Pharmacology, Clinical Uses, and Adverse Effects of Ceruletide, A Cholecystokinetic Agent
Miriam E.Vincent,M.D.,Steven M.Wetzner,M.D.,
and Alan H. Robbins,M.D.
Ceruletide,a decapeptide, is a potent cholecystokinetic agent with a direct spasmogenic effect on the gallbladder muscle and bile ducts in humans and animals. It was recently approved by the Food and Drug Administration for use as an adjunct in x-ray examination of the gallbladder and small bowel.The drug causes a coordinated propulsive activity from the duodenum to the ileum and segmenting activity in the colon.Because of this stimulatory effect,ceruletide is useful not only diagnostically as an aid in x-ray examination of the small bowel,but also therapeutically for treatment of postoperative ileus, intestinal atonia,and chronic fecal stasis. Because of its pancreatic stimulatory action, it is useful in evaluation of exocrine pancreatic function.In therapeutic doses the adverse effects noted are mild,transient exten-sions of the drug’s pharmacologic actions and are manifest as nausea, vomiting, abdominal pain, and rarely hypotension and tachycardia. On the basis of current evidence, ceruletide is a safe and effective cholecystokinetic agent and small bowel and exocrine pancreatic stimulant.
Smooth Muscle of the Gastrointestinal Tract
Gastric and Pancreatic Secretion
Pharmacokinetics and Metabolism
From the Departments of Radiology,Veterans Administration Medical Center,New England Baptist Hospital,and Tufts Univer-sity School of Medicine,Boston.
Address reprint requests to Miriam E. Vincent, M.D.,Depart-ment of Radiology,Veterans Administration Medical Center,150 South Huntington Avenue,Boston,MA 02130.
Smooth Muscle of the Gastrointestinal Tract
Gastric and Pancreatic Secretions
Small Bowel Studies
Evaluation of Exocrine Pancreatic Function
Treatment of Intestinal Atonia and Paralytic lleus
Dosage and Administration
Contraindications and Precautions
Ceruletide is a decapeptide isolated from metha-nol extracts of the skin of the Australian frog Hyla caerulea.1.2 It is similar chemically and biologically to the human gastrointestinal hormones cholecysto-kinin-pancreozymin (CCK) and gastrin II.Ceruletide stimulates gallbladder contraction, pancreatic exo-crine secretion,gastric secretion, and motility in the distal duodenum, jejunum, ileum and colon,while
VOLUME 2,NUMBER 4,JULY/AUGUST 1982
delaying gastric emptying and inhibiting motility in the proximal duodenum.Synthetic ceruletide (Tym-tran” Adria Laboratories) was recently approved by the Food and Drug Administration for use as a chole-cystokinetic agent during x-ray examination of the gallbladder and as a stimulant of small bowel motility during x-ray examination of the small bowel.
Synthetic ceruletide has a structure that is identi-cal to the naturally occurring decapeptide:L-pyroglutamyl-L-glutaminyl-L-aspartyl-L-tyrosyl -(O-sulfate)-L-threonylglycyl-L-tryptophanyl-L-methionyl-L-aspartyl-L-phenylalaninamide.The empirical formula is CsH3N,,O2,S2;the molecular weight is 1352.The biologically active C-terminal heptapeptide is similar to the terminal heptapeptide of the human hormone CCK and differs only by the substitution of a threonyl residue for the methionyl residue of CCK in position 6 from the C-terminus (Figure 1). The C-terminal pentapeptide of ceruletide is identical to the C-terminal pentapeptide in gastrin Il(the C-terminal tetrapeptide being the biologically active portion of gastrin). The C-terminal heptapep-tide of ceruletide differs from that of gastrin II by substitution of a sulfated tyrosine in position 6 and alanine in position 7 fromthe C-terminus.Although the sulfation of the tyrosine in gastrin does not affect its physiological activity,3-5 the sulfation of the tyro-sine in position 7 from the C-terminus in both cerule-tide and CCK enhances their ability to stimulate pan-
Figure. 1.The chemical configuration of the carboxy-ter-minal heptapeptides of ceruletide,cholecystokinin and gastrin 11.
creatic and gastric secretion and gallbladder contraction.3-7
Adria Laboratories supplies ceruletide parenteral aqueous solution in 2-ml ampules. Each milliliter contains 20 mcg of ceruletide free acid (as the diethylamine salt) and 1.1 mg of sodium thiomalate as an antioxidant; the pH is adjusted to 7.0 with sodi-um hydroxide.
Ceruletide has a direct spasmogenic effect on the smooth muscle of the gallbladder and the intra-and extra-hepatic bile ducts.8-16 In vitro studies on isolat-ed gallbladders or longitudinal strips of gallbladder muscle from guinea pigs,rabbits, cats, sheep,and cows showed an increase in muscle tone proportion-al to the concentration of ceruletide,which ranged from as low as 0.03 to 2.0 ng/ml.The action of ceru-letide was not blocked by atropine,tetrodotoxin,sco-polamine,propranolol, phentolamine or K+ depolar-ization.8-12 In vivo studies confirmed the chole-cystokinetic activity of ceruletide with threshold doses of 150-200ng/kg when given subcutaneously and 0.23-1.95 ng/kg when given by intravenous bo-lus.8-10.12-15 This effect was unaltered by (1) bilateral vagotomy and splanchnicectomy,(2)reserpinization and bilateral adrenalectomy, or (3) i.v. atropine. Hex-amethonium produced a moderate reduction in con-tractile response in guinea pigs but not in dogs.8.16
Ceruletide is a more potent cholecystokinetic agent than CCK in vitro and in vivo.Recent studies using synthetic CCK show that ceruletide is 2 to 6 times more active than CCK on a molar basis.1° In isolated strips of guinea pig gallbladder,the maximal response to CCK and ceruletide were similar,but the Cso values (concentrations required to elicit a half maximal response) for ceruletide were one-half those of CCK.” In guinea pigs, ceruletide was found to be 10 times more active on a weight basis than CCK, and 3 times more active on a molar basis.8
In the guinea pig, cat, dog, and chicken, ceruletide has a strong direct spasmolytic action on the intact sphincter of Oddi that is unaltered by atropine, pro-pranolol, or tetrodotoxin.8,12,13.17 The spasmolytic threshold dose is as low as 5 ng/kg.Morphine-in-duced spasm of the sphincter of Oddi in guinea pigs was abolished by 50-100 ng/kg of ceruletide.Rab-bits showed both an increase in electrical activity of the sphincter and increased bile flow,indicating re-laxation of the sphincter.13,18 In the rat, an animal without a gallbladder, ceruletide caused reduction in theflow of bile, indicating sphincter contraction.17 Ceruletide has a greater spasmolytic effect on the sphincter of Oddi in dogs and guinea pigs than CCK, pentagastrin,or glucagon.8.19
Ceruletide has a choleretic effect. In isolated-per-fused greyhound livers, 5-25 mcg of ceruletide con-sistently increased bile flow after an initial transitory
EVALUATION OF CERULETIDE
decrease.Ceruletide had no effect on the output of bilirubin or cholate but increased the output of chlo-ride,bicarbonate, and alkaline phosphatase in the bile.2° In intact rats, dogs,chickens,and rabbits,cer-uletide caused a moderate increase in the rate of hepatic bile flow that was often preceded by a tran-sient decrease.Bicarbonate and chloride concentra-tions in the bile increased; bile salt concentrations increased,decreased,or were unchanged.Premed-ication with atropine had no effect on the biliary flow response to ceruletide.15.21-26
Smooth Muscle of the Gastrointestinal Tract
Ceruletide exhibits both stimulatory and inhibitory effects on the gastrointestinal tract, with distinct ac-tions on different areas of the gut. Although the re-sponse and mechanism of action may differ from species to species, the effect appears to be primarily cholinergic but may, in part, be a direct myogenic effect.184.108.40.206-38
In the intact conscious dog, i.v. injections of 0.4-0.5 mcg/kg and s.c. injections of 3-4 mcg/kg of ceru-letide caused emesis and evacuation of the bowel. Recovery was complete 15-30 min after i.v.adminis-tration and 2-4 hr after s.c. administration.8
Isolated guinea pig and hamster stomachs exhibit-ed sustained contraction in ceruletide baths, with contractions declining with time despite continued presence of active peptide. Tachyphylaxis was ab-sent in the guinea pig stomach, but marked in the hamster’s.8.27 The response was blocked by atro-pine, reduced by tetrodotoxin and hexamethonium, and potentiated by eserine.In bath concentratis 20 times threshold, there was a significant increase in acetylcholine release.27 In dogs with denervated fundic pouches,ceruletide caused increased tone and motility, and the spasmogenic activity was re-duced by atropine.8Antral tone in anesthetized dogs was not altered, but amplitude of the contractions was increased.28 However,an approximately 20% decrease in intragastric pressure was seen in healthy gastric fistula dogs with i.v. doses as low as 62.5 ng/kg/hr. The decrease rose to 50% with infu-sion of 500 ng/kg/hr of ceruletide.29 Ceruletide re-duced or abolished muscular activity in the fore stomach of sheep but stimulated the proventriculus of anesthetized chickens.15.30
Ceruletide had a marked spasmogenic effect on the pylorus of rats with an i.v.threshold dose of 5-15 ng/kg and a dose-response relationship up to 100-200 ng/kg.Tachyphylaxis was variably present.The effect was not appreciably affected by sympathetic or parasympathetic drugs.8,31.32
