Cholecystokinetic Tolerance
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E. NICHOLAS
SARGENT,1
Cholecystography: Study of Sincalide HARVEY
I. MEYERS,1
normal
physiologic
contraction
is set
mechanism
in motion
resulting
by food
SO3H Asp-Tyr-Met--GIy-Trp-Met-Asp-Phe--_.NH2,
mi-
which
Since it is supplied in vials containing 5 jig of drug and 45 mg of sodium chloride, it was reconstituted with 5 ml of sterile water for injection (U.S.P. ; pyrogen free, no preservatives). When reconstituted, each milliliter of solution contained 1 pg of sincalide. The drug was administered intravenously over a 60 sec interval (20 ng/kg body weight). Thus an average adult patient weighing 70 kg required 1 .4 pg (1 .4 ml) of the reconstituted solution. Gallbladder radiographs were obtained at 0, 1 , 3, 5, 1 0, and 15 mm after injection. Gallbladder size (area) was determined by multiplying the maximum length and width. The minimum criterion for a satisfactory response was a 40% reduction of the gallbladder area on at least one radiograph after injection of sincalide. If reduction in gallbladder size was less than 40%, a repeat intravenous dose of 20 ng/kg was administered. Radiographs were again obtained at the same time intervals.
tiates neural and hormonal stimuli that stimulate the biliary system. Cholecystokinin is released from the duodenal mucosa in response to the presence of fat and lipolytic products in the small intestine and, to a lesser degree, by amino acids and small peptides. It stimulates contraction of the gallbladder and simultaneous relaxation of the sphincter of Oddi, inhibits gastric emptying, and increases intestinal motility
[1].
Contraction
with cholecystography of gallbladder function. Cholecystokinin
of the
may permit
gallbladder
in conjunction
an additional
assessment
comprised
of 33 amino
is a polypeptide
HUBSHER2
visualization.
in gallbladder
ingestion,
JEROME
and
Other views included anteropostenior recumbent, right lateral decubitus, and upright compression spot films. Sincalide (Kinevac) is a sterile lyophilized powder of the Cterminal octapeptide of cholecystokinin, prepared by synthesis. At the time of manufacture it is placed in vials in which the air has been replaced with nitrogen. The vials are stored at -4’C until use. The chemical stucture of sincalide is
The intravenous administration of sincalide, the C-terminal octapeptide fragment of cholecystokinin, affords a safe and effective means for gallbladder contraction with resultant cystic and common bile duct visualization. Intravenous sincalide circumvents the problem of unpredictability of response of the gallbladder to a fatty meal and variability in the rate of release of endogenous cholecystokinin. Peak gallbladder contraction occurs earlier than with a fatty meal.
The
AND
Efficacy
acids [2]. The C-terminal octapeptide fragment (sincalide) reproduces all the known biologic activities of the intact molecule [2, 3] The purpose of this study was to determine the effect of sincalide administration on gallbladder con.
traction
in patients
undergoing
Results
cholecystognaphy.
Of Subjects
and
Methods
the
showed A total of 40 patients were studied, 1 1 males and 29 females. Ages ranged from 22 to 61 years (average, 41 years) ; weights ranged from 54 to 145 kg (average, 81 .3 kg). All patients had symptoms which required cholecystography as part of their clinical evaluation. Indiduals with a recent history of acute cardiovascular, hematologic, renal, metabolic, or allergic disorders and those found to have numerous biliary calculi were excluded from the study. Patient preparation consisted of a fatty meal for lunch on the day prior to the examination and a fat-free evening meal. A 3 g dosage of sodium ipodate (Oragrafin#{174}) was administered orally 1 2 hr prior to examination. If the gallbladder was not visualized adequately, an additional 3 g was given and the patient reexamined the following day. Clinical and laboratory tests included physical examination, vital signs, complete blood count, urine, liver and renal function tests, serum electrolytes, and serum calcium, phosphorous, and blood sugar. These tests were performed prior to and 24 hr after drug administration. Electrocardiograms were performed on 33% of the patients immediately before and after the study. A preliminary film was obtained with the patient recumbent, left side elevated, to determine the optimal position for gallbladder
1
to
Received February 1 2, 1 976 Los Angeles County-University E. N. Sargent.
2
Am
; accepted
Squibb Institute
for Medical
J Roentgenol
1 27 : 267-271
after of Southern
revision California
Research, Princeton,
, 1976
40
patients
cholelithiasis
March 29, Medical
1 976. center,
after
a normal
Maximum
ng/kg
(fig.
to
1 .0 to 7.8
The average preinjection (1 5%)
3). and
was
penia from
(average,
2.5
duct bile
duct
New Jersey 08540.
