RESUMEN
Effects of dexamethasone and N(G)-nitro-L-arginine methyl ester (L-NAME), the nitric oxide (NO) synthase inhibitor, on caerulein-induced acute pancreatitis were examined in rats. Acute pancreatitis was induced by caerulein (20 mug/kg, s.c.) given repeatedly 2 or 4 times every hour, and serum amylase levels, pancreas weight and myeloperoxidase (MPO) activity were measured 6 h after the first injection of caerulein. Dexamethasone (3 mg/kg) and L-NAME (30 mg/kg) were administered p.o. 30 min before the first injection of caerulein. Caerulein caused moderate or severe pancreatitis, depending on the times of injections, resulting in different degrees of increase in serum amylase levels and pancreas weight, and the marked elevation of MPO activity was observed only after injections of caerulein given 4 times per hour. Both dexamethasone and L-NAME suppressed the severity of pancreatits, yet the effect of L-NAME as compared with dexamethasone was more potent against mild pancreatitis but less potent against severe pancreatitis. These results suggest that caerulein-induced acute pancreatitis shows different responsiveness to L-NAME and dexamethasone, depending on the severity; the former is more effective against pancreatitis with less inflammation, while the latter is more effective against pancreatitis with severe inflammation. It is assumed that endogenous NO may be involved in oedema formation as the early event in the development of acute pancreatitis.
Asunto(s)
Dexametasona/uso terapéutico , NG-Nitroarginina Metil Éster/uso terapéutico , Pancreatitis/tratamiento farmacológico , Enfermedad Aguda , Administración Oral , Amilasas/sangre , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Ceruletida/administración & dosificación , Ceruletida/análogos & derivados , Ceruletida/toxicidad , Dexametasona/administración & dosificación , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Inyecciones Subcutáneas , Masculino , NG-Nitroarginina Metil Éster/administración & dosificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Tamaño de los Órganos/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/patología , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Índice de Severidad de la EnfermedadRESUMEN
The skin secretions of female and male Litoria splendida have been monitored monthly over a three-year period using HPLC and electrospray mass spectrometry. Two minor peptides are present only in the skin secretion of the male. The first of these is the female-attracting aquatic male sex pheromone that we have named splendipherin, a 25 amino acid peptide (GLVSSIGKALGGLLADVVKSKGQPA-OH). This pheromone constitutes about 1% of the total skin peptides during the breeding season (January to March), dropping to about 0.1% during the period June to November. Splendipherin attracts the female in water at a concentration of 10-11-10-9 M, and is species specific. The second peptide is a wide-spectrum antibiotic of the caerin 1 group, a 25 residue peptide (GLLSVLGSVAKHVLPHVVPVIAEKL-NH2) named caerin 1.10. The neuropeptides of L. splendida are also seasonally variable, the change identical for both the female and male. During the period October to March, the sole neuropeptide present in skin secretions is caerulein [pEQDY(SO3)TGWMDF-NH2]; this is active on smooth muscle and is also an analgaesic. During the southern winter (June to September), more than half of the caerulein is hydrolysed to [pEQDYTGWMDF-NH2], a peptide that shows no smooth muscle activity. In place of caerulein, a new peptide, Phe8 caerulein [pEQDY(SO3)TGWFDF-NH2], becomes a major component of the skin secretion. Perhaps this seasonal change is involved in thermoregulation, that is, with the initiation and maintenance of the inactive (hibernation) phase of the animal.
