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Regional effects of ceruletide, a cholecystokinin-8 analog, on the striatal monoaminergic systems in food-deprived mice.

To clarify the pharmacological mechanism by which ceruletide affects involuntary movements, we used 20-h food-deprived mice to examine the acute effects of ceruletide (600 micrograms/kg, i.p.) on the histochemistry of striatal dopaminergic and serotonergic systems. The latter was unchanged but a reduction in catecholamine fluorescence was seen which was restricted to the ventrolateral (VL) portion of the striatum. Biochemical assays also indicated decreased levels of dopamine (DA) and its metabolites in this restricted region of the striatum with little or no change in noradrenaline, serotonin or their metabolites. In all regions examined, except the dorsomedial part of the mid-striatum, the ratio of dopamine metabolites to dopamine was higher in the ceruletide-treated group than in controls, suggesting increased DA release. Further pharmacological experiments showed that, compared to results in mice receiving only ceruletide: the ceruletide-induced decreases in DA and dihydroxyphenylacetic acid (DOPAC) in VL were less after alpha-methyl-p-tyrosine treatment; ceruletide caused no significant decrease in either DA or DOPAC after pargyline pretreatment, although the low levels of homovanillic acid (HVA) were still further significantly reduced; and the ceruletide-induced decrease of DA was reduced, that of DOPAC was abolished and that of HVA enhanced by nomifensine pretreatment. These results suggested that ceruletide might induce a more rapid degradation of DA in VL and increased efflux of HVA through the blood-brain barrier. This evidence suggests that ceruletide has a regionally specific effect on the striatal dopaminergic system which may relate to the amelioration of involuntary movements.

3,4-Dihydroxyphenylacetic Acid

Long-lasting effect of ceruletide on dyskinesia and monoaminergic neuronal pathways in rats treated with iminodipropionitrile.

In a model of dyskinesia induced by the administration of iminodipropionitrile (IDPN) in the rat, we evaluated the effects of ceruletide, an analogue of cholecystokinin, on behavioral abnormalities and monoaminergic neuronal function. Vertical head twitching in the IDPN-treated animals was inhibited for over 5 h following a single subcutaneous dose of 160 micrograms/kg ceruletide. In animals dosed daily for 2 or 3 days, the number of head twitches at 24 h after the last dose was about one-third of the number before treatment. After repeated daily doses of ceruletide for 6 days, the number of head twitches was reduced to low levels and remained significantly below pretreatment levels until the 4th posttreatment day. These results indicate that the inhibition of dyskinesia by ceruletide was long-lasting. Assays of monoaminergic neurotransmitters and their metabolites in various brain regions indicate that an imbalance between dopaminergic and serotonergic neuronal systems plays a major role in the pathogenesis of the IDPN-induced dyskinesia, i.e. the ratio of (DOPAC+HVA)/5-HIAA was significantly greater in the striatum but significantly smaller in the hippocampus of the IDPN-treated vs normal animals. This initially abnormal ratio of (DOPAC+HVA)/5-HIAA in the striatum and hippocampus of IDPN-treated animals returned to normal following treatment with ceruletide, corresponding with the reduction of the head twitching. The alterations in monoaminergic neuronal function induced by repeated administration of ceruletide persisted for at least 3 days, even though its plasma half-life is several minutes. Ceruletide also exerted a marked effect on monoaminergic neuronal function in the IDPN-treated rats, in contrast to only a slight effect in normal animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Systemic administration of a cholecystokinin analogue, ceruletide, protects against ischemia-induced neurodegeneration in gerbils.

