Download Double Blind Crossover Study of Cromolyn

Double
Blind
Crossover
Sodium
Inhibition
Study
of Aerosol
of Cromolyn
Antigen
Challenge
Michael
H. Grieco,
M.D.#{176}
Six
men
patients,
during
four
and
fourth
istered
treated
delivered
doses
test
FVC
as a powder
measurements
tive is a white
administered
cent absoprtion.2
Lacking
both
tory activity,
inhibitor
of
allergen
lung.
this drug
has
the
release
and
reaginic
Inhibition
been
human
demonstrated
lung
passively
the bronchi
heat-labile
interaction
anaphylaxis
in
and
(SRA-A)
from
portions
sensitized
with
of
rat
inhibition
cell
#{176}Director,
ment
of
histamine
actively
vitro,2
to be an
following
of histamine
the marmoset.
homocytotropic
of
mast
degranulation
Allergy
of Medicine,
and
cell
and
Infectious
St. Luke’s
histamine
homologous
Disease
Hospital
the
slow
the
were
first
admin-
the patients
in a double
bronchial
ranging
and
This
were
blind
challenge.
from
or
to 61.3
20.3
rat
of
sodium
of
pig
has
is
responses
SRS-A,
It
appears
involved
sodium
cannot
pig
that
in
shown
does
not
mediators
in
cromolyn
of guinea
pig
5-hydroxytryptamine,
432
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21537/ on 06/18/2017
of mediators
related
to the
does
of
since
human
with
In
tissue
effect
release
from
vitro.
inter-
release
of histais mediated
by a
antibody
of the
interfere
sodium
ileum
to
with
in
from
actively
The
inability
of
inhibitory
histamine
be demonstrated
but
of
lung
a pulmonary
the
on
compound
up to 1 mg/mI,
demonstrated
pig
to inhibit
the release
lung in vitro may be
class.9
of known
a pathreagin
antibodies
inhibition
been
gamma-i
This
dem-
pollen-
rat
guinea
this
mediator
basophils.8
specificity
ity
Assistant
IgGa
Although
that
the immunologic
SRS-A
in the guinea
noncomplement-fixing
or leukocytes.
Clinical
Professor
of Medicine,
Columbia
University
College
of Physicians
and Surgeons,
New
York.
Reprint
requests:
Dr.
Grieco,
St.
Luke’s
Hospital
Center,
113th
Street
and
Amsterdam
Avenue,
New
York
City
10025
heat-stable
SRS-A.7
observation
mine
and
heat-stable
release,
study
against
(PCA)
suggesting
the human
and
release
has not been
passively
sensitized
release
guinea
cromolyn
inhibition
blind
protection
addition
cromolyn
sodium
inhibits
antigen-induced
release
of histamine
cromolyn
studies
have
Depart-
double
to provide
subjects.
cromolyn
sodium
from guinea
pig
has
passive
Division,
Center;
pollen
to antigen
of FEy,
changes.
In
fere
with
sensitized
of
chopped
human
rea-
Other
antibodies
these
by homologous
not the release
which
is
10 per-
serum
after
exposure
to specific
antigens.3
drug
also
inhibits
passive
sensitization
by
reaginic
antibody
of the skin
of monkeys
shown
mast
release
prior
sodium
asthmatic
systems.4-6
intraperitoneal
anti-inflamma-
been
considered
of mediators
antibody
of the
substance
and
with
and
grass
studied
During
and third
periods
sodium
or placebo
minutes
were
apart.
or
cutaneous
anaphylaxis
way
common
to both
deriva-
powder
less than
bronchodilator
reacting
ginic
This
human
chromone
hydrated
crystalline
by inhalation
with
antigens,
week
ragweed
in a decrease
paralleled
sodium
(1, 3-bis
[2-carboxychromon-5yloxyl-2
hydroxypropane,
disodium
salt)
has
been
introduced
by Altounyan’
for the
manageThis
30
resulted
of cromolyn
in sensitive
Cromolyn
asthma.
of
During
the second
capsule
of cromolyn
of antigen
the ability
obstruction
induced
bronchial
extracts
pollen
one
with
onstrates
of
to
approximately
a mean
of 35.5 percent.
Pretreatment
with
cromolyn
sodium
in 21.9 to 100 percent
protection
with a mean
of 65.3 percent
which
with the -12.4
±24
percent
protection
following
placebo
(P<0.005).
percent
resulted
contrasts
ment
I hypersensitivity
aqueous
via a nebulizer.
with a single
The
type
periods
periods,
fashion,
The
with
separate
the
this
skin
activ-
concentrations
not
in vitro
acetylcholine,
affect
the
to histamine,
nico-
CROMOLYN
tine,
SODIUM
or bradykinin,
prostaglandin
nor
E,
or
human
bronchial
bronchoconstriction
mine
in
with
ten
INHIBITION
does
muscle.
induced
inhalation
the
effects
on
F2a
has
cromolyn
of
been
(Arthus
ing
in
reaction)
asthma”’5
a
hypersensitivity
but
Herxheimer
reactions
and
a double
of cromolyn
pollen
antigen
lenges
crossover
study
type
I aerosol
in six
such
as
excluded
sensitive
those
in
from
study
may
mechanisms
asthmatic
dust
mold
type
(Acrone,
Syntex;
men
asthmatic
studied
AND
component.