Isolated segments of guinea pig duodenum re-sponded to ceruletide threshold bath concentrations of 100 ng/ml with increased tone.Ultimately,the iso-lated segments became rhythmically active and, after reaching a maximum,activity declined sponta-neously, despite the continued presence of the pep-tide. Isolated rabbit duodenum responded to a
threshold bath concentration of 0.2-1 ng/ml with a slight increase in tone that declined spontaneously. Tachyphylaxis was present in both species. Isolated segments of rat and hamster duodenum contracted in ceruletide baths with threshold concentrations of 0.1 mcg/ml and 50-100 ng/ml,respectively.There was no effect on isolated cat duodenum or on fresh dog duodenum at bath concentrations of 2 ng/ml and 1.5 mcg/ml,respectively.However,dog duodenum preparations maintained for 24 hours in 4° C Tyrode solution were stimulated by the peptide at concentra-tions above 0.1 ng/ml.8Ceruletide caused contrac-tion of the isolated chicken duodenum.15
The action of ceruletide on the isolated guinea pig ileum was similar to that on the duodenum but with a lower threshold concentration. Tachyphylaxis was variably observed. The response to the peptide was antagonized by atropine,hexamethonium,and tetro-dotoxin and potentiated by eserine.8.9.33 Auerbach’s plexus is suggested as a site of action by the obser-vation that in guinea pig ileum bathed in ceruletide plexus neurons exhibited increased electrical activity that was unaltered by atropine or hexamethonium. A substantial release of acetylcholine occurred in strips of guinea pig ileum exposed to ceruletide baths.Tetrodotoxin inhibited this release, whereas hexamethonium did not, suggesting specific peptide receptors in the parasympathetic ganglion cells. 34.35 In isolated rabbit small intestine, both rhythmic con-tractions and increased muscle tone have been ob-served;both were blocked by tetrodotoxin.9.33 Ceru-letide inhibited electrical and mechanical activity in isolated cat small intestine.The electrical response to acetylcholine was overcome by ceruletide while the peptide’s inhibitory effect was not blocked by tetrodotoxin. This suggests, that, in this species at least, ceruletide has a direct action on the muscle.33
Intact anesthetized dogs showed prompt and in-tense increase in tone and contractions in the je-junum and ileum, with a threshold dose of 1-5 ng/kg i.v. The response of the duodenum was similar, but here the drug increased the amplitude more than the frequency of contraction. Atropine caused a marked inhibition of the response.8.28
In the rabbit,ceruletide increased amplitude of contraction and tone, but had no effect on the fre-quency of peristaltic waves.Ceruletide accelerated ileal motility in vagotomized,splanchnicectomized rabbits and in reserpinized, bilaterally adrenalecto-mized rabbits.9
Isolated segments of rabbit, guinea pig, hamster, cat, frog,toad, and,after 24 hours bath in 4° C Ty-rode solution, dog colon were all stimulated by ceru-letide;however,the colon is much less sensitive than the small bowel.8.36 In isolated distal colon of the guinea pig and rabbit, ceruletide reduced the thresh-old for intramural balloon stimulation of the peristaltic reflex and increased the velocity of propulsion.37
Ceruletide had no effect on the gastrointestinal suture line in dogs who had undergone partial bowel resection 48 hours prior to i.m. injection of 0.5 or 1
VOLUME 2,NUMBER 4,JULY/AUGUST 1982
mcg/kg of the peptide. Intestinal contractions were registered 10 min after injection, and bile was found in proximal intestine of the treated dogs, but not in the control dogs,when they were sacrificed 3 hr after treatment.Microscopic examination revealed no dif-ference in the suture line between the control and treated animals.38
Gastric and Pancreatic Secretion
Ceruletide is a potent gastric secretory stimulant that causes an increase in the output of acid and pepsin in dogs, cats, rats, and chickens.5.39-51 In con-scious Heidenhain pouch (denervated) dogs,the threshold dose was 0.15-0.5 mcg/kg s.c.,and 0.25-0.5 mcg/kg/hr i.v. infusion.A dose-related increase in the volume of gastric acid and pepsin and an in-crease in acid and pepsin concentrations occurred with administration of up to 2 mcg/kg s.c. If basal secretions were high,the sensitivity to ceruletide de-creased. Subcutaneous atropine blocked at least 90% of the effect of ceruletide on gastric secretions; hexamethonium had no effect.39 Ceruletide adminis-tered to histamine-treated dogs caused a rapid re-duction in acid output and gastric volume in one study39and increased acid output in another.41 Cats and rats showed an increase in gastric acid secretion when ceruletide was injected during histamine infu-sion.39.45 Ceruletide inhibited pentagastrin-induced acid secretion in dogs and cats with vagally innervat-ed Pavlov pouches.42.52 In rats,neither i.v.hexa-methonium or bilateral cervical vagotomy altered the gastric acid output response to ceruletide; atropine had no effect or caused a minimal decrease in re-sponse.39,47 In the chicken,atropine blocked the se-cretory response to ceruletide.49 In the rat, the secre-tion of intrinsic factor increased by 100 and 350% in response to a ceruletide dose of 0.5 and 5 mcg/kg, respectively.53
The pancreas is the secretory organ most sensi-tive to ceruletide.Like CCK(pancreozymin), cerule-tide is a stimulant of both exocrine and endocrine function.5,14.15,21,24.54-63 In dogs and rats,ceruletide had an atropine and propranolol-resistant stimula-tory effect and increased the volume of pancreatic juice and protein output.5,21,54.55 The bicarbonate concentration was unchanged or slightly increased. The threshold dose for exocrine pancreatic secretion was 1-5 ng/kg i.v.,50-100 ng/kg s.c.,and 0.25-1.0 ng/kg/min i.v. infusion. The s.c. threshold dose was 30-40 times less than the dose that produced eme-sis in conscious dogs.21 Ceruletide produced a marked increase in amylase, protein, calcium,and zinc concentrations of pancreatic juice secreted in response to submaximal doses of secretin in dogs.64 Ceruletide is 3-6 times more potent, on a molar ba-sis,than CCK,and 7 to 50 times more potent than gastrin on pancreatic exocrine secretion.Secretin, except in rats,stimulates flow 2.5 to 20 times more than ceruletide on a molar basis.10.65
Intravenous ceruletide increased plasma insulin in
dogs, an effect which was potentiated by adrenalec-tomy.58-61.66 Additionally, ceruletide caused in-creased glucagon levels in dogs.58.59,61 An increase in plasma insulin in anesthetized rats and release of glucagon from isolated perfused rat pancreas has been demonstrated.62.63
Ceruletide stimulates output from Brunner’s glands in dogs and cats and calcitonin release from surgically isolated pig thyroid gland in situ.67.68
Ceruletide, like other naturally occurring peptides, affects the cardiovascular system.Systemic blood pressure response to ceruletide shows species vari-ation and occurs at doses much higher than those used to provoke the described actions on the gall-bladder, intestines, and pancreas.69-72 In anesthe-tized dogs,ceruletide caused a reduction in blood pressure that was dose-related in both duration and intensity.Atropine caused a 20-40% reduction in the intensity of the hypotensive response but not the duration;dibenamine prolonged the duration and in-creased the intensity of the response. No alteration was observed with propranolol. The hypotensive re-sponse threshold doses were 10-100 ng/kg i.v.5-10 mcg/kg s.c. and 5-15 ng/kg/min i.v.infusion.Doses up to 100-1,000 mcg/kg by rapid i.v. infusion (10 to 100 thousand times threshold) were tolerated with full recovery in 3 to 9 hr.69.70 In the rabbit and cat, ceruletide also caused hypotension. The hypoten-sive response in the rabbit was atropine-resistant. The cat was less sensitive than the dog or rabbit, and tachyphylaxis was present. Atropine caused a mod-erate and inconsistent hypertensive response in the ceruletide-treated cat.9.13.70 The rat,chicken,and sheep had a primarily hypertensive response that varied with dose and became bi-and tri-phasic with a hypotensive component.13.70.73
When marked hypotension was produced in dogs, the electrocardiogram showed signs of severe myo-cardial anoxia that were felt to be due to hypotension and not a direct effect of ceruletide. In the isolated rabbit heart, the effects of ceruletide were variable and not dose-dependent. A reduction of contractile force was seen, but an increase was present in 2 of 10 experiments. A-V conduction was moderately al-tered;this change was completely reversible.70 In isolated spontaneously beating cat atria, amplitude and rate of contraction were increased by ceruletide.74
Pancreato-duodenal blood flow is very sensitive to ceruletide.At threshold doses for exocrine pancreat-ic secretion, flow in the inferior pancreato-duodenal artery was increased and paralleled the increase in exogenous pancreatic secretion. At higher,hypoten-sive doses, the pancreato-duodenal blood flow de-creased.58.71.75-77
Pharmacokinetics and Metabolism
S35-labeled ceruletide was injected intramuscular-
EVALUATION OF CERULETIDE
