Effect of ceruletide on microvibration in schizophrenics

Ceruletide, a potent analogue of cholecystokinin, was administered by injection to eight schizophrenics treated with neuroleptics. We examined the dose–response effect on microvibration (MV) recorded from the chin of these patients. After 15 min of bed rest, MV was recorded for 5 min as a control recording. Subsequently, saline or ceruletide, at a dose of either 0.4 m?g/kg or at 0.8 m?g/kg, was injected according to a Latin square design with an interval of 4 weeks for washing out the drug effect and MV was recorded for 30 min. MV data obtained were subjected to the fast Fourier transform and an average power spectrum was computed. A three-way analysis of variance for these data was performed upon dose-effect, time-effect after treatment, and band-effect of the average power spectrum. The present results were similar to previous findings which had revealed effects of ceruletide on tardive dyskinesia symptoms, namely, the effects of ceruletide on MV were different according to the subjects (three cases: facilitation followed by inhibition, three cases: inhibition, two cases: no effects). The dose-response curve of ceruletide appears to be linear in some cases and an inverted U-shape in other cases. Present findings showed small doses of systemically administered ceruletide would modify muscle tonus of schizophrenics under chronic treatment of neuroleptics, and provided further reason for the therapeutic drug of tardive dyskinesia.     

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)     

Acceleration of small intestine contrast study by ceruletide

The effect of ceruletide on the small bowel transit time of barium sulfate suspension was studied in 165 patients. The control group consisted of 115 cases. An intramuscular injection of 500–750 ng/kg body weight ceruletide was given in 106 cases (group A), 20 ng/kg ceruletide was intravenously injected in 35 patients (group B), and 40 ng/kg was intravenously injected in 24 cases (group C).The mean transit time in group A was 62±41 min (¯x±SD), and 126±62 min in the corresponding control group of 83 cases. (P< 0.001). The mean transit time in group B was 65±50 min, and 69±56 min in group C, whereas in the corresponding control group of 32 cases the mean transit time was 137±79 min (P<0.01). A normal radiographic pattern was found in 75%, and slightly increased segmental contractions in 21%. Overtonicity and pronounced segmental contractions were seen in 4%.The recommended standardized small bowel study using ceruletide reduces the examination time by roughly one-half and produces simultaneous and uniform opacification of the jejunum and ileum.     

Ceruletide and neostigmine in postoperative intestinal paralysis

A double-blind and randomized clinical trial, which included 48 patients with postoperative intestinal paralysis on the third day after laparotomy, demonstrated no difference between treatment with ceruletide (0.3 μg/kg body weight) and neostigmine (5.0 μg/kg body weight) in restoring normal intestinal function.     

Effects of ceruletide on the dopamine receptor-adenylate cyclase system in striatum and frontal cortex of rats chronically treated with haloperidol

Chronic treatment of rats with haloperidol decanoate (30 mg/kg and 100 mg/kg IM every 4 weeks for 52 weeks) increased [³H] SCH 23390 binding in striatal membranes by 25% and 50% and in frontal cortical membranes by 56% and 125% in 30 and 100 mg/kg haloperidol treatment groups, respectively. These increases in [³H] SCH 23390 binding to the membranes were restored to control levels after ceruletide treatment (100 µg/kg IP twice a day for 5 days). [³H] Spiperone binding to the rat striatal and cortical membranes also increased after chronic haloperidol treatment (by 66% and 99% in striatal membranes and by 27% and 62% in cortical membranes in the 30 and 100 mg/kg haloperidol treatment groups, respectively). Administration of ceruletide to haloperidol-treated rats reduced the increased [³H] spiperone binding to the cortical membranes toward the control level, but ceruletide was not effective in reducing the haloperidol-induced increase of [³H] spiperone binding to the striatal membranes. Activation of adenylate cyclase by dopamine (1 µM or 100 µM) or Gpp(NH)p (1 µM) was reduced in striatal and cortical membranes from haloperidol-treated rats. Ceruletide restored the lowered level of dopamine-stimulated or Gpp(NH)p-stimulated adenylate cyclase activity in the membranes from haloperidol-treated rats to control levels. These findings indicate that systemically administered ceruletide is capable of reversing alterations in D₁ dopamine receptor/D₁ dopamine receptor coupling to adenylate cyclase in striatum and frontal cortex induced by chronic treatment of rats with haloperidol decanoate.     

Ceruletide vs. metoclopramide in postoperative intestinal paralysis

Sequential analysis of a double-blind clinical trial involving 26 patients demonstrated a statistically significant superiority of ceruletide over metroclopramide in restoring peristalsis in intestinal paralysis after abdominal surgery (P<0.05).     

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.     

Clonidine and yohimbine separate the sedation and the ptosis caused by cholecystokinin octapeptide and ceruletide

The central depressant effects of ceruletide (CER, 0.04 mg/kg s.c.) and cholecystokinin octapeptide (CCK-8, 0.25 mg/kg s.c.) were compared with those of clonidine (0.04 mg/kg s.c.). At doses that were nearly equipotent with respect to motor inhibition (catalepsy, reduction in ambulation and exploratory rearing), only the peptides produced ptosis. Yohimbine (1 mg/kg s.c., 30 min) antagonized the effect of clonidine but not of the peptides. Clonidine (0.07-0.2 mg/kg s.c., 30 min) antagonised the ptotic action of the peptides, and this effect was abolished by yohimbine (0.2-1 mg/kg i.p.) but resistant to haloperidol (0.05 and 0.15 mg/kg i.p.). These results separate the behavioural effects of the peptides from those of clonidine and also the ptotic effect of the peptides from their effect on motor activity. The antiptotic effect of clonidine may originate from activated adrenergic autoreceptors.     

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.     

Evaluation of intramuscular ceruletide for shortening small bowel transit time

A double-blind crossover study in 31 normal volunteers showed that intramuscular injection of ceruletide (0.3 g/kg) significantly accelerated small bowel transit of barium when compared to placebo. The only adverse effect was frequent pain at the injection site. There was a significant degradation in the quality of small bowel coating and distension in only 10% of the volunteers. Despite these problems, intramuscular administration of ceruletide may become a useful method for decreasing the prolonged time required for most small bowel examinations.