aerosol
bronchodilator
prior
to
ranging
study
Each
patient
one
forced
clinical
considered
Five
patients
were
in
age
from
Based
to
was
to the
challenge
for
statistical
third
percent
periods
by
the
to
the
57,
results
correla-
an
oral
or
discontinued
being
room
grasses
over
a one
air
in
treated
of
pollen
During
the
allergen
with
first
FEy,
was
Forced
Expiratory
1
FEV,
predicted
air and
minute
(0.1
nil,
PNU/ml)
1,000
over
via
501)
were
and
Volume
ranged
Comparison
in
from
of Pollen
antigen
mixed
challenge
carbol-saline
assess
challenge
or
greater
aerosol
change
which
the
in
for
3t)
reacted
were
fourth
a
periods
20
percent
by
delivering
1.0
CHEST,
VOL.
at
at
5,
30
10,
20
aerosol.
Isoproterenol,
Medical
Equipment
Port
orchard,
Port
short
61,
One
Second
flow
challenge
greater
rate
dose
10
PNU/ml,
minute
Company,
Washington,
June,
red
Washington,
ragweed
pollens.
NO.
5,
MAY
of
room
a one
10,000
and
following
was
not
grass
mixed
4
and
study
at 5
decreases
recorded
from
of
of 100
used
in
usually
noted
10
1.
The
to
in
PNU/ml
decrease
with
30
FEV,
PNU/ml
1,000
minutes
to
two
(P <0.35).
decrease
the
mean
-12.6
the
significant
a significant
given
concentration
was
of
a
pollen
a similar
between
not
FEy,
to
concentration
with
Repeat
difference
was
of FEV,
a range
statistically
was
6 developed
protein
grasses
(100,
units
per
ml)
fall
4 led
with
consisting
5,000
percent.
FEy,
The
Patient
a
percent
-61.3
1
and
and
mixed
nitrogen
in study
fall
in study
in
maximal
minutes
after
100
FEV,
minutes
1-200,
percent
breathing
following
challenge.
increasing
and
30
101.3
of
PNU/mI,
intervals.
and
of
decrease
gradually
PNU/ml,
(FEy,)
Challenges
1,000
35.5
challenge
study
(DeVilair
the
or
5,000
minute
#{176}#{176}Center
Laboratories,
grasses:
timothy
pollens.
tCenter
Laboratories,
ragweed:
tall and
maximal
decrease
I
to
doses
(100,
to
studies
with
delivered
nebulizer
a compressed
in
study.
patients
-20.3
40.1 percent
-54.5
percent.
nonspecific
unsuitable
of
extract
minutes
adminis-
Effect
Minneapolis.
New
top,
York.
sweet
Mixed
vernal
New
York.
Mixed
of Cromolyn
Pretreatment
delivered
as
FEy,
#{176}International
percent
study
75.9
Extract
ragweed
in a mean
range
forced
30
to
a DeVilbiss
PNU/ml,
measured
for
maximal
six subjects
while
did not change
significantly
carbol-saline
aerosol.
resulted
record
and
over
minute
at
to
(FEy,)
ragweed
PNU/ml,
one
-
I
the
formula:
in the
The
approxi-
used
saline)
to
type
determined
concentrations
PNU/
second
10 percent
period
in
following
maximal
by
determined
=
Protection
-Table
corti-
minute.
resulting
significance
was
12
periods
was
considered
mixed
3*0
separate
observations
with
were
minute
per
one
isotonic
air
compressor,
of 12 liters
four
a one
in
extracts
(mixed
in
Subjects
from
anti-
extrinsic
receiving
was
Vitalograph#{176}
Control
following
responsiveness.
Aqueous
on
A
phenol
to
double-blind
aerosol.
decrease
study
delivered
prior
by
protection
percent
of
studied
(FVC).
percent
E’EV,
each
and
prior
The
placebo
administered
analyzed
the
sodium
RESULTS
21
on
have
were
which
none
apart.
recorded
(0.5
received
decrease
therapy.
volume
capacity
of
croimmolyn
minutes
were
symptom-allergen
were
but
was
week
expiratory
vital
FVC
t test.
30
were
nitrogen
units
per
ml)
1,000
and
10,000
protein
mately
patient
lactose
percent
Protocol
biss
were
or
device
hypersensitivity
fast.
therapy
or injection
nomogram
of
Antigens
METHODS
overnight
and
subjects
allergic
costeroid
an
tests
these
bours
subjects,
following
intradermal
tions,
early
values
the
each
capsule
Fisons)
drugs
technique
second
mg
a delivery
These
data
Percent
as
Predicted
from
periods
20
Intal,
challenge.
The
Six
necessary,
aerosol.
obtained
third
single
by
“Student”
Subjects
were
were
and
a
a powder
the
when
challenge
involved.
be
MATERIALS
of
second
of
The
sodium
chal-
extracts
III
FVC
the majority
the results
of
subjects.
and
since
in
the
crossover
resultBewers-
this
reports
inhibition
have
the
co-workers.’7
contents
gen
sodium
type III
dorff’6
were
unable
to confirm
of their
patients.