ly in rats, rabbits, and mice in concentrations more than 100 times the physiologically effective dose to study the peptide’s absorption, distribution, and me-tabolism.78.79 Radioactivity in the blood reached a maximum at 5 and 15 min in rats and rabbits respec-tively and then decreased rapidly. Physiological ac-tivity of the peptide was present in blood of rabbits, but not rats,collected up to 30 min after injection.78
Radioactivty in the brain, cecum, and colon paral-leled that in blood, decreasing rapidly as blood levels dropped. The radioactivity in the kidneys, liver,pan-creas, stomach, duodenum, and jejunum decreased more slowly. The highest radioactivity was in the kidneys.78 Whole body auto-radiograms of mice show similar patterns for distribution of S35-labelled ceruletide.79
Radioactivity in the bile of rats reached 8.76% of the injected dose in 1 hr and continued to show phys-iological activity for 2 hr after injection. 13% of the radioactive dose was excreted in the bile in 24 hr. Bile radioactivity in rabbits peaked at 30 to 45 min after administration,with only 1.61% of the injected radioactivity being excreted in the bile in 6 hr.Rabbit bile assays never showed physiological activity. In rat and rabbit, 88% and 64% of the injected radioac-tive dose,respectively,was recovered in the urine in 24 hours and 4.5% and 1.4% in the feces.No physio-logical activity of the peptide was shown in the urine.78
Incubation of ceruletide with rat blood did not cause loss of physiological activity.However,when incubated with kidney or liver homogenate, inactiva-tion occurred; it was especially rapid in the kidney homogenate.78
At least four metabolites of ceruletide were found in rat urine using paper chromatography and electro-phoresis. None of the metabolites caused gallblad-der contraction. Attempted analysis of these metab-olites suggested that the peptide is split between tryptophan and methionine and that hydrolysis of the Trp-Met bond is the rate-determining step in the me-tabolism of ceruletide. The most abundant radioac-tive metabolite (63.1%) was indirectly identified as a peptide fragment of ceruletide; the second most abundant is a non-peptide compound, probably formed by transfer of S35-labelled sulfuric acid to oth-er substances.78
Acute toxicity studies of ceruletide in mice show an i.v.LDso of 1012 mg/kg.Death occurred in a few minutes and appeared to be the result of cardiovas-cular collapse; the animals exhibited dyspnea, cyan-osis,and prostration.80
Chronic toxicity was studied in rats receiving ceru-letide 10,50 and 250 mcg/kg s.c. and in dogs receiv-
ing 2 and 6 mcg/kg i.m.for up to six months.In the rat study, sporadic deaths due to bacterial pneumonia occurred; the deaths were unrelated to dose or length of treatment.80-85
The pancreas was the only organ to show sub-stantial morphological or functional changes.Organ weight in rats receiving the low dose increased after six months of treatment; it decreased significantly with the intermediate dose after 3 and 6 months of treatment and with the high dose after 1,3, and 6 months. At all doses, weight returned to normal six months after cessation of treatment. At low dose, minor reversible signs of acinar tissue hypertrophy were present. At higher doses there was focal dam-age to acinar cells, centroacinar hypertrophy,and stromal edema and infiltration with inflammatory cells.After 3 months,parenchymal atrophy with dif-fuse acinar cell damage was seen; after 6 months, interacinar and intralobular fibrosis appeared.Pan creatic islet cells were not damaged,although there was peri-insular fibrosis. The histological changes were reversible except for the atrophy and fibrosis at the highest dose in rats. The pancreas of dogs re-ceiving 2 and 6 mcg/kg of ceruletide showed no ab-normalities.80-83 Intravenous infusion of 20 ng/kg/min of ceruletide for up to 24 hours in dogs caused ultras-tructural changes,with destruction of most of the existing organelle structure of the cytoplasm of the acinar cells.Most of the ultrastructural changes dis-appeared 12 to 24 hr after termination of the infu-sion.84 Minimal hypertrophy of the gastric parietal cells and increase in the weight of the duodenum were seen in rats at the highest doses.80 No other morphologic or histological abnormalities were discovered.
Hematological studies and urinalysis were normal, as were serum biochemical studies except for serum amylase and inorganic phosphates. Serum amylase was minimally increased in dogs receiving 6 mcg/kg i.m. and in rats receiving 10 mcg/kg s.c. In rats re-ceiving 250 mcg/kg s.c., serum amylase was mini-mally decreased after 3 and 6 months of treatment. Serum inorganic phosphates showed a minimal in-crease in all groups of rats treated for 6 months. Fat absorption was impaired in rats receiving 250 mcg/ kg for 6 months,remained abnormal 3 months after cessation of treatment, but returned to normal 6 months after cessation.There was no abnormality in oral glucose tolerance.80
Reproductive studies were performed in rats and rabbits treated throughout pregnancy with daily s.c. injections of ceruletide in high doses (50 mcg/kg in rats and 10 and 25 mcg/kg in rabbits). There was no evidence of adverse effect on the dams or of terato-logic action on the fetuses.80.85
Extensive clinical trials in normal volunteers and
VOLUME 2,NUMBER 4,JULY/AUGUST 1982
patients without biliary disease have shown that cer-uletide has strong cholecystokinetic properties when given intravenously and intramuscularly and by na-sal insufflation.86-95 The threshold dose in man fr spasmogenic activity in the gallbladder is 0.5-1.0ng/ kg i.v.,0.02-0.05 mcg/kg i.m.,and 0.1 mcg/kg by nasal insufflation.86-88.91 The optimal dose for con-traction of the gallbladder in man is 0.2-0.3 mcg/kg i.m. This dose produces maximum contraction(50-100%) in 15 to 30 min. The effect dissipates in 1 to 3 hr with return of the gallbladder to pre-treatment size.89.96 When administered intravenously, the on-set of action is within one minute, peaks at 20 to 30 min and then rapidly tapers off.92 The speed,intensi-ty, and duration of the spasmogenic effect of cerule-tide is dose-related up to high doses.9° The contrac-tion of the gallbladder begins in the neck and infundibulum and is followed by contraction of the fundus and body and subsequent evacuation of con-trast into the biliary ducts.91 With high doses,espe-cially when given intravenously,marked spasm of the neck of the gallbladder occurs which prevents emptying.This accounts for the loss of dose relation-ship at high doses. Spasm is not seen when the peptide is given in doses of 0.3-0.5 mcg/kg i.m.93 Ceruletide causes contraction of the extrahepatic
and intrahepatic bile ducts and relaxation of the sphincter of Oddi,overcoming morphine-induced spasm.87.88 A choleretic effect has been demon-strated.91.92.97
The cholecystokinetic effect of ceruletide is more rapid and more intense in children, with a threshold of 0.01-0.02 mcg/kg i.m. It is less intense and of shorter duration in the elderly, with a threshold of 0.5 mcg/kg i.m.91.92
The spasmogenic effect of ceruletide on the biliary system is not affected by premedication with atro-pine,which indicates that, as in laboratory animals, the effect is a direct one on the gallbladder and not mediated via the nervous system.87
Smooth Muscle of the Gastrointestinal Tract
Except in the stomach and proximal duodenum, ceruletide has a stimulatory effect on the gastrointes-tinal tract.It causes coordinated propulsive activity from the distal duodenum to the terminal ileum and segmental activity in the colon.87.88,98-112
Ceruletide reduces the lower esophageal pres-sure in both normal man and in patients with esopha-geal achalasia.This may be due to competition with gastrin for receptor sites.98.99
There are conflicting reports on the action of ceru-letide on gastric muscle. In vitro, the peptide causes a moderate, constant stimulation of antral motility at a threshold dose of 0.5-5 ng/ml in a nutrient bath.100 However,when electrical and manometric activity were examined in vivo, ceruletide, 0.6-12.5 ng/kg/ min i.v., caused a dose-related decrease in frequen-cy and amplitude and an increase in duration of the pace-setter potential-basal electrical rhythm(BER)
in the gastric antrum. The rapid spikes of electrical activity or action potentials (AP) showed a decrease in frequency, duration, and amplitude and finally dis-appeared altogether at the higher dose. There was a dose-related decrease in the mechanical activity of the stomach,with a decrease in the number of waves/min and in the average amplitude and dura-tion of the waves. A dose of 2.5 ng/kg/hr i.v.was necessary to totally inhibit manometric waves in the stomach. After stopping the peptide infusion, a re-bound phenomenon was seen in both electrical and manometric activity.Amplitude of both BER and AP increased to above pre-peptide levels, as did gastric propulsive motility.Fluoroscopically,the waves were seen to proceed more slowly from the body to the pylorus,becoming superficial and almost impercepti-ble. At higher doses, the propagating waves in the stomach were absent. In the body and fundus of the stomach, the effect of ceruletide was less constant than in the antrum.When subjects were premedicat-ed with a-blockers, ceruletide had no inhibitory effect but the post-peptide rebound showed motility higher than with ceruletide alone. Administration of penta-gastrin and ceruletide caused an increase in the in-hibitory effect without a rebound phenomenon.The authors postulated an action of ceruletide via both the cholinergic (stimulatory) and adrenergic (inhibi-tory) systems.101. 102 On a molar basis, ceruletide was more effective in inhibiting gastric motor activity than CCK,but less effective than secretin and glu-cagon.102.103