The neuroprotective action of a cholecystokinin octapeptide analogue, ceruletide, was evaluated in models of cerebral ischemia using Mongolian gerbils. Ceruletide significantly suppressed the hyperactivity and amnesia induced by ischemia when injected s.c. 30 min before 5-min occlusion of the bilateral common carotid arteries at room temperature or immediately after their reperfusion. Ceruletide also reduced behavioral changes in ischemic gerbils whose body temperature was maintained at 37 degrees C during the 3-min occlusion. In these groups, delayed neuronal cell death in the hippocampal CA1 area following ischemia was markedly attenuated by s.c. administration of ceruletide. On the other hand, ceruletide could not inhibit the behavioral changes or the neurodegeneration induced in the hippocampal CA1 area by 5-min occlusion at 37 degrees C. These findings indicate that peripheral injection of ceruletide produces a neuroprotective action against moderate cerebral ischemia, which is the first evidence suggesting the efficacy of ceruletide in neurodegenerative diseases.

Amnesia

Effect of ceruletide on plasma monoamine metabolites in the rabbit.

Ceruletide, a cholecystokinin octapeptide-like substance, has been shown to have some effect on tardive dyskinesia. We, too, previously examined the effect of ceruletide on various types of involuntary movement, and found that responders tended to have high plasma homovanillic acid (HVA) levels. It is generally accepted that both central and peripheral sources make a contribution of plasma HVA. In this study, the response of plasma HVA in rabbits to ceruletide was investigated after pretreatment with debrisoquin sulfate, a drug which selectively blocks peripheral HVA production by inhibition of MAO. As a result, 8 and 50 micrograms/kg ceruletide treatment showed a tendency to decrease plasma HVA levels, but showed no significant differences; however, 140 and 200 micrograms/kg ceruletide showed a significant reduction of plasma HVA. These results are important to the understanding of the mechanism of ceruletide's effect on the brain, as well as to predict the effect of ceruletide on involuntary movements.

Animals

Treatment of tardive dyskinesia with ceruletide: a double-blind, placebo-controlled study.

The effectiveness of a once-weekly i.m. injection of ceruletide (0.8 microgram/kg) in suppressing the symptoms of neuroleptic-induced tardive dyskinesia (TD) was evaluated in a double-blind, placebo-controlled, matched-pairs study. Global evaluation of the severity of TD symptoms over the 8-week study period revealed a significant improvement with ceruletide as compared with placebo. Analysis of the therapeutic response to ceruletide over the course of treatment revealed a slow, but long-lasting improvement of TD symptoms. Side effects, which were mild and transient, consisted mainly of nausea and epigastric discomfort. The incidence of side effects did not differ between the ceruletide- and placebo-treated groups. Ceruletide appears to be a novel and practical treatment that can substantially alleviate the symptoms of dyskinesia.

Adult

Late onset and long-lasting suppressive effects of ceruletide, an analogue of cholecystokinin, on c-fos mRNA expression in the rat striatum.

C-fos mRNA expression by stimulation with subcutaneous (s.c.) administration of saline or cycloheximide (CHX) was examined in the rat striatum with or without pretreatment with ceruletide, an analogue of cholecystokinin. The c-fos mRNA induction 1 h after CHX stimulation (25 mg/kg, s.c.) was significantly suppressed by ceruletide pretreatment (80 micrograms/kg, s.c.) 2 h before CHX stimulation in the striatum, and tended to be suppressed by ceruletide pretreatment 4 h before saline or CHX stimulation. Long-lasting and inhibitory effects of ceruletide on dyskinesia and on dopaminergic (DAergic) neuronal systems, and c-fos mRNA expression by activation of the DAergic system have been reported. The present findings together with previous reports suggest that ceruletide might have late onset and long-lasting suppressive effects on the expression of c-fos mRNA in the striatum and that these effects might be related to its effects on DAergic neuronal transmission.

Animals

[Improvement of oral cholecystography and cholangiography with ceruletid (author's transl)].

