
there are
extremely
small numbers of adverse
reports
and no reports
confirming
causative
effects.
Ira Liebson,
M.D. of the Johns
will
be available
to personally
at your convenience.
Thank
you
for
your
courtesy
Hopkins
report
University
who supervised
this study
on this very important
study to you
and attention.
Sincerely
yours,
THO?iPSON MEDICAL COMPAhY, INC.
ELS:fj
Enclosures
(3)
cc:Dr.
William
Edward L. Steinberg,
Vice Chairman of the
Gilbertson
M.Sc.,O.D.
Board
-\
Supplement
to Clinical
82-8(A)
Protocols
and 82-8(B)
EVALUATION OF PHENYLPROPANOLAMINE
(75 mg) EFFECTS ON
STANDARDIZEDMEASURESOF DRUG EFFECT AND AFFECTIVE STATE
.
Study Site:
Behavioral
Pharmacology Research Unit
The Johns Hopkins University
School of Medicine
Baltimore City Hospitals
D-5-West
4940 Eastern Avenue
Baltimore,
Maryland
21224
Contact:
Frank R. Funderburk
Director,
Clinical
Consulting
ANTECH, Inc.
(301) 997-0880
Date:
December 6, 1982
1
(c_ .
SUPPLEMENTTO CLINICAL PROTOCOLS
82-8(A) and 82-8(B)
Evaluation
of Phenyl propanol amine Effects on
Standardized
Measures of Drug Effect and Affective
State
Sponsor:
Thompson Medical Company, Inc.
919 Third Avenue
New York, NY 10022
Investigators:
Ira Liebson
George Bigelow
Roland Griffiths
Frank Funderburk
Alistair
MacKenzie
Protocol
c- - '
Contact:
Date:
developed
by:
The Clinical
Consulting
ANTECX, Inc. and the
Behavioral
Pharmacology
Frank Funderburk
(301) 997-0880
_ December 6, 1982
!
.
Group
Research Unit
TABLE OF CONTENTS
1. Addiction
2. Profile
Statistical
Research
Center
of Mood States
Analysis
Inventory
(ARCI) ,,,*,*,a
(POMS) ,1,,1,,,~..,1,11##B9a
,*,,,,,~,.1111,.,~,*,,#~,.*#,,..~.@
RESULTS,,,L,,,,,,,,,,,,,,,,,,.#,~,,,~,,,.,...,~,,,,B.~~~~~b8
Parallel
Crossover
2
3
4
4
Groups Design I.l,~#,ll,,Ol..B‘,,~,,,,,,..,.~~
4
Design ,,..,‘,..0,1.‘,.,*.,..~.,,,‘~,.,.49@8@
6
DISCUSSION ,,.,1,,1,,,,~~,11,,,~,..,,,‘.~~.~,#‘,,.~~.,,~~~.~
REFERENCES‘1,,,,,,,,,,,01,,,,,,,,.,.‘~~~@~,,@,~,~~,~,,.‘,
9
12
ABSTRACT
Additional
Clinical
analysis
Protocols
comparison
of
These
analyses
sustained
reactions,
evaluation
were
or sedation.
to
experimental
that
not
of
PPA, in doses
the
session
fatigue
with
of
focused
other
of
and boredcm
state
25 mg t.i.d.
euphoria,
which
on a
or
suggested
with
'
drugs
("mood").
75 mg
amphetamine-like
associated
unstimulating
of
(INS-active
on affective
was found
in a relatively
as part
analyses
those
PPA effects
associated
collected
These
with
Some evidence
reduce
on data
and 82-8(B).
PPA effects
indicated
release,
PPA functioned
12 hour
82-8(A)
subjective
and a more rigorous
was undertaken
that
a
environment.
*
-l-
c
cc-
INTRODUCTION
Previous
examined
reports
from our laboratory
the effects
of phenylpropanolamine
and mood (including
In a large
sample
25 mg t.i.d.
subjective
ratings
(N = 150) parallel
and 75 mg sustained
on clinical
measurements
drug effect
and drug liking
concluded
that
(Funderburk
of drug effect)
groups
on the clinical
support
in a statistically
pulse,
more powerful
compared the 75 mg sustained
release
or subjective
crossover
study
with
effects
ratings
session.
conclusion
formulation
pulse,
PPA doses of
was not associated
This
studied.
1982b)
pressure,
to have minimal
experimental
studied
1982a,
in normal volunteers.
study,
were found
over a 12-hour
measures
design
pressure,
PPA at the dose levels
effects
(PPA) on blood
release
of blood
--et al.,
of
The authors
with
received
adverse
further
(N = 59) which
placebo
on these
same measures.
The present
It describes
report
is a supplement
additional
on the subjective
two key issues
analysis
effects
and well
sensitive
In both instances
standardized
to the effects
Particular
evaluation
instruments
and 82-8(B).
additional
attention
will
of PPA with
of PPA effects
our measures will
psychometric
82-8(A)
to provide
(1) A comparison
drugs and (2) A more rigorous
("mood").
undertaken
of PPA.
of concern:
to Protocols
be focused
other
be derived
our previous
Subject
reports.
on
CNS-active
on affective
from widely
state
used
which have been proven
of CNS drugs.
INVESTIGATIVE METHODS
Subjects.
information
characteristics
In the parallel
are identical
groups
design
.
to those
150 healthy
described
normal
in
-2-
.fl
C-
subjects
participated
the crossover
'(N = 50 in each of three
study
59 healthy
normal subjects
exposed to each of two experimental
experimental
groups).
In
participated
(each being
conditions).
Design and Procedure.
The measures described
participated
82-8(B)
in Clinical
[crossover
to subjects
short
c
prior
version
comparison
drugs.
The other
allows
an evaluation
design].
More detailed
ARC1 scales
inventory
Inventory
of drugs
were developed
(group
various
to reflect
scales
study,
patterns
and the characteristics
(POMS).
test
CNS-active
with
test
drug
to administer.
Detailed
The empirical
description
drug scales
items which differentiated
morphine,
scales)
This
This
associated
than 5 minutes
(ARCIL
and alcohol.
variability
(ARCI).
follows:
(1974).
by selecting
including
less
tests
Inventory
state
and
One form was a
those of other
of Mood States
required
of these
pyrahexyl,
with
in affective
by Haertzen
were developed
LSD, amphetamine,
effects
design]
who
forms were administered
Research &enter
of changes
Center
test
from subjects
groups
occasion.
form was the Profile
was given
[parallel
measurement
of PPA subjective
Research
from a variety
82-8(A)
to each clinical
descriptions
Addiction
were obtained
Two standardized
Each form generally
treatment.
report
Protocols
of the Addiction
allows
this
in this
pentobarbital,
In addition,
which they reflect
on this
placebo
chlorpromazine,
clusters
which combined items
of drug effects.
of the
The scales
are:
of items
from the
used in
-3-
empirical
(7) AMP:
scale
amphetamine
which measures
to benzedrine
scale
which measures similarity
effects.
of intellectual
(3) MBG:
to
effects.
group variability
(2) BG:
similarity
Interpreted
as a measure
efficiency
and energy.
scale
which measures a
group variability
morphine-benzedrine
effect.
Interpreted
as a
measure of euphoria.
(4) PCAG:
group variability
scale
which measures
pentobarbital-chlorpromkne-alcohol
Interpreted
effects.
as a measure of sedation,
fatigue,
and low motivation.
(5) LSD:
empirical
scale
effects.
Interpreted
tension,
difficulty
depersonalization,
Also interpreted
Profile
of Mood States
assessing
transient,
by factor
analyticVmethods
both normals
Droppleman,
these
effects
scales).
--
a more detailed
and psychomimetic
changes.
,
as a measure of dysphoria.
The POMS scales
provide
These scales
of subject
populations
discussion
volunteers.
manipulations
The POMSmeasures
six
a means of
were developed
populations
(see,
McNair,
including
Lorr,
of the development
The POMS has been found to be a sensitive
experimental
to LSD
as a measure of anxiety,
mood states.
patient
similarity
in concentration,
in a variety
and specialized
of various
in normal
(POMS).
fluctuating
1971, for
which measures
and
of
measure of the
(including
drug administration)
identifiable
mood or affective
states
as well
The scales
as various
specialized
used in this
study
affective
states
and global
mood.
were:
(1) Tension-Anxiety
(2) Depression-Dejection
(3) Anger-Hostility
(4) Vigor-Activity
TV
(5) Fatigue-Inertia
(6) Confusion-Bewilderment.
(7)
"Friendliness"
(8) Total
Statistical
In the para'itel
assignment
occasion
while
analyses
groups
(placebo,
measurement
design
administration
were conducted
design
factors
occasion
first
JIS-. active
Order of drug administration
and measurement
involving
(e.g.,
occasion
repeated
Geisser
were within
and Greenhouse,
studied
results
are summarized
.w
factor
in the
of treatment
and measurement
factor
while
drug treatment
In both analyses
a conservative
occasion.
tests
Etest
1953).
Parallel
of the analysis
below:
Factors
order
factors.
using
variables.
and measurement
was a between-group
drug first),
subject
measures were evaluated
Results:
Specific
release)
was a between groups
of
were drug treatment
factor.
assignment,
analysis
each of the dependent
assignment
was a within-subjects
were drug treatment
(placebo
for
mixed design
in the analysis
Treatment
etc.).
using
75 mg sustained
25 mg t.i.d.,
(0 hr, % hr,
crossover
Data were analyzed
Analysis.
Separate
variance.
f- %
Mood Oisturbance.
Groups Design
of variance
for
each of the variables
-5-
ARC1 Variables
AMP.
No main effect
for
drug treatment
A significant
main effect
for
measurement occasion
~~0.05)
for
reflecting
subjects
a general
in all
condition
decrease
in AMP scores
groups.
No significant
treatment
was identified.
was found
over
(I=
3.91,
the session
interactions
were
identified.
-BG.
No main effect
A significant
~~0.05)
for
for
main effect
reflecting
subjects
for measurement
a general
in all
drug treatment
decrease
treatmenr
condition
occasion
in BG scores
was identified.
was found
4.80,
over the session
No significant
groups.
(f=
interactions
were
identified.
MBG. No significant
3.
main effects
PCAG. No main effects
treatment.
identified
A significant
(F- = 7.46,
(PCAG score)
with
the middle
drug treatment
identified.
*
or interactions
main effect
~~0.01)
to be lowest
for
early
No other
and late
This
were identified.
were found
measurement
which reflected
of the session.
groups.
or interactions
general
trend
drug
occasion
a tendency
in the session
main effects
for
for
was
sedation
as compared
was present
or interactions
in all
were
s
POMS Variables
Tension-Anxiety.
No significant
main effects
or interactions
were
identified.
Depression-Dejection.
No significant
main effects
or interactions
were identified.
*LSD.
No significant
main effects
or interactions
were identified.
-6-
Anqer-Hostility.
No significant
main effects
or interactions
were
identified.
Viqor-Activity.
NO main effects
drug treatment.
A significant
was identified
vigor
(f=
10.37,
over the course
in all
drug treatment
or interactions
main effect
~~0.01)
reflecting
of the session.
groups.
for
This
No other
were found
for
measurement occasion
a general
genera?
decrease
trend
main effects
in
was present
or interactions
were identified.