Asunto(s)
Bufonidae/metabolismo , Ceruletida/análogos & derivados , Fragmentos de Péptidos/metabolismo , Feromonas/metabolismo , Caracteres Sexuales , Piel/metabolismo , Secuencia de Aminoácidos , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , Australia , Conducta Animal/efectos de los fármacos , Bufonidae/fisiología , Ceruletida/síntesis química , Ceruletida/química , Ceruletida/metabolismo , Ceruletida/farmacología , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Espectrometría de Masas , Datos de Secuencia Molecular , Peso Molecular , Músculo Liso/efectos de los fármacos , Neuropéptidos/síntesis química , Neuropéptidos/química , Neuropéptidos/metabolismo , Neuropéptidos/farmacología , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Feromonas/síntesis química , Feromonas/química , Feromonas/farmacología , Estaciones del Año , Piel/química , Especificidad de la EspecieRESUMEN
Peptides present in a methanol extract prepared from skin of the Costa Rican frog Agalychnis callidryas of the Phyllomedusinae subfamily were studied by sequence analysis and pharmacological tests. Members of five different peptide families-tachykinins, bradykinins, caerulein, opioid peptides and sauvagine-were found. In particular, the extract contained a number of tachykinins with the following sequences: Gly-Pro-Pro-Asp-Pro-Asn-Lys-Phe-Ile-Gly-Leu-Met-NH2, Gly-Pro-Pro-Asp-Pro-Asp-Arg(Lys)-Phe-Tyr-Pro-Gly-Met-NH2, pGlu-Pro-Asp-Pro-Asp-Arg-Phe-Tyr-Pro-Gly-Met-NH2, Gly-Pro-Pro-Asp-Pro-Asn-Lys-Phe-Tyr-Pro-Val-Met. The latter three peptides have the unusual C-terminal sequence Pro-Gly(or Val)-Met-NH2 rather than Gly-Leu-Met-NH2 found in many other members of the tachykinin family. The observed amino acid substitutions may be the reason for the marked decrease in the biological activity observed in all in vitro and in vivo tests, even through the spectrum of tachykinin activities was retained. A kassinin-like peptide, with the sequence Gly-Pro-Pro-Asp-Pro-Asn-Lys-Phe-Ile-Gly-Leu-Met-NH2, was also found in the A. callidryas skin. While kassinin has a much higher affinity for NK-3 than for NK-1 receptors, the opposite is true for this A. callidryas peptide. The extract from A. callidryas skin also contained a new caerulein (pGlu-Asp-Tyr(HSO3)-Lys-Gly-Trp-Met-Asp-Phe-NH2) and a phyllokinin (Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg-Ile-Tyr), as well as the opioid peptides dermorphin and [Hyp6]dermorphin, both previously isolated from different Phyllomedusa species.
Asunto(s)
Oligopéptidos/química , Oligopéptidos/aislamiento & purificación , Piel/química , Taquicininas/química , Taquicininas/aislamiento & purificación , Animales , Anuros , Bioensayo , Bradiquinina/análogos & derivados , Bradiquinina/química , Bradiquinina/aislamiento & purificación , Bradiquinina/metabolismo , Ceruletida/análogos & derivados , Ceruletida/química , Ceruletida/aislamiento & purificación , Ceruletida/metabolismo , Costa Rica , Kasinina/análogos & derivados , Kasinina/química , Kasinina/aislamiento & purificación , Kasinina/metabolismo , Oligopéptidos/metabolismo , Péptidos Opioides , Taquicininas/metabolismoRESUMEN
The dried skin secretion from Phyllomedusa bicolor, 'sapo', is used by the Matses Indians of the Northern Peru, in shamanic rites mainly designed to improve luck in hunting. When rubbed into burned, exposed areas of the skin, the drug causes the prompt appearance of violent peripheral gastrointestinal and cardiovascular effects soon followed by remarkable central effects (increase in physical strength, heightening of senses, resistance to hunger and thirst, exalted capacity to face stress situations). All the peripheral and most of the central effects of 'sapo' can be ascribed to the exceptionally high content of the drug (up to 7% of its weight) in potently active peptides, easily absorbed through the burned, inflamed areas of the skin. The concentration in 'sapo' of the single peptides (phyllocaerulein, phyllomedusin, phyllokinin, demorphins and deltorphins) has been determined by bioassay, and peptide contents were correlated with the different symptoms of the 'sapo' intoxication.