Following oral cholecystography in 100 patients, the conventional "fatty meal" was replaced by an intramuscular injection of Ceruletid in a dose of 0.4 microgram/kg body weight. The synthetic decapetide Ceruletid is a substance with a hormone-like effect on the gastro-intestinal tract. It contracts smooth muscle in the gut and stimulates secretion in the stomach and the exocrine pancreas. Compared with other substances producing contraction which are given orally, Ceruletid acts more quickly and more powerfully in producing contraction of the gall bladder muscle. In 86% of positive cholecystograms, this resulted in satisfactory demonstration of the bile duct, 66% better than for oral substances. Many abnormalities, particularly localised adenomyomatosis, can only be diagnosed after good contraction of the gall bladder. Side effects, such as nausea, dizziness and a feeling of heat were transitory. In three patients it led to vomiting. The rapid and certain effect of Ceruletid during oral cholecystography requires reassessment of the role of intravenous cholangiography in diagnosis. Particularly amongst out-patients, with a high proportion of normal gall bladders, it is possible to complete the examination in one stage by demonstrating the bile duct with Ceruletid.

Bile Ducts

Inhibitory effect of CCK-8 and ceruletide on glutamate-induced rises in intracellular free calcium concentrations in rat neuron cultures.

To study the mechanism by which cholecystokinin octapeptide (CCK-8) and its potent analogue, ceruletide, prevent glutamate-induced neuronal cell death in rat neuron cultures, we examined the effect of both peptides on glutamate-induced increases in the intracellular free calcium concentrations ([Ca2+]i), which are known to be a crucial trigger of the neurodegeneration induced by glutamate. CCK-8 itself did not alter [Ca2+]i in rat neuron cultures. Glutamate increased [Ca2+]i in neuron cultures rapidly and markedly. CCK-8 and ceruletide significantly suppressed the increases in [Ca2+]i induced by glutamate. The maximum inhibitory effects of CCK-8 and ceruletide at 10(-6) M reached 43 and 46% of the response to glutamate, respectively. Gastrin-I and CCK-4 also significantly attenuated the increases in [Ca2+]i induced by glutamate. The inhibitory effect of CCK-8 was completely blocked by the selective antagonist for CCK-B receptors, (+)L-365,260, but not by (-)L-364,718, which is a selective antagonist for CCK-A receptors. CCK-8 significantly suppressed [Ca2+]i response to kainate and high concentrations of extracellular K+, but not to N-methyl-D-aspartate. With cultured astrocytes, CCK-8 did not inhibit the increment of [Ca2+]i induced by glutamate. These findings clearly demonstrated that CCK-8 and ceruletide inhibit glutamate-induced increases in [Ca2+]i in neuron cultures through CCK-B receptors, suggesting that CCK-8 may participate in the central actions of glutamate.

Animals

Acute reduction and long-term improvement of chorea with ceruletide (cholecystokinin analogue).

We studied the effects of ceruletide, a cholecystokinin analogue, on choreic involuntary movement in several neurological diseases by clinical scoring and electromyography in 11 patients. Ceruletide brought about a brief reduction of choreic movement reaching its maximum within 60 min and another long-lasting improvement over several weeks by single administration. The levels of homovanillic acid in cerebrospinal fluid before treatment were significantly higher in cases with long-lasting improvement than those in cases without improvement. We suggest that ceruletide may reduce choreic movement for a long period through effects on the central dopamine system and speculate that such a long-term effect may be accounted for by the change in transmission after the second messengers in neurons.

Adult

Controlled study of the effect of nicardipine and ceruletide on the sphincter of Oddi.