Fatique-Inertia.
No significant
main effects
or interactions
were
identified.
Confusion-Bewilderment.
No significant
main effects
or interactions
were identified.
"Friendliness."
identified.
over
A significant
(E = 19.98,
found
the course
No significant
Total
No main effect
pcO.01)
main effect
reflecting
of the session
interactions
for
for
drug treatment
for
measurement
a general
subjects
decrease
in all
condition
occasion
was
was
in "friendliness"
drug treatment
groups.
were identified.
Mood Disturbance.
No significant
main effects
or interactions
were identified.
Results:
Specific
studied
results
are summarized
Crossover
of the analysis
below:
Design
of variance
for
each of the variables
-7-
,-r
t.
\
ARCI Variables
AMP.
treatment
No significant
were identified.
was identified
(c = 3.14,
over the course
treatment
groups.
treatment
or interactions
A significant
in scores
-BG.
-,
‘c
main effects
~~0.05)
main effect
which reflected
of the session
No significant
main effects
were identified.
(E = 3.56,
peO.05) which reflected
in scores
over
the course
of the session
treatment
groups.
(F- = 5.40,
was identified
in scores
PCAG. A significant
pco.03).
(reflecting
less
with
placebo.
for
reflected
session
Overall
fatigue)
This
interaction
subjects
subjects
or interactions
subjects
for
for
a general
lower
fn subjects
(c=
identified
in PCAG scores
in both drug treatment
was identified.
time course
drug treatment
reported
second session
increase
drug
decrease
in both drug treatment
was strongest
was also
decrease
with
main effect
subjects
time course
in both drug
5.72,
(E=
was identified
as compared
who received
pzO.02).
2.57,
the
A main
p<O.O5) which
over the course
groups.
groups.
PCAG scores
under the 75 mg PPA treatment
effect
time course
a general
for
for
for
drug
a general
which reflected
main effect
75 mg PPA dose in their
effect
~~0.05)
over the session
(E = 4.97,
for
A significant
were identified.
decrease
with
main effect
main effects
time course
a general
or interactions
was identified
treatment
for
drug
subjects in both drug
for
A significant
MBG. No significant
with
No-drug
of the
x time
-8-
c
rc
(E=
LSD.
A significant
7.69,
peO.01).
(reflecting
with
less
placebo.
main effect
Overall
dysphoria)
No other
for
subjects
drug treatment
reported
lower
was identified
LSD scores
under the 75 mg PPA treatment
main effects
or interactions
as compared
were identified.
POMS Variables
Tension-Anxiety.
(f = 4.86,
anxiety
A main effect
Overall
~~0.05).
scores
treatment.
for
subjects
drug treatment
obtained
under the 75 mg PPA treatment
No other
main effects
tension
and
as compared with
or interactions
No significant
Depression-Dejection.
lower
was identified
placebo
were identified.
main effects
or interactions
were identified.
c
A main effect
Anger-hostility.
(r = 5.27,
scores
~~0.025).
Overall
main effects
Viqor-Activity.
were identified.
~~0.05)
lower
or interactions
f _-
greater
as compared with
or interactions
for
scores
measurement
a general
over time.
was identified
anger-hostility
placebo
for
occasion
drug condition
(t=
tendency
No other
treatment.
for
5.23,
subjects
main effects
were identified.!
~~0.01)
fatigue
lower
No main effects
vigor-activity
No significant
or time course
8.64,
obtained
were identified.
which reflected
Fatigue-Inertia.
order,
drug treatment
or interactions
A main effect
was identified
to obtain
(I=
subjects
under the 75 mg PPA treatment
No other
for
main effects
were identified.
was identified
was reported
for
A drug x order
which reflected
under placebo
drug treatment,
interaction
the fact
that
as opposed to 75 mg PPA in
-9-
one group of subjects
group of subjects.
while
the opposite
No other
significant
lower
was identified
Confusion-Bewilderment
*
No other
under placebo.
"Friendliness."
drug treatment
found
(E = 6.62,
friendliness
scores
for
Overall
subjects
of interactions
No significant
main effects
A significant
which reflected
to decrease
were identified.
drug
obtained
under the 75 mg PPA treatment
main effects
pcO.01)
in the other
main effect
pcO.01).
scores
were identified.
"friendliness"
f
c..
(E = 7.00,
was present
interactions
A significant
Confusion-Bewilderment.
condition
trend
were identified.
or interactions
time course
a general
over the course
did tend to increase
than
effect
tendency
of the session,
at the last
with
was
for
although
measurement
occasion.
Total
No significant
Mood Disturbance.
main effects
or interactions
were identified.
DISCUSSION
The present
study
evaluated
forms of PPA (75 mg sustained
placebo
in a parallel
crossover
design
placebo.
Measures obtained
of a variety
effects
i
t.
groups
which
release,
affective
effects
75 mg sustained
drug effects
a comparison
as well
of two dosage
in comparison
These assessments
included
states.
subjective
25 mg t.i.d.)
design.
compared-the
of CNS-active
on various
the acute
were repeated
release
.
with
in a
dose with
of PPA effects
as an 'evaluation
with
those
of PPA
-lO-
“.(
c
In the parallel
of placebo
to feel
more sedated
effect
of this
or tired
prior
differences
effect
was not related
with
less
of the session
effects
showed reliable
circadian
our previous
studies,
early
reported
feeling
or euphoria
effects
provided
less
found in our previous
1982b) and with
euphoric
effects
PPA functioned
experimental
setting
increase
settings.'
to reduce
mental
indicated
alertness
dysphoria
less
later
the dysphoria
and reduce
As in
generally
felt
and less
Subjects
confused
placebo.
is consistent
there
appears
with
(Funderburk
(1981).
and relatively
fatigue
most measures
of these effects.
study
it
of
in the session.
Overall
that
et al.,
bland
1982a,
no reliable
is some evidence
and boredom associated
Thus,
the
no evidence
subjects
hostile,
PPA, 'although
during
of the session.
of PPA mood effects
laboratory.
and
and placebo
As expected,
confirmation
in the restricted
The extent
reliable
However,
as compared with
for
of
the 75 mg PPA treatment
that
of Seppala --et al.
were noted
of a research
placebo.
as compared with
analysis
tended
lessening
PPA treatment
and less
in the present
the findings
session
release
tense or anxious,
of results
with
some statistically
over the course
further
groups
of the session.
was found.
effects
under the 75 mg PPA treatment
The pattern
progressed,
design
sedation-fatigue
these
in all
on the ARCI scales
in the sessions
The POMSmeasures
Subjects
from those
to drug treatment.
as compared with
amphetamine-like
"better"
crossover
In particular,
was associated
were not different
as the session
between the 75 mg sustained
were identified.
f
PPA effects
to the conclusion
In the more powerful
course
design
on any of the measures studied.
the sedative
nature
groups
with
that
a 12-hour
environmental
that
PPA may serve
in relatively
unstimulating
to
-ll-
In the
which
doses
would
studied
be indicative
or amphetamine-like
likely
with
such
our
from
Overall
effects
these
fz.
low
chosen
that
placebo.
present
findings
state
may be limited
design.
or euphoric
of
suggest
it
these
to
of subjective
The absence
effects
suggest
affective
stimulation.
effects
"drug
that
liking"
states
At the
were
noted
for
is
PPA is
PPA were
not
not
beneficial
and reduces
not
measured
same time,
even
euphoric
is consistent
alertness
however,
of
effects
by someone
PPA may have mildly
increases
effects,
that
self-administration
Such an interpretation
in that
of
for
ratings
of
of environmental
amphetamine-like
a pattern
liability,
as a drug
effects.
The magnitude
findings
crossover
6
those
on affective
levels
abuse
high
produce
or st? Ldtive-type
finding
the
dysphoria.
of
psychological
previous
different
not
effects
to be knowingly
seeking
PPA did
in the
large.
under
Further,
unusually
no evidence
m-e
powerful
of
a
-12‘
,
.
REFERENCES
Bigelow,
G. E. --'
et al
assessment:
Development
Progress
report
Unit
of The Johns Hopkins
City
Hospitals.
Proceedings
Problems
Funderburk,
pulse,
of the 44th Annual
F. R. --•
et al
Company.
October
Funderburk,
and mood:
Geisser,
1982.
S.,
Haertzen,
Institute
McNair,
of Medicine
Research
and Baltimore
Meeting,
Institute
The Committee
on
on Drug Abuse Research
8, 1982.
(a)
Effects
Crossover
design.
Report
on blood
to Thompson Medical
of phenylpropanolamine
design.
Report
pressure,
on blood
pressure,
to Thompson Medical
Company.
(b)
and Greenhouse,
S. W.
An extension
in multivariate
of Box's
analysis.
results
Annals
on the
of Mathematical
1958, 29-, 885-891.
An appendix
CA:
of Addiction
Research ,Center
and manual of scales.
on Drug Abuse,
D. M. --et al.
San Diego,
Pharmacology
of phenylpropanolamine
groups
C. A. .An overview
(ARCI):
abuse liability
Problems of Druq Dependence 1982:
National
Parallel
use of the 1 distribution
Statistics,
(Ed.)
Scientific
Effects
F. R. --•
et al
October
School
for
1982.
and mood:
pulse,
University
In L. S. Harris
Series,
procedures
from the Behavioral
of Drug Dependence.
Monograph
of clinical
1974.
DHEWPublication
EDITS manual for
Education
Washington,
the Profile
and Industrial
Testing
Inventory
Scales
D, C.:
National
NO. (ADM) 74-92.
of Mood States.
Service,
1971.
-13-
t-y. -
Seppala,
T. --et al.
antihistamines
subjeciive
Siigle
dose comparisons
and phenylpropanoiamine:
appraisals
1987, 12, 179-188.
i .
and repeated
of sleep.
British
Psychomotor
Journal
of three
performance
of Clinical
and
Pharmacology,
r
(r
’
.
A N E V A L U A T IO NO F T H E A C U T EE F F E C T SO F
P H E N Y L P R O P A N O L A MININEN O R M A LV O L U N T E E R S :
( C R O S S O V EDRE S IG N )
-
S tu d y S ite :
B e h a v i o r a l P h a r m a c o l o g y R e s e a r c h Unit
J o h n s H o p k i n s University
School of Medicine
B a l tim o r e City Hospitals D - & W e s t
4 9 4 0 E a s te r n A v e n u e
B a l tim o r e , M a r y l a n d 2 1 2 2 4
C o n tact:
Frank R . F u n d e r b u r k
Director,
Clinical
C o r m 1 tin 9
A N T E C H , Inc.
(301) 997-0880
D a te :
O c to b e r 2 2 , 1 9 8 2
b
(
FINAL REPORT OF
CLINICAL PROTOCOLNO. 82-8(A)
An Evaluation
of the Acute Effects of
Phenylpropanolamine
in Horma'l Volunteers:
(Crossover Design)
sponsor:
Thompson Medical Company, Inc.
979 Third Avenue
New York, NY 10022
Investigators:
Ira Liebson
George Bigelow
Roland Griffiths
Frank Funderburk
Protocol
by:
developed
Contact:
The Clinical
Consulting
ANTECH, Inc. and the
Behavioral
Pharmacology
Frank Funderburk
‘
Project
Start
Date:
Project
Completion
(301) 997-0880
25 June 82
Date:
31 August 82
Group
Research
Unit
,
c-
TABLE OF CONTENTS
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..~............~............