Asunto(s)
Anuros/metabolismo , Bradiquinina/análogos & derivados , Ceruletida/análogos & derivados , Alucinógenos/farmacología , Neuropéptidos/farmacología , Oligopéptidos/farmacología , Secuencia de Aminoácidos , Proteínas Anfibias , Animales , Conducta Animal/efectos de los fármacos , Bradiquinina/química , Bradiquinina/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Ceruletida/química , Ceruletida/farmacología , Cromatografía en Capa Delgada , Diuresis/efectos de los fármacos , Combinación de Medicamentos , Femenino , Cobayas , Alucinógenos/química , Humanos , Técnicas In Vitro , Indígenas Sudamericanos , Masculino , Datos de Secuencia Molecular , Músculo Liso/efectos de los fármacos , Narcóticos/farmacología , Neuropéptidos/química , Oligopéptidos/química , Hormonas Peptídicas , Péptidos/química , Péptidos/farmacología , RatasRESUMEN
2,3-Epoxy-4-hydroxy-4-((E,E)-3,6-octadienyl)cyclopentanone (dl-carbacerulenin 5) was synthesized via the epoxyketones 15a and 15b as a mimic of the active form of the antibiotics cerulenin 1, a potent inhibitor of fatty acid synthetase (FAS). The monobenzyl ethers (12 and 13), synthetic intermediates of 15, were prepared by direct benzylation of the epoxycyclopentene (7). Inhibitory activity of synthesized 5 toward yeast FAS was less than that of cerulenin by a factor of 1000.
Asunto(s)
Cerulenina/análogos & derivados , Ceruletida/análogos & derivados , Ácido Graso Sintasas/antagonistas & inhibidores , Cerulenina/síntesis química , Cerulenina/farmacología , Ceruletida/síntesis química , Ceruletida/farmacología , Espectroscopía de Resonancia Magnética , Espectrometría de MasasRESUMEN
The effects of ceruletide diethylamine (CLT), a cholecystokinin (CCK)-related peptide, on the spontaneous and haloperidol (HPD)-induced release of striatal dopamine (DA) were investigated with the in vivo microdialysis method. The striatum was perfused with Ringer solution containing different concentrations of K+. (1) When the dialysis tube was perfused with 4 mM K(+)-containing Ringer solution, CLT exerted no influence on the spontaneous and HPD-induced release of DA. (2) Increasing the K+ concentration in the perfusate from 4 to 15 mM failed to change the spontaneous and HPD-induced DA release. In this perfusion condition, the HPD-induced increase in DA release was significantly attenuated by CLT. (3) Perfusion of the striatum with the 20 mM K+ significantly reduced both the spontaneous and HPD-induced output of DA. (4) Even under the condition of perfusing the dialysis tube with the 4 mM K+, CLT significantly decreased the HPD-stimulated DA release in rats given HPD alone for the first 7 days and with CLT for the last 3 days. (5) Sixty consecutive daily administrations of HPD alone markedly reduced HPD-induced DA release from the striatum perfused with the Ringer solution containing 4 mM K+. From these results, we suggest that CLT, under the appropriate depolarization, can facilitate or induce depolarization inactivation of the A9 DA cells and/or nigrostriatal DA terminals, and consequently, produce significant inhibition of HPD-induced DA release from the rat striatum.
Asunto(s)
Ceruletida/análogos & derivados , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Haloperidol/farmacología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Ceruletida/farmacología , Cuerpo Estriado/efectos de los fármacos , Haloperidol/antagonistas & inhibidores , Cinética , Masculino , Perfusión , Potasio/farmacología , Ratas , Ratas EndogámicasRESUMEN
The memory effects of caerulein (CER) and its analogs ([des-Gln2]-CER and [Leu5,Nle8]-CER) were compared with that of cholecystokinin octapeptide (CCK-8) using active and passive avoidance responses in rats. In the active avoidance test, single subcutaneous (SC) injection of CER and its analogs immediately after the learning trials at doses of 10 and 100 ng/kg prevented extinction of learned task for 10 days, and at a dose of 1000 ng/kg for at least 15 days, but the effect of CCK-8 was somewhat weaker. In the saline control group, the number of responses decreased after 5 days. In the passive avoidance response, electroconvulsive shock (ECS)-induced amnesia was partially prevented by CCK-8 at doses of 100 and 1000 ng/kg SC, while CER and its analogs at doses of more than 100 ng/kg totally prevented the ECS-induced amnesia. Intraperitoneal administration of scopolamine caused complete amnesia which was also partially prevented by CCK-8, while CER could totally prevent the amnesia following SC injection of 2 micrograms/kg. These results indicate that CER and its analogs are more effective than CCK-8 for preventing experimental amnesia.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Ceruletida/farmacología , Memoria/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Ceruletida/análogos & derivados , Electrochoque , Inyecciones Subcutáneas , Masculino , Datos de Secuencia Molecular , Nociceptores/efectos de los fármacos , Ratas , Ratas Endogámicas , Tiempo de Reacción/efectos de los fármacos , Escopolamina/farmacología , Sincalida/farmacología , betaendorfina/farmacologíaRESUMEN
The sulfated form of cholecystokinin octapeptide (CCK-8) and ceruletide (CER), but not their non-sulfated forms of CCK-4, significantly decreased the rates of locomotor activity and rearing during the first 10 min test session 10 min after intracerebroventricular (ICV) administration at doses more than 25 and 3.125 mg, respectively. CER-S antagonized methylphenidate-induced hypermotility after ICV administration at a dose of 800 ng. Plasma levels of CER-like immunoreactivity (CER-LI) measured at 120 min after subcutaneous injection, when the locomotor suppressive activity induced by 100 and 200 micrograms was no longer observed, were similar to or much higher than that 30 min after ICV administration at a dose of 800ng, suggesting that the effects of ICV CER-S are not mediated by a peripheral redistribution. These findings indicate that (1) the structural requirement for the locomotor suppressive activity is sulfated tyrosine residue; (2) the behavioural effects of ICV-administered CCK-8-S and CER-S are due to their central actions and mediated by the/inhibition of the central dopamine (DA) function; and (3) CCK-8-S in the brain is functionally associated with the central DA system.