Although sphincter of Oddi dysfunction is a recognised cause of post cholecystectomy pain, the control mechanisms involved in sphincter of Oddi function are poorly understood. Pharmacological relaxation of the sphincter of Oddi may have a beneficial effect particularly in sphincter of Oddi dysfunction where basal sphincter pressure is high. The aim of this study was to investigate the effects of calcium channel blockade (nicardipine) and synthetic cholecystokinin (ceruletide) on sphincter of Oddi pressures. Nineteen patients (median age 49 years; range 21-75) attending for routine endoscopic retrograde cholangiopancreatographic (ERCP) examination were studied. No patients with evidence of sphincter of Oddi dysfunction were included in the study. Each patient was randomly allocated to receive a three minute intravenous infusion of nicardipine 3 mg (six) ceruletide 5 ng/kg (seven) or placebo (six). Endoscopic biliary manometry was done with recording of basal sphincter of Oddi pressures, sphincter of Oddi phasic wave amplitude and frequency before and after intravenous infusions. In the nicardipine group patients showed a decrease in both basal and phasic amplitude sphincter of Oddi pressure (mm Hg) from the preinfusion values (mean (SEM)) of 24.7 (3.6) and 112.3 (13.4) to 12.9 (2.9) (p less than 0.01) and 89.9 (12.4) (p less than 0.03) after infusion respectively. Ceruletide produced a decrease in sphincter of Oddi phasic wave frequency (c/min) from 3.4 (0.3) before infusion to 2.6 (0.5) after infusion (p less than 0.05). We conclude that nicardipine effectively decreases sphincter of Oddi pressure. This drug may therefore be of value in the treatment of sphincter of Oddi dysfunction where raised sphincter pressures are thought to be the primary pathogenic feature.

Adult

Ceruletide-assisted cholecystography: a clinical assessment.

The cholecystokinetic effect of ceruletide, a synthetic decapeptide similar in action to cholecystokinin, was examined in both a randomized and nonrandomized study in 81 patients scheduled for routine oral cholecystograms. Intramuscular injection of ceruletide in a dose of 0.3 microgram/kg resulted in a mean maximum contraction of the gallbladder of 68% and a mean time until maximum contraction of 28 minutes. Visualization of the cystic duct occurred in 57 patients (70%); the common duct was seen in 67 (83%). Ceruletide demonstrated superior gallbladder contraction when compared to fatty meals and demonstrated no interference with a subsequent upper gastrointestinal series.

Adult

Differential antagonism of the stimulant effects of MK-801 and methamphetamine by ceruletide: evaluation by discrete shuttle avoidance response in mice.

A noncompetitive NMDA antagonist MK-801 (0.03-0.3 mg/kg, i.p.) increased the response rate of mice trained under the discrete shuttle avoidance situation to a degree similar to the increase by methamphetamine (0.1-1 mg/kg, i.p.). The cholecystokinin-like decapeptide ceruletide significantly reduced the response-increasing effect of MK-801 (0.1 mg/kg) at 0.001 micrograms/kg; however, only 10 micrograms/kg of ceruletide, which per se inhibited the response, attenuated that of methamphetamine (0.3 mg/kg). The coadministration of MK-801 (0.1 mg/kg) and methamphetamine (0.3 mg/kg) produced no potentiation of the effect, and almost the same effect was maintained even after the additional administration of ceruletide (0.1 microgram/kg).

Animals

Cholecystokinetic cholecystography: efficacy and tolerance studies of ceruletide.

The effect of intravenous and intramuscular administration of ceruletide on gallbladder contraction was investigated in 67 normal volunteers and patients. Of the 45 normal volunteers, 33 received the drug intravenously and 12 intramuscularly in graded ascending doses. By either means of injection, ceruletide produced a substantial contraction of the gallbladder with a measurable reduction in gallbladder area. Based on findings in these groups, the 22 patients requiring oral cholecystography for clinical evaluation received 0.3 microgram/kg intramuscularly. The intramuscular administration of synthetic ceruletide after oral cholecystography, in a dose of 0.o microgram/kg, afforded a safe and effective means of gallbladder contraction, with resultant cystic and common bile duct visualization. Side effects occurred less frequently when the drug was administered intramuscularly and were minimal and self-limiting. Peak contraction (40% or greater reduction in size) occurred as early as 5-15 min after after intramuscular injection and in most instances within 30 min.

Adult

Cholecystokinetic cholecystography: comparison of the effect of intramuscular ceruletide to a fatty meal.