This
paper
blind
of
On
symptoms
after
and
and
433
asthmatic
minutes
FEy,
Kory
as
of cromolyn
antibody)
and
to relieve
10
for
hista-
observed
sodium’#{176} suggesting
that
prior
inhalation
type
I (reaginic
CHALLENGE
tered
as
of
direct
action
on bronchial
smooth
muscle.
Several
previous
studies
in human
beings
indicated
will
inhibit
ANTIGEN
isolated
However,
inhibition
by intravenous
subjects
of
AEROSOL
it block
prostaglandin
asthmatic
OF
period
with
a powder
values
during
but
resulted
Drug
and
Crepea
of
Dr.
Peter
Massachusetts,
Sodium
delivery
Syntex
Mawdsley
20
by
the
in
mg of cromolyn
inhalation
did
30
a
minutes
16.1
observation
±
devices
supplied!
by
Laboratories,
Palo
Alto,
of Fisons
Corporation,
1972
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21537/ on 06/18/2017
sodium
not alter
19.2
percent
Dr.
Seymour
California,
\Vilmington,
B.
and!
MICHAEL
434
Table
1-Double
Blind
Study
Effects
of
Cromolyn
Sodium
on
FEV1
(Ml)Changes
with
.5 ntigen
Antigen
H.
Challenge
Challenge
Max
Predicted
Patient,
Age,
Sex
Date
FEV
Air
10
Mm
20
Ragweed
1
37
2
M
33
4150
M
4000
38
M
3430
June
2300
2200
2000
June
15
3050
1800
1800
-.
Study
3-Cromolyn
June
24
3025
2525
2575
2500
Study
4-Antigen
July
2
2950
1700
Mixed
1900
Grass
100
Study
1-Antigen
July
1
4050
Study
2-Cromolyn
July
8
4050
Study
3-Placebo
July
15
4150
Study
4-Antigen
July
27
4400
Na
3154)
(101.3%)t
Study
1-Antigen
Study
2-Placebo
Study
3-Cromolyn
Study
4-Antigen
Na
(S7.5%)t
24
M
4650
3050
4050
3400
21
M
57
1
3700
3050
-*
-28.1
2350
1700
1700
1600
-27.3
9
2750
2450
2500
2550
July
15
2350
2300
1700
2350
2350
-20.3
2200
2250
-32.3
July
15
3300
3000
3350
3250
-
July
23
3250
1550
1600
-.
Study
3-Cromolyn
Study
4-Antigen
3150
(67.7%)t
1-Antigen
July
5
4200
2550
-.
-.
-41.4
July
13
4250
2550
-.
-.
-40.0
July
20
3700
2750
2850
2900
-28.6
July
27
4400
2100
-.
-.
-52.3
3-Cromolyn
4-Antigen
Na
Study
1-Antigen
July
23
3300
Study
2-Placebo
July
30
2850
800
Study
3-Cromolyn
2600
1250
Study
4-Antigen”
2950
1950
Na
Aug.
6
Aug.
20
(83.8%)t
-35.5
±
4
-40.1
± 16.7
Na
to
administered.
decrease
39.0
±
from
16.0
following
of
Administration
resulted
contrasts
placebo.
in
revealed
a p value
65.3
±
t
Vital
Capacity
The
FVC
ranged
and
did
test
six
not
patients
change
carbol-saline
aerosol.
Comparison
of Pollen
to
which
following
significances
PNU/Ml.
significantly
room
following
the
-47.9
+21.9
-54.4
-
Teat
Mean,
-
Protection
Percent
±
Teat
the
antigen
percent
14.7
30
of
delivery
F\TC
did
minute
of
terms
ence
was
significant
34.2
and
-30.7
sodium
and
± 24.0]
p <0.005
of
change
observation
28.9
placebo
percent
±32.8
cromolyn
significantly
period,
was associated
of this lung
(P
placebo
mg
20
not
challenge
decrease
with
the mean
noted
following
in
± 34.5]
-12.4
Sodium
the
sequent
+65.3
value.
predicted
of
powder
pressed
of
-.
1300
of Cromolyn
during
±
percent
-*
1700
p <0.35
tPercent
contrasts
104.8
-11.9
J
FyC
breathing
while
100
-61.3
-68.6
p <0.05
Following
2
73.8
± 16.0
-.
Percent
<0.351
sodium
0.005.
(FVC)-Tahle
± 19.2
-39.0
-
j
Effects
placebo
sodium
protection
percent
statistical
than
grass
as compared
lactose
24.0
of
from
the
in
±
of less
Forced
predicted
12.4
-
mixed
cromolyn
percent
34.4
with
the
Student
used
carbol-saline
percent
pretreatment.
air
#{149}
‘Antigen
-16.1
-30.9
-‘
-.
