Effects of rotigotine and rotigotine extended-release microsphere therapy on myocardial ischemic injury in mice.

Rotigotine is a dopamine receptor agonist that can improve motor function in Parkinson's disease (PD) patients. Rotigotine extended-release microsphere (RoMS) is an extended-release intramuscular formulation that exhibits a sustained release of rotigotine over a 14-day period. The clinical trials of RoMS has been carried out in USA and China. The purpose of this study is to observe the effects of RoMS therapy on myocardial ischemic injury in mice, to know whether RoMS alleviate or deteriorate the myocardial ischemic injury while PD patient has onset of myocardial ischemia concurrent after administered with RoMS. A mouse model of myocardial ischemia was established using isoproterenol, and mice were pretreated with rotigotine or RoMS before inducing myocardial ischemic injury. The effects of rotigotine or RoMS therapy on the degree of myocardial ischemic injury were studied by evaluating troponin I level, creatine kinase-MB (CK-MB) activity, and histopathological changes in cardiomyocytes. The dopamine receptor blocker chlorpromazine was used to further investigate the effects of rotigotine or RoMS on myocardial ischemic injury. Furthermore, serum rotigotine concentrations were also assayed. When myocardial ischemia occurred during rotigotine or RoMS administration, troponin I level and CK-MB activity were decreased, and ischemia-induced histopathological changes in cardiomyocytes were alleviated. The effects of rotigotine were maintained only 12 h and after that no protective effect was observed. RoMS releases continuously into the circulation after intramuscular injection. The cardioprotective effects of RoMS were maintained 14 days after a single RoMS administration. When combined with chlorpromazine, the protective effects of rotigotine on myocardial ischemic injury were eliminated, and the protective effects of RoMS were also partially abolished. In the animal model of myocardial ischemia, pretreatment with rotigotine or RoMS does not deteriorate, but can alleviate cardiomyocyte injury. Furthermore, RoMS pretreatment show long-term and continuous protective effects on cardiomyocyte injury. RoMS therapy in PD patients at high risk for cardiovascular diseases may attenuate the degree of cardiomyocyte injury caused by ischemia.

Effect of Dai-kenchu-to (Da-Jian-Zhong-Tang) on the delayed intestinal propulsion induced by chlorpromazine in mice.

This study was conducted to evaluate the effect of Dai-kenchu-to on chlorpromazine-induced hypoperistalsis in mice. Oral administration of Dai-kenchu-to (30-300 mg/kg) dose-dependently improved small intestinal and distal colonic propulsion decreased by chlorpromazine (3 mg/kg, p.o.). Although the improvement of small intestinal propulsion due to Dai-kenchu-to was partially inhibited by atropine (1 mg/kg, s.c.), this action was completely inhibited by the concomitant administration of lorglumide (10 mg/kg, i.p.), a CCKA receptor antagonist. The distal colonic propulsion-improving effect of Dai-kenchu-to was abolished by atropine (1 mg/kg, s.c.). When the effects of the respective components of Dai-kenchu-to were evaluated, oral administration of Zanthoxylum Fruit improved both delayed small intestinal and distal colonic propulsion caused by chlorpromazine. On the other hand, Malt Sugar was effective against only delayed small intestinal propulsion. The action of Zanthoxylum Fruit was completely inhibited by atropine (1 mg/kg, s.c.), and the effect of Malt Sugar was inhibited by lorglumide (10 mg/kg, i.p.). These results demonstrated that Dai-kenchu-to improves chlorpromazine-induced hypoperistalsis via cholinergic systems and that Zanthoxylum Fruit is the main contributor to this action of Dai-kenchu-to. In addition, endogenous CCK due to Malt Sugar may also contribute to this effect of Dai-kenchu-to.

Attenuation by nimodipine of amitriptyline-induced avoidance impairment in mice.

The effects of the dihydropyridine calcium channel blocker nimodipine on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box training and in previously trained mice of the DBA/2 strain. Nimodipine (0, 0.5, 1, 2.5, or 5 mg/kg) had no effect alone, but attenuated the avoidance impairment induced by 5 mg/kg amitriptyline on avoidance acquisition, as well as on a previously learned avoidance response. The avoidance improving action of the calcium channel blocker was less evident in mice receiving a larger dose (7.5 mg/kg) of the antidepressant drug. The effect of nimodipine did not appear to be specifically related to the avoidance impairment induced by amitriptyline, because the calcium antagonist also attenuated the avoidance impairing action of the neuroleptic chlorpromazine. The avoidance impairment induced by amitriptyline and chlorpromazine, and the related ameliorating action of nimodipine, seem imputable to drug effects on the performance of the avoidance response, rather than to interferences with learning processes. The results suggest that, in the case of concomitant administration, nimodipine could alleviate adverse side effects of tricyclic antidepressant, i.e., psychomotor disturbances.