Asunto(s)
Conducta Animal/efectos de los fármacos , Ceruletida/farmacología , Actividad Motora/efectos de los fármacos , Sincalida/farmacología , Animales , Ceruletida/análogos & derivados , Ceruletida/sangre , Relación Dosis-Respuesta a Droga , Hipercinesia/inducido químicamente , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Metilfenidato/farmacología , Ratones , Sincalida/análogos & derivados , Tetragastrina/farmacología , Factores de TiempoRESUMEN
The biologically active conformations of a series of four peptides [four cholecystokinin (CCK)-related peptides and enkephalin] in their interactions with gastrointestinal receptors have been deduced using conformational computational analysis. The two peptides that interact exclusively with peripheral-type CCK receptors are the heptapeptide COOH-terminal fragment from CCK (CCK-7) and the analogous sequence from cerulein (CER-7) in which threonine replaces the methionine proximal to the NH2 terminus. The two peptides that interact exclusively with the gastrin receptor in the stomach are the active COOH-terminal fragment of little gastrin and the COOH-terminal tetrapeptide sequence common to all of these peptides, CCK-4. We find that preferred conformations for the peripherally active peptides CCK-7 and CER-7 are principally beta-bends, whereas little gastrin and CCK-4 are fundamentally helical. In the class of lowest energy structures for both CCK-7 and CER-7, the aromatic rings of the tyrosine and phenylalanine lie close to one another whereas the tryptophan indole ring points in the opposite direction. This structure is superimposable on the structures of a set of rigid indolyl benzodiazepine derivatives that interact with complete specificity and high affinity with peripheral CCK receptors further suggesting that the computed beta-bends are the biologically active conformation. The biologically active conformation for CCK-4 and the little gastrin hexapeptide has also been deduced. By excluding conformations common to CCK-7 and CCK-4, which do not bond to each other's receptors, and then by selecting conformations in common to CCK-4 and the gastrin-related hexapeptide, which do bind to each other's receptors, we deduce that the biologically active conformation at the gastrin receptor is partly helical and one in which the indole of tryptophan and the aromatic ring of phenylalanine are close to one another while the methionine and aspartic acid side chains point in the opposite direction. These major differences in preferred structures between the common CCK-7/CER-7 peptides and the common CCK-4/little gastrin peptides explain the mutually exclusive activities of these two sets of peptides. We have observed that [Met]enkephalin strongly antagonizes the action of the naturally occurring peripherally active CCK-8 (CCK-7 with an NH2-terminal aspartic acid residue added). The computed lowest energy structures for this opiate peptide closely resemble key features of the computed CCK-7/CER-7 structure, further supporting the proposed structure.
