ceruletide and Dyskinesia--Drug-Induced

This article reviews current topics in tardive dyskinesia (TD), a movement disorder associated with the prolonged use of neuroleptic agents, especially therapeutic and preventive strategies which have been or are now being studied in Japan. Tardive dyskinesia has become a major problem in the clinical psychiatric field since the early 1970s in Japan, lagging behind Western countries by more than 10 years. The average prevalence rate of TD has been estimated as 7.7% in Japan, while it has been reported in the English literature at around 15 to 20%. Clinical trials of treatments for TD have been or are now being performed in Japan with a number of novel compounds, such as ceruletide, meclofenoxate, and rolipram; however, no effective treatment has yet been established and measures to prevent TD have therefore been emphasized. These include (i) the development of new antipsychotic drugs which are free from TD, (ii) the identification of risk factors from prospective longitudinal studies, and (iii) the investigation of genetic variations that could act as a marker to identify especially vulnerable patients within the whole population of patients who need neuroleptic therapy.

Topics: Antipsychotic Agents; Central Nervous System Agents; Ceruletide; Clinical Trials as Topic; Cross-Cultural Comparison; Dyskinesia, Drug-Induced; Humans; Japan; Meclofenoxate; Psychotic Disorders; Pyrrolidinones; Risk Factors; Rolipram; Treatment Outcome

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.

Topics: Adult; Aged; Antipsychotic Agents; Ceruletide; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Male; Matched-Pair Analysis; Middle Aged; Neurologic Examination; Schizophrenia; Schizophrenic Psychology

1. In a double-blind placebo-controlled study of 37 patients with tardive dyskinesia, the therapeutic effect of ceruletide was evaluated. 2. The patients were assigned at random to two groups that received either intramuscular injections of 0.8 micrograms/kg of ceruletide or placebo once weekly for 4 weeks. Conventional neuroleptic medication was not changed 3 weeks prior to and throughout the study period. Tardive dyskinesia was assessed using the Abnormal Involuntary Movement Scale over an 8-week period. 3. Ceruletide had a more pronounced effect on TD than the placebo however, because of the limited number of subjects examined, the difference between the two groups was not significant. Ceruletide was more effective than placebo in patients under 60 years of age (p less than 0.05) and whose antipsychotic medication was mainly butyrophenones. 4. No serious side effect was noted. 5. The findings suggested that ceruletide therapeutically benefits patients with tardive dyskinesia.

Topics: Ceruletide; Clinical Trials as Topic; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Injections, Intramuscular; Male; Middle Aged

In chronic alcohol abusers with no pancreatic disease, secretin was found to induce a paradoxical spasmodic response in the sphincter of Oddi (SO) instead of the relaxation observed in controls. Cerulein, on the contrary, had a normal relaxing effect on the SO.. We previously reported SO dyskinesia in cases of chronic pancreatitis. Here we investigated whether chronic alcohol consumption may have contributed to the genesis of this dyskinesia.. SO and main pancreatic duct pressures were recorded endoscopically with a dual electronic pressure sensor in 27 chronic alcohol abusers and compared with the values obtained in 15 normal controls. These pressures were recorded both in the basal state and after applying hormonal stimulation by injecting either secretin (1 CU/kg) or cerulein (75 ng/kg).. Cerulein relaxed the SO in both the controls and the chronic alcohol abusers, whereas it transiently enhanced the main pancreatic duct (MPD) pressure. Secretin induced a wave of MPD hyperpressure (+15.4 +/- 3.0 mm Hg) in both groups of subjects, but in the alcoholic group, instead of relaxing SO, it significantly enhanced the amplitude of phasic contractions (+32.6 +/- 8.4 mm Hg). The SO basal pressure was also paradoxically enhanced by secretin in the alcoholic patients (28.8 +/- 8.2 vs 10.1 +/- 2.4 mm Hg).