±
p
-
+3.4
PNL’/Ml
Decrease
14.91
1
Study
1,000
1200
Percent
Study
-‘
Grass
-
PNU/MI
2-Placebo
Placebo
maximum
/0,000
-83.7
3.2
Study
Study
(96.5%)t
Grass
-
-59.1
-51.6
Study
Study
-
2300
Croniolyn
aerosol
-27.9
2350
July
+100
!‘NU/Ml
3450
June29
Maximal
1-200
1550
5,000
-
+2.8
0
9
1-Antigen
Mean,
laoproterenol
-
2
Mixed
6
+2.4
-12.6
8
2-Placebo
4350
-24.1
-.
July
Study
+100
PNU/M1
July
Mixed
5
-
0
3150
-.
1700
+55.1
-24.7
June
Study
Na
16.6
-
PNL’/MI
4050
100
-11.9
-41.9
4050
2500
-
Protection
-37.0
-.
3300
3800
%
%
Saline,
-41.4
3600
3750
Carbon
i’.vL/Ml
1,000
l-Antigen
Ragweed
4
Mm
2-Placebo
Ragweed
3
30
Study
1
(75.9%)t
Mm
Study
Na
Dec
from
(1970)
GRIECO
±
13.9
but
sub-
with
volume.
10.8
This
fall
percent
pretreatment.
protection,
the
< 0.005)
with
noted
following
of
Ex-
differ-
+ 63.8
cromolyn
±
respectively.
DIsCuSsION
The
in
a
-11.5
4 led
range
there
FC
pollen
mean
extract
23.0
Extracts
challenges
fall
percent
to -43.2
percent.
to a similar
decrease
of
-8.2
was a more
in percent
to
Challenges
-42.0
marked
of initial
in
in
F\TC
The
study
1 resulted
with
a range
Repeat
challenge
of 24.4 percent
percent.
As
decrease
values.
in FEy,
can
of
in study
with
a
be
than
seen
of
chromone
khellin,
the
active
eastern
Mediterranean
plant
been
used
as an antispasmodic
ancient
times.
muscle
induce
relaxing
coronary
relaxation,
because
Although
the
drug
of unpleasant
CHEST,
khellin
properties
dilation
principle
has
specific
which
in
the
and in the lung
has
side
VOL.
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21537/ on 06/18/2017
of an
(Ammi
visnaga)
for renal
colic
has
from
smooth
heart
can
bronchial
not
been
widely
used
effects.
The synthesis
of
61,
NO.
5,
MAY
1972
CROMOLYN
SODIUM
Table
INHIBITION
2-Double
Blind
Study
OF
on
AEROSOL
Effect
o/
ANTIGEN
Cron,olyn
435
CHALLENGE
Sodium
on
FVC
(Ml)
Changes
with
Antigen
Challenge.
Challenge
#{149}1
ntigen
Max
Patient,
Age,
Predicted
Date
VC
(1970)
Sex
Air
10
Mm
20
Ragueed
1
37
5200
M
1-Antigen
June
1
3800
Study
2-Placebo
June
15
3850
2650
Study
3-Cromolyn
June
24
3850
Study
4-Antigen
33
3
M
38
4880
M
24
3550
:4650
:tsoo
-
2750
3050
-.
-27.6
2
38.50
July
1
4800
4300
4300
4050
-14.7
July
8
4700
4700
4750
4700
-
-25.3
Gram
21
Study
3-Placebo
July
15
4800
4100
4000
3550
Study
4-Antigen
July
27
4800
445.0
-.
-.
100
18
3950
3300
3500
July
2
3500
2750
2800
2800
-20.3
Study
3-Cromolyn
July
9
3950
3650
3850
3850
-
Study
4-Antigen
July
15
3500
2600
2700
2650
-16.1
1-Antigen
June29
July
Study
3-Cromolyn
Study
4-Antigen
Na
5050
(88.9%)t
5180
5,000
57
4350
4350
-
42.50
4100
-18.0
July
15
5050
4850
.5100
5100
-
July
23
5200
3250
3400
1-Antigen
July
5
5400
2-Placebo
July
13
5450
4400
-.
Study
3-Cromolyn
July
20
5100
4600
4800
Study
4-Antigen
July
27
5600
Study
1-Antigen
July
23
4800
Study
2-Placebo
July
30
Study
3-Cromolyn
Study
4-Antigen
Na
Aug.
4650
Aug.
1-200
structurally
aerosol
administrated.
related
compounds
of cromolyn
sodium,
pound
is characterized
pyrone)
the
two
rings joined
strongly
There
linkage
take
is free
which
up
solubility
and
is
only
inhalation.
Of the
-26.4
+
4100
3400
3150
four
classification
type
I is best
about
twO
the
of positions
the
central
chromone
relative
it is virtually
effective
not
clinically
types
other.
and
by
has
been
The
reaction
in the
body
on
the
causation
I hypersensitivity
type
antigen
mast
cells
such
release
61,
of
NO.
5,
MAY
leads
of
of allergic
reacantiE.2#{176}
reaginic
release
of chemical
mediators
The cell source
leading
to the
VOL.
surface
and
in
role
heat-labile
reaginic
as immunoglobulin
identified
between
reactions
the
<0.101
tPercent
A),
slow
antito
the
as histamine.
of the acidic
of
predicted
reacting
A role
involving
for
type
immune
±
-30.7
±:42.8
subjects,
antigen
from
sodium
to
approximately
protection
was
one
minute.