1
INTRODUCTION .............................................................
2
OBJECTIVE AND RATIONALE ..................................................
2
METHODS ....................................................
INVESTIGATIVE
Design
1.
c
’c
2.
and Procedure
General
..........
Procedures
a.
Subject
b.
Meals
C.
Drug Administration
d.
Clinical
Design
Control
3
3
.............................................................
Subjects
..............................
..o......
4
...............................................
4
..............................................
4
and Food Restrictions
Measurement
'
..................................
..........................................
.........................................
...........................................................
4
5
6
6
RESULTS ..................................................................
6
DISCUSSION ...............................................................
8
REFERENCES ...............................................................
11
APPENDIX .................................................................
13
FIGURES ..................................................................
36
.
1
‘<
,
..c i
ABSTRACT
t
Fifty-nine
(59)
participated
effects
healthy
in a double
blind,
of a 75 m g sustained
blood
pulse,
pressure,
experimental
sessions,
subjective
(prior
10 hr,
M ixed
analysis
for
pressure
drug
showed statistically
between
placebo
of
effect,
in
under the active
two
drug
was randomly determined.
standing,
and supine),
9 times
revealed
standing
but
-
active
during
the
1 hr,
2 hr,
hr,
pulse,
session
and
- at
4 hr, 6 hr,
of
no statistically
significant
pulse
mood.
Nearly
was an
exception)
systolic
drug condition.
insignificant
j In all
active
was extremely
or
measure
clinically
under the
however,
conditions
on measure
reliable
was slightlylhigher
and the other
and at l/2
variance
(the
and the
participated
dosing.
treatment
pressure
this
of
measures
subject
(sitting,
to drug,administration)
design
main effects
HCl on
were obtained
and 12 hr post-initial
= 25.5)
dosage form of phenylpropanolamine
Each
crossover
age
of the
to treatment
("mood")
(mean
evaluation
placebo
pressure
volunteers
controlled
mood.
one under
drug effect
baseline
blood
release
and
Measurements of blood
(.
placebo
Order of exposure
treatment.
8 hr,
normotensive
drug
small
-
cases,
treatment.
(the
all
differences
the mean blood
The magnitude
mean differences
ranged
between .83 and 3.37 m m Hgl.
most
As anticipated,
(circadian
effects),
subjective
state
however,
generally
suggests
that
has m inimal
/’ .
d_
the
measures showed main
indicating
the
changed over the course
independent
of
75 m g sustained
- and clinically
pulse, or mood of normotensive
-
that
the
of the
drug
release
insignificant
individuals.
effects
subjects'
of
day
and
These changes were,
condition.
dosage form of
- effects
tim e
physiological
session.
treatment
for
This
study
phenylpropanolamine
on the
blood
pressure,
2
,L
c
t\
An Evaluation
of the Acute Effects
of Phenylpropanolamine
in Normal Volunteers:
(Crossover
Design)
INTRODUCTION
Phenylpropanolamine
actions
less
similar
ephedrine.
than
ephedrine.
(OTC) in
United
States
weight
control
the
safety
Vol.
47,
aid.
Recently
No. 39,
of
1980;
the agency
requested
additional
of
parameters
side
effects.
generally
PPA is
currently
In the
Dietz,
present
of.75
these
parameters.
normotensive
course
of 12 hours.
Fifty-nine
pressure,
release
adults
questions
about
Register,
1982).
In their
on the effects
crossover
mg sustained
and as a
PPA (Federal
Lancet,
blood
report,
was used to compare the effects
of
1981;
over-the-
decongestant
have raised
with
to produce
marketed
information
including
compound
believed
as a nasal
OTC availability
Horowitz,
safety
a synthetic
PPA is
in both
1982;
. on a variety
is
the FDA and others
and appropriateness
Pub1 ication,
reported
the
(PPA)
However,
CNS stimulation
counter
i,.
to
hydrochloride
were
pulse,
of PPA
and self-
experimental
PPA with
studied
design
placebo
over
on
a time
OBJECTIVE AND RATIONALE
This
study
laboratory
adults
was designed
(Funderburk
participated
PPA (25 mg t.i.d.,
effects
pressure,
for
drug
pulse,
to
et al.,
in
extend
1982).
a study
or mood.
In that
comparing
75 mg sustained
treatment
previous
were
Although
release)
found
the
the
investigation,
effects
with
on
research
any
relatively
of
placebo.
of
the
large
conducted
in
our
150 normotensive
two dosage
forms
No significant
measures
sample
size
of
main
of
blood
in
that
3
study
provided
considerable
more sensitive
subject
comparison
would serve
Several
subjects
low
however,
(Funderburk
design
normal
investigated
et al.,
rather
statistical
it
was believed
by a crossover
provided
the
1980;
small
1982)
a rather
that
study
samples
recent
which
powerful
effects
Hoebel , 1982).
The
study, using
an even more powerful
acute
subject
power.
et al.,
The present
subjects.
provide
have
involved
relatively
groups
would be afforded
Silverman
have generally
power,
an even
in which each
as his own control.
studies
(e.g.,
statistical
evaluation
in
of
PPA effects
studies
therefore,
our
150 subjects
design,
normal
these
and have,
of the effects
a crossover
PPA in
However,
study
employed
test
of
had
laboratory,
in a parallel
of PPA on normal
was implemented
in a large
group
to
of
volunteers.
INVESTIGATIVE
METHODS
Subjects
Subjects
were
25.5).
The study
American
Indian.
the following
59
normal
volunteers
population
consisted
All
had given
between
b.
no current
18-55 years
no physical
used in this
no
and
female,
33 Caucasians,
consent
mean age
25 blacks,
and had been screened
=
and
1
to meet
history
drug abuse
of age
use of medications
which
would
compromise
the
validity
of
of the test products
the evaluation
d.
informed
of
male
criteria:
a.
C.
(both
contraindications
to consunption
of PPA at the dose levels
study
of
severe
emotional
disturbance,
chronic
alcoholism,
or
.,,
evidence
e.
that
the .subject
would
participate
in
the
research
and be
cooperative
f.
good
general
within
based
on a medical
one month of the study
female
90
health
subjects
baby for
certified
the duration
start
that
history
interview
and a recent
they
were
not
conducted
phys-fcal
examination
pregnant
or
nursing
a
of the protocol.
Design and Procedure
Subjects
were randomly
(n = 30)
group
received
and the 75 mg sustained
order
of treatment
two treatment
minimize
the
possible
to
placebo
release
was reversed
sessions
any
assigned
for
two treatment
treatment
treatment
were always
treatment
one of
on their
sequences.
first
testing
on the second testing
subjects
in the other
separated
carryover
by at
occasion
session.
This
group (n = 29).
least
effects.
One
one washout
The basic
The
day to
investigative
r
(.
procedures
1.
foll'owed
General
.
a.
for
were excluded.
vision.
Subjects
test
with
coffee,
below.
week prior
to the
substances
Study medications
remained
at the test
were
instructed
first
administration
which
compromised
were administered
facility
for
to
be
free
of a test
the
validity
under clinical
the entire
testing
of
all
product.
of
the
superperiod
days.
a choice
tea,
Subjects
control.
who had ingested
b.
Q
the
study
during
are detailed
Procedures
Subject
medications
Subjects
for each subject
Meals and food restrictions.
of
cola)
standard
noontime
were not permitted
On test
meals.
on study
days subjects
Foods containing
days.
were provided
xanthines
(e.g.,
Drug administration.
c.
dose
of
a test
compared with
product
placebo.
In this
containing
PPA (75
On each test
tions
of
a test
product
(either
given
at 4 hour
intervals
(e.g.,
investigation
mg sustained
day subjects
actjve
a currently
approximately
release
received
medication
or
8:00
marketed
three
placebo).
PPA) was
administraDoses were
am, 12:OO noon,
and 4:00
pm).
Subjects
first
test
release
day.
product
subsequent
dosings.
the
second
treatment
t
illustrated
were randomly
to one of two treatment
One group
of subjects
at
first
dosings.
their
The other
After
at
least
leg
of
the
not
assigned
in Table
dosing
group
one washout
crossover.
administered
(Group A) received
on
the
matching
on the
the 75 mg sustained
placebo
capsules
(Group 5) received
placebo
at all
day,
returned
the
subjects
During
this
session,
first
day.
This
they
dosing
to
on
three
complete
received
schedule
the
is
1.
Table
Dosing
(approx.
1
Schedule
Dose 1
Q
and
conditions
8:DO am)
Dose 2
(approx.
12 noon)
Dose 3
(approx.
4:00
Session
Group A
75 mg sustained
placebo
placebo
One
Group B
placebo
placebo
placebo
Session
Group A
placebo
placebo
placebo
Two
Group B
75 mg sustained
placebo
placebo
pm)
d.
obtained
Clinical
9 times
administration
12 hr
during
(0 hr)
following
standing,
Association
state
were obtained
study
of
of the
the dependent
hr,
l/2
factor
4 hr,
analogue
6 hr,
Blood
procedures
1980).
ratings
of
reports
of
may be viewed
as a 2(drug
drug
and pulse
were
to initial
drug
8 hr,
of
effects.
and
(sitting,
by the
measures
subjects
10 hr,
pressure
recommended
Clinical
by subjective
American
subjective
These measures
and the
first
hr,
etc.).
while
drug
For all
was used
Greenhouse,
procedures
observations
in
release
analyses
in the analysis
of
order
treatment
administration
involving
evaluating
repeated
statistical
data
for
each of
condition
occasfon
was a between
occasion
were
factors,
significance
(see,
this
administration
and measurement
measures
Mixed
from
conducted
treatment
first),
measurement
design.
evaluate
of
treatment
and
x 2lorders
were drug treatment
placebo
of
mixed
wre
placebo),
treatment
tests
used to
vs.
Order
conditions)
occasions)
were
Separate
Factors
vs.
treatment
x 9imeasurement
variance
variables.
drug
factors.
test
using
investigation.
mg sustained
(active
2 hr,
administration.
et al,,
administration)
analysis
component
(75
Once prior
session:
1 hr,
pressure
Design
treatment
design
using
hr,
of blood
staff.
This
of
drug
(Kirkendall
were supplemented
2.
and at l/2
was measured
Heart
Measures
each experimental
initial
supine)
research
measurements.
within
groups
subject
a conservative
E
e.g.,
&
Geisser
1958).
RESULTS
Specific
studied
results
are sunmarized
of
the
below.
analysis
of
variance
for
(0
each of
the
variables
c
Pulse
-.
tended
approximately
under
both
drug
groups.
than
reliable
was small
treatment
conditions,
4 and 12 hours
Sitting
post-initial
difference
between
interactions
than
treatments
placebo
was 2.09
occurred
treatment
was
for
subjects
in both
higher
Although
this
effect
magnitude
= 2.26
pressure
under
was
of the effect
mm Hg).
tended
the
Under
both
to show peaks at
2 < .Ol).
tended
under
drug
at
were identified.
the overall
6.81,
peak
effect
to be slightly
blood
(I=
pressure
stable
treatments
diastolic
dosing
blood
treatment
e < .Ol),
a
were identified.
placebo.
between
standing
systolic
drug
under
(r = 7.41,
(mean difference
tended
This
for
or interactions
pressure
showing
1 < .Ol).
pressure was relatively
blood
treatment
session
or interactions
No main effects
diastolic
the
No main effect
conditions.
blood
statistically
to
be
slightly
(1
= 4.46,
hSgher
1
mafn
the
The mean
< .05).