Topics: Alcoholism; Ceruletide; Cholecystokinin; Dyskinesia, Drug-Induced; Female; Humans; Male; Manometry; Middle Aged; Pancreatic Ducts; Reference Values; Secretin; Sphincter of Oddi

To clarify the mechanism of long-lasting ceruletide action, an analogue of cholecystokinin, in relieving the dyskinesia induced by the iminodipropionitrile (IDPN), we investigated the changes in dopaminergic neuronal system in the striatum. In the control rats, ceruletide had no significant effect on the concentrations of dopamine (DA), DOPAC or HVA or on the turnover of DA in the striatum. The concentration of DA was decreased and the turnover of DA [(DOPAC + HVA)/DA] was increased in the striatum of IDPN-treated rats. Chronic administration of ceruletide (160 micrograms.kg-1.day-1 x 10 days) increased DA concentration and decreased DA turnover only transiently. Both D1 and D2 receptors and their mRNAs were decreased in the striatum of rats given IDPN. After chronic ceruletide treatment, D1 receptor rose to the control level for 3 days, while the D2 receptor rose to a level 1.5 times the control level for 3 days. Even at the 7 days after chronic ceruletide treatment, D2-R rose significantly as compared with the IDPN-treated rats. Both D1 and D2 receptor mRNAs were significantly increased for 3 days in the IDPN-treated rats. These observations indicate that the synthesis of DA receptors is increased by ceruletide treatment in the striatum of IDPN-treated rats. These changes in DA receptors and their mRNAs closely paralleled the changes in dyskinetic movement of the IDPN-treated rats after repeated daily administration of ceruletide, as previously reported. The parallel changes between the DA receptors and dyskinetic movement suggest that an up-regulation of DA receptors in the striatum corresponds with an improvement of dyskinesia in the IDPN-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Benzazepines; Blotting, Northern; Ceruletide; Corpus Striatum; Dopamine; Drug Administration Schedule; Dyskinesia, Drug-Induced; Homovanillic Acid; Male; Neurotoxins; Nitriles; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; RNA, Messenger; Spiperone; Time Factors

1. One schizophrenic patient with drug-induced tardive dystonia was treated with ceruletide. 2. After the injection, dystonia showed a tendency toward rapid amelioration in 3 days; meanwhile, however, mental manifestations became exacerbated within 3 weeks. 3. We discuss some aspects of the effects of ceruletide.

Topics: Adult; Ceruletide; Dyskinesia, Drug-Induced; Electroconvulsive Therapy; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Schizophrenia

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)

Topics: Animals; Biogenic Amines; Ceruletide; Dopamine; Dyskinesia, Drug-Induced; Head; Male; Neural Pathways; Neurons; Nitriles; Rats; Rats, Inbred Strains; Serotonin; Time Factors

Chronic administration of iminodipropionitrile (IDPN), a neurotoxin, to rats produces a persistent behavioral syndrome characterized by lateral and vertical head twitching, random circling and hyperactivity. Conventionally, this IDPN-induced dyskinesia has been considered to be due to abnormalities in the serotonin neuronal system. However, the present study also demonstrated marked alterations in the dopamine (DA) and acetylcholine (ACh) neuronal systems. These were activation of DA neurons in the nucleus accumbens and thalamus + midbrain, decreased activity in the other brain areas and a decrease in D1 DA receptors. ACh contents were decreased in most brain areas while muscarinic ACh receptors were increased in the striatum, superior colliculus and geniculate nucleus. These alterations in the ACh neuronal system may be secondary to abnormalities in the DA neuronal system. IDPN-induced dyskinesia was enhanced by administration of L-dopa, which increases DA concentration, but was completely inhibited by ceruletide, which inhibits DA release. The dyskinesia was also inhibited by sulpiride, a central antagonist of D2 DA receptors. Interestingly, apomorphine and bromocriptine, which are DA receptor agonists, did not aggravate, but decreased dyskinesia in the IDPN-treated rats. These results strongly suggest that dyskinesia is caused not by abnormality of postsynaptic receptors in the DA neuronal system but by abnormally enhanced function of the presynaptic DA neurons themselves. In addition, ceruletide may be useful in the treatment of dyskinesia, and bromocriptine alone or in combination with L-dopa may be effective in Parkinson's disease without the development of dyskinesia. Thus, the IDPN-treated rat model is useful for clarifying the biochemical pathophysiology of dyskinesia and developing drugs for its treatment.