Ceruletide causes pylorospasm in man. Man-ometric and fluoroscopic observations show a no-ticeable and short-lasting pylorospasm after rapid i.v. administration, a less marked effect after i.m. administration and no effect after nasal insuf-flation.100,104.105
Ceruletide inhibits peristalsis in the proximal du-odenum both in vitro and in vivo. 101. 106-108 Ceruletide, 2 ng/kg/min i.v.infusion, inhibited manometric and electric activity in the first and second portion of the duodenum with a decrease in slow-wave frequency and in the percentage of spike duration;the effect was immediate and lasted as long as the infusion. With a single 1-2 ng/kg i.v.injection, the duration was 3-4 min. The reduction in contractile activity was not accompanied by a change in tone. Unlike the effect in stomach, there was no change in the amplitude ofspikes and slow waves.101,107,108
The remainder of the small intestine is stimulated by ceruletide in a dose-related manner.87.100.106-110 In vitro,tone and spontaneous peristalsis increased; the threshold concentration was less than 1 ng/ml for jejunum and 10 ng/ml for ileum.The effects were reversible with washing, and tachyphylaxis was rare-ly observed.There was no difference in sensitivity of longitudinal and circular muscle.However,the effect on the longitudinal muscle was immediate;there was a latent period for contraction of the circular muscle that coincided with the relaxation of the longitudinal
EVALUATION OF CERULETIDE
muscle and led to propulsive activity.Atropirie and tetrodotoxin blocked the effect of ceruletide,with up to a 90% reduction of stimulation. The threshold dose for in vivo stimulatory effects on the jejunum and distal ileum was 1-2 ng/kg i.v.and 10-20 ng/kg i.m., respectively. Ceruletide’s action on the intestine is mediated primarily through the release of acetyl-choline from ganglion cells.87.106.112 Anticholinergic agents reduced but did not abolish the stimulatory effect of ceruletide.87.88,100.107-109,112
The colon is also stimulated by ceruletide but is much less sensitive than other portions of the GI tract.106 Subj ,ctively, participants in some studies re-ported an urge to defecate. Manometric meas-urements showed an increase in frequency,percent manometric activity, and motility index in the sigmoid colon. Fluoroscopy revealed increased local seg-menting activity in the colon with rare peristaltic ac-tivity. The effect was not dose-related but was inhibit-ed by atropine.87,107,109,111
Gastric and Pancreatic Secretions
Ceruletide causes a moderate increase in volume of gastric secretion,acid output,and acid concentra-tion-an increase less than that produced by penta-gastric stimulation.The threshold for gastric stimula-tion is 0.05 mcg/kg i.m.The response is dose-related up to 0.5 mcg/kg; then the response decreases.The onset of response is within 15-30 min after injection, with a duration of 75-90 min.113-116
In both normals and patients with peptic ulcer dis-ease, ceruletide,acting as a competitive inhibitor or partial agonist, decreases pentagastrin stimulation of both the volume and degree of acidity of gastric secretions by 50-80%. Ceruletide minnally poten-tiated the inhibitory effect of secretin and glucagon when administered to a pentagastrin-stimulated pa-tient.117-120 When administered with histamine, ceru-letide caused a 20% increase in acid output.117
Ceruletide has a strong stimulatory effect on pan-creatic exocrine function and it.creases the volume of secretions and enzyme concentration.Threshold doses are 0.01 mcg/kg i.v.and 0.1 mcg/kg i.m.There is a latency period of 1-5 min, and th.e peak volume occurs at 15-30 min.Secretion returns to normal one hr after i.v. administration but lε sis beyond one hr after i.m. administration.
Duodenal aspirate showed a significant increase in bicarbonate concentration. In combination with se-cretin,ceruletide caused a greater increase in vol-ume,bicarbonate concentration, and enzyme con-centration than when secretin was used alone.The ceruletide-secretin combination produced results similar to CCK-secretin pancreatic stimulation. 116. 121-124 Ceruletide, 10-45 ng/kg i.v.,produced an in-crease in serum glucagon but had no effect on serum insulin in normal persons.125 Ceruletide 0.2 mcg/kg i.m. caused an increase in plasma pancreatic poly-peptide, an effect that was markedly decreased by atropine.126
Doses of ceruletide clinically useful in the biliary system,Gl tract smooth muscle, and gastric and pancreatic secretory functions are 10-40 times low-er than the doses used to achieve a response of the vascular smooth muscle in animals.70.100 One study evaluated many cardiovascular parameters in hu-mans receiving ceruletide 0.5-0.75 mcg/kg i.m.,and no significant effects on the cardiovascular system were observed.127 Cardiovascular parameters have been monitored during other studies,and significant changes from basal values were not noted, except for rare, mild, transient tachycardia with high i.v. doses87.90,91.93.94,96,121
Biliary System.Thecholecystokinetic activity of ceruletide facilitates radiographic diagnosis of gallbladder pathology, small stones, and hyper-plastic cl olecystoses, and visualization of the bile ducts during oral cholecystography (OCG).The peptide is a more rapid, consistent and effective cholecystokinetic agent than the “fatty meal” (Table 1).86,93,96,128-132 It causes greater contrac-tion of the gallbladder and higher frequency of duct visualization than sincalide (Kinevac®),an-other commercially available,synthetic, CCK-like drug.133 The optimal dose for gallbladder contrac-tion and visualization of the bile ducts during OCG is 0.3 mcg/kg i.m. This dose is well-tolerated and avoids hypercontraction of the neck of the gallbladder.
Table 1. Cholecystokinetic Effect
Number Percent of
Reference Subjects Dose Contraction
Sargent132 40 0.3 μg/kg IM 56%
40 fatty meal 29%
Wetzner128 17 0.3 μg/kg IM 72.5%
17 fatty meal 46%
When ceruletide, 0.1 mcg/kg i.v., is given 15 min prior to contrast infusion for intravenous cholangiog-raphy (IVC),there is better visualization of the ductal system and gallbladder, since the biliary system has already been emptied by ceruletide. In addition, due to the choleretic effect, good opacification can be
VOLUME 2,NUMBER 4,JULY/AUGUST 1982
achieved with half the normal dose of contrast medi-um.220.127.116.11 Ceruletide has been used during oper-ative cholangiography to relax the sphincter of Oddi, prevent reflux of contrast medium into the pancreatic ducts and to differentiate between stricture and spasm of the sphincter of Oddi.135.136 The diagnosis of motor disorders of the biliary system is a highly debated subject; the possibility of hypo-or hyperkin-etic states of the gallbladder being related to disease is still under discussion. Ceruletide has shown nor-mal contractility in gallbladders that had been hypo-tonic to the fatty meal. The peptide has also been used to make the diagnosis of cystic duct syndrome, showing marked hypercontractibility of the gallblad-der neck preventing emptying of the gallblad-der.98, 129, 131,137-139 Ceruletide should be useful in any imaging modality especially radionuclide or ultra-sound studies where contraction of the gallbladder is desired to facilitate evaluation of pathology.
Small Bowel Studies. Transit time during barium small bowel examination is markedly reduced after the administration of ceruletide and thereby de-creases radiation and examination time (Table 2).139-144 When ceruletide 0.3 mcg/kg is given intramuscu-larly after sufficient barium (20-30 cm of barium-filled jejunum) has passed the ligament of Treitz,the entire small bowel can be rapidly and simultaneously visualized,leading to easier diagnostic evaluation. Ceruletide permits improved diagnostic detail,espe-cially in patients with deformity or stricture in the ileocecal region.140.144-146 The use of i.v.ceruletide, higher i.m.doses,or insufficient barium in the je junum prior to injection may lead to poor small bowel detail, because of marked spasm of the small bowel and pylorus and the hypotonic effect in the duode-num.107,140-142,145,146 The hypotonic effect in the du-odenum may also provide a useful adjunct to the study of that portion of the gastrointestinal tract dur-ing the small bowel examination.
Table 2.Small Bowel Transit Time
Reference Patients Treatmenta (minutes)
Lorber140 14 ceruletide 10
6 placebo 52.5
Sargent141 17 ceruletide 15
8 placebo 80
Robbins142b 32 ceruletide 19
16 placebo 59
aCeruletide 0.3 mcg/kg im in all studies.
bRecalculated data-personal communication (values given as mean transit time in reference 142).