A comparison study of 80 patients using either intramuscular ceruletide or a fatty meal to contract the gallbladder after oral cholecystography is described. The maximum mean percentage reduction of the gallbladder area was significantly greater with ceruletide (59%) compared to a fatty meal (29%). At all time intervals, a 40% or more reduction in gallbladder area occurred in a higher percentage of patients receiving ceruletide, with improvement in cystic and/or common duct visualization occurring at an earlier time than with a fatty meal. There were no adverse effects after gallbladder contraction when large or small calculi were present.

Ceruletide

[Effects of ceruletide in the treatment of postoperative paralytic ileus].

After a short analysis of the pathogenetic causes which can lead to paralytic ileus and the drugs at present available for treatment of this serious morbid form, the paper reports results obtained with Ceruletide, a decapeptide which has proved active on intestinal peristalsis in experimental and clinical trials. The results of this study, carried out on 20 patients subjected to surgical operation on the abdomen, treated with Ceruletide by intramuscular route 24-48 hours after the operation, showed that this drug is capable of leading to a quick recovery of intestinal motor activity without causing the patient unpleasant effects for the patient. The practical utility of Ceruletide is evident since by leading to earlier canalisation of the intestine it also allows the venous hydro-electric delivery to be reduced, nasogastric aspiration to be eliminated early and hence the postoperative course to be made more acceptable to the patient.

Ceruletide

[Conservative treatment of severe paralytic ileus. Clinical experiences with Ceruletid].

After the failure of other medicamentous treatment attempts for paralytic ileus, Ceruletid (Takus) was used in 20 surgical patients. Ceruletid was applied as an infusion of 40 microgram in 250 ml or 500 ml physiological saline solution over a period of 2-3 hours. During this time the occurrence of bowel sounds, flatulence and defecation was observed. The most important clinical and serological parameters were measured before and after treatment. Treatment was successful in 17 cases, in 3 cases no success was achieved. Severe side effects did not occur. The use of Ceruletid in the described form of administration can be recommended for the treatment of paralytic ileus.

Ceruletide

Comparison of in vivo and in vitro responses to sulfated and non-sulfated ceruletide.

Responses of, guinea pig gall bladder to sulfated and non-sulfated ceruletide were compared in vitro and in vivo. Tested in vivo, sulfated ceruletide was 75 times more potent than non-sulfated. In vitro, sulfated was 150 times more potent. Thus, differences in potency are substantially less when tested in vivo, and reported differences in relative potency reflect not only chemical structure but also the method used for testing.

Animals

[Diagnosis of chronic pancreatitis. Studies of duodenal juice after stimulation with the secretin-ceruletide test. Decision limits and evaluation of various parameters].

187 patients were checked up over 4 years by the secretin-ceruletide test. Independently of the test results they were assigned to various disease groups on the basis of clinical assessment. 131 subjects were divided in a pilot investigation into: subjects with a healthy pancreas (n = 55); subjects with chronic pancreatitis (n = 50); subjects whose pancreatic condition could not be classified clearly (n = 26). 8 parameters were compared by univariate and multivariate statistical procedures in order to confirm or rule out the presence of chronic pancreatitis. The discriminatory power of the following parameters in duodenal fluid proved to be sufficiently high, with less than 15% frequency of misclassification: chymotrypsin (activity) and/or; lipase (activity) and/or; amylase (activity); viscosity. Under routine conditions measurement of the activity of two of these enzymes is sufficient. Their contribution to discrimination proved to be approximately equal. The diagnostic sensitivity and specificity of the parameters bicarbonate, lipase (concentration), trypsin (activity) and volume of duodenal fluid are lower. The classification rules derived from the above pilot group were confirmed by a diagnostic study under routine condition in a test group of 38 patients. Limitation to examining only volume and a maximum of 3 parameters which proved best in distinguishing between patients with chronic pancreatitis and healthy subjects, together with the omission of the first-hour samples after a secretin bolus, considerably reduced laboratory workload without altering the discriminatory power of the secretin-ceruletide test.

Adult