Pepys
binding
with
and
breeders’s
that
inhibited
and
by
broncho-
extrinsic
allergic
lung.2’
prior
inhalation
the
of
extracts
degree
60
administered
within
lenge
and
only
60
when
the antigen-drug
hypersensitivity
in patients
immediate
allergens
asthin
three
in two and guinea
pig.
of protection
varied
percent
one subject
a detectable
sisted
for 18 hours
after
ble
III
(SRS-
type skin test reactions,
delayed
bronchial
reac-
inhalation
mixed
pollen
in one.
The
p <0.005
precipitating
IgG
antigens
is suggested
challenge
reaction
I
complement
the demonstration
of Arthus
precipitating
antibody,
and
of cromolyn
Test
34.21
+63.8
of anaphylaxis
complexes
of heat-stable,
1gM immunoglobulins
and
to antigen
±
value.
substance
is unknown.
reactions
Protection
Percent
p <0.25
J
PNU/MI.
9.3
I
pulmonary
aspergi1losis,2m23
alveolitis
including
pigeon
Althounya&
demonstrated
orally
given
Coombs,’9
)
Mean.
J
tions
soluble
to its poor
absorbed
of hypersensitivity
of Cell
nonprecipitating,
body
CHEST,
carbon
nuclei
to
when
<0.451
Test
I
lipid,
com(benzo-
to each
powder
is moderately
in alcohol.
Owing
established
asthma.
In
bronchial
the
This
p
±
-
-42.0
Percent
± 14.7
100
2750
Decrease
Percent
-28.9±13.9
synthesis
--
-39.2
matic
the
tions
to the
-15.5.
-54.6
-10.8
by a flexible
linking
chain
and
polar
carboxylic
acid
groups.
rotation
allows
a variety
lead
-
PN(’.’mI!
1,000
-.
-24.4±13.3]
grass
+36.1
-.
-23.0±11.11
mixed
-13.2
18.50
1
=
0.0
4950
2500
4
used
-
4150
Study
a bis-chromone.’8
by two
chromone
This
white
hydrated
in water
but insoluble
liquid
“Antigen
-20.7
4400
Study
Na
-
-43.2
20
Placebo
+82.6
-.
Maximal
Cromolyn
2.0
-36.9
-20.7
-
-.
Gram
-
-56.5
P.51./MI
4400
(104.8%jt
11.5
2700
6
Mean,
‘Isoproterenol
10,000
Study
4580
M
+94.0
PNU/M!
4250
4300
Study
Na
-
+12.9
1.4
5000
(104.2%)f
-
-23.3
9
Gcass
-72.1
(7.11!
June
Mixed
6
P.V
I-Antigen
2-Placebo
+92.5
8.2
2-Placebo
Study
1,1
-
Study
Study
+68.0
--
Study
Na
(93.8%)t
Ragweed
-41.8
7.8
!‘.V(/.If!
1-Antigen
2-Cromolyn
5680
M
100
Protection
-:44.6
July
(98.2’)t
“
%
-24.4
Mixed
5
-
Study
Na
Saline,
(#{149}/f4
Study
4210
M
P\
Mm
2950
Ragweed
4
30
Carbon
3200
.%Iixed
2
Mm
1,000
:soso
(73.8)t
Study
Na
f)e,’
from
to
80
percent.
In
degree
of protection
pera 20 mg dose.
No detecta-
observed
when
the
drug
was
15 minutes
after
antigen
chalpercent
protection
was
noted
time interval
was reduced
to
and
co-workers”
1972
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found
that,
in
MICHAEL
436
a
.9
a
a
extracts
a
a
0
.0
5
.
Cl
a
,.,
.
222
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.0
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..
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0
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0
.0
,..
and
the
with
to
a
patients
and
reactions
three
avian
additional
antigens.
sodium
in
the
subjects
This
study
inhibited
not
only
reactions
but also type
III
to
precipitating
antibody.
that
this effect
on late reacinhibition
of the immediate
been
found
to be
the
production
intradermal
tests
colleagues12
studied
absence
of placebo
extract
lung
closely
asso-
of Arthus
type
in man.
Booij-Noord
the effects
control,
with
to
have
positive
to pollen
extracts,
1,000
I
as a one
water
for
significant
a
zI
inhalation
in 17
disease.
Only
four
reported
ered
0
I
utes
III
of this drug,
in
dust and mold
I
.0
II
with
a
I
I
I
be
I
I
2
0
I
in
a
a
all
late
of
14
Ce
tony
a
-
.14
6
,_0
C.
C
cromolyn
C
Of
26
a
.
0
a
.
to placebo,
contents
completely
reaction
in a
antigen
challenge.
patients
sensitive
of
a
5
protection
was
five
subjects
4 to 12 hours
after
bronchial
challenge,
noted
protection
with
percent
to
with
10
a closed-circuit
nonforced
vital
flow
rate
administo unspeci-
this
drug
percent
but
aerosol
recording
capacity
Herxheimer
full,
partial
challenged
and
or possible
with
flour
the
in one patient
14 percent
rise
immediate
to grass
of FEy,
was
to Dermatophagoides
inhalation
cromolyn
of
also
asth-
pollen
and
following
noted
culinea
in four
mite
sodium
those
not
was
sensitive
house
a single
prechallenge
a 20 mg capsule
Protection
a
a
V
inhibited
in distilled
statistically
ten min-
Of
occurring
extract
deliv-
of
spirometer
and expiraBewersdorff’6
protection
antigen
hut
in five
lack of
0
a
a
I:
This
studied.