No other
mm Hg.
under
effects
or
were identified.
Sitting
diastolic
post-initial
drug
trealment
over
(1 = 9.45,
systolic
drug
Overall,
post-dosing
main effects
drug treatment
Standing
slightly
No other
Standing
active
increase
6 hours
identified.
active
to
dosing
sitting
treatment
under
diastolic
than
between treatments
pressure
blood
both
treatment
blood
under
was 2.75
tended
pressure
placebo
peak at
conditions
tended
(E = 11.28,
No other
mm Hg.
to
4 and
(P- = 5.26,
to be higher
p < .Ol).
main effects
under
12
1
hours
C .05).
the active
The mean difference
of interactfons
were -
identified.
Supine
post-initial
peak effect
systolic
dosing
at
blood
under
4 hours
pressure
both
tended
treatment
was most
evident
to
conditions
for
peak
at
4
(c = 7.33,
subjects
under
and
12
hours
E < .Ol).
The
the active
drug
c,
treatment
(resulting
Overall,
drug
supine
trea%nent
between
in
a drug
systolic
than
treatments
blood
under
x
time
pressure
placebo
interaction,
tended
E = 4.10,
to be higher
(I: = 7.35,
E < .Ol).
No other
main effects
was 2.52 mm Hg.
E
under
<
the
.05).
active
The mean difference
or interactions
were
identified.
Supine diastolic
blood
initial
dosing
both
supine
diastolic
treatment
than
treatments
for
differences
measures
between
(rating
peak
conditions
tended
to
(5 = 11.91,
The time
at
4 and 12 hours
(r = 6.22,
be higher
p < .Olf.
course
orders
approximately
of drug
the
of "drug
and rating
other
placebo
to
under
the
Overall,
active
The mean difference
of this
(4.15,
E ( -05).
drug
& < .05).
post-
drug
between
effect
was slightly
No other
main effects
were identified.
Subjective
bad,"
under
pressure
the two treatment
or interactions
studied
blood
tended
treatment
was 3.37 mm Hg.
different
f.
under
pressure
effect,"
of "drug
and mood
treatment
conditions
rating
of "feeling
liking").
revealed
on
of "drug
post-initial
dosing
under
or
interactions
were identified
of
means,
no
any
good,"
Ratings
6 hours
main effects
drug
effect
of
the
rating
effect"
both
significant
of "feeling
tended
treatment
measures
to peak at
groups.
for
any of the
and
analysis
No
subjective
measures.
Summary tables
results
for each variable
standard
studied
deviations,
are presented
in the Appendix
of
to this
variance
report.
DISCUSSION
The present
of
study
evaluated
dosage
form
design,
in which each subject
the acute
phenylpropanolamine
served
in
effects
comparison
of a 75 mg sustained
with
as his own control,
release
placebo.
A crossover
was used.
Measures of
(1
drug
effect
on blood
subjective
state
As in
("mood")
our
differences
pressure
pressure
were
reliable
small.
can be attributed
design.
As compared
a larger
the
per group
overall
error
variance
(a result
Both of
these
features
of
is quite
effects
which are clinically
trivial
study,
for
conditons
ranged
mean blood
diastolic)
with
such small
overall
from
effects
found
consistent
with
1964;
Rose,
circadian
to
(see,
of
varfation
Millar-Craig
et al.,
1966;
Drug
variations.
This
result
also
replicated
subjectSve
study
drug
effects.
treatment
did
not
is consistent
Overall
our
with
previous
our
own control).
analysis
power.
reliable
In the present
between
drug
to
mm Hg (supine
3.37
treatment
Obviously,
significant.
in blood
pressure
This
of blood
1978;
appear
had
as a lower
statistical
session.
on circadian
present
statistically
as clinically
daily
This
study
than 2 mm Xg.
differences
blood
the
as well
Cohen, 1969).
of less
the
of
present
increase
systolic)
of
statistically
as his
to identify
difference
course
the
differences
overall
measures
power
n =L 50)
to
e.g.,
pressure
1980).
The present
served
and
were identified.
each subject
significant
the literature
Bock & Kreuzenbeck,
using
are not regarded
the
e-9*,
(n = 59 vs.
lg82),
however,
statistical
possible
overall
statistically
over
study,
mm Hg (standing
an average
As expected,
generally
.83
present
pulse,
period.
al.,
on
investigatfon,
design
it
example,
placebo
drug and placebo
of
the
et
and
previous
supine),
testing
(Funderburk
increased
with .our
sample size
the
the active
to
Under such conditions,
t;'
study
In
between
result
both
reported
and
over a 12-hour
phenylpropanolamine
very
differences
standing,
were obtained
previously
between
(sitting,
to
fInding
pressure
Wchardson
affect
investigation
failed
et al.,
normal
report.
with
to
is
(see,
these
our previous
were
respect
reveal
any
systematic
drug
differences
effect
better
or
variability
our
or drug
any
in
worse
Overall,
the
effects
on blood
of
considered
that
of
our
pressure
or subjective
relevant.
state.
of
the
present
previous
were
treatments
placebo.
Somewhat
these
in
study
for
effects
Likewise,
subjective
drug
report.
noted
on
the active
was observed
the
phenylpropanolamine,
clinically
drug
of
effect
results
in
the
The effect
than
subjective
investigation.
presented
pulse
liking.
previous
results
form
between
this
are
quite
Although
the
was not
study
extremely
no adverse
rated
less
compatible
statistically
small
effects
of
as any
circadian
as compared
75 mg sustained
were
ratings
witi?
with
the
reliable
release
dosage
and
were
not
were
noted
on
11
c
REFERENCES
Bock,
K.
D.,
& Kreuzenbeck,
hypertension:
the
The effect
incidence
of
therapy:
Principles
Springer,
1966.
Cohen,
J.
A. J.
Federal
Geisser,
the
et
al.
J.
in
Effects
of
D. et al.
in anorectic
New York:
phenylpropanolamine.
Journal
of
607-602.
of
phenylpropanolamine
on blood
pressure,
S. N.
of Box's
results
on the use of
An extension
multivariate
analysis.
phenylpropanolamine
communicatSon,
Annals
al.
by sphygmomanometers.
Heart
editorial.
Association,
(75 mg b.i.d.1
Thompson Medical
Medicine,
Hypertensive
and decongestant
W. M. et
1982, 839.
sciences.
8, 1982.
in Philadelphia
Lancet
Berlin:
October
be published
American
Symposium.
Company.
Personal
tion
Antihypertensive
to Thompson Medical
volunteers.
Kirkendall,
(Ed.),
with
of Mathematical
1958, 29-, 885-891.
B. G.
Horowitz,
to
1981, 245,
Effects
Report
E distribution
Hoebel,
Gross
in
47, No. 39, 1982.
& Greenhouse,
Statistics,
variations
and correlations
for behavioral
reactions
Association,
Vol.
and mood.
S.,
F.
An International
power analysis
Medical
F. R.,
pulse,
therapy
In
and practice,
pressure
1969.
Register,
Funderburk,
blood
of antihypertensive
Amphetamine-like
the American
Spontaneous
complications.
Statistical
Academic Press,
Dietz,
W.
Company.
Abstract
to
1982.
responses
preparations.
Recommendations
Report
on normotensive
induced
Lancet,
for
by phenylpropanolamine
1980, Jan.
human blood.pressure
of the Postgraduate
Education
12, 60-61.
determinaCommittee,
1980.
Phenylpropanolamine
over
the
counter.
Lancet,
April
lo,,
12
c
Millar-Craig,
M. W., Bishop,
Lancet,
'pressure.
Richardson,
D.
Variation
W.,
in
Science,
April
Honour,
(Eds.),
The hypertensive
1.
et
phenylpropanolamine
three-phase
study.
E.
Circadian
variation
of
blood
Fenton,
G.,
throughout
Stott,
the
day
F.,
& Pickering,
and
night.
Clinical
450-460.
The measurement
H.
A.,
pressure
Rose, G.
Silverman,
& Raferty,
15, 1978, 795-799.
arterial
1964, 2,
C.,
of blood
pressure.
pattent.
al.
and
Current
Lack
In A. J. Marshall
Pitman Press,
of
side
Therapeutic
1980, pp. 22-38.
effects
phenylpropanolamine
from
with
Research,
& D. W. Barritt
orally
caffeine:
1980, E,
administered
A controlled
785-194,
G.
4
APPEWIX
KEY:
(A
c = ORDER OF DRUG ADMINISTRATION
= 75MG SUST INED RELEASE
ON FIRST SESSIO
PLACEBO ON SESSION TWO;
p” = PLACEBO ON
FIRST SESSION,
MG SUSTAINED RELEASE ON SESSION TWO,)
9s
D = DOSE ADMINISTERED,
T=
IME OF M ASUREMENT
1 = 75MG SUSTAINED
(~=BASEL
NE
T=2HOUR, 5=4 HOUR, 6=6HouR,
7=6HO;R,
RELEASE,
2 =. PLACEBO.
2=30MINUTES ~=~HOUR
8=10HOUR,‘9=12 HO&)
FOR EACH VARIABLE
STUDIED,
MEANS AND STANDARD DEVIATIONS
AT EACH *
MEASUREMENT OCCASION ARE PRESENTED IN ONE.TABLE,
WHILE ANALYSIS OF
VARIANCE RESULTS ARE PRESENTED IN ANOTHER,
CONSERVATIVE F-TEST
WAS USED TO EVALUATE THE RESULTS OF ALL FACTORS INVOLVING
REPEATED
MEASURES,
A
a
MARFI
N&L
77+46743
7#+57778
78.03201
I
COUNT
i
I
‘
;
J- Ii
FTkr<l~kKD
DEVIkTIONS
29
FOR
I-ST
30
Cct-F’EbtDENT
59
Vht?I.I:fci..E
VARIABLE 1:
PULSE
I3
_^ -_
llfl
Ir.fmQr;
120.87534
a1.72772
U$-4Ly
.
-
-.
.---e.---w-----L
1
1
51
120.87634
6 1 . 7 I.?7 7 %
-vi9-233
2.' 4,A
III-
+ 84963
*43388
I-
-..---v
---ml...-
. ..e..w.-
* 3 h .I,
* 5 I.3
---_
__I--
WC-
-
-e--c
,-
-
2
*a
L
?
2
c;
13<655151
13 ef7271
7
8
Y
12+4,5?3&
33#.3?372
16,53438
10,7’!4dj
13,?‘5333
15.93723
--
.-_--
__.--_
---
P”
VARIABLE 2:
P-7
..__..-._-_
_-____--_
i
STANDING SYSTOLIC FLOOD PRESSURE
tswlh
--.-
_-
32296
--
.
_
_
-.
_
-
--
-----
-.---------
l
80640
456
70.82633
_
--...
_I---^
-
------I-c-I-
-
--
.---“LI
*’
.
!
1
1
,:,VAR~ABLE 3:
STANDING DIASTOLIC BLOOD PRESSURE
.
