Appetite and weight gain in children: A double-blind trial using cyproheptadine and methandrostenolone


Kibel, M.A.

Central African Journal of Medicine 15(11): 229-232

1969


Ninety-eight anorexic, underweight but other-wise normal children were investigated in a double-blind trial utilising cyproheptadine, a placebo and methandrostenolone. The appetite stimulating properties of cyproheptadine and the concomitant effect on weight gain were clearly demonstrated. A group of children taking both cyproheptadine and methandrostenolone together showed by far the greatest increase in weight. It is suggested that this effect of cyproheptadine could be utilised clinically.

Vol
.
15.
No.
10.
OCTOBER.
1969
tue
CEN
MAL
AFRICA
no
JOURNAL
or
MEDICI
PM
established
by
measuring
the
rate
of
fall
of
haemoglobin,
and
hence
the
severity
of
the
disease,
over
the
coming
weeks
and
months.
As
the
stimuli
for
haemopoiesis
include
anaemic
hypoxia,
it
is
proposed
to
maintain
the
haemo-
globin
at
a
relatively
low
level
(around
8-9
G.
per
cent.).
Additionally,
this
will
help
to
reduce
the
ultimate
iron
load.
It
is
also
proposed
to
use
iron
chelating
agents
(e.g.,
desferrioxamine)
in
conjunction
with
any
transfusion
as
an
additional
measure
to
prevent
or
at
least
delay
the
onset
of
haemosiderosis.
CONCLUSION
A
case
of
congenital
erythroid
hypoplasia
(Diamond-Blackfan
syndrome)
in
a
four
months
old
African
child
is
presented.
This
is
believed
to
be
the
fi
rst
case
described
in
Central
Africa.
Aetiology
and
problems
in
management
of
such
children
are
briefly
discussed.
REFERENCES
I.
DIAMOND,
L.
K.
&
BLACKFAN,
K.
D.
(1938).
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J.
Dis.
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463.
2.
JOSEPHS,
H.
W.
(1930).
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307.
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TMANN,
K.
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&
MILLER,
G.
(1953).
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SHAPIRO,
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W.,
DISEKER,
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&
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inr.
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En,
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M.
&
MAGII
I.
F.
B.
(1961
).
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403.
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SHaHlot,
N.
T.
&
DIAMOND,
L.
K.
(19591.
Amer.
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98,
293.
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N.
T.
&
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K.
(1961).
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Ent?.
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Med.,
264,
953.
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K.
&
KEIGI4LEY,
G.
(1960).
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DAVEL,
J.
G.
A.
&
CRONJE,
R.
E.
(1962).
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W.
O'G.
(19611.
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TUCKER,
S.
M.
&
PINCKNEY,
C.
P.
(1965).
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roy.
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693.
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FORARE,
S.
A.
(1963).
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Paed.,
52,
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IBRAHIM,
J.
M.,
RAWSIRON,
J.
&
BOOTH,
J.
(1966).
Arch.
Dis.
Child.,
41,
213.
5.
Acknowledgments
Our
acknowledgments
are
due
to
Dr.
M.
H.
Webster
(Secretary
for
Health)
for
permission
to
publish
the
case,
Professor
R.
Lightwood
for
assistance
in
the
preparation
of
the
paper,
Dr.
W.
M.
Buchanan
for
preparing
the
photomicro-
graphs,
Dr.
K.
G.
Gadd
for
the
amino
-acid
estimations,
and
Dr.
R.
F.
Lowe
for
the
normal
marrow
preparation.
Appetite
and
Weight
Gain
in
Children:
A
DOUBLE-BLIND
TRIAL
USING
CYPROHEPTADINE
AND
METHANDROSTENOLONE*
BY
M.
A.
KI
BEL,
M.B.,
CH.B.
(Rand.),
M.R.C.P.
D.C.H.
Consultant
Paediatrician,
Bulawayo.
Cyproheptadine
is
an
antagonist
of
both
hista-
mine
and
serotonin
and
has
been
in
clinical
use
for
some
eight
years.
In
1962,
Lavenstein
and
co-workers
described
an
interesting
side
-effect
associated
with
the
administration
of
this
drug.