Evaluation of Exocrine Pancreatic Function
With its affinity for pancreatic acinar cells, cerule-tide provides an excellent method for evaluating exo-crine pancreatic function.Because ceruletide does not increase the bicarbonate concentration as much as it affects volume and enzyme secretion, it has been used in combination with secretin, a potent bicarbonate, volume, and enzyme (especially lipase, trypsin,and chymotrypsin) stimulant, to evaluate pancreatic exocrine function. The synergistic action of ceruletide and secretin,like that of CCK-secretin, increases all three parameters in duodenal aspirates in normal volunteers. In patients with chronic pan-creatitis,stimulation is decreased; the bicarbonate and enzyme concentrations are more affected than the volume.There is disagreement as to the tech-nique (i.v. bolus, i.v.infusion,or i.m.)and the se-quence (simultaneous or one of the two drugs first)of administration.123.147-156 With i.v. bolus secretin and ceruletide, there is a 15-20% overlap of values in normals and patients with chronic pancreatitis.With continuous i.v. infusion of secretin and ceruletide in doses of 0.5-1.0 CU/kg/hr and 75-100 ng/kg/hr re-spectively for 90 min,and 3-30 minute collections of duodenal aspirates, there is a decrease in the en-zyme output in the 30-60 min collection in patients with exocrine pancreatic impairment; this decrease is even more pronounced in the final 30 min. In nor-mals, the stimulation is sustained until the infusion is stopped.Prolonged stimulation in patients with even minor impairment of exocrine pancreatic function may deplete the gland's reserves in a way that a bolus injection does not, allowing for a more sensi-tive test of pancreatic dysfunction.151,152 Although ini-tial studies showed secretin-ceruletide stimulation to be greater than secretin-CCK stimulation, this has not been corroborated by later studies.The two com-binations are essentially identical in their exocrine pancreatic stimulation.149,157,158
Treatment of Intestinal Atonia and Paralytic lleus
In patients with non-obstructive ileus, ceruletide is effective in stimulating peristalsis, flatus,and defeca-tion.Dose and route of administration vary from 0.5-0.75 mcg/kg i.m.in single injections or repeated ev-ery 12-24 hr to 2-3 ng/kg/min i.v. infusion. In most cases, bowel sounds are heard less than one hr after onset of treatment, and passage of gas occurs in less than 12 hr and feces in 24-48 hr.87,100,159-169 Nasogastric tube output was markedly reduced in cholecystectomy patients given i.m.ceruletide 0.5 mcg/kg 24 hr after surgery. The output was greater than 50 ml/24 hr prior to the injection in 28/29 pa-tients and in 1/29 in the 24 hr post treatment.162 When post-operative patients, including those who had gastric and small bowel resections,were given ceru-letide 24 hr postoperatively, resumption of bowel ac-tivity, as indicated by defecation, was twice as rapid in the ceruletide group as the control group.169 No
EVALUATION OF CERULETIDE
deleterious effects have been noted on suture lines or anastomoses in any of the studies. Ceruletide is effective in ileus when conventional methods,includ-ing enemas,neostigmine and metoclopramide,have failed.159,164.168 It is also effective in patients with chronic fecal stasis.Ceruletide has been used suc-cessfully in children with non-Hirschprung megaco-lon,but found unsuccessful in the aganglionic colon segments.87,100.160
When used in the recommended doses,ceruletide is well tolerated. Side effects are primarily dose-re-lated extensions of the drug's pharmacologic actions -nausea,vomiting,abdominal cramping,borboryg-mus, diarrhea, flushing,tachycardia, dizziness,and hypotension. They are usually mild, short-lived,and self-limited, requiring no treatment. Abdominal cramps and nausea occur in about 1 of 10 treated patients, vomiting in about 1 of 100. Dizziness and hypotension are rarely seen, often accompany the gastrointestinal side effects, and may be secondary to them;however a direct effect cannot be ex-cluded.170 Pain at the site of i.m. injection was fre-quently reported when undiluted ceruletide was giv-en.Mixing the peptide with 0.5 ml normal saline largely eliminates this side effect.128
Dosage and Administration
Ceruletide 0.2-0.5 mcg/kg i.m.causes cholecys-tokinesis and stimulates small bowel motility for diag-nostic use in biliary examintions and small bowel roentgenographic studies. The recommended ap-proved dose in the United States is 0.3 mcg/kg i.m. This dose has been used therapeutically,as has 1-3 ng/kg/min i.v. infusion, for postoperative ileus, intes-tinal atonia, and chronic fecal stasis. The i.m. dose may be repeated every four hours up to four times a day. Exocrine pancreatic stimulation can be achieved with ceruletide doses of 0.1-0.75 mcg/kg i.m.,1-2 ng/kg i.v.,or 75-100 ng/kg/hr i.v.infusion in combination with varying doses of secretin, depend-ing on the test being used.
Contraindications and Precautions
Ceruletide is contraindicated in patients with a known hypersensitivity to it and in patients with intes-tinal obstruction. Cholelithiasis is a relative contrain-dication to any cholecystokinetic agent, and there-fore ceruletide probably should not be given to patients with known gallstones or a nonvisualized gallbladder by OCG. However, in several studies, ceruletide was given without deleterious effect to pa-tients whose cholecystokinetic studies subsequently showed gallstones.93,128,132 Although there are no known deleterious effects to the use of ceruletide in patients with obstruction of the biliary system, acute cholecystitis, or acute pancreatitis, ceruletide should
be used with caution in these patients. Since there are no studies of ceruletide in pregnant women, and since it has a stimulatory effect on smooth muscle, the drug should not be administered to pregnant women.170
No clinically significant overdose incidents have been reported.However, overdosage would be ex-pected to lead to an accentuation of the drug's phar-macologic actions and result in nausea, vomiting, diarrhea, abdominal cramping,and hypotension These effects should be self-limited and short-lived, and the patient should need only supportive treatment.170
Ceruletide is similar in action and chemical struc-ture to the active portion of human polypeptide CCK. Its cholecystokinetic,exocrine pancreatic stimulant, and small bowel motility stimulant actions make it useful both diagnostically and therapeutically.Ceru-letide is more effective and more reliable than the traditional “fatty meal" for cholecystokinetic activity, a fact that should outweigh any increase in cost. It is more expensive than sincalide (Kinevac"), a syn-thetic C-terminal octapeptide of CCK currently avail-able for i.v.use only.Further comparative studies of ceruletide and sincalide are necessary before a defi-nite statement can be made comparing the two agents.Pharmacological doses of ceruletide cause mild, infrequent side effects. In summary, on the ba-sis of available evidence, ceruletide is a safe, effec-tive agent for use in diagnostic radiology,exocrine pancreatic function evaluation, and treatment of non-obstructive ileus.
The authors wish to thank Andrea J.Baxter,Ann T.Walsh,and Dorothy Geiser for their assistance in preparing this manuscript.
1.Anastasi A,Erspamer V,Endean R. Isolation and structure of caeru-lein,an active endecapeptide from the skin of Hyla caerulea.Exper-ientia.1967:23:699-700.
2.Anastasi A, Erspamer V, Endean R. Isolation and amino acid se-quence of caerulein,the active decapeptide of the skin of Hyla caeru-lea.Arch Biochem Biophys.1968;125:57-68.
3.Gregory RA,Tracy HJ.The constitution and properties of two gas-trins extracted from hog antral mucosa.Gut.1964;5:103-17
4.Vagne M,Grossman MI.Cholecystokinetic potency of gastrc intesti-
nal hormones and related peptides. Am J Physiol.1968:215:831-4. 5.Stening GF,Grossman MI. Gastrin-related peptides as stimulants of pancreatic and gastric secretion.Am J Physiol.1969;217:262-6.
6.Johnson L,Stening G,Grossman MI.Effect of sulfation on the
VOLUME 2,NUMBER 4,JULY/AUGUST 1982
gastrointestinal action of caerulein.Gastroenterology.1970:58:208-16.
7.JohnsonL,Stening GF,Grossman MI.Relative potencies of natural and desulphated caerulein (abstract).Gastroenterology.1969; 56:1255.
8.Bertaccini G,DeCaro G,Endean R et al.The action of caerulein on the smooth muscle of the gastrointestinal tract and the gallbladder.Br J Pharmacol.1968:34:291-310.
9.Nakamura N,Koyama Y,Kojima T et al. [Effects of caerulein on intestinal tract and gallbladder](Jpn).Jpn J Pharmacol.1973:23:107-20.
10.Bertaccini G.Active polypeptides of nonmammalian origin.Pharma-col Rev.1976;28:127-77.
11.Yau W,Makhlouf G,Edwards L et al.The action of cholecystokinin and related peptides on guinea pig small intestine. Can J Physiol Pharmacol.1974:52:298-303.
12.Nakayama S,Neya T,Tsuchiya K et al.[Effects of caerulein on the movements of the gastrointestinal tract and the biliary system](Jpn. Eng abstract).Pharmacometrics.1972:6:1163-73.
13.Lembeck F,Juan H.Comparative action of peptide on the gallblad-der and sphincter of Oddi.Adv Exp Med Biol.1972:21:337-46.
14.Linari G,Linari M.Effect of bombesin on pancreatic secretion and
gallbladder motility of the chicken.Eur J Pharmacol.1975;34:305-10.
15.Angelucci L,Baldierei M,Linari G.Action of caerulein on secretions and motility of the digestive tract in the chicken. In:Mantegazza P. Horton EW,eds.Prostaglandins,Peptides and Amines.New York: Academic Press:1969:64-5.
16. Bertaccini G,Ballarini G,Agosti A et al.Action of caerulein on the biliary system of the dog.Arch Int Pharmacodyn.1970;183:261-9.
17.Agosti A,Mantovani P,Mori L.Action of caerulein and related substances on the sphincter of Oddi. Naunyn Schmiedebergs Arch Pharmacol.1971;268:114-8.
18. Sarles J,Bidant J,Devaux M et al.Action of cholecystokinin on the rabbit sphincter of Oddi. Digestion.1976;14:415-23.
19.Lin TM,Spray GF.Effect of pentagastrin,cholecystokinin,caerulein and glucagon on the choledochal resistance and bile flow of con-scious dogs (abstract).Gastroenterology.1969;56:1178.
20.Beaugie JM.Gastro-duodenal hormones and bile flow.Ann R Coll Surg Engl.1972;50:164-81.
21.Bertaccini G,DeCaro G,Endean R et al.The action of caerulein on pancreatic secretion of the dog and biliary secretion of the dog and rat.Br J Pharmacol.1969:37:185-97.
22.Dangouma J,Balabaud C,Bussieri-Leboeuf C et al. Influence of pentagastrin,cholecystokinin and caerulein on the bile secretion in the rat.J Pharmacol(Paris).1977;8:197-204.