267
North
State
ranged
Six of the
visualization
40
patients (fig.
in 31 of 40
(78%),
in 88%
pain,
of
gallbladder (35
cramps,
of 40).
or nausea
oc-
of patients. No definite evidence of drugrenal, hepatic, or hematologic abnormalities
except
Street
patient
size was 52% of the
occurred
for
one
patient
injection
4,300
(the
cells/mm2).
rise in the eosinophil count serum lactic dehydrogenase
1 200
reof
jig).
emptying
abdominal
a dose
1 ). The injection contraction
to each
5.5%-iOO%).
visualization
mild
to
of
patients
with
gallbladder
in gallbladder
(range
24 hr after 5,000
evidence other
occurred
maximum
complete
in 48% cardiac, found,
contraction
reduction
common
curred related
pg
showed
Transient
All
dose administered
area
Cystic
showed
of 40 patients, or 60% (fig. (40%) required a second
achieve
2). The total
from
five
gallbladder.
gallbladder
of 20 ng/kg in 24 maining 16 patients 40
studied, cholecystography.
Los
Angeles,
from from
California
who
white One
had
blood other
a mild
cell
leuko-
count
patient
fell had
a
7% to 10% and a rise in 330 to 530 U/mI.
90033.
Address
reprint
requests
SARGENT
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
268
Discussion
When injected intravenously, sincalide produces a substantial contraction of the gallbladder with a measurable reduction in gallbladder size. The evacuation of bile that resuits is similar to that which occurs physiologically in response to endogenous cholecystokinin. Maximum contraction (40% or greater reduction in size) occurs within 5-1 5 mm after injection and is limited in duration. By comparison, a fatty meal causes a progressive contraction of the gallbladder that becomes maximal after approximately 40 mm [4].
ET AL.
For prompt contraction of the gallbladder, a dose ng/kg of sincalide administered as an intravenous over
a 1 mm
gallbladder 40
ng/kg
cystic and radiographs injection. tervals
period
does may
is recommended.
not occur be
within
administered.
If contraction
1 5 mm, a second For
visualization
of 20 bolus of the
dose of
of the
common duct it is usually necessary to take at 1 mm intervals during the first 5 mm after Radiographs
are then
usually
taken
at 5 mm
in-
up to 1 5 mm.
The results of this study are similar to those reported by Levant and Sturdevant [5]. They studied 30 patients using a slightly
different
formulation
of sincalide.
In their
study,
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
CHOLECYSTOKINETIC
each vial contained 5 jzg of the drug hydrochloride as carrier. The present mg of sodium
chloride
stable product. Gastrointestinal dominal half
pain,
of
the
as carrier
symptoms cramps,
patients
or nausea studied.
with 1 mg of cysteine formulation using 45
appears such
to provide
as
patients stones
in almost
one-
sincalide
are
mani-
mild
phenomena
festations of the physiologic actions of the drug layed gastric emptying and/or increased intestinal ity). transient
Other
investigators dizziness
and
have flushing.
also
reported
a more
Sincalide
(i.e., demotil-
occasional
269
is contraindicated
drug, and its safety has not yet been
ab-
transient
occurred
These
CHOLECYSTOGRAPHY
with with
small biliary lodgement
should
Several diagnostic
be used
potential value
cholecystography
in patients
for use in pregnant established. Since calculi in the
could cystic
cautiously
clinical uses of gallbladder is still
uncertain.
cystography
may
be
helpful
in the
cholecystitis
[6]
if a relationship
sensitive
to the
women on in children cholecystokinesis in result in passage of or common duct,
in such
cases.
exist for sincalide. The contraction following Cholecystokinetic diagnosis can
be
choleof acalculus
established
be-
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
270
tween
SARGENT
gallbladder
contractility
and
cholecystitis.
It may
be
helpful in visualizing small gallstones not seen without gallbladder contraction. In some instances, it might eliminate the need for intravenous cholangiography by affording good visualization of the cystic duct and common bile ducts. of
the
pain
of cholecystokinin
pattern in patients
been suggested as possibly occurrence of cholelithiasis tients
pain
pattern
trolled of the the
with
suspected
biliary
produced
following
in-
without
gallstones
has
helpful in predicting the future [7]. In future studies of padyskinesia,
the
spontaneous
may
possibly
gallbladder gallbladder
duodenum
be used secretion
Correlation jection
ET AL.
with for
be reproduced
[8]
contraction with provides bile that for
diagnostic
purposes.
secretin
as an adjunct
diagnostic
purposes
following
con-
sincalide. Contraction may be aspirated from Sincalide
to stimulate
can
also
pancreatic
[9].