While
comparing
the
action
of
cyproheptadine
and
chlorpheniramine
in
children
with
hay
fever
and
bronchial
asthma,
they
noted
a
striking
in-
crease
in
weight
and
a
lesser
but
significant
increase
in
linear
growth
in
those
children
taking
cyproheptadine.
This
unexpected
effect,
ap-
parently
unique
to
cyproheptadine
among
the
known
compounds
pharmacologically
antagonistic
to
histamine
or
serotonin,
has
since
been
con-
fi
rmed
by
others
in
both
allergic
and
non
-allergic
subjects
(Bergen,
1964;
Drash
et
al.,
1966;
Fran-
cini
et
al.,
1968),
but
has
received
scant
attention
in
the
paediatric
literature.
The
present
study
attempts
to
assess
the
action
of
cyproheptadine
further
by
comparing
the
appetite,
weight
gain
and
linear
growth
in
four
groups
of
anorexic,
underweight
children.
METHODS
These
children
presented
with
poor
appetite
and
physical
under
-development.
All
were
below
the
fi
ftieth
percentile
for
weight
on
the
Stuart
an-
thropometric
charts.
Physically
they
were
other-
wise
normal
and
children
with
significant
anaemia
(haemoglobin
below
11
gm.
per
cent.)
were
excluded.
A
normal
erythrocyte
sedimentation
rate
and
a
urine
free
of
protein,
sugar
and
formed
elements
were
also
required
for
admission
to
the
study.
Other
investigations
were
per-
formed,
where
indicated,
but
yielded
uniformly
negative
results.
Th
e
experimental
population
comprised
96
subjects,
whose
ages
ranged
from
15
months
to
13
years
5
months.
There
were
84
white
children
and
12
of
mixed
race.
Each
was
allocated
at
random
to
one
of
four
groups
in
a
sequence
not
known
to
the
author.
The
numbers
in
each
group
are
indicated
in
Table
1.
*
Presented
in
part
at
S.A.
Paediatric
Congress,
Cape
Town.
September,
1968.
229
OCTOBER,
1969
APPETITE
AND
WEIGHT
GAIN
IN
CHILDREN
TER
CENTRAL
Alf1110111
JOURNAL
OF
MEDICINE
Table
I
Group
A
B
C
D
Male
Female
14
14
13
14
10
13
12
8
Total
28
27
23
20
Average
age
(years
and
months)
5.9
5.2
6.5
5.3
Average
initial
height
(centimetres)
110.9
109.4
111.5
109.5
Average
initial
weight
(kilograms)
17.58
17.72
17.39
17.40
Table
If
Period
and
Drug
Per
cent.
of
Initial
Height
Per
cent.
of
Last
Height
Per
cent.
of
Initial
Weight
Per
cent.
of
Last
Weight
GROUP
A:
1.
Cyproheptadinc
..._
-0.3
-0.3
4.9
4.9
2.
Cyproheptadine
.
..
...-
-2.3
-1.9
6.0
1.0
3.
Placebo
......
.....
-0.4
1.9
5.6
-0.4
4.
Placebo
......
.....
__
..__
1.7
2.1
6.7
1.0
5.
Nil
__.
1.1
-0.6
4.1
-2.4
GROUP
B:
1.
Placebo
......
0.1
0.1
0.8 0.8
2.
Placebo
.
..
0.5
0.4
-0.7
-1.5
3.
Cyproheptadine
2.1
1.6
3.0
3.7
4.
Cyprohcptadine
......
2.5
0.4
8.0
4.8
5.
Nil
0.6
-1.8
3.2
-4.4
GROUP
C:
1.
Cyproheptadine/
Methandrostenolone
0.5
0.5
7.7
7.7
2.
Cyproheptadine/
Methandrostenolone
1.3
0.8
12.4
4.3
3.
Placebo
1.9
0.6
9.7
-2.4
4.
Placebo
1.8
0.1
8.9
-0.7
5.
Nil
1.9
0.1
6.9
-1.8
GROUP
D:
1.
Placebo/Methandrostenolone
0.5
0.5
3.7
3.7
2.
Placebo/Methandrostenolone
0.9
0.5
5.8
2.0
3.
Cyproheptadine
.
0.7
-0.2
6.7
0.9
4.
Cyproheptadine
2.7
1.9
10.6
3.6
5.