23.Jones RS,Grossman MI.Choleretic effects of cholecystokinin,gas-trin Il,and caerulein in the dog. Am J Physiol. 1970:210:1014-8.
24.Angelucci L,Baldieri M,Linari G.The action of caerulein on pancre-atic and biliary secretions of the chicken. Eur J Pharmacol. 1970;11:217-32.
25.Angelucci L,Baldieri M,Linari G.Features of the choleretic action of caerulein.Eur J Pharmacol.1974:25:296-301.
26.Angelucci L,Micossi L,Cantalamessa F et al.The choleretic and cholagogue actions of caerulein in the rabbit.Arch Int Pharmacodyn Ther.1972;196:92-4.
27.DelTacci M,Pacini S, Amato G et al.Action of caerulein on the isolated guinea pig stomach.Eur J Pharmacol.1972:17:171-4.
28.Mantovani P,Bertaccini G.Action of caerulein and related sub-stances on gastro-intestinal motilityof the anaesthetized dog.Arch Int Pharmacodyn Ther.1971:193:362-71.
29.Valenzuela JE,Grossman MI.Effect of pentagastrin and caerulein on intragastric pressure in the dog. Gastroenterology.1975; 69:1383-4.
30.Faustini R,Beretta C,Chieli R et al. Some effects of caerulein on the motility of sheep forestomach and gallbladder.Pharmacol Res Commun.1973;5:383-7.
31.Bertaccini G,Impicciatore M,DeCaro G.Action of caerulein and related substances on the pyloric sphincter of the anaesthetized rat. Eur J Pharmacol.1973;22:320-4.
32.Bertaccini G,Impicciatore M,DeCaro G et al.Further observations on the spasmogenic activity of caerulein on the rat pylorus.Pharma-col Res Commun.1974;6:23-34.
33.Yau W.The actions of cholecystokinin and related peptides on the small intestinal muscle.In:Chey WY,Brooks FP,eds.Endocrinology of the gut.Thorofare,NJ:Charles B.Slack;1974:212-9.
34. Sato T, Takayanagi I,Takagi K. Effect of acetylcholin-releasing drugs on electrical activity of Auerbach's plexus of the guinea pig ileum.Jpn J Pharmacol(abstract).1973;23(suppl 21):21.
35.Vizi ES,Bertaccini G, Impicciatore M et al. Evidence that acetyl-choline released by gastrin and related polypeptides contributes to their effect on gastrointestinal motility.Gastroenterology.1973; 64:268-77.
36.Mantovani P, Impicciatore M. Isolated rabbit colon preparation,a
sensitive method for the bioassay of caerulein and related sub-stances.Arch Pharm(Weinheim).1971;271:330-4.
37.Frigo GM,Lecchini S,Falaschi C et al.On the ability of caerulein to increase propulsive activity in the isolated small and large intestine. Arch Pharm(Weinheim).1971;268:44-58.
38.Fregnan GB.[Absence of noxious effects of ceruletide on surgical sutures of the dog's gastrointestinal tract] (lta). Milan:Farmitalia Re-search Center,Report No.498,January 27,1972.
39.Bertaccini G,Endean R,Erspamer V et al. The action of caerulein on gastric secretion of the dog and the rat. Br J Pharmacol. 1968;34:311-29.
40.Gadacz TR,Way LW.Comparison of the effect of several gastrin-related compounds on acid secretion in dogs.Am Surg 1972;123:143-8.
41.Stening GF,Johnson LR,Grossman MI.Effect of cholecystokinin and caerulein on gastrin and histamine-evoked gastric secretion. Gastroenterology.1969;57:44-50.
42. Konturek SJ,Radecki T, Biernat J et al. Effect of caerulein on pentagastrin-induced gastrin acid secretion and peptic ulcer in cats. Scand J Gastroenterol.1970:5:613-6.
43.Way LW.Effect of cholecystokinin and caerulein on gastric secretion in cats.Gastroenterology.60:560-5.
44.Konturek SJ,Radecki T,Biernat J et al.The influences of caeru-lein-like peptides on gastric secretion and peptic ulcer formation in cats.Digestion.1972;5:1-8.
45. Konturek SJ,Radecki T,Biernat J et al.Effect of caerulein on histamine-induced gastric secretion and peptic ulcers in cats.Diges-tion.1972:6:101-13.
46.Braganza JM,Gibbs AC,Howat HT.The interaction of secretin and stimulants of gastric acid secretion in anaesthetized cats. J Physiol (Lond).1976;258:73-81.
47.Mantegazza P,Naimzada M,Riva M.Effect of caerulein on the gastric acid secretion in the rat.In:Mantegazza P.Horton EW.eds. Prostaglandins,Peptides and Amines.New York:Academic Press: 1969:157-65.
48. Cannata B, Alonso A,Bealite C et al.Caerulein action on gastric secretion in normal and hypoxic rats.Acta Gastroenterol Latinoam. 1972:4:21-4.
49.Angelucci L,Linari G.The action of caerulein on gastric secretion of the chicken.Eur J Pharmacol.1970;11:204-16.
50.Mantovani P.Effect of caerulein on peptic secretion of the rat.Arznei-mittelforsch.1970:20:1588-90.
51.Mantovani P.Activity of caerulein on peptic secretion in the rat. Pharmacol Res Commun.1969;1:97-9.
52.Konturek SJ,Tasler J,Obtulowicz W.Mechanism of the inhibitory action of endogenous cholecystokinin and caerulein on pentagastrin-induced gastric secretion.Scand J Gastroenterol.1972;7:657-62.
53.Melchiorri P,Sopranzi N.The action of caerulein on gastric secre-tion of the intrinsic factor in the rat Pharmacol Res Commun. 1970:2:135-42.
54. Dockray GJ.The action of secretin,cholecystokinin-pancreozymin and caerulein on pancreatic secretion in the rat. J Physiol. 1972;255:679-92.
55.Linari G,Linari MB.The action of caerulein on the pancreatic secre-tion of the rat.Farmaco (Sci).1977:32:611-6.
56.Ishihara Y.Effect of tetragastrin,caerulein and pancreozymin on the enzyme secretion of the rabbit pancreas in vitro and in vivo. Jpn J Pharmacol.1972:22:728-30.
57.Meldolesi J.Effect of caerulein on protein synthesis and secretion in the guinea pig pancreas. Br J Pharmacol.1970;40:721-31.
58.DeCaro G,Importa G,Melchiorri P.Effect of caerulein infusion on glucagon secretion in the dog.Experientia.1970:26:1145-6.
59.Ohneda A,Horigome K,Ishu S et al.Effect of caerulein upon insulin and glucagon secretion in dogs.Horm Metab Res.1978;10:7-11
60.Costa G,Scarpignato C.Comparative effects of pentagastrin and ceruletide on the insulin secretion in the anesthetized dog.Farmaco (Sci).1977;32:195-204.
61.Adrian TE,Bloom SR,Hermansen K et al.Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas.Diabetologia.1978:14:413-7.
62.Agosti A.Hypoglycemic activity of caerulein in the rat.Pharmacol Res Commun.1969;1:94-6.
63.Assan R,Plouin PF,Girard JR et al. Study of glucagon secretion using in vitro perfusion of rat pancreas pieces. Diabete Metab. 1975;1:101-11.
64.Nakajima S.The action of the C-terminal octapeptide of cholecysto-kinin and related peptides on pancreatic exocrine secretion.Gut. 1973;14:607-15.
65.Erspamer V,Melchiorri P.Active polypeptides of the amphibian skin and their synthetic analogs.Pure Appl Chem.1973;35:463-94.
66.Bertaccini G,DeCaro G,Melchiorri P.The effects of caerulein on insulin secretion in anaesthetized dogs.Br J Pharmacol.1970;40:78-89.
EVALUATION OF CERULETIDE
67.Stening GF,Grossman Mi.Hormonal control of Brunner's glands. Gastroenterology.1969:56:1047-52.
68. Care AD,Bruce JB,Boelkins J et al.Role of pancreozymin-chole-cystokinin and structurally related compounds as calcitonin secreto-gogues.Endocrinology.1971:89:262-71.
69.Erspamer V.Progress report: Caerulein.Gut. 1970;11:79-87.
70.Bertaccini G,DeCaro G,Endean R et al.The action of caerulein on the systemic arterial blood pressure of some experimental animals.Br J Pharmacol.1968;33:59-71.
71.Glaesser AH.[Vascular actions of eledoisin and caerulein in man and in animals] (Ita).Boll Chim Farm.1972;111:284-92.
72.Mantovani P,Piccinin GL,Bertaccini G.Activity ratio between in-testinal and cardiovascular actions of caerulein and related sub stances in the anaesthetized dog.Pharmacol Res Commun. 1969;1:172-4.
73.Ormas P,Pompa G,Beretta C et al.Effects of some polypeptides on sheep blood pressure.Folia Vet Lat.1975;5:45-54.
74.Lee W,Beaulnes A. Myocardial effects of caerulein and structurally-related polypeptides.Read at the 14th Annual Meeting of the Canadi-an Federation of Biological Societies,Toronto,June 15-18,1971
75.Dorigotti L,Glaesser AH.Comparative effect of caerulein,pancreo-zymin and secretin on pancreatic blood flow. Experientia. 1968:24:806-7.