ACKNOWLEDGMENTS We are indebted to Dr. Andre Schulman, Neal K. Duenas, and Betty J. Burton for technical assistance and to Patricia McColgan for preparation of the manuscript.
CHOLECYSTOKINETIC
CHOLECYSTOGRAPHY
REFERENCES
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
5.
Sleisenger MH, Fordtran J : Gastrointestinal Disease.Pathophysiology, Diagnosis and Management. Philadelphia, Saunders, 1973 2. Ondetti MA, Aubin B, Engel SL, Pluscec J, Sheehan JT: Cholecystokinin-pancreozymin : recent developments. Am J Dig Dis 15:156-159, 1970 3. Aubin B, Engel SL Drungis AM, Dzelzkalns M, Grigas EO, Waugh MH, Yiacas E: Cholecystokinin-like activities of Cterminal octapeptide of cholecystokinin in guinea pigs and dogs. J PharmacolSci58 :955-959, 1969 1
.
4, Saccheth
G, Madelli
V. Roncoroni
L, Montanan
G : Influence
age and sex on gallbladder emptying induced by a fatty normal subjects. Am J Roentgenol 119: 40-45, 1973
of
meal in
6. 7.
8.
9,
271
Levant JA, Sturdevant RAL : Use in C-terminal octapeptide of cholecystokinin in cholecystography. Am J Roentgenol 1 21 380-383, 1974 Nora PF, McCarthy W: Cholecystokinin cholecystography in acalculus gallbladder disease. Arch Surg 1 08 : 507-51 1 , 1 974 Backlund V : Cholecystokinin vid A#{244}ntzenunders#{246}kninger. Lakartidningen 64:2473-2476, 1967 Valbert LS, Jabarni M, Kerr JW, Curtis AC, Ramehand 5, Prentice ASA: Biliary pain in young women in absence of gallstones. Gastroenterology 60 : 1 020-1 026, 1 971 Jonpes JE, Mutt V (eds) : Secretin, cholecystokinin, pancreozymin, and gastrin, in Handbook of Exp Pharmacology, vol. 34, Berlin, Springer-Verlag, 1973, pp 234-240
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
E. NICHOLAS
SARGENT,1
Cholecystography: Study of Sincalide HARVEY
I. MEYERS,1
normal
physiologic
contraction
is set
mechanism
in motion
resulting
by food
SO3H Asp-Tyr-Met--GIy-Trp-Met-Asp-Phe--_.NH2,
mi-
which
Since it is supplied in vials containing 5 jig of drug and 45 mg of sodium chloride, it was reconstituted with 5 ml of sterile water for injection (U.S.P. ; pyrogen free, no preservatives). When reconstituted, each milliliter of solution contained 1 pg of sincalide. The drug was administered intravenously over a 60 sec interval (20 ng/kg body weight). Thus an average adult patient weighing 70 kg required 1 .4 pg (1 .4 ml) of the reconstituted solution. Gallbladder radiographs were obtained at 0, 1 , 3, 5, 1 0, and 15 mm after injection. Gallbladder size (area) was determined by multiplying the maximum length and width. The minimum criterion for a satisfactory response was a 40% reduction of the gallbladder area on at least one radiograph after injection of sincalide. If reduction in gallbladder size was less than 40%, a repeat intravenous dose of 20 ng/kg was administered. Radiographs were again obtained at the same time intervals.
tiates neural and hormonal stimuli that stimulate the biliary system. Cholecystokinin is released from the duodenal mucosa in response to the presence of fat and lipolytic products in the small intestine and, to a lesser degree, by amino acids and small peptides. It stimulates contraction of the gallbladder and simultaneous relaxation of the sphincter of Oddi, inhibits gastric emptying, and increases intestinal motility
[1].
Contraction
with cholecystography of gallbladder function. Cholecystokinin
of the
may permit
gallbladder
in conjunction
an additional
assessment
comprised
of 33 amino
is a polypeptide
HUBSHER2
visualization.
in gallbladder
ingestion,
JEROME
and
Other views included anteropostenior recumbent, right lateral decubitus, and upright compression spot films. Sincalide (Kinevac) is a sterile lyophilized powder of the Cterminal octapeptide of cholecystokinin, prepared by synthesis. At the time of manufacture it is placed in vials in which the air has been replaced with nitrogen. The vials are stored at -4’C until use. The chemical stucture of sincalide is
The intravenous administration of sincalide, the C-terminal octapeptide fragment of cholecystokinin, affords a safe and effective means for gallbladder contraction with resultant cystic and common bile duct visualization. Intravenous sincalide circumvents the problem of unpredictability of response of the gallbladder to a fatty meal and variability in the rate of release of endogenous cholecystokinin. Peak gallbladder contraction occurs earlier than with a fatty meal.