ORDER
DOSE.
STFF’DO
'1
e.*
TT Pl‘E
1
E
A
12.60464
10 .2Y7&4
VARIABLE 3:
STANDING DIASTOLIC BLOOD PRESSURE
4
___--
.-.
MECtN
__._--.r.:r-.
9298587.56250
1*87695
85579.4Y9707
f,RROf(
1
.l
57
2863
439HS87
* Sb%SO
1.87&95
150% .-3Y468
*
_.-_-I
‘I’I)
t:RROR
---II-
2382,68311
‘2.38 ~39038’
19?37*593!51
_---...
._
--
_-._
8
8
29.7 , 83!:*3Y
29*79880
4 3 ‘ 7 2 :2 7 9
456
----
__-I
_
.
-
_--
_._
-_
* 062LY
t00125
, ($()I)
*Y-Q ^ - -. _._
(3KY
6 a
0
.68X54
- .._-. ^._ . . .
* 000
,705
_
--
: VARIABLE 4:
SITTING
SYSTOLIC BLOOD PRESSURE
VARIABLE 4:
_I---
Cl
II0
ll: 13I<0 R
SITTING SYSTOLIC ELOOD PRESSURE
lltrY18YbOO
113,91513
14!:Iki35,‘r’5425
. ,
,
-1.
1
:5 7
1165+%Y600
113r91113
261.14446
4*46456
* 4--3630
-‘L-p
.93Y
l !5 --1”L.m.....- .
,’VARIGLE
5:
c-
SITTING
*-
DI~TOLIC
CELL
PI-Eki!S
BLOOD PRESSURE
FUN
l-ST
Di~F’Eii’IlEr!T
VtGKIAbLE
\
9
II9
MkRGIb!AL
66+03831
66*7?254
66.42135
VARIABLE 5:
4...-,rr
SITTING DIASTOLIC ELOOD PRESSURE
^.
.-.
..---
.
tiEAN
----A!
53331.09814
D
0
kl?RC)R
lYY~.95837
22*13:171
1006Ef. 87 133
.
. ..--_...
1
151 + 00328
ERROR
.--
.
_..
..
_
_-_
_--
.
. .
. ..-
I__--.-..-
-
*
4683147*75OOO
0
--
_
-a
*
1
57
4683147
* ‘I::;wo
l”jl+OO928
.
500!5,3:?3Yl
; 0 0 !I
*16140
l
935,6;zY;30
1
1
57
h8Y
--.. --.
11.28782
+ 1---.%5P’J-
1993.95837
22* 131 '/I
176.44-tih
,001
. -a...-....
7 “’
A..*
‘3 - --
i
._I_...._
_ --.
. ..-
--
..-...
-_
.
..-
,
VARIABLE6:
SUSPINESYSTOLIC BLOOD PRESSURE
c
c'..
_-_-.
-..1 -ST
c dI
!./
._
MARGINAL
111.05747
DE PENUENT
1.15.25370
Viz:RIfrf:l.E
113~19115
‘!
..-._-
*
VARIABLE 6:
SUPINE SYSTOLIC BLOOD PRESSURE
..
SUBPSC%
SOUFtCE
( 1.
n EAN
-.-_I
0
k RRUR
.
135Y4134*5GGGG
4673r67’369
1393”1G.
22070
L. .
QEriREES
OF
FREEDQM
,
1
1
57
,’
-
.
ME AH
SII~~.JARE
PROEi,
F
13.1593 134 t 5OGGG
4673.67969
2442 4 WHf933
5564
r GGG
,172
# 336O’it
lhL310
. .
.,
D
-.-- -
m
c
I._
F
EXCEELIE
i
i
/
SUM OF
SwunqEs
SIJEPS12
,.
.-a..
.‘
VARIABLE 7:
SUPINE DIASTOLIC~LOOD PRESSURE
SiJBF”itG
SLlEiF’Il5
3.
I
1
J
2
3
4
64 c 482’76
69.75862
70.13799
‘72 , 48276
1
5
72*2Od.l9G
3.
1
6
7
1
H
b3+86207
b3 ‘ 3s 034
t,SFOL896
1
E;UEiF’DZ!G
.
6URF’CIC
hP.f3333
67 + 93333
LR*46617
70.2OOGG
76s 13333
7’2,2ocJoo
70,33333
69+4&657
67 < osos5
ss*s3051
6?,1%3S2
71 a32203
1/17*203’;59
68+ 10169
65<S$iJ6
-67.79661
!
i
f
i
i
‘
‘.
i
VARIABLE 8:
SUBJECTIVE RATING OF DRUG EFFECT :
a
2
t
a
mc
W
>
VARIABLE 9:
SUBJECTLVERATING OF '%OOD" EFFECTS
CELL
MEANS
FOR
I-ST
DEF’Elt!DENT
VfiRWJ.~~RI,E
t9lhRfl
OKLlER
DOSE
1
1.
1
G00D20
1
GOOD40
GOOD60
1
1
1
2
3
4
5
&
G0 U Ii C.
GOOD1 20
1
1
8
9
GODrIo
G 0 0 iI 5
G 0
*
c. .
0
II
1 0
Goor
c
1‘
"
,I
1’1‘
k
.
'
t
2
t
1
1
I
4.
5
6
7
HAL
I
i
E
3 t 10000
3.63333
4 c 50000
5. S(r000
q.73333
: 5.066567
4+03333
.3+bbt67
3*40000
I.10345
5.00G00
ct*3??31
5.27516
4.58521.
3*55cji7
3.31034
1 l 34483
1.13793
5.19165
'IO.92180
13*8031?
,.-. $0 *1o.747
10+12605
7.31572
7,3:<1?38
G00B10 I 3,
GOODS
.
=
TIME
'.
-.
11‘ s3092
11e38505
ll+d7594
'ix 3 fi ,5
Goorizo
Gc)uri30
G00i140
fiiili TLC
19 I
GOOIiC
' G00i~120
O@C)TIO?
G
G&r2
0 F1[I 5 2
2
23
7.75652
7.3907" J
11.04553
9.49313
Gq n it 2 0 3:
2
4
Gfi 0 yr4 (12
GO051602
2
2
s
&
5.8102’
. .!a
6 .29293
7.97162
IO.32957
9.44707
6*17522
2<.1jE:64
4 l 30508
544 2373
5*389t(3
4.66102
4.37288
3*67797
3& f. s 1.':; 42
2*2r;a14
!
1
i
i
_,'
.'
12.93467
12*93467
. . 5 .
11.59171
'.
I
.I”
*
)
AI
I..
>
.
.
c
‘YARI~BLE 10:
-.--
c
SUBJECTIVE RATINGOF "BAD" EFFECTS
CELL
M,C~\~JS
FOR
l-s’]
~&f~PEi!<~?T
RBLE
Vf+~-kj
L!
f4ARFf
El
1
xrBillS0
1
*17241
RE-bOOT
1.
AT
2
10:50+..~,10
2*4482%
1
1.
3
4
1.
1
1.
6
7
8
J3kIl60
-_- 13k D ii 0
BADC
' -$rl 1 3 I?,
1
'2
2
2
2
2
‘3
- 3
s
BAD
2
6
a
3
7
8
9
c* CJ 2
b g.jEl8 0 2
R&1‘1r.?
‘E$J~t12G2
2
1 t33333
2.7GGGO
3,GOOGO
4.30OOO
4,%b667.
2.G666i
.
.
t 56667
2.5GOGG
5.86667
6* 63333
4.100OQ
6.80000
4*?GGOG
.94915
2+08475
3+91525
4‘0tt475
3,*86441.
4 * 22034
3.23729
3.4f?438
A.
4.fj”jA!iR
4:I.:<y*-r,15
2.93333
1 . fr?n90
,29
COUNT
*
EAT10
FADS
FAD10
BAD20
PkIl4O
Bhil&O
BADSO
: %I
BAl[Il20
BAD02
FOH
I.-ST
fJkUf:R
=
A
-
UCiSE
1
1
1
1
TIiiE
‘1
3
3
4
5
6
7
8
Y
1.
2
3
*4
5
1
1
1
1.
..l
2
F! Ai! 53
2
ImIlX’;
EkI1202
EAD402
.*-J
5
2
i
bAPb02
PAD802
PADCZ
Fklil202
2
2
2
I.
-
I
I
t
67 8
9
-
_-
..‘;
,;60172
7;497@0
7,44322
5.60392
1*18280
‘. ,1+889%2
.:. .’ 4;36294
I.48639
1.19832
5.78962
5.40~*%5
5.35420
4.88866
5127472
44.92930
.‘?5398
7.36103
7 dZZ8%4
*
-
’
2*6?492
3 4 539A.7
3
l
I
.5443A
,
,*,,’
DE’.‘1 AT IONS
f
qs,
1,34’+83
1.65517
1.89655
1644628
1.58621
1.55172
1 b51724
+.
i ’
L
I
I
1
“i
I
t
a
I
f
1
-1.86441
2,23729
1.79661
2.67797
3‘20339
1 s 50847
1
*
I
1
1 l 83051
1 c 23333
2.44829
HARBTNAI
STANDAI?D
.32203
#&"Qjj,
1
2
flADG2
PArI
EiAl[IX2
BA0 2 0 2
EfG11402
*
hXf4...l,.th.+q.
l
9
\
,46667
2‘51724
1*75862
,5s17=!
1 UOOOO
1.48276
,93103
f?fiL
59
30
DEF’EHSrENT
rJhR1 ABLE
P
..
l
.’ ’ 2.02967
2.71247
2 l 78T70
I6.13’7399
8 * !?#!?%I 2
10.00396
11.05701
4,04230
8.42583
?1+81342
5.8Z?947
12.08228
1%. 16X%9
9 *fit5773
‘-
’
1 ‘(.
__
._
10.4399%
?*33422
12.22#$5)2
7.83121
.----
_ ..
/,--
.---
VARIABLE 10:
.
.. .
,
SUBJECTIVE RATING OF '%AD" EFFECTS
~,
.--em
r--.-T.
..-7-c-
*
I
I
P
!
SIS
---- hr4AL.Y
--
OF
VAFi XAMCE
FOH
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SOURCE
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FINAL REPORTOF
ClINICAL PROTOCOLNO. 82-8(A)
An Evaluation
of the Acute Effects of
Phenylpropanolamine
in Normal Volunteers:
Parallel
Groups Desdgn
Sponsor:
Thompson Medical Company, Inc.
919 Third Avenue
New York, NY 10022
Investigators:
Ira Liebson
George Bigelow
Roland Griffiths
Frank Funderburk
Protocol
developed
The Clinical
Consulting
ANTECH, Inc. and the
Behavioral
Pharmacology
by:
Frank Funderburk
Contact:
(301) 997-0880
Project
start
date:
Project
completion
25 June 82
date:
31 August 82
Group
Research
Unit
i
TABLE OF CONTENTS
ABSTRACT C................................................~.............
INTRODUCTION ...........................................................
2;
OBJECTIVE ...............................................................
2
RATIONALE ..............................................................
3
INVESTIGATIVE
Subjects
Design
METHODS ..................................................
3
..........................................................
3
and Procedure
1. General
..............................................
Procedures
a.
Subject
b.
Meals
c.
Drug administration
d.
Clinical
2. Design
control
and food
4
.........................................