Topics: Animals; Apomorphine; Autoradiography; Benzazepines; Brain Chemistry; Bromocriptine; Ceruletide; Dyskinesia, Drug-Induced; Levodopa; Male; Neurotoxins; Neurotransmitter Agents; Nitriles; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Muscarinic

1. Seven patients with TD were treated with a single dose of ceruletide 0.8 microgram/kg i.m. 2. EMG and MV were recorded, and the average power spectrum was computed. 3. Effect of ceruletide on TD within 2 hr after injection was varied (3 cases: inhibitory, 2 cases: facilitatory, 2 cases: no effect). 4. Two patients with severe TD, who showed improvement after a single administration, received repeated administration of ceruletide (0.6 microgram/kg i.m.) and their TD symptoms were recorded on videotape for blind consensus ratings. In both patients ceruletide caused a marked decrease in severity of TD, and the effects lasted for several weeks. 5. The present findings might contribute to further understanding of the role of CCK in the brain and to the treatment of TD.

Topics: Adult; Antipsychotic Agents; Ceruletide; Dyskinesia, Drug-Induced; Electromyography; Female; Humans; Male; Middle Aged; Schizophrenia

Topics: Adult; Ceruletide; Dyskinesia, Drug-Induced; Humans; Male; Middle Aged

Seven patients with bucco-lingual dyskinesia were treated with a single dose of ceruletide 0.8 micrograms/kg IM, a potent analogue of cholecystokinin octapeptide. Time-course effects of the drug were then followed up to 6 weeks after injection in the longest case. To assess changes in severity of dyskinesia objectively, electromyogram and microvibration were recorded. These data were subjected to the Fast Fourier Transform and an averaged power spectrum was computed. The effect of ceruletide on dyskinesia within 2 h after injection differed (three cases: inhibitory, two cases: facilitatory, two cases: no effect). It was notable that a long-lasting inhibitory effect of this peptide was observed in two severe irreversible cases. The present findings might contribute to further understanding of the physiopathophysiological role of cholecystokinin-like peptides in the brain and to practical treatment of tardive dyskinesia.

Topics: Adult; Aged; Ceruletide; Dyskinesia, Drug-Induced; Electromyography; Female; Humans; Male; Middle Aged; Pilot Projects; Schizophrenia

A 55-year-old schizophrenic inpatient with buccolingual dyskinesia was treated with a single dose of ceruletide 0.8 micrograms/kg IM. Time-course effects of the drug were then followed for up to 6 weeks after injection. To assess changes in severity of bucco-lingual dyskinesia objectively, electromyogram (EMG) and microvibration (MV) were recorded. Simultaneously, bucco-lingual dyskinesias were also evaluated by using a five-point rating scale. Before injection of ceruletide, severity of dyskinesia was "moderate" and 3-4 Hz of dyskinetic oral movements were dominant. "Extremely severe" and repetitious gross oral movements (around 1 Hz) were observed within a few minutes after injection and continued for up to 1 h. Thereafter, oral movements tended to decrease, and they disappeared completely 3 weeks after injection. This biphasic and long-lasting effect of ceruletide on tardive dyskinesia might contribute to further understanding of the physio-pathophysiological role of cholecystokinin-like peptides in the brain, and provide a basis for practical treatment of tardive dyskinesia.

Topics: Ceruletide; Dyskinesia, Drug-Induced; Humans; Middle Aged; Mouth; Tongue