Asunto(s)
Ceruletida/análogos & derivados , Encefalina Metionina/metabolismo , Gastrinas/metabolismo , Fragmentos de Péptidos/metabolismo , Sincalida/metabolismo , Tetragastrina/metabolismo , Secuencia de Aminoácidos , Benzodiazepinas/metabolismo , Ceruletida/metabolismo , Indoles/metabolismo , Modelos Moleculares , Unión Proteica , Conformación Proteica , Receptores de Colecistoquinina/metabolismo , Receptores Opioides/metabolismoRESUMEN
The effects of several doses of cholecystokinin octapeptide sulphate ester (CCK-8-SE) and nonsulphated cholecystokinin octapeptide (CCK-8-NS), and two CCK-related peptide analogues Ac-Thr5-caerulein, and nonsulphated Ac-Thr5-caerulein were investigated on electroshock-(ES)-induced seizures after intraperitoneal administration in mice. As parameters, the duration of the tonic and clonic phase of the fit, and those of postictal coma and behavioural depression were measured. CCK-8-SE decreased the duration of the clonic phase; its highest dose, 3.2 mumol/kg, shortened the coma. CCK-8-NS antagonized only slightly the clonic phase of seizure. Ac-Thr5-caerulein did not influence ES-induced seizures in any dose, only increased the duration of behavioural depression. Similarly to CCK-8-NS, the nonsulphated form of Ac-Thr5-caerulein inhibited selectively the clonic phase of seizures. The reference drugs, diazepam and phenobarbital, antagonized dose-dependently and most effectively the tonic phase of ES-induced seizures, but in much higher doses than did the CCK-related peptides. Besides, diazepam increased and phenobarbital decreased the duration of postictal coma. The results showed that the tested CCK-related peptides inhibit prevalently the clonic phase of ES-induced seizures after peripheral administration.
Asunto(s)
Anticonvulsivantes , Ceruletida/análogos & derivados , Sincalida/análogos & derivados , Animales , Ceruletida/farmacología , Diazepam/farmacología , Electrochoque , Masculino , Ratones , Fenobarbital/farmacología , Sincalida/farmacología , Relación Estructura-Actividad , Ácidos SulfúricosRESUMEN
In ten healthy controls and in ten patients with biopsy-proved mild liver disease, we studied fasting and postcholecystokinetic bile acid levels to assess their diagnostic value compared with standard liver tests. Cholecystokinetic bile acid elevation was standardized by evacuating the gallbladder with intramuscular ceruletide diethylamine (cholecystokinin decapeptide) in a double-blind, randomized, placebo-controlled crossover design. Radioimmunoassay of primary conjugated bile acids was adequately sensitive to separate controls from patients even on the basis of fasting serum bile acid levels. In both controls and patients, the 180-minute postcholecystokinetic bile acid time curve was significantly higher after ceruletide than after placebo. Nevertheless, neither this response nor any of the 30-minute postcholecystokinetic interval bile acid levels separated controls from patients better than the fasting bile acid values, which discriminated better than standard liver tests or the indocyanine green clearance at 20 minutes. Alanine aminotransferase separated the two groups with a sensitivity equal to fasting bile acid levels.
Asunto(s)
Ácidos y Sales Biliares/sangre , Ayuno , Vesícula Biliar/metabolismo , Hepatopatías Alcohólicas/diagnóstico , Ceruletida/análogos & derivados , Ensayos Clínicos como Asunto , Método Doble Ciego , Vesícula Biliar/fisiopatología , Humanos , Cinética , Pruebas de Función Hepática , Masculino , Radioinmunoensayo , Distribución AleatoriaRESUMEN
UNLABELLED: Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 7 analogues of ceruletide, were studied for antagonism of stereotyped gnawing and cage climbing, induced by apomorphine in mice that were sensitized by either administration of scopolamine (1 mg/kg, s.c., 15 min before) or teflutixol (5 mg/kg, i.p., 4 days before). Three neuroleptics (haloperidol, trifluoperazine and teflutixol) served as reference drugs. All peptides reduced or abolished the fully developed gnawing activity and were (on a molar basis) often more potent than the reference drugs. In contrast to the neuroleptics, the peptides did not antagonize the climbing activity. In mice pretreated with scopolamine, the peptides were more potent than in mice pretreated with teflutixol. With the neuroleptics, the influence of the sensitizing pretreatments was converse, and this applied also to the anticlimbing effect. The relationships between peptide structure and antistereotypic effect were different from those found previously in a study on the antagonism of gnawing induced by methylphenidate. CONCLUSIONS: CCK-like peptides are able to antagonize stereotyped behaviour caused by direct and indirect dopaminergic agonists; the mechanism of action of the peptides differs from that of the reference neuroleptics.