4
.........................................
4
restrictions
.............................
.....................................
measurements
...................................
. . . . . . . . . . . . . . ..**................**...*.........*...
5
5 6
6
RESULTS ................................................................
G
DISCUSSION .............................................................
8
REFERENCES .............................................................
10
APPENDIX ...............................................................
12
FIGURES . . . . . . . . . . . . . . . . . . . ...*.............*.*..**...........*......*..
35
ABSTRACT
One hundred
participated
of
fifty
in
of
t.i.d.1
HCL on blood
in comparison
drug treatment
capsules
received
the
release
(Group
were studied
Measurements
and subjective
at baseline
treatment
Cl
(prior
design
on any
received
blood
pressure
analysis
of
effects
for
logical
and subjective
the
of
time of day (circadian
changes were not,
state
however,
related
each
occasfon
and
in another
B).
group
Subjects
medication
in
occasion.
and supine),
9 times
revealed
during
hr,
1 hr,
no main
As expected,
effects),
changed
(Group A) received
the
2 hr,
pulse,
session
4 hr,
6
dosing.'
variance
measures.
to one of
(Group
and at l/2
initial
assigned
Subjects
standing,
were obtained
to drug administration)
and 25 mg
session.
(sitting,
(“mood")
and 12 hr post
at
effects
Two dosage
medication
occasion
for a 12 hour testing
of
first
placebo
the
release
in one group
occasions.
each medication
drug effect
8 hr, 10 hr,
Mixed
at
were randomly
on thefr
of
and mood.
(75 mg sustained
Subjects
two dosing
(mean age = 25.9)
comparison
pulse,
Subjects
dose
on the other
group
pressure,
conditions.
25 mg capsules
other
Subjects
placebo.
volunteers
controlled
were studied
with
75 mg sustained
placebo
normotensive
placebo
phenylpropanolamine
the three
the
healthy
a double-blind,
phenylpropanolamine
forms
hr,
(150)
over
all
measures
indicating
the
course
to the drug treatment
effects
that
of
the
for
showed main
subjects'
session.
condition.
drug
physioThese
2
.c-.
Final
An Evaluation
Report:
of the Acute Effects
Phenylpropanolamine
of
in Normal Volunteers:
Parallel
Groups Design
INTRODUCTION
Phenylpropanolamine
actions
less
similar
to ephedrine.
CNS stimulation
counter
hydrochloride
(OTC)
in
control
safety
and appropriateness
No.
39,
information
blood
aid.
ephedrine.
United
weight
47,
In
pulse,
to provide
synthetic
PPA is
currently
both
as a nasal
publication,
self-reported
of
to
marketed
agency
safety
side, effects.
produce
and
questions
as
about
Register,
requested
with
over-the-
decongestant
have raised
the
compound
believed
of PPA (Federal
of PPA on a variety
and
a
generally
FDA and others
their
is
PPA is
of OTC availability
on the effects
was designed
States
Recently
1982).
pressure,
However,
than
the
(PPA)
a
the
Vol.
additional
parameters
including
The present
project
such information.
OBJECTIVE
The proposed
the
effects
of
12 hour testing
research'aimed
PPA on various
session.
to
provide
behavioral
an objective
and physiological
characterization
parameters
of
over
a
.
RATIONALE
PPA has been
ingredient
used as an anorexiant
in many over-the-counter
1980).
Recently,
generally
in
United
however,
doses
Silverman
dose
.:
c
et
of
(paper
side
al.
in
study
pressure,
clinical
of
1980;
was undertaken
and
to
in
or
the
other
1981).
effects
100 mg of
PPA--
of
a 25 mg
caffeine.
effects
Hoebel
of
150 mg
individuals,
extend
subjective
use
Dietr,
hypertensive
normotensive
that
effects
hypertensive
been an
Silverman,
over-the-counter
Horowitz,
with
e.g.,
suggesting
hypertensive
no adverse
six
(see,
appeared
for
and has long
adverse
combination
noted
pulse,
have
no adverse
in
in a group
The present
controlled
or
1982)
preparation,
blood
(e.g.,
40 years
products
approved
with
reported
alone
PPA (75 mg b.i.d.)
on
effects
(1980)
PPA either
those
associated
be
amphetamine-like
than
over
cough-cold
some reports
higher
States--may
for
the
examination
state
in
a
of
PPA effects
large,
carefully
investigation.
INVESTIGATIVE METHODS
Subjects
Subjects
and
All
The
female).
orientals,
had
criteria:
were 150 healthy
study
and 1 American
given
informed
normal
population
Indian.
consent
volunteers
consisted
Approximately
and
had been
(mean age = 25.9)
of
83 Caucasians,
58% of
screened
the
to
(both
63 blacks,
subjects
meet
male
the
3
were men.
following
a.
between 18 and 55 years
b.
no current
use of medications
validity
of the evaluation
no physical
c.
which would compromise the
of the test
contraindications
the dose levels
d.
of age
no history
to consumption
used in this
of
severe
products
of PPA at
study
emotional
disturbance,
chronic
alcoholism,
or drug abuse
e.
evidence
that
the
subject
would participate
in the
research
and
be cooperative
f.
good
general
conducted
within
physical
i
health
based
on a medical
one month
of
the
history
study
start
interview
and
a
recent
examination
-
< .-
female
9*
subjects
a baby for
certified
that
the duration
they were not pregnant
or nursing
of the study.
Design and Procedure
Subjects
entry
into
subject
were
the
randomly
study.
are detailed
1.
General
a.
medications
The basic
control.
of
study
testing
were
supervision.
period
three
investigative
Subjects
the week prior
who had ingested
clinical
one of
treatment
procedures
groups
followed
for
upon
each
below.
Subjects
the
to
Procedures
Subject
for
assigned
to the first
substances
excluded.
instructed
administration
which could
Study
Subjects
(approximately
were
remained
13 hours)
the
on the test
be free
of a test
have compromised
medications
at
to
were
test
day.
facility
all
product.
the validity
administered
for
of
under
the entire
5
provided
b.
Meals
with
a choice
coffee,
(e.g.,
tea,
c.
marketed
wre
of
test
received
identical
of
were
and 4:00
pm).
Subjects
were
tions.
One group
of
release
product
placebo
at
dosi ngs.
of
at all
being
the
given
subjects
Another
neither
to
Dosing
Dose 1
8:00
A)
and
medication
of
schedule
group
is
75
placebo
(Condition
one
day
the
was
being
8:00
treatment
the
matching
test
approximately
three
received
condi-
mg sustained
capsules
B) received
(Condition
illustrated
C)
on
25 mg
received
in Table
1
Schedule
on a Test
Dose 2
am)
so
(e.g.,
one
of 'subjects
Table
(approx.
that
code
intervals
dosing
75 mg
medications
Finally,
This
dosings.
and
Study
which
dosings.
t.i.d.
product.
know
group
25 mg,
currently
a test
could
dosing
two
On each
(Condition
first
xanthines
placebo.
in
assigned
were
with
labeled
4 hour
containing
investigation
were
at
randomly
three
three
and
of
subjects
days.
PPA (PPA,
compared
subject
their
this
days
Foods
on study
containing
appearance
the
meals.
In
administrations
Doses
each
permitted
three
administered.
PPA at
were not
were
nor
subsequent
noontime
products
investigator
On test
standard
PPA)
in
am, 12 noon,
restrictions.
administration.
release
subjects
food
cola)
Drug
doses
sustained
and
(approx.
12 noon)
Day
Dose 3
(approx.
4:00
pm)
Condition
A
75 mg sustained
placebo
placebo
Condition
B
25 mg PPA
25 mg PPA
25 mg PPA
Condition
C
placebo
placebo
placebo
1.
6
c.
d.
Clinical
were obtained
9 times
drug administration
and
12 hr
standing,
following
Heart
Association
state
wre
indicated
of
that
procedures
2 hr,
procedures
7980).
they
felt
effect.
Once prior
6 hr,
Blood
pressure
recommended
These
8 hr,
10 hr,
(sitting,
by the
American
measures of subjective
mood-scales
a drug
pulse
to initial
4 hr,
Clinical
analogue
may be viewed
occasions)
were
analyses
analysis
measurement
used
on
effect
measures
which
and their
were
subjects
subjective
supplemented
of research
to
design.
evaluate
were drug
occasion
For
involving
used in evaluating
hr,
while
l/2
statistical
from
treatment
design
by
staff.
this
assignment
hr,
etc.).
component
measures
factors,
significance
(Condition
(see,
of
variance
of the
variables.
x 9
study.
Factors
A vs B vs C) and
Treatment
occasion
conditions)
analysis
each of the dependent
measurement
repeated
Mixed
data
treatment
(0
factor
tests
mixed
as a 3 (drug
were conducted for
between-groups
all
1 hr,
of subjects and the observations
study
(measurement
the
visual
which
.
drug
session:
and
Design
This
in
to
using
et al.,
using
extent
hr,
blood pressure
of
drug 'administration.
was measured
subjective reports
Separate
and at l/2
(Kirkendall
the
Measures
each experimental
initial
obtained
impression
c.’.
during
(0 hr)
supine)
2.
measurements.
assignment
was a within-subjects
a conservative
was
a
factor.
t
test
was
e.g.,
GeSsser
& Greenhouse,
for
each of
the
1958).
RESULTS
Specific
4
c A..<
results
of
the
studied are summarized below.
-
analysis
of
variance
variables
7
Pulse
16.67,
drug
tended
e < .Ol)
Standing
systolic
(E = 4.34,
main
marked
effect
blood
subjects
all
treatment
for
treatment
the
systolic
group
session
lowest
groups
blood
tended
pressure
to
show decreased
as compared
with
Sitting
1
< .Ol).
subjects
effect
for
drug
No main
shown in Figure
in
in
diastolic
for
for
in
This
the
trend
No
E < .05).
initial
diastolic
medication
No main
for
effects
for
the
blood
in
all
treatment
lowest
the
75
at
hours
post
mg sustained
systolic
blood
25 mg t.i.d.
pressure
1-4
release
pressure
later
or placebo
groups
was generally
treatment
groups
lower
CF- = 11.22,
These
was identified.
results
at
1
<
are
1 (attached).
systolic
1
group
<
blood
.Ol).
pressure
This
(5 = 4.44,
identified.
Supine
diastolic
post
dosing
IL
was identified.
post
sitting
subjects
dosing
initial
later
Standing
hours
(F- =
effect
groups.
was identified.
Subjects
.05).
post
treatment
session
hdgher
!E = 3.39,
was generally
<
4-8
(E = 11.09,
the
.No main
treatment
group
8-10
1
.05).
‘Supine
all
(E = 13.80,
e (
.Ol).
at
of
generally
placebo
condition
(5 = 3.65,
hours
in
course
conditions.
was
subjects
in
treaQnent
(E = 4.01,
treatment
for
the
treatment
pressure
subjects
drug
all
over
was identified.