Nil
2.7
0.0
8.6
-1.8
Table
III
Group
First
Six
Weeks
Second
Six
Weeks
A
B
Cyproheptadine
Placebo
6.0
-0.7
Placebo
Cyproheptadine
0.6
8.8
C
Cyprohcptadine
/
Methandrostenolone
12.4
Placebo
-3.1
D
Placebo/
Methandrostenolone
5.8
Cyprohcptadine
4.6
230
OCTOBER,
1969
APPETITE
AND
WEIGHT
GAIN
IN
CHILDREN
Tat
CINTIAL
ICAfg
Jousatt.
as
M.IUCINE
Group
A
received
cyproheptadine
4
mgm.
twice
a
day
before
meals
for
six
weeks,
followed
by
a
placebo
for
the
next
six
weeks.
Group
B
received
the
placebo
for
the
first
six
weeks,
followed
by
cyproheptadine
4
mgm.
twice
a
day
for
six
weeks.
Group
C
received
methandrostenolone
.04
mgm.
per
kilo
in
a
single
morning
dose,
together
with
cyproheptadine
4
mgm.
twice
a
day,
both
for
the
fi
rst
six
weeks,
followed
by
a
placebo
for
the
following
six
weeks.
Group
D
received
methandrostenolone
.04
mgm.
per
kilo
in
a
single
morning
dose,
together
with
a
placebo
for
six
weeks,
followed
by
cyprohepta-
dine
4
mgm.
twice
a
day
for
the
following
six
weeks.
The
cyproheptadine
and
placebo
tablets
were
identical
in
appearance
and
their
nature
was
unknown
to
the
author
or
subject
during
the
trial.
Weight
and
height
were
measured
at
the
com-
mencement
and
thereafter
at
three
-weekly
inter-
vals
for
the
12
weeks
of
the
trial,
with
a
fi
nal
measurement
three
weeks
after
completion
—that
is,
15
weeks
after
the
initial
assessment.
At
each
interview
details
of
intercurrent
illness
and
unusual
symptoms
were
noted.
A
rough
subjective
assessment
of
the
child's
appetite
by
the
parent
or
guardian
was
also
made,
using
a
grading
system
from
0
to
3
(0
as
at
onset
or
worse.
1
=slight
improvement.
2
great
improve-
ment,
3
—excessive).
Advice
was
given
initially
and
reinforced
at
each
subsequent
interview
regarding
food
values
and
feeding,
and
generally
present
faults
in
meal-
time
practice
on
the
part
of
the
parents
were
discussed
(Rothney,
1968).
After
completion
of
the
study
the
actual
and
percentage
increases
in
weight
and
height
were
calculated
for
each
three-week
period
in
each
case
and
averaged
for
the
whole
group,
using
an
electronic
computer.
The
percentages
of
weight
and
height
gained
were
calculated
over
both
the
initial
levels
and
over
each
preceding
level.
Finally,
the
bone
ages
in
fi
ve
children
selected
at
random
from
each
group
were
estimated
at
the
commencement
of
the
study
and
15
weeks
there-
after.
RESULTS
The
percentage
increases
in
height
and
weight
are
indicated
in
Table
II.
A
statistical
analysis
of
the
data
was
carried
out
by
Professor
J.
E.
Kerrich,
of
the
University
of
Witwatersrand,
Johannesburg.
Weight
Data
All
three
"active"
treatments
gave
significantly
better
results
than
the
placebo.
The
cyprohepta-
dine/methandrostenolone
combination
was
signi-
fi
cantly
better
than
cyproheptadine
or
methandro-
stenolone
alone.
There
was
no
significant
difference
between
the
latter
two
preparations.
Height
Data
Here
the
statistical
evidence
was
less
clear
cut
and
most
of
the
differences
examined
were
not
significant.
Slight
but
significant
increase
in
height
occurred
in
Groups
C
and
D
at
15
weeks
as
compared
with
Groups
A
and
B.
Appetite
Scores
When
tested
at
the
5
per
cent.
level,
results
over
the
fi
rst
three
weeks
of
treatment
showed
the
mean
score
for
cyproheptadine
(1.5)
to
be
better
than
that
for
either
the
combination
(1.3)
or
the
placebo
(0.7)
and
methandrostenolone
(1.9)
to
be
better
than
the
placebo.
After
the
fi
rst
three-week
period
none
of
the
differences
were
statistically
significant.