15 asthmatic
pateints
were not provided.
peak
noted
subjects
a
8.
Io
challenge.
reactions
cromolyn
and
for measuring
C
dissolved
resulted
in
administered
patients
or mold
co-workers’3
aerosol
details
Using
a
.2.
17
dust
and
further
II0
0
sodium
solution
per
units
fied antigen
challenge
and
noted
some
degree
of
protection
in eight
patients
studied.
In a recent
abstract,
Kabe
and associates15
reported
protection
a
00
percent
reactions
nitrogen
cromolyn
sodium
in two
cases.
Minette’4
tered
20 mg of the drug
one hour
prior
a
0
the
intracutaneous
protein
of cromolyn
allergen
in
house
One
subjects
with
obstructive
of these
patients
were
three
minutes,
protection
when
before
noted
a
matic
resulted
has
mJ. Six milligrams
a
a
0
m
of the
sodium
+ 31
be
a
contrast
0 and
pretreatment.
also inhibited
in two
aspergillosis
systemic
cromolyn
which
ciated
reactions
0
2
that
reaction
8
0
and
type
I hypersensitivity
reactions
attributed
Pepys
has suggested
tions
may
result
from
0
a
asthmatic
-8,
sodium
this drug
asthmatic
reaction
bronchopulmonary
two
patients
and
precipitins
against
suggested
a
..g
late
same
with
.
a
0
of + 20,
0
Z
.2be
.
changes
0.0.
u
I
FEy1
the immediate
with
allergic
.
aa
with
percent
following
cromolyn
Prechallenge
inhalation
of
H. GRIECO
dust.
effect
protected
to flour,
The
in
the
remaining
patients.
from
induced
five to pollen
reasons
for
the
asthma,
one
and
two
to
variance
those
of other
investigators
clear.
As indicated
in Table
3 there
were
differences
in methods
of cromolyn
sodium
results
from
tration
(aerosol
of bronchial
utilized
vs
response
for bronchial
Micronized
cromolyn
CHEST,
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21537/ on 06/18/2017
powder),
method
measurement,
of
these
were
not
significant
adminis-
and
duration
and
antigens
challenge.
sodium
VOL.
61,
provides
more
than
NO. 5, MAY
1972
CROMOLYN
SODIUM
50 percent
by
INHIBITION
weight
of 2 to 6
OF
size
t
particles
30 to 60 t size lactose
crystals
the inadequate
flow of the micronized
At the
present
time
the
powder
is
aerosol
administration
for the practical
contains
the
high
water
viscosity
would
provide
the
had
an
only
important
to
cromolyn
siveness
tion
clearly
antigens
reduced
which
demonstrated
six
more
of
pronounced
tions of this
As
which
21.9
to
same
measurements.
pulmonary
lack
these
antigen
sodium
drug
is also
asthma.2527
lead
to an
cromolyn
after
inhibiting
studies
responses
allergens,
double-blind
effective
This
mediator
latter
eral
which
patients
on bronchial
children
management
CHEST,
svith
of
VOL.
with
histamine
this
by
in
mild
drug
to
may
NO.
have
6
cromoglycate
inhibitor
of reaginic
Nature
Sheard
P,
extrinsic
A large
sodium
sponsored
Academy
of
the
United
Orr
9
of
mast
cell
by
phospholipase
not
10
a
not
pig
and
two
homologous
inhibition
with
KF:
of
in
JW,
slow
Soc
Bloch
KJ:
of
reacting
Exper
sub-
Biol
Biologic
release
lmmunol
effect
of
102:327,
disodium
in
vitro
pig
h)asophil
DJ,
Austen
Med
properties
by two
mediated
1969
cromoglycate
anaphylactic
leukocytes.
KF,
Bloch
anti
histamine
release
mt
Allergy
Arch
KJ:
release
(SEA-A)
of
in
the
Antibodies
in-
slow
reacting
stmb-
guinea
pig
and
rat.
1967
Covindaraj
M,
drugs
and
hypersensitivity
Patel
KR:
Effect
disodium
in
of
alpha-recep-
on
cromoglycate
bronchial
asthma.
Brit
histaMccl
J
1970
J,
Pepys
Chan
M,
chisodiuni
H,
One
GM,
bronchial
of
et
al:
Inhibitory
effects
allergen-inhalation
and
in
Allergic
London,
A:
antigen
challenge
H,
tests.
on
Disease,
Butterworths,
tests.
1972
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21537/ on 06/18/2017
In
of
al:
Protective
and
bronchial
Cromo-
J,
Frankland
p 33
inhalation
Disodium
disodiurn
1970
Disodium
(Pepys
1970,
effect
Protection
46:1,
nasal
in
al:
with
Z, et
Pehikan
challenge.