Sitting
the
blood
was generally
in
medication
in
E < .05)
for
pressure
slightly
'subjects
was identified.
was more
in
for
increase
treatment
session
drug
to
e
= 17.70,
was generally
increase
< .05).
blood
tended
No main
pressure
2 < .Ol).
higher
to
be
effect
tended
No main
later
largest
for
drug
to be lowest
effect
for
in
the
session
in
the
placebo
condition
at
drug
6-10
was
hours
condition
Subjective
differences
between
significant
changes
measures
of "drug
6.35,
2 c .Ol),
drug
liking
subjects
(more
measures
the
These
e c .Ol)
for
course
"bad"
the
in
the
ratings
course
E < .Ol),
of
the
and
subjective
more
state,
and were not considered
however,
These
of feeling
placebo)
session
were,
session.
(5 = 5.30,
the
no significant
There
of
1 < .Ol),
over
in
small
included
"good"
(F- =
and ratings
session.
In general,
reported
feeling
dysphoric
later
although
of
better
in
the
statistically
clinically
relevant.
Figure
effects.
Summary tables
results
conditions.
groups (including
variations
these
the
feeling
early
were very
2 illustrates
of
and mood revealed
drug
(F- = 8.53,
treatment
pleasurable)
reliable,
three
effect“
Cc 5.30,
session.
effect
in mood over
ratings
in all
of drug
of
standard
means,
each variable
studied
deviations
are presented
and
analysis
in the Appendix
of
variance
to this
report.
DISCUSSION
The
present
study
phenylpropanolamine
standing,
and
the
(75 mg sustained
Measures
placebo.
evaluated
of
supine)
drug
and
acute
effects
on
subjective
two
25 mg t.i.d.1
release,
effect
of
pwl se,
state
blood
("mood")
dosage
forms
in comparisgn
pressure
were
of
with
(sitting,
obtained
over
a
l&hour testing period.
No significant
the measures.
very small.
observed.
mafn effects
Differences
No consistent
for
in blood
pattern
On some measurement
drug
pressure
treatment
between
of differences
occasions,
were observed
on any of
drug treatment
groups was
between
subjects
drug
receiving
.!
treatments
active
was
drug
9
c
treatments
showed
placebo
higher
treatment.
statistically
any of
On
As expected,
over
pressure
Our results
are
had no systematic
effect
were
not
finding
that
As
as
also
with
with
over
treatment
groups
reported
in
Overall,
dosage
forms
the
the
session.
the
present
studied)
pressure, pul se,
or
suggest
that
subjects
was
receiving
reversed.
treatments
or
were
No
found'on
mood.
of
effects
feeling
findings
is
not
drug
than
Seppala,
of
drug
the
suggest
associated
that
effect
of
and
subjects
subjectfve
state
early
that
with
blood
19781.
forms
studied,
or drug
liking.
on
two PPA treatments
the
placebo.
Korttila
in
the
showed
subjects
session
phenylpropanolamine
effects
as
in
PPA.
with
(trmoodu)
general,
a
This
(1981)
treated
In
adverse
of
were observed
the
for
session.
"better"
dosage
of
were
& Raftey,
treatments
Nuotto,
were noted
pressure,
course
of
pressure
variation
the
The effects
worse
blood
Bishop,
PPA, in
between
any
that
in
Circadian
ratings
liking.
blood
changes
later
drug
Millar-Craig,
literature.
better
circadian
with
e.g.,
this
drug
euphoric
case
effect
session.
differences
or
consistent
the
did
differences
on subjective
any
no significant
was
with
effect
rated
between
daily
(see,
reliable
drug
is
the
consistent
results
of
this
significant
of
The present
measures
than
occasions.
documented
No statistically
.
c.._
differences
course
well
pressures
occasicns,
statistically
the
is
blood
.
other
significant
the measurement
found
mean
in
all
compared
(in
on
the
blood
10
.
c
REFERENCES
Dietr,
A.
J.
Amphetamine-lfke
the American
Federal
Register,
Geisser,
the
Medica)
S.,
Association,
Vol.
47,
Hoebel,
1958,
2,
of
multivariate
Personal
be published
in Philadelphia
Horowitz,
J.
D. et
in anorectic
Kirkendall,
determination
Committee,
McNair,
by
al.
et
M. W.,
pressure.
of
manual
use of
Mathematical
for
1978,
N.,
April
on normotensive
Company.
Abstract
to
Lancet,
Report
by
phenylpropanolamine
1980,
Jan 12, 60-61.
for
of
the
human
blood
Postgraduate
pressure
Education
1980.
the
and Industrial
C.
mg b.i.d.1
induced
Recommendations
al.
Edits
Lancet,
on the
1982.
preparations.
Association,
Bishop,
results
Annals
(75
responses
Heart
Educational
California:
: blood
Hypertensive
sphygmomanometers.
American
D. M. et
Millar-Craig,
M.
Box's
Thompson Medical
Medicine,
and decongestant
W.
of
l
communication,
al.
of
601-602.
analysis.
phenylpropanolamine
volunteers.
Journal
.
An extension
885-891.
Effects
B. G.
245,
phenylpropanolamine.
1982.
S. 'rl.
in
to
1981;
No. 39,
& Greenhouss,
E distribution
Statistics,
reactions
Profile
of Mood States.
Testing
& Raftey,
Servjce,
E.
15, 795-796.
B.
San Diego,
1971.
Circadian
variation
of
11
Seppala,
of
T.,
three
and
Nuotta,
& Korttila,
antihistamines
subjective
Pharmacology,
Silverman,
E.,
H.
K.
Single
and repeated
and phenylpropanolamine:
appraisals
of
sleep.
dose comparisons
Psychomotor
British
performance
Journal
of Clinical
orally
administered
1981, l2-, 179-188,
I.,
et
al.
Lack
phenylpropanolamine
and
three
Current
phase study.
of
side
effects
phenylpropanolamine
Therapeutic
with
Research,
from
caffeine:
A controlled
1980, 28-, 185-194.
APPENDIX
C = DRUG CONDITION (Hk75MG
SUSTAINED RELEASE: LO=~~MG T&D,:
P=PLACEBO)
2=30 MINUTES;
3=1 HOUR; 4=2 HOUR; 5=4 HOoR; 6=6 HOUR; 7=8 HOUR; 8=10 HOUR;
9=12 ioiik.
R = REPEATED KE~UREMENT OCCASIONS (~=BASELINE;
FOR EACH VARIABLE STUDIED, MEANS AND STANDARD DEVIATIONS AT EACH
MEASUREMEN+OC~AS~N ARE PRESENT& ii
ONE TABLE; WHILE ANALYSIS 0~
VARIANCE RE&JLT& ARE PRESENTED IN ANOTHER,
WAS USED TO EVALUATE THE RE&&
MEASURES,
A CONSERVATIVE E-TEST
0F ALL FACTORS INVOLVING REPEATED
EFFECTS OF PHENYLPROPANOLAMINE
ON BLOOD PRESSURE,
PULSE, AND MOOD:
PARALLEL GROUPSDESIGN
Study Site:
Behavioral
Pharmacology Research Unit
Johns Hopkins University
School of Medicine
Baltimore City Hospitals
D-!&West
4940 Eastern Avenue
Baltimore,
Maryland 21224
Contact:
Frank R. Funderburk
Director,
Clinical
Consulting
ANTECH, Inc.
(301) 997-0880
Date:
October
8, 1982
VARIABLE 1:
f ‘.?j
.tzj
.'4
It
I:,f,,i
i, i
L!,
1
t
PULSE
R
Y
PULS
PULl.0
put 30
PUL40
ruL60
1
3”
n
5
(5
lO,~Oi)
11.7633;3
30.64369
It
.04SAl
10.31749
11 .533t?7
1.0 +iJ 2 f,:!0 I:r
10.03370
8.41000
9&4pS&f
9*3c,13s
11*06339
10*1?735
10.49857
11 .78924
ll&6937Tz
1l.x. i'078sj
13,?i9l$;'2
VARIABLE
1:
PULSE
x
.
SOURCE
8lJM tw
SC~ll$lKf!i
t.lEGf?filtS
FRELiiiiM
OF
MEAN
SQUAf\‘E
rRoB*
F
r.XCEt:rwD
F
--
----
II_.
*
C,’
..
STANDING SYSTOLIC BLOOD PRESSURE
VARIABLE 2:
IIARGJWL
I
*:
c 0 b! D
1
STBPSO
I
99.44000
100. on000
1.00. 2OOC)O
STANDARD
97.E0000
79 I52noo
37*E4000
7u.
c/
)‘
l
100.76000
103.
1.01 ,00000
lOf.OOi~Oz~
DE’JIATIONS
=
CONKI
FOR
2..ND
100
l
tab67
:Z’>
2.’
DEFENDENT
-~-
P
LO
l-i s
.04000
R
4
12
36UOO
00000
~~
I
c
P
LO
Ii1
sTT.Fqo
ST&
STEPS10
qTrtpcJ20
. ,a: '. fi
I.
1.1 (),.
1')
l.3. Wi202
12.11482
12*10161
12,30125
lb.84484
I5 * 73005
17.s173x
\1.33&&,~
19.3319'7
STEPS40
STKfPSSO
2
3
4
5
6
95556
1.3.37530
J.2+OlYcc4
t2.71074
lb + 3:;scJs
16 * 70024
STEPS12
9
17+10763
14.60243
1
J
.e,&y";o
,'.T)../.
1
l
.,;
.I..1
VARIABLE 3:
STANDING DIASTOLIC ELOOD PRESSURE
PIARG JNRL
COMD
\
I
::
:-I I
r
LO
I3
1
STBfDO
C14637333
62.80000
63<3CIOOO
66 > ooaoo
65.24000
63.20000
61 ..52000
63.36000
63 c 56000
hl.64000
60.03000
60 + 7'2000
16
l
96000
65.76000
1
1
!
=
CONE
)I4
STEF’DlO
rs 3
3
4
t: I
lO*iJt395
11*32592
STEPD40
STLIP D&O
CJ
0
7
10.15902
_ lO*SG373
10 3JeJ59
8
SfEPDlt
?
,I0472217
il.69413
453333
54.38667
63.44000
60.31333
64
p
LO
8.94619
9.70374
6.56724
9.35457
7.93247
.
Z1.29558
10.23033
12.313755
ll.&‘irJ29
12.13093
13.15378
1”
p7]9sq
12.45767
14.124t~l
l
:T
I
-
’
i’
VARIABLE 3:
9OtJRCE
UEAN
r
ERROR
_%
:.
i
.%.
-
STANDINGDIASTOLIC BLOODPRESSURE
.*
SUN iW’
SWARES
Dt33REES O F
FREEDOU
1
53f30216.&2SOO
3
/&&,33-@7
147
113269‘29492
XV302
F
MEAN
mutmE
16 * 62:!POO
PROD*
F :
CXCEFDED
6976
t 24384
l 000
771.21969
I
R
WC
4574.J4139
w2,95117
8
16
571 l /31tJ30
53.33445
* 000
,138
13*70:;14
1 s.30117
.-e--m-
i
VARIABLE 4:
SITTING SYSTOLIC BLOOD PRESSURE
CELL
MEAH:;
FOR
4-l-H
DEF’ENCJENT
VAR1;ADtE
..
COND
f
::
R
SIBPSO
$Tqlpqc
SIBPSlO
SIBP320
SIBPS40
SIDP360
..
-c
-P
LO
0
.