Percentage
Gains
Over
"Normal"
Observed
increases
in
weight
and
height
12
weeks
after
the
onset
of
treatment
were
compared
with
normal
expected
increases.
These
were
calculated
in
each
case
by
referring
to
the
appro-
priate
percentile
line
on
the
Stuart
anthropometric
charts.
The
gain
in
per
cent.
of
normal
was
obtained
by
dividing
the
observed
increase
by
the
expected
increase
and
multiplying
by
100.
The
results
were
then
averaged
for
each
group.
There
was
no
significant
departure
from
normal
with
regard
to
linear
growth
in
any
group.
How-
ever,
the
differences
in
weight
gain
were
striking:
Percentage
of
"Normal
Gain"
169
244
360
315
Group
A
B
C
D
Bone
Age
In
no
case
was
abnormal
acceleration
of
epi-
physeal
development
noted
in
those
studied
radiologically.
COMMENTS
The
respective
gains
in
weight
in
the
four
groups
are
summarised
in
Table
Ill.
There
can
be
no
doubt
from
the
results
reported
in
this
study
that
cyproheptadine
induces
an
in-
crease
in
appetite,
increased
food
intake
and
weight
gain,
thus
confirming
in
non
-allergic
under-
weight
children
the
fi
ndings
reported
by
Laven-
stein
et
al.
(1962)
and
Bergen
(1964)
in
asthmatic
subjects,
and
more
recently
by
Francini
et
al.
(1968).
The
study
provides
no
new
evidence
as
to
its
mode
of
action.
The
children
showed
no
bodily
changes
suggestive
of
adrenal
cortical
over
-activity.
virilisation
or
hypothyroidism,
nor
231
OCTOBER,
1969
APPETITE
AND
WEIGHT
GAIN
were
there
symptoms
of
hypoglycaemia.
Cypro-
heptadine
appears
to
increase
body
weight
primarily
by
stimulating
appetite
and
hence
in-
creasing
food
intake
(Lavenstein
et
al.,
1962).
Drash
et
at.
(1966),
investigating
normal
adults
receiving
cyproheptadine.
documented
a
small
but
statistically
significant
depression
of
the
fast-
ing
blood
glucose,
and
suggested
that
the
increase
in
appetite
might
result
from
this.
They
tenta-
tively
concluded
that
decrease
in
blood
sugar
in
their
subjects
was
not
insulin
mediated
and
that
the
action
of
cyproheptadine
may
be
on
the
cell
membrane,
causing
an
increased
permeability
to
glucose.
Appetite
stimulation
is
apparently
unique
to
the
human
and
cannot
be
reproduced
experimentally
(Stone
et
al.,
1961;
Lavenstein
et
al.,
1962).
No
significant
side
-effect
could
be
attributed
to
cyproheptadine.
In
fi
ve
children
only
was
drowsi-
ness
noted,
and
this
passed
off
within
a
few
days.
A
further
six
children
taking
cyproheptadine
were
reported
to
"sleep
better
at
night."
Appetite
enhancement
occurred
even
though
cyproheptadine
was
given
only
twice
a
day
and
not
four
times
daily
as
in
other
studies
(Laven-
stein
et
al.,
1962;
Bergen,
1964).
Cannon
(1968)
has
noted
that
cyproheptadine
has
perhaps
the
longest
duration
of
action
of
any
antihistaminic
—up
to
48
hours.
If
this
is
so,
then
the
problem
of
drowsiness
as
a
side
-effect
might
be
obviated
altogether
by
giving
the
cyproheptadine
only
at
night.
This
aspect
is
being
investigated
further.
Two
children
who
had
had
methandrostenolone
for
six
weeks
showed
slight
hypertrophy
of
breast
tissue
with
minimal
alveolar
pigmentation.
This
side
-effect
of
methandrostenolone
is
well
recog-
nised.
Signs
of
virilisation
or
other
untoward
effects
were
not
noted.
Enhanced
weight
gain
was
not
maintained
in
any
group
on
stopping
the
"active"
treatment.
It
is
for
this
reason
that
the
gain
in
weight
at
12
weeks
as
a
percentage
of
"normal
gain"
was
only
169
per
cent.
in
Group
A
compared
with
244
per
cent.
in
Group
B.