Asunto(s)
Apomorfina/antagonistas & inhibidores , Ceruletida/farmacología , Sincalida/farmacología , Conducta Estereotipada/efectos de los fármacos , Animales , Antipsicóticos/farmacología , Ceruletida/análogos & derivados , Relación Dosis-Respuesta a Droga , Haloperidol/farmacología , Humanos , Irritantes/farmacología , Masculino , Ratones , Escopolamina/farmacología , Tioxantenos/farmacología , Trifluoperazina/farmacologíaRESUMEN
The synthetic analog of ceruletide, (beta-Asp9) ceruletide, which in previous studies was found to retain some central effects of ceruletide with virtually no effect on gallbladder contraction, was studied for its stimulatory effect on pancreatic secretion. This peptide was shown to induce an increase in the volume of pancreatic juice similar to that provoked by the parent compound. Its activity was 4% of that of ceruletide, as regards volume, dry residue and protein content of the pancreatic juice. It was concluded that the dissociation between central and peripheral effects concerned only the gallbladder contractility, since its potency as a pancreatic stimulant was of the same order of magnitude as that shown on the central nervous system.
Asunto(s)
Ceruletida/análogos & derivados , Jugo Pancreático/metabolismo , Secuencia de Aminoácidos , Animales , Ceruletida/farmacología , Dimaprit , Perros , Vesícula Biliar/efectos de los fármacos , Imidazoles/farmacología , Impromidina , Contracción Muscular/efectos de los fármacos , Secretina/farmacología , Tasa de Secreción/efectos de los fármacos , Relación Estructura-Actividad , Tiourea/farmacologíaRESUMEN
The decapeptide from the frog Hyla caerulea, caerulein (caerulein diethylammonium hydrate, ceruletide, CER) is chemically closely related to the C-terminal octapeptide of cholecystokinin (CCK-8). Like CCK-8, CER and some of its analogues produce many behavioural effects in mammals: inhibition of intake of food and water; antinociception; sedation; catalepsy; ptosis, antistereotypic, anticonvulsive and tremorolytic effects; inhibition of self-stimulation. Effects of CER in man comprise sedation, satiety, changes in mood, analgesia and antipsychotic effects. A modulation of central dopaminergic functions appears to be one possible mechanism of CER and its analogues. A common denominator for all effects of CER is, at present, not evident.
Asunto(s)
Ceruletida/farmacología , Animales , Anticonvulsivantes , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Blefaroptosis/inducido químicamente , Regulación de la Temperatura Corporal/efectos de los fármacos , Catalepsia/inducido químicamente , Ceruletida/análogos & derivados , Conducta de Ingestión de Líquido/efectos de los fármacos , Electrofisiología , Conducta Alimentaria/efectos de los fármacos , Humanos , Hipnóticos y Sedantes , Actividad Motora/efectos de los fármacos , Dolor/fisiopatología , Trastornos Psicóticos/tratamiento farmacológico , Autoestimulación/efectos de los fármacos , Sueño/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-Actividad , Trastornos Relacionados con Sustancias/fisiopatología , Temblor/fisiopatologíaRESUMEN
The smooth muscle stimulatory effects of cholecystokinin octapeptide (CCK-8), ceruletide (CER), ten analogues of CER, and carbachol were studied in isolated organs of the guinea pig and the mouse (stomach, ileum, duodenum, colon and gallbladder). On a molar basis, CCK-8 and CER had in all organs except stomach greater potency (lower EC50) than carbachol. The effectiveness (Emax) of CCK-8 and CER was in the gut less than that of carbachol, in the guinea pig gallbladder equal with and in the mouse gallbladder superior to that of carbachol. The alteration of peptide structure was virtually without influence on effectiveness; however, it greatly modified the potency and the organ selectivity of the effect. There was no clear-cut correlation between the potency to stimulate smooth muscle and to alter the behavior of the mouse.