Airways
Protective
et
J Allerg
cromoglycatc
allergen
Minette
WC,
challenge
thiazinamiumn.
Booij-Noord
after
Berg
allergen
disodium
reactions
ed)
FE,
on
1968
(In
glycate
1-langreave
cromoglycate
Booij-Noord
AW,
by
Proc
J
125:127,
cromoglycate
13 One
NCM,
14
induced
dissociation
and
Histamine
anaphylaxis
Med
blocking
effect
the
KF,
III.
antigen-induced
of
tests
perennial
Pharmacologic
rats.
inhibitor
release
1968
histamine
Austen
Lancet2:134,
12
anticromo-
an
histamine
223:197,
in
in
reagin-like
disodium
cromoglycate,
and
release
1967
anaphylaxis
1969
Disodium
Austen
passively
2 16:283,
cutaneous
16:749,
JSC:
on
Stechschulte
of
Nature
induced
lung
1969
2:139,
11
Antigen
with
specific
of antibodies.
MW:
The
guinea
mine
(“Intal”):
mecha-
human
Passive
III,
from
tor
670)
AMJN:
from
serum.
antibodies.
inhibitors
Kerr
PL
AMJN:
anaphylaxis
other
Exp
Blair
A. Nature
HD
Morse
J
(F
1968
stance
in
only
of
by
Acta
antibody-antigen
SRS-A
degranulation
HP,
volved
bron-
in
Cox
Orange
asthma
intaI.”
reaginic
Immunology.
36:497,
of
PC,
and
with
TSC,
experimental
1967
Kilhinghack
J, Blair
Goose
classes
8 Creaves
drug
has
216:1328,
of hitanaine
of rat
in sev-
not
drug
1967
immunologic
sodium
role
significant
disease.30-33
of
A specific
glycate.
5
7
of a direct
Inoue28
has
a
especially
cromoglycate,
Disodium
129:836,
histamine
moderate
MAY
the
inhibited
cromolyn
asthma,
5,
30
in
of
from
hypersensitivity
bronchial
61,
effect
drug
has
of guinea
of Kerr
possibility
muscle.
this
patients,
cromolyn
Inhibition
the
rat,
induced
bodies
and
its
indicate
resulting
sodium
pretreatment
Thus,
FVC
in reduc-
far
a
studies,29
of the American
underway
in
JSC:
sensitized
4
that
reaginic
may act by
by intravenous
raises
the
smooth
3
REC:
release
mechanism
thus
not
cromolyri
induced
bronchial
asthma.
with
of
of
committee
currently
22:487,
Cox
nisms.
exercise-
action
of the
release
that
that
The
to limited
conseveral
uncontrial
indicate
hypersensitivity
reaction.
While
this
been
shown
to affect
the responses
ilei,m
to histamine,2
the demonstration
co-svorkers’#{176}
Allerg
2
reducantigen
in reducing
with
their
to
compound-disodium
stance
effective
asthma
choconstriction
new
challenge.
challenge
some
REFERENCES
FEy,
reported
be related
is probably
in
study
drug
is
clinical
effective
sodium
in the
must
await
the
States.
protec-
sodium
patients
may
understanding
exercise-induced
true
of cromolyn
asthma
induced
conclu-
ob-
of
been
delineated.
Since
it is unlikely
antibody
is involved,
cromolyn
sodium
reduced
be
was
marked
following
airways
obstruction
release.
Although
the role
bronchial
of
reactions,
hypersensitivity
of extensive
by the
Allergy
responI but not
of FVC.
to be
of
study
ing bronchoconstrictive
centrations
of extrinsic
trolled
studies
and
one
reported
sions
regarding
management
double-blind
antigen
dosages
resulting
in
reduction
of vital
capacity
to the ten minute
limitation
function
cromolyn
asthmatic
action
and
subjects
component
reduce
those
more
pollen
sensitive
and
Bewersdorff’8
part
to the use of
percent
or greater
three
subjects
and
may
children
allergic
view
averaged
65.3
percent
100
percent
was
less
appeared
The
in the
five
Herxheimer
induced
of
In
previously
than
subjects
with
flow measurement
The
this
to
degree
noted
marked
FEy,
from
in
air
challenge.
that
appears
technique
some
patients.
were
While
completion
to
to
crossover
III
in
drug
micronized
order
I and
the
nebulizer
bronchial
elicit type
In
type
1 Altounyan
protection
l)ut
varied
that
blocking
but also by reducing
by exercise
Or histamine
whether
a double-blind
all
changes
and
437
CHALLENGE
to improve
drug
alone.
superior
to
reason
that
dose.24
demonstrate
study
in
of
therapeutic
hypersensitivity.
server
bias,
employed.
This
solubility
ANTIGEN
8 of 66 antigen
challenge
studies
involved
pollen
allergy,
it appeared
sodium
to these
III
low
a power-operated
adequate
fact that
specifically
type
and
require
AEROSOL
of
Cromoglycate
Intal
in
in
MICHAEL
438
15
Allergic
Airways
London,
Butterworths,
J,
Kabe
with
posium
on
Allergy
Rome,
1970,
Suppressive
inhalation
antigens.
and
ed)
effect
Disodium
of
provocation
of
Anglo-Japanese
Oct
10,
H,
Bewersdorff
prevention
H:
of induced
Disodium
cromoglycate
asthma.