The
children
in
Group
A
had
been
off
cyproheptadine
a
full
six
weeks,
whereas
those
in
Group
B
had
just
completed
their
course.
No
increased
rate
of
linear
growth
was
noted
in
the
two
groups
on
cyproheptadine
alone.
Lavenstein
et
al.
(1962),
who
administered
the
cyproheptadine
continuously
for
six
months.
described
a
small
acceleration
of
growth
in
their
series.
They
concluded
that
this
resulted
purely
from
the
increased
intake
of
food,
as
seen
in
normal
children
with
"exogenous"
obesity
(Talbot
and
Sobel,
1947).
IN
CHILDREN
Tim
CENTIIAL
APRICAN
JOURNAL
OP
MONO'
N
A
Functional
feeding
problems
in
children
stem
largely
from
parental
misconceptions,
from
failure
to
respect
the
normal
developmental
aspects
of
infant
feeding
or,
more
seriously,
from
disturbed
mother
child
relationships.
Advice,
guidance
and,
if
necessary,
psychiatric
help
are
patently
fundamental
in
such
problems,
and
the
common
practice
of
fobbing
the
child
and
mother
off
with
a
"tonic"
or
multivitamin
mixture
must
he
deprecated.
In
the
author's
opinion
the
appetite
stimulating
properties
of
cyproheptadine
could
he
utilised
with
advantage
in
selected
cases
of
anorexia
in
children.
The
risks
of
premature
epiphyseal
closure
are
not
present,
as
is
the
case
with
the
anabolic
steroids,
and
no
other
significant
side
-effects
have
been
reported.
In
severe
appetite
disturbances
and
in
grossly
debilitated
subjects
the
combined
use
of
cyproheptadine
and
methan-
drostenolone
also
merits
further
trial.
SUMMARY
Ninety-eight
anorexic,
underweight
but
other-
wise
normal
children
were
investigated
in
a
double-blind
trial
utilising
cyproheptadine,
a
placebo
and
methandrostenolone.
The
appetite
stimulating
properties
of
cyproheptadine
and
the
concomitant
effect
on
weight
gain
were
clearly
demonstrated.
A
group
of
children
taking
both
cyproheptadine
and
methandrostenolone
together
showed
by
far
the
greatest
increase
in
weight.
It
is
suggested
that
this
effect
of
cyproheptadine
could
be
utilised
clinically.
BIBLIOGRAPHY
BERGEN,
S. S.
(1964).
A.M.I.
Dis.
Child.,
108,
270.
CANNON,
P.
J.
(1968).
Practitioner,
200,
53.
DRASH,
A.,
ELLIOTT,
J.,
LANGS,
H..
LAYENSIEIN,
A.
F.
and
COOKE,
R.
E.
(1966).
Clin.
Pharm.
and
Ther.,
7,
340.
FRANCINI,
F.
C.,
SANTANA,
J.
C.
&
KITROSEN,
N.
J.
(1968).
Orient.
Med..
795,
126.
LAVENSTEIN,
A.
F.,
DACANEY,
E.
P.,
LASAGNA,
L.
&
VAN
METRE,
T.
E.
(1962).
.I.A.M.A.,
180,
912.
ROTHNEY,
W.
B.
(1968)
in
Current
Pediatric
Therapy,
3,
Gellis,
S. S.
&
Kagan,
B.
M.
W.
B.
Saunders
Com-
pany,
p.
49.
STONE,
C.
A.,
WENGER,
H.
C.,
LUDDEN,
C.
T.,
STAVORSKI,
J.
M.
&
Ross,
C.
A.
(1961).
I.
Pharmacol.
and
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Therap..
131,
73.
TALBOT,
N.
B.
&
SOBEI
,
E.
H.
(1947).
Advance
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2,
238.
Acknowledgments
I
am
indebted
to
Professor
J.
E.
Kerrich
and
Miss
Stakesby-Lewis,
of
the
Department
of
Statis-
tics,
University
of
Witwatersrand,
for
the
statistical
analysis,
to
Mr.
D.
Hadden
for
processing
the
data
and
to
Dr.
S.
M.
Kaplan
for
his
help.
The
cyproheptadine
and
placebo
tablets
were
supplied
by
Merck,
Sharp
&
Dohme
Ltd.,
and
the
methandrostenolone
tablets
and
drops
by
Ciba
Ltd.
232