76. Papp M,Feher S,Varga B et al.Humoral influences on local blood flow and external secretion on the resting dog pancreas.Acta Med Acad Sci Hung.1977:34:185-98.
77. Dorigotti L,Glasser AH. Relationship between vasodilator and pan-creatic stimulating properties of some caerulein-like peptides.In: Mantegazza P,Horton EW, eds. Prostagiandins,Peptides and Amines.New York:Academic Press:1969:181-3.
78.Tokiwa T,Uemura I,Murakami H et al.Studies on caerulein(FI 6934).Absorption,distribution,metabolism and excretion of caeru-lein.Jpn J Pharmacol.1975:25:747-62.
79.Miyoshi K,Tokiwa T.Distribution of 35S-caerulien(FI 6934) in mice. Pharmacometrics.1975:10:465-70.
80.Chieli T, Bertazzoli C,Ferni G et al. Experimental toxicology of caerulein.Toxicol Appl Pharmacol.1972:23:480-91.
81.Bertazzoli C,Caccia G,Chieli T et al.[Caerulein:Study of chronic toxicity in rats) (lta). Milan:Farmitalia Research Center,Report No 363,March 8,1971.
82.Solcia E, Capella C,Chieli T et al.Effect of chronic caerulein overdosage on the pancreas and gastrointestinal tract.In:Deming L, ed.International symposium on gastrointestinal hormones.Erlangen. August 1971:103-13.
83. Bertazzoli C, Bellini O, Chieli T et al.[Caerulein-Fl6934:Chronic toxicity in dogs] (Ita).Milan:Farmitalia Research Center,Report No 357,Feb 2 1971.
84.Tardini A,Anversa P,Bordi C et al.Ultrastructural and biochemical changes after marked caerulein stimulation of the exocrine pancreas in dog.Am J Pathol.1961:62:35-48.
85.Bertazzoli C,Chieli T,Massa R.[Caerulein.FI 6934,Toxicity Studyl (Ita).Milan:Farmitalia Research Center,Report No 350,Jan 15, 1971.
86.Bertaccini G,Braibanti T,Uva F.Cholecystokinetic activity of the new peptide caerulein in man.Gastroenterology.1969:56:862-7.
87.Bertaccini G.Action of caerulein on the motility of the biliary system
and the gastrointestinal tract in man.Med Chir Dig.1973:2:133-8.
88.Carratu R,Ramorino M,Pallone F et al.[Pharmacological and clinical-pharmacological studies on ceruletide on the gastro-enteric tract](Ita).In:Bertelli A,ed.Il trattamento farmacologico delle epato-patie.Pisa:Pacini Editore, 1973:297-8.
89.Miyoshi K,Kiyonaga G.[Investigation of cholecystokinetic action of caerulein.Il](Jpn).Med Treatment.1973:6:69-75.
90.Nakazawa E,Hattori T,Naito V et al.[Cholecystokinetic functional test with caerulein](Jpn,Eng abstract)Med Treatment.1973;6:160-8 91.Orlandini l,Agosti A.[Use of the peptide caerulein in the study of the biliary ducts](lta).Radiol Med.1969;55:1061-70.
92.Orlandini I,Agosti A.[Cholecystokinetic action of caerulein and its use in cholangiocholecystography](Ita). Boll Soc Ital Biol Sper. 1969:45:782-4.
93.Sargent EN,Bowell W,Hubsher J.Cholecystokinetic cholecystog-raphy: Efficacy and tolerance studies of ceruletide. AJR 1978:130:1051-5.
94.Tada K,Tanabe M.[Study on cholecystokinetic action of caerulein] (Jpn).Clin Report.1974:8:181-92.
95.Agosti A,Bertaccini G.Nasal absorption of caerulein (letter).Lan-cet.1969;1:580-1.
96.Matsumoto T.[Study on the cholecystokinetic activity of caerulein] (Jpn).Shinryo to Shinyaku.1973;10:207-13.
97.Colagrande G,Parrella RE,Cecconi L.[Effect of caerulein prelimi-nary administration on radiographic results in cholangiography](Ita). Minerva Gastroentrol.1974:20:97-106.
98.Gruppo Montedison-Farmitalia.Ceruletide product monogram yel-
low book.Milan:Arnoldo Mondadori Publisher;1963:31.
99.Siewart R,Waldeck F,Peiper HJ.[Gastro-intestinal hormones and the lower esophageal sphincter] (Ger).Chirurg.1974;45:28-33.
100.Bertaccini G,Agosti A,Impicciatore M.Caerulein and gastrointes-tinal motility in man.Rendic R Gastroenterol.1971;3:23-7.
101.Bortolotti M,Miglioli M,Lanfranchi GA et al.[The activity of cerule-tide on the electrical and mechanical activity of the stomach in man] (Ita).Riv Gastroenterol.1970:22:147-79.
102.Bortolotti M,Labo G.[A comparison between the effects of cerule-tide and cholecystokinin-pancreozymin on the electric and mano-metric activities of the human stomach](Fre,Eng abstract).Acta Gastroenterol Belg.1975:38:111-24.
103.Bortolotti M,Sansone G,Sanavio C.Effects of some gut hormones on gastric myoelectric and mechanical activity in man.(abstract). Rendic R Gastroenterol.1975:7:135.
104.Chapman M,Janowitz H.Pyloroduodenal dysfunction and dyspep-sia in relation to gastritis and ulcer.Clin Gastroenterol.1977;6:581-96.
105. Comino E,Fava C,Ragni G et al. [Effect of ceruletide on motility of the gastrointestinal tract) (Ita). Minerva Med. 1973;64:4686-91.
106.Bertaccini G,Agosti A,Mantovani P et al.[Caerulein action on the human gastrointestinal tract in vitrol (Ita).Boll Soc Ital Biol Sper. 1972:48:322-5.
107. Bertaccini G, Agosti A. Action of caerulein on intestinal motility in man.Gastroenterology.1971;60:55-63.
108.Labo G,Barbara L,Lanfranchi GA et al. Modification of the electri-cal activity of the human intestine after serotonin and caerulein.Am J Dig Dis.1972;17:363-72.
109.Ramorino ML,Ammaturo MV,Anzini F.Effects of caerulein on small and large bowel motility in man. Rendic R Gastroenterol. 1970:2:172-5.
110.del Tacca M,Soldani G,Crema A.Effects of caerulein on the isolat-ed human ileum.Rendic R Gastroenterol.1974;6:165-7.
111.Lanfranchi GA,Bortolotti M,Miglioli M et al.[Action of ceruletide on colon motility] (lta).Minerva Gastroenterol.1973;19:78-86.
112.Corazziari E,Tonelli F,Pozzessere C et al.The effects of graded doses of caerulein on human jejunal motor activity. Rendic R Gas-troenterol.1976:8:190-2.
113.Agosti A,Biasoli S, Bertaccini G. Action of caerulein on gastric secretion in man.Gastroenterology.1970:59:727-30.
114.Agosti A,Biasoli S,Naranjo G. [Action of ceruletide on human gastric secretion)(Ita).Boll Soc Ital Biol Sper 1969:45:778-81.
115.MacGregor I,Trupin J,Hubsher J.Comparison of porcine cholecys-tokinin(CCK) and synthetic caerulein on pancreatic, biliary and gas-tric secretion in man(abstract).Gastroenterology.1977:72:69/1092.
116.Konturek SJ,Bienart J,Grzelec T.Augmentation of secretin-in-duced pancreatic secretion by caerulein.Am J Dig Dis.1972:17:643-7.
117.Konturek SJ,Gabrys B.Effect of caerulein on histamine and penta-gastrin-induced gastric secretion in man.Am J Dig Dis.1970:15:791-5.
118.Brooks AM,Agosti A,Bertaccini G et al.Inhibition of gastric secre-tion in man by peptide analogues of cholecystokinin.N Engl J Med. 1970;282:535-8.
119.Kisfalvi I.Inhibitory effect of glucoagon,secretin and caerulein on gastric acid secretion stimulated by pentagastrin in patients with du-odenal ulcer.Acta Hepatogastroenterol (Stuttg).1978:25:487-91.
120.Agosti A,Missale G,Bertaccini G. Inhibitory effect of a caerulein-like peptide on human gastrin secretion. Eur J Pharmacol. 1976:38:193-5.
121.Agosti A,Biasoli S,Bertaccini G.Action of caerulein on pancreatic secretion in man.Pharmacol Res Commun.1970;2:125-33.
122.Robberecht P,Cremer M,Vandermeers A et al.Pancreatic secre-tion of total protein and of three hydrolases collected in healthy sub-jects via duodenoscopic cannulation.Effects of secretin,pancreozy-min and caerulein.Gastroenterology.1975:69:374-9.
123.Ribet A,Tournut R,Duffaut M et al.Use of caerulein with submaxi-mal doses of secretin as a test of pancreatic function in man.Gut. 1976;17:431-4.
124.Gullo L,Costa PL,Fontana G et al.Investigation of exocrine pan-creatic function by continuous infusion of caerulein and secretin in normal subjects and in chronic pancreatitis.Digestion.1976;14:97-107.
125.Fallucca F,Carratu R,Tamburrano G et al.Effects of caerulein and pancreozymin on insulin secretion in normal subjects and in patients with insuloma.Folia Endocrinol.1971:24:100-7.