The
AND
Efficacy
acids [2]. The C-terminal octapeptide fragment (sincalide) reproduces all the known biologic activities of the intact molecule [2, 3] The purpose of this study was to determine the effect of sincalide administration on gallbladder con.
traction
in patients
undergoing
Results
cholecystognaphy.
Of Subjects
and
Methods
the
showed A total of 40 patients were studied, 1 1 males and 29 females. Ages ranged from 22 to 61 years (average, 41 years) ; weights ranged from 54 to 145 kg (average, 81 .3 kg). All patients had symptoms which required cholecystography as part of their clinical evaluation. Indiduals with a recent history of acute cardiovascular, hematologic, renal, metabolic, or allergic disorders and those found to have numerous biliary calculi were excluded from the study. Patient preparation consisted of a fatty meal for lunch on the day prior to the examination and a fat-free evening meal. A 3 g dosage of sodium ipodate (Oragrafin#{174}) was administered orally 1 2 hr prior to examination. If the gallbladder was not visualized adequately, an additional 3 g was given and the patient reexamined the following day. Clinical and laboratory tests included physical examination, vital signs, complete blood count, urine, liver and renal function tests, serum electrolytes, and serum calcium, phosphorous, and blood sugar. These tests were performed prior to and 24 hr after drug administration. Electrocardiograms were performed on 33% of the patients immediately before and after the study. A preliminary film was obtained with the patient recumbent, left side elevated, to determine the optimal position for gallbladder
1
to
Received February 1 2, 1 976 Los Angeles County-University E. N. Sargent.
2
Am
; accepted
Squibb Institute
for Medical
J Roentgenol
1 27 : 267-271
after of Southern
revision California
Research, Princeton,
, 1976
40
patients
cholelithiasis
March 29, Medical
1 976. center,
after
a normal
Maximum
ng/kg
(fig.
to
1 .0 to 7.8
The average preinjection (1 5%)
3). and
was
penia from
(average,
2.5
duct bile
duct
New Jersey 08540.
267
North
State
ranged
Six of the
visualization
40
patients (fig.
in 31 of 40
(78%),
in 88%
pain,
of
gallbladder (35
cramps,
of 40).
or nausea
oc-
of patients. No definite evidence of drugrenal, hepatic, or hematologic abnormalities
except
Street
patient
size was 52% of the
occurred
for
one
patient
injection
4,300
(the
cells/mm2).
rise in the eosinophil count serum lactic dehydrogenase
1 200
reof
jig).
emptying
abdominal
a dose
1 ). The injection contraction
to each
5.5%-iOO%).
visualization
mild
to
of
patients
with
gallbladder
in gallbladder
(range
24 hr after 5,000
evidence other
occurred
maximum
complete
in 48% cardiac, found,
contraction
reduction
common
curred related
pg
showed
Transient
All
dose administered
area
Cystic
showed
of 40 patients, or 60% (fig. (40%) required a second
achieve
2). The total
from
five
gallbladder.
gallbladder
of 20 ng/kg in 24 maining 16 patients 40
studied, cholecystography.
Los
Angeles,
from from
California
who
white One
had
blood other
a mild
cell
leuko-
count
patient
fell had
a
7% to 10% and a rise in 330 to 530 U/mI.
90033.
Address
reprint
requests
SARGENT
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
268
Discussion
When injected intravenously, sincalide produces a substantial contraction of the gallbladder with a measurable reduction in gallbladder size. The evacuation of bile that resuits is similar to that which occurs physiologically in response to endogenous cholecystokinin. Maximum contraction (40% or greater reduction in size) occurs within 5-1 5 mm after injection and is limited in duration. By comparison, a fatty meal causes a progressive contraction of the gallbladder that becomes maximal after approximately 40 mm [4].
ET AL.
For prompt contraction of the gallbladder, a dose ng/kg of sincalide administered as an intravenous over
a 1 mm
gallbladder 40
ng/kg
cystic and radiographs injection. tervals
period
does may
is recommended.
not occur be
within
administered.
If contraction
1 5 mm, a second For
visualization
of 20 bolus of the
dose of
of the
common duct it is usually necessary to take at 1 mm intervals during the first 5 mm after Radiographs
are then
usually
taken
at 5 mm
in-
up to 1 5 mm.