1
107.7%000
d
107.80000
23
109.000OQ
108.17333
3
1117,e;qQRO
1117,.CIROQII
* [)e;
y of,nbnnn
3
4
5
6
107.22000
lO6.52000
108.E4000
110*96000
106.96000
105r44000
104.04000
10s c 23000
106 *96000
106.16000
10ti.16000
110,1200~5
&Q&Jp(,
110.44000
lOSr4ZJQW
111.92000
105*95772?
fO7.9E1667
107.42444
10:-j 16001)
109.9&000
105.40000~’
107.320311‘1
l
9
‘
.l s
.
t
.
I
MARGINN..
107.04667
106.04000
106.01333
103.12000
14444,&q
107.86667
107.25333
i gC)?nnnrt
SIBPS12
1i
IiARGIiwL
NI
,,.:
.
.y,:.,p
._:
, x6:
:
STANDARD
DE'JIATIUNS
=
f Ifi?
4-TH
1;.,.A
'>
VWI&M.E
DWEiDENT
t0
14I
.“’
P
K
SIEPSlO
STrtra .’c: 3 a
SIEPS40
SIDPSSO
S
6
7
SIEPSl.2
13&&373c,
li.93654
12.45283
tl, @JBw
14 .C3564
13.01327
't.
7-x
0
12.41520
7
14.74823
11 .?aR4?.7
qn,t$(J”;rnn
lO.33039
10.89147
14.45522
14*93511
11
-79AA7
.
l!K.fZ&?lr;
11.74206
ll.ll72Q
14,92242
l&.20730
11*s.t.pfa
18,n7,0;3
13,fJ347
12.60320
14‘88437
lS.02412
( : ._*.<g
r y‘
..$’““2
. y$~~;$
I
.&,.
.;
fh
VARIABLE
4:
SITTING
S~sTouc
ELooD PRESSURE
---
VARIABLE5:
-,
SITTING DIASTOLICELOODPRESSURE
!.
I
CELL
1lERNS
FOR
S-W
I
t:
COND
SIEPDO
R
UftRI4BLE
n
F
4s:
LO
HI
6E(.OOOOO
1
DEBENDEEfT
69.96000
#ARGINAl..
611.36000
x7
SIEPDlO
3
68.60000
09+65)000
6R.56000
63.16000
6ff.77333
,.I)
67.16000
67.70000
68i10667
68.34667
66.12000
zi7,fio222
STANDAFdl
DEUIATIONri
f
COND
FOR
SyTH
1-II
DEFk4DENT
UAHIAULE
F
LO
R
i
!I
i ”
I@
I*
SIf-FD()
.: *
1
8.04071
fj,djyp#j3
¶(.Lb5;14
SIDPD5
SIBPDlO
SIDPD20
SIE(F‘D40
SIBPDJO
s I HPD80
SISPDC
SIEPDl2
2
11.46772
9.6557h
3
8.92829.
a.79740
4
5
6
7
8
9
,tO.738?#
10.64461
9.73096
12.0991D
10.34617
IO.92916
A63465
10.18274
12e35239
10.79S99
12+lJS25
9.73686
10.14386
11*62713
-.
10.15062
c*73wt3
3.930133
7.34723
7.02387
8.55l32
"
VARIABLY
__-
..
:
,,,
.: . I_
ME/rN
WACNfNG
c
ERROR
R
EHRtiR
SITTING DIASTOLIC FLOOD PRESSURE
-.
:.:
RYmFH
5:
1
hOR0394.56250
-
MAX
6000394,56250
1041.27734
56037.03044
2
147
3946.07451
8
51694*99854
520, (1Sl$67
505.29182
493 t 3:iY31
43 t YbO33
1176
.,
r;
10303*65442
,000
F’Ar<‘;CC
l
38054
11 . 3’
a..&
z’t’s.*,,
IJI
,413
&e
c
VARIABLE 6:
SUPINE SYSTOLIC BLOOD PRESSURE
CELL
HEANS
Ffbl?
, &-TM
DEPEMUENT
VRRIAIILE
MARGINCIL
::
COHf!
HI
LO
P
1
108.54000
111.12000
110.52000
l10.08000
SUI3P520
4
SUEPS40
SUEPS60
5
0
112 + 64000
116rE4000
115 22or>o
112e7QOQU
110*24000
113*?209#
110~7400c)
111.24000
llS.5600r)
112.04000
j12.77333
1.12.35111
113.12444
113*19111
f 12.8OE~89~
1
R
SUUFSO
*
l
MARGINAL
.’
1:
COUNT
STANDARD
c*
.‘.I.,,
DEVIATIONS
FOR
e*
dS-fl4.
to
DEPTNDENT’
VAt2Ic?!Rt.E
is
e
COND
, 1
II
1’
.j
1
7
i:,’
1q
1
HI
LO
-
115+23333
,wn
~._’“ii., *’
t.. 2...
,>‘:(.
::
P
I?
SUBPSO
SUIrPSS
SUBPS10
2
S(Inpspo
3.
SUE:FS40
sunPs&o
$1 I~SRO
SUEPSC
SUBFE12
5
4
7
8
9
11.272
‘2
12.35935.
11+142?&
.,:,
.
14.EO259
.12*12065
1a,Q26ni
11~84002
12.4408%
,‘I,
1,2.34142.
23.73589:
t.2 rr7.ta
12.34629
10 .!52354
10,XPAXf
if.74206
12.70475
l
14,9351;8
11.244%8
1!%~2.
13.73742
13.57092
,
i3*SbW%
17.813380
_:
:p2, _:
,.<,.’?;‘;F
-?-.
f
VARIABLE 6:
‘..____
. .
.
SUPINE SYSTOLIC FLOOD PRESSURE
_,_
.h.--.L
..-
,
SOURCE
17%
HE AN
.
1720424f.~.00000
ERROR
143991.43047
K
kc
5707.95410
4572r07422
i
,,
1
,
147
3
16
1 3z!Q4%4(2 .ooooo
,000
‘979 * WY37
.713,74426
235.75464
ll*QY191
4 * 44076
*OOQ
,000
“
VARIABLE 7:
SUPINE .DIASTOLIC BLOOD PRESSURE
NARGINfaL
CON0
)
::
HI
LO
P
R
SUBF@rJO
1
SUBPBlO
3
66.!32000
A9 .&&an
70.32000
69.36000
71 Ao~cro
72.04000
67.96000
67 * 94667
69 + 64000
70.66667
f
.b
VARIABLE
‘
7:
SUPINE DIASTOLIC FLOOD PRESSURE
:-------
HEAN
ERROR
R
RC
6453451
39671
1
t 7:5000
.f#ilOW$
5711.99512
147
3
.
6453451..
75000
----40!57Y.21S4S
1 .w
.ooo
17-z
610*01231
7 13 , WVB’ir
1 lOOa
12 * 7042%
1.70575
,000
c\
*-
VARIABLE
8:
SUBJECTIVE
CELL
I
HEANS
RATINGOF DRUGEFFECT
FW?
,8-TH
VARIAI(LE
DEPE.NDENT
I I
?
1
:I1
LO
P
R
DRUGEFO
I
2:
CCiND
MARL
1
,480OO
.64000
.::
ys,
.j+
)
.
1.18000
.76667
-
!
DRUGE20
0
4
3.8t3000
5.84000
3.3f~OOO
4.50000
SrJ2567
4‘12667
5.22000
_
Q
4
i
!
-
,^i\
t
t
.-“-
.
VARIABLE 8:
SUBJECTIVERATING of DRUGEFFECT
.
---.--_
.
\
.
.
.
.
-__-__
*
I
..--
.-
.. .--
c
,
c-\
t
VARIABLE 9:
SUBJECTIVE RATING OF #GOOD" EFFECTS
CELL
!
MEAHS
.’
’
CONrl
*::
FftH
9.-l%
”
,,
141
VARIABLE
r
#ARGXNAL
P
LO
R
GO000
DEPEHDENT
‘,
_‘,
1
2.02000
1.0~000
2
6
4.44000
4.20000
4.16000
5.7~000
4,~UOOO
s. 10000
7*3(3000
S.16000
4.70000
l
38000
1
l
r~aooo
6.24000
GO01160
STANDARb
h.
DEUIATICINi
FOR
‘T-TH
DCPENDENT
VARIABLE
6.03333
4 78000
4.55333
l
c
1
VARIABLE 9:
t
HEkN
r
1
2‘) 1 % ij .70%98
*Q&&&&p
:
291%5~70%9%
34,55’)5%
9
c)
124142.12500
ERROR
R
RC
SUBJECTIVERATING OF "GOOD" EFFECTS
147
2006.i8027
534 + :JO615
. em
%44*50425
8
250 * 713503
16
33.39413
6.3479%
.%452%
“,f
‘..
_’
..
:.
* 000
* 634
VARIABLE 10:
SUBJECTIVE RATING OF "BAD" EFFECTS
CELL
1
.
f:
COND
FIlR
10 -Tit
DEPENDEHT
VARKADLE
HARGIN,AL
P
LO
HI
R
!
BADO
!’
MEANS
1
l
52000
.92000
l
137333
\
_.
lrOZOOO
2.30000
3.54000
5.50000
3 * 6@QOO
4.31000
..,
\
STANDARD
DEUIATIOHS
FQR
IO- TW DEPENDEHT
UAl?IAf(LE
2.74667
4.30667
i
t
VARIABLE 1C:
HEAN
c
ERF;QR
RRC
SUBJ~CT~JE RATING O F "BAD" EFFECTS
1
14~65.22002
46639
+ 73781
15134.04395
851
r32910
1416~-%QoZ
147
-
44 + n46?.4
3 “I)eJjl
,000
3
16
117c,
19UtOQtJ49
53 + 201307
;
e
.
317*2’)726
I’
.w
057
5.29571
1 * 42306
‘..,,.
* 000
,122
-r
c\
11:
VARIABLE
I
SUBJECTIVE RATING OF "DRUG LIKING"
ffARG1 N#?L
1:
COND
.
30+74000
29.2nooo
LIKE0
*
LO
HI
c
:J
3
LIKE10
3
4
29.68000
29 l 35000
LIKE20
STANXMRD llEUIATIONS
*
00
P
31.33()()()
30.7fmoo
39,74()(j()
3Oe26667
30.37333
3J.36000
30.80000
28.76000
27 l 74OOrl
%9.966&7
29;30000
VAR.1ABt.E
FOR
;'
1
11.39817’
__
_I
_:*
., .:. .;’
:(, ‘.‘. .--is
.c
r..
f
/
.
?
VARIABLE 11:
tIEAN
P
ERROR
R
KG
,
1203744,/0933
ii-43
57217.E3008
l97,59Oc12
738.48047
SUBJECTIVE RATING,• F "DRUG CnwwF
1
147
CI
3092.5754’t
.$-&g&,
9 000
r-7
367 ,236(i’4
8
i6
1%03744.609a7
24rJiw3S
46 l l::i503
,58547
1.09307
,791
355
l
‘_I
FM!RF: 1:
w:
SITTING ELOOD PRESSUREOVER THE COURSE OF A DAILY SESS
l ~.SIJSTAIWED RELEASE
A2fjMG T.I.D.
*PlACEBO
I
0
I
s
I
1.0
I
2.0
I
4,O
I
8
I
1
6.0
8‘0
10.0
12.0
Trm SINCEINITIALDOSING WRS,)
i
.
t.
-;
=
t,
c
t
(
T
I
I
*I