Brit
in
J
Med
Callahan
RC,
Function.
I.
Med
30:243,
Cox
JSG:
R, Boren
19
of
specific
and
in
20
PCH,
Coombs
underlying
munology.
Ishizaka
Oxford,
K, Ishizaka
antibodies.
International
vember
5-11,
21
gress
Series
Pepys
J:
Roy
22
the
that
Airway
London,
FG,
Poppius
classification
of
Blackwell,
1968,
chap
T:
Characterization
1967,
262,
13,
Sixth
Allergology,
Excerpta
Di30
Effect
of
Medica
International
inhaled
organic
chial
31
reof
32
the
No-
33
Con-
London,
Stanczyk
DJ,
2:42,
J
antigen.
34
1967
Lonigro
et
Allergic
American
North
aspergillosis-a
al:
JE,
disodium
cromoglycate.
Mathison
DA,
JAMA
Bernstein
IL,
study
of
stract)
of
J Allerg,
1969
double-blind
trial
of
allergic
in
the
of
bron-
W:
AlIerg
JJ,
A
43:158,
Lovejoy
Trials
216:1454,
control
of
1969
Franklin
J
clinical
trial
of
1963
FW
Jr,
et
al:
Cromo-
in corticosteroid-dependent
1971
ML,
cromoiyn
Brown
sodium
American
47:95,
cromogiycate
1966
FC,
the
AngloCromo-
71:1212,
treatment
63:96,
Brandon
airway
Disodium
cromoglycate
of asthma.
asthmatic.
on
Disodium
A
the
2:539,
Condemi
treatment
asthma
1970
children.
Med
REC:
Lowell
J 4:337,
and
Intern
Chest,
Farnhan
1969
Exercise
Italy
Disodium
Brit J Dis
al:
Med
E Jr:
in
Lancet
exercise-
cromoglycate
3:176,
asthmatic
Rome,
Middleton
MCS:
et
Allergy
Ann
J
cromoglycate
in
Altounyan
asthma.
committee
rarity.
KE,
disodium
1970,
L,
Disodium
Med
Bnit
cromoglycate
blind
AJ,
RS:
Kreus
on
1968
Bnit
on
asthma.
Kennedy
lyn
p 258
to
10,
JBL,
asthma.
p 575
of human
Congress
Montreal,
Oct
H, Molk
disodium
Im-
of
Symposium
Howell
3:593,
5, McNeill
hypersensitivity
Chai
cromoglycate
J
cromoglycate.
S:
of disodium
1989
disodium
A,
aspergil-
Administration
2:634,
Med
Muittani
in bronchial
allergic
Aspects
of
Bnit
disodium
lnoue
PS:
J
allergic
1970
asthma.
H,
glycate,
29
In
Med
Games
histamine
toxicity,
properties
Disease,
Pepys
1970,
p 13
Clinical
In
EB,
et al: A
sponsored
Academy
by
of
doublethe
Allergy.
drug
(Ab-
1971
Expression
for FDA clearance
see cromolyn
sodium
are
not
enthusiastic
intrinsic
variety
of asthma,
the drug
has definite
use
of bronchial
28
J
Amer
cromoglycate.
The
disease.
bronchopulmonary
Reports
Ward
and
Pulmonary
men,
anti-allergic
disodium
ERA:
Physicians
Editorial
Veterans
pharmacology,
Proceedings
Association
of
No
RC,
Prospects
expect
to
of
Hypersensitivity
Coil
Slavin
chemistry,
in Allergic
Butterworths,
reactions
aginic
of
normal
in
side-effects,
vivo
Cromoglycate
Frankland
AW.
Cell
Study
spirometry
Hartley
Bnit
Effect
Pulmonary
72:398,
JH,
asthma.
Japanese
sodium
J,
et al: The
HG,
Cooperative
Clinical
Review
vitro
Bell
SF:
H:
Med
in exercise-induced
1961
metabolism,
in
26
2:220,
27
Kory
JSG,
Davies
306
Patterson
Intern
induced
Administration-Army
18
25
Italy
Herxheimer
Ann
Cox
1969,
TM,
cromoglycate.
1969
17
24
Med
Golbert
losis.
Sym-
Cromoglycate,
J
Amer
23
M:
upon
causative
AW,
p 45
Muranaka
cromoglycate
asthma
the
T,
J, Frankiand,
(Pepys
1970,
Miyamoto
disodium
16
Disease,
H. GRIECO
asthma
mediated
are good
on our
on
its
and we may
scene
soon.
effectiveness
but indications
in the intrinsic
by
IgE
in
are
type
globulin.
itory
In
laboratory
of the
addition,
properties,
use
because
the
in
pathogenesis
drug
furthering
of
of
bronchial
Raymond
immuno-
CHEST,
of
VOL.
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21537/ on 06/18/2017
its
promises
61,
unique
to
our
be
inhibof
great
understanding
asthma.
G. Slavin,
M.D.
St. Louis,
Missouri
NO.
5,
MAY
1972