The results of this study are similar to those reported by Levant and Sturdevant [5]. They studied 30 patients using a slightly
different
formulation
of sincalide.
In their
study,
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
CHOLECYSTOKINETIC
each vial contained 5 jzg of the drug hydrochloride as carrier. The present mg of sodium
chloride
stable product. Gastrointestinal dominal half
pain,
of
the
as carrier
symptoms cramps,
patients
or nausea studied.
with 1 mg of cysteine formulation using 45
appears such
to provide
as
patients stones
in almost
one-
sincalide
are
mani-
mild
phenomena
festations of the physiologic actions of the drug layed gastric emptying and/or increased intestinal ity). transient
Other
investigators dizziness
and
have flushing.
also
reported
a more
Sincalide
(i.e., demotil-
occasional
269
is contraindicated
drug, and its safety has not yet been
ab-
transient
occurred
These
CHOLECYSTOGRAPHY
with with
small biliary lodgement
should
Several diagnostic
be used
potential value
cholecystography
in patients
for use in pregnant established. Since calculi in the
could cystic
cautiously
clinical uses of gallbladder is still
uncertain.
cystography
may
be
helpful
in the
cholecystitis
[6]
if a relationship
sensitive
to the
women on in children cholecystokinesis in result in passage of or common duct,
in such
cases.
exist for sincalide. The contraction following Cholecystokinetic diagnosis can
be
choleof acalculus
established
be-
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
270
tween
SARGENT
gallbladder
contractility
and
cholecystitis.
It may
be
helpful in visualizing small gallstones not seen without gallbladder contraction. In some instances, it might eliminate the need for intravenous cholangiography by affording good visualization of the cystic duct and common bile ducts. of
the
pain
of cholecystokinin
pattern in patients
been suggested as possibly occurrence of cholelithiasis tients
pain
pattern
trolled of the the
with
suspected
biliary
produced
following
in-
without
gallstones
has
helpful in predicting the future [7]. In future studies of padyskinesia,
the
spontaneous
may
possibly
gallbladder gallbladder
duodenum
be used secretion
Correlation jection
ET AL.
with for
be reproduced
[8]
contraction with provides bile that for
diagnostic
purposes.
secretin
as an adjunct
diagnostic
purposes
following
con-
sincalide. Contraction may be aspirated from Sincalide
to stimulate
can
also
pancreatic
[9].
ACKNOWLEDGMENTS We are indebted to Dr. Andre Schulman, Neal K. Duenas, and Betty J. Burton for technical assistance and to Patricia McColgan for preparation of the manuscript.
CHOLECYSTOKINETIC
CHOLECYSTOGRAPHY
REFERENCES
Downloaded from www.ajronline.org by 218.173.64.120 on 10/13/15 from IP address 218.173.64.120. Copyright ARRS. For personal use only; all rights reserved
5.
Sleisenger MH, Fordtran J : Gastrointestinal Disease.Pathophysiology, Diagnosis and Management. Philadelphia, Saunders, 1973 2. Ondetti MA, Aubin B, Engel SL, Pluscec J, Sheehan JT: Cholecystokinin-pancreozymin : recent developments. Am J Dig Dis 15:156-159, 1970 3. Aubin B, Engel SL Drungis AM, Dzelzkalns M, Grigas EO, Waugh MH, Yiacas E: Cholecystokinin-like activities of Cterminal octapeptide of cholecystokinin in guinea pigs and dogs. J PharmacolSci58 :955-959, 1969 1
.
4, Saccheth
G, Madelli
V. Roncoroni
L, Montanan
G : Influence
age and sex on gallbladder emptying induced by a fatty normal subjects. Am J Roentgenol 119: 40-45, 1973
of
meal in
6. 7.
8.
9,
271
Levant JA, Sturdevant RAL : Use in C-terminal octapeptide of cholecystokinin in cholecystography. Am J Roentgenol 1 21 380-383, 1974 Nora PF, McCarthy W: Cholecystokinin cholecystography in acalculus gallbladder disease. Arch Surg 1 08 : 507-51 1 , 1 974 Backlund V : Cholecystokinin vid A#{244}ntzenunders#{246}kninger. Lakartidningen 64:2473-2476, 1967 Valbert LS, Jabarni M, Kerr JW, Curtis AC, Ramehand 5, Prentice ASA: Biliary pain in young women in absence of gallstones. Gastroenterology 60 : 1 020-1 026, 1 971 Jonpes JE, Mutt V (eds) : Secretin, cholecystokinin, pancreozymin, and gastrin, in Handbook of Exp Pharmacology, vol. 34, Berlin, Springer-Verlag, 1973, pp 234-240