126.Tsuda K,Seino Y,Sakurai H et al. Cerulein-induced pancreatic polypeptide secretion.Am J Gastroentrol.1980;74:355-8.
127. Astorri E, Malagnino G, Impicciatore M et al.[Cardiodynamic ob-servations after ceruletide administration in man] (lta). Farmaco (Prat).1971:26:687-91.
128.Wetzner S,Vincent M,Robbins A.Ceruletide-assisted cholecystog-raphy:A clinical assessment.Radiology.1979;131:23-6.
VOLUME 2,NUMBER 4,JULY/AUGUST 1982
129.Monti C,Mattei M,Sciarretta G.[Use of ceruletide in clinical radiolo-gy of biliary ducts:A study of 60 cases] (Ita). Atti Accad Med Lomb. 1975:30:69-89.
130.Mosca LG,Brasseur O,Mosca LE.[The utilization of ceruletide,a cholecystokinetic agent,in the radiology of the biliary ducts)(Spa Eng abstract).Prensa Med Argent. 1975;62:83-87.
131.Carratu R,Arcangeli G,Pallone F.Effects of caerulein on the hu-man biliary tract. Rendic R Gastroentrol.1971:3:28-33.
132.Sargent EN,Wieler M,Halls J.Cholecystokinetic cholecystography: Comparison of the effect of intramuscular ceruletide to a fatty meal. AJR 1979;133:489-92.
133.Arnold JD,Boyer RN,Shemano I.Comparitive cholecystokinetic effects of intramuscular ceruletide,intravenous sincalide,oral fatty meal,and intramuscular placebo (abstract).Clin Pharmacol Ther. 1980;27:245.
134.Monti C,Baraldi G,Malagola C et al.The role of caerulein in the differential diagnosis of common bile duct stenosis. Radiology. 1978;129:611-4.
135. Pliteri S,Mortara G,DeSimone M et al. [The use of ceruletide in operative cholangiography-Preliminary results](Fre).In:Commu-nications third international symposium on digestive endoscopy. Brussells,February 24-26,1977.
136.Carpino A,Salvatori G.[The intraoperative use of ceruletide in sur-
gery of the biliary tract) (ltal).Farmaco (Sci).1975:30:615-20.
137.Lanfranchi GA,Sciutti R,Turci G.Effect of caerulein on hypokinetic gallbladders.Rendic R Gastroenterol.1975:7:53-5.
138.Conte VP,Pinotte HW,Brito T et al.Cholecystokinin cholecysto-gram in the diagnosis of the cystsic duct syndrome.Am J Dig Dis. 1971;16:971-5.
139. Bierti L, Santamaria A, Marchi R et al.Ceruletide in radiological diagnosis of gallbladder dyskinesia(abstract).Communications inter-national symposium on gastrointestinal hormones and pathology of the digestive system.Rome,June 13-15,1977:173.
140.Lorber S,Phaosawasdi H,Lapayowker M et al.[Effect of ceruletide on the x-ray study of the small intestine](Ger).Therapiewoche. 1981:31:2744-52.
141.Sargent EN,Halls J,Colletti P et al. Efficacy and tolerance of ceruletide in radiography of the small intestine. Radiology. 1980:136:57-60.
142. Robbins AH,Wetzner S,Landy M.Ceruletide-assisted examination of the small bowel.AJR 1980:134:343-347
143.Novak D.Acceleration of small intestine contrast study by ceruletide. Gastrointest Radiol.1980;5:61-5.
144.Yamazaki M,Sato T,Shiina M.[Use of caerulein in order to acceler-ate roentgenographic examination of the small intestine](Jpn).Jpn J Clin Radiol.1979;24:693-8.
145.Lorber S. Small bowel transit time (letter). AJR 1980 135:648-9. 146.Orlandinil,Agosti A,Bertaccini G.[Use of caerulein in the radiolog-
ical study of the digestive tract] (Ita).Radiol Med.1970:56:651-5.
147.Arvanitakis C,Cooke AR. Diagnostic tests of exocrine pancreatic function and disease.Gastroenterology.1978:74:932-48.
148.Bornshein W.(Quantitative endoscopic pancreatic secretion analy-sis as a short test (secretin-caerulein short test)] (Ger).Verh Dtsch Ges Int Med.1978:84:1033-6.
149.Cavallini G,Mirachian R,Angelini G et al.The role of caerulein in tests of exocrinepancreatic function. Scand J Gastroenterol. 1978:13:3-15.
150.Gislon J,LeFevre R,Fiesse-Vandale PY et al.[Functional explora-tion of the pancreas by duodenal tubage after associated secretin and ceruletide stimulation)(Fre).Arch Fr Mal App Dig.1976:65:463-72.
151. Gullo L,Costa PL,Fontana G et al.Investigation of exocrine pan-creatic function by continuous infusion of caerulein and secretin in normal subjects and in chronic pancreatitis.Digestion.1976;14:97-107.
152.Gullo L,Costa PL,Labo G.A comparison between injection and infusion of pancreatic stimulants in the diagnosis of exocrine pancre-atic insufficiency.Digestion.1978;18:64-9.
153.Lankisch P,Schmack B,Simonet al.[Normal or impaired function of the pancreas? Which clinical methods presently permit a correct assessment?(Ger).Med Welt.1980:31:279-81.
154.Lupano F,De LaPierre M.[Comparison between various exocrine pancreatic function tests](lta).Minerva Dietol Gastroenterol. 1978:24:185-90.
155.Van Der Hoeden R,Mesa AV,Delcourt A.Function exploration of chronic pancreatitis by duodenal intubation.Comparitive study of the Lundh meal and duodenal hormones based on a survey of literature. Secretin-caerulein test carried out by the authors.Acta Gastroenterol Belg.1976;39:509-21.
156.Ishi K,Nakamura K.[Clinical studies on the pancreatic exocrine function test with caerulein and secretin] (Jpn).Jpn J Clin Med 1974:32:2983-9.
157.Minaire Y,Descos L.Comparison of caerulein and cholecystokinin effects upon enzyme concentrations in duodenal aspirates.Diges-
158.Conte VP, Mott GB, Bettarello A. [The action of caerulein on the pancreatic exocrine function in patients with hepatosplenic form of schistosomiasis](Por). Rev Hosp Clin Fac Med San Paulo. 1978:33:227-30.
159. Agosti A, Paolucci R, Zannella E et al. [Preliminary studies on the effects of caerulein in paralytic ileus](Ita).Chir Gastroenterol. 1972,6:117-28.
160.Bonomo E,Calabi V,Fantoni A et al.[Preliminary results on the use of caerulein in the treatment of post-operative paralytic ileus and of chronic fecal stasis] (Ita). Ann Med.1972;16:171-9.
161.Fumoto T,Watanuki T.Effect of ceruletide on post-operative intesti-
nal peristalsis.Farmaco (Prat).1975;30:579-84.
162.Sirchi M,Peroni L.(Ceruletide in the management of cholecystecto-my patients] (lta).Atti Accad Med Lomb.1975:30:25-8.
163.Aloisio F,Giannoni MF,Montesani C et al.[Effects of ceruletide in
the treatment of post-operative ileus] (Ita).Chir Ital.1976;21:846-53.
164.Carpino Boeri A,DiNegro G.[Study of the therapeutic activity of ceruletide in recognized paralytic ileus)(Ita) Atti Accad Med Lomb. 1976:31:1-5.
165.Horn JM.The effect of caerulein on the post-operative intestinal atonia(abstract).Communications international symposium on gas-trointestinal hormones and pathology of digestive system.Rome, June 13-15,1977:69-70.
166.Uggeri F,Santamaria A.Ceruletide and intestinal atony:preliminar results.(abstract).Communications international symposium on gas-trointestinal hormones and pathology of the digestive system.Rome. June 13-15,1977:176.
167.Pandolofo N,Mortola GP, Parodi E et al. [The use of ceruletide in the treatment of post-operative paralytic ileus] (Ita). Rif Medica. 1978:93:149-52.
168.Haas W,Rueff FL.[Caerulein in the therapy of the post-operative intestinal atony and the paralytic ileus](Ger).Therapiewoche. 1978:28:8939-44.
169.Montero VF,Laganga AM,Garcia EA.Usefuiness of caerulein in the treatment of post-operative intestinal atonia. J Int Med Res. 1980:8:98-104.
170. Adria Laboratories Inc.Tymtran package insert.Columbus, OH: December,1981.
Ceruletide is a synthetic decapeptide that resembles natural cholecystokinin and has similar pharmacologic ef-fects. This comprehensive review by Vincent,Wetzner, and Robbins appropriately stresses the radiologic applica-tions of the drug because it is in this field where it will initially make its impact. This will be especially so in the examination of the gallbladder during oral cholecysto-graphy and examination of the small bowel.With ultra-sound fast replacing oral cholecystography in the primary diagnosis of gallbladder disease, we may see ceruletide used mostly to make the small bowel examination more efficient; this is an especially attractive option because reported side effects of appropriate dosage are few and diagnostic accuracy apparently is not significantly compro-mised by this pharmacologic acceleration of an otherwise prolonged examination.
The authors note one other intriguing use for this drug that could potentially overshadow its radiologic applica-tions:it can be effectively used to treat nonobstructive ileus and may help accelerate postoperative recovery time and decrease the morbidity caused by profound ileus occa-sionally encountered in other patients.
Department of Radiology
Brigham and Women's Hospital