Asunto(s)
Ceruletida/farmacología , Colon/efectos de los fármacos , Vesícula Biliar/efectos de los fármacos , Íleon/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Sincalida/farmacología , Animales , Ceruletida/análogos & derivados , Duodeno/efectos de los fármacos , Cobayas , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Especificidad de Órganos , Estómago/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide diethylamine, a cholecystokininlike peptide, in a placebo-controlled, double-blind, cross-over study. Ceruletide or placebo was administered intramuscularly twice a day for four consecutive days while patients received a constant dose of fluphenazine hydrochloride. Cholecystokinin octapeptide was also administered to four different schizophrenic patients in a double-blind, cross-over study. Cholecystokinin or placebo was administered as a slow intravenous infusion daily for four days. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo, ceruletide, or cholecystokinin administration. Furthermore, there was no tendency for the patients' conditions to either improve or worsen during the course of ceruletide or cholecystokinin treatment. In contrast to previous reports from uncontrolled studies, cholecystokininlike peptides appear to be devoid of antipsychotic properties when administered parenterally.
Asunto(s)
Ceruletida/análogos & derivados , Esquizofrenia/tratamiento farmacológico , Adulto , Ceruletida/uso terapéutico , Enfermedad Crónica , Ensayos Clínicos como Asunto , Método Doble Ciego , Femenino , Humanos , Masculino , Placebos , Escalas de Valoración Psiquiátrica , Psicología del Esquizofrénico , Sincalida/uso terapéuticoRESUMEN
The action of Ceruletide, a decapeptide with a chemical formula close to that of the terminal acid amines of cholecystokinin pancreozymin, was investigated during oral cholecystography. Intramuscular injections of Ceruletide provoked gallbladder contractions that were stronger and occurred more rapidly than after the conventional "fatty meal". Visualization of the extrahepatic biliary pathways was improved, the duration of the examination shortened, and the number of films required reduced, the useful time in approximately 3 out of 4 cases being equal to or less than 6 minutes.
Asunto(s)
Ceruletida/análogos & derivados , Colecistografía , Vesícula Biliar/efectos de los fármacos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacosRESUMEN
Haloperidol in low doses antagonized the apomorphine-induced cage-climbing behaviour of mice, whereas ceruletide (CER) and its analogue, Nle8-CER-(4-10) had very weak anticlimbing efficacy; Nle8-CER and diazepam were inactive. The ptosis caused by CER and cholecystokinin octapeptide (CCK-8) was antagonized by apomorphine in doses 27 times smaller than those effective against the haloperidol-induced ptosis. No such differences occurred when either methylphenidate or picrotoxin replaced apomorphine. Low-dose haloperidol was an antagonist to the antiptotic effect of apomorphine versus both CER and CCK-8. The rearing inhibiting effect of CER and haloperidol, in contrast to that of clonazepam, was very resistant to apomorphine. Methylphenidate was weakly effective against clonazepam and haloperidol but inactive versus CER. Picrotoxin was no antagonist to either rearing inhibiting agent. The results taken together suggest presynaptic sites of the dopaminergic system as important for the production of ptosis by CCK-like peptides.
Asunto(s)
Antipsicóticos , Ceruletida/farmacología , Sincalida/farmacología , Animales , Apomorfina/farmacología , Conducta Animal/efectos de los fármacos , Blefaroptosis/inducido químicamente , Temperatura Corporal/efectos de los fármacos , Ceruletida/análogos & derivados , Clonazepam/farmacología , Antagonismo de Drogas , Haloperidol/farmacología , Masculino , Metilfenidato/farmacología , Ratones , Fragmentos de Péptidos/farmacología , Picrotoxina/farmacologíaRESUMEN
Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 10 analogues of ceruletide, were studied in mice for antagonism of the tremors induced by harmine (5 mg/kg, s.c.), ibogaine (20 mg/kg, s.c.) and oxotremorine (0.2 mg/kg, s.c.). The following reference drugs were tested for comparison: prolyl-leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam. All treatments were subcutaneous, the antagonists being given 10 min (in some trials 30 min) before the tremorogen. Tremorolytic potency (ED50) was calculated from dose-response curves. Against the tremors induced by either harmine or ibogaine, CCK-8 and ceruletide, as well as many of the analogues of ceruletide had greater tremorolytic potency than the reference drugs. Against oxotremorine, however, ceruletide and its most potent analogue, Nle8-CER (other analogues were not tested) were inactive and MIF showed very little effectiveness. Additional experiments on hypothermia and sedation as well as evaluation of previous studies on other central actions suggested that the tremorolytic effect of CCK-like peptides is independent of other central effects. The CCK-like peptides may play a physiological role in the regulation of extrapyramidal motor activity.