Identification of class-determining residues in G protein-coupled receptors by sequence analysis.

G protein-coupled receptors (GPCRs) form a large superfamily of receptors that are characterised by a seven transmembrane helical motif. The functions they perform, such as binding ligands and G proteins, are related to the presence of certain amino acids in critical positions. We have developed a computational sequence pattern correlation technique for the recognition of such function-determining residues. The method searches for residues that are conserved in one class of proteins with a certain function but are different in other classes. The basic idea is that such residues are probably involved in this particular function. This technique was used to find residues that play a role in the binding of endogenous as well as exogenous ligands to various receptors. Many of the residues that were detected have been experimentally determined as important for ligand binding. More importantly, however, we also detected residues that are interesting targets for future mutation studies aimed at elucidating the sequence-function relationship in GPCRs. The information obtained may help improve three-dimensional GPCR models and can be useful for the study of receptor-ligand interactions.

Protective effects of neutral amino acids against amphipathic drug-induced hemolysis.

Some neutral amino acids were compared for their anti-hemolytic effects with sugars which are well-known colloid-osmotic protectants. The kinetic studies in isotonic suspensions of erythrocytes indicated that the hemolysis induced by the amphipathic drug chlorpromazine (CPZ) or flufenamic acid (FA) was retarded by addition of sugars, and the degree of the anti-hemolytic effect increased with increases in molecular size. Phenylalanine (Phe), the largest among the amino acids tested, showed the greatest inhibitory effect on CPZ-induced hemolysis, but not on FA-induced hemolysis. This demonstrated that the anti-hemolytic effects of amino acids were not the result of colloid-osmotic protection. Hemolytic actions of amino acids were also examined to determine their interaction with the erythrocyte membrane, and the mechanism of their inhibitory effects against amphipathic drug-induced hemolysis was discussed.

Serotonin2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibits chlorpromazine- and haloperidol-induced hypothermia in mice.

Chlorpromazine- and haloperidol-induced hypothermia were examined in mice. The alpha 1 receptor agonist phenylephrine partially antagonized the hypothermia, while the dopamine D2 receptor agonist apomorphine did not inhibit it. The central serotonin2 (5-HT2) receptor agonist I-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) strongly inhibited the chlorpromazine- and haloperidol-induced hypothermia. Both drugs at doses which can elicit hypothermia antagonized head twitch responses mediated by the central 5-HT2 receptor. These results suggest that the chlorpromazine- and haloperidol-induced hypothermia may be mediated by the blockade of the central 5-HT2 receptor.

Effect of chlorpromazine on the synthesis of neutral lipids and phospholipids from [3H]glycerol in the primordial human placenta.

Addition of chlorpromazine (CPZ) of 100 microM final concentration to fragments of primordial human placenta incubated in vitro with [3H]glycerol results in the following changes in the labelling of various neutral lipids and phospholipids: (1) rapid accumulation of [3H]phosphatidic acid (PA) to a 2.31 +/- 0.12-fold (mean +/- s.d., P < 0.05) higher steady-state level within 5 min; (2) a dramatic, 5-6-fold (5.74 +/- 0.31, P < 0.01) increase in [3H]phosphatidylinositol (PI) synthesis within 5-10 min, followed by progressive PI accumulation; (3) gradual accumulation of [3H]1,2-diacylglycerol (DAG) reaching approximately 1.7-fold (1.72 +/- 0.14, P < 0.05) higher steady-state level at 30 min; and (4) an approximately 20 and 30% decrease in [3H]triacylglycerol (TG) and [3H]phosphatidylcholine (PC) formation, respectively, which begins to become evident between 10-30 min. As dose-response studies indicate, accumulations of PI and DAG are most susceptible to CPZ. They respond in the concentration range of 10-50 microM, while only higher drug concentrations (100-250 microM) affect the synthesis of PA, PC and TG significantly. Finally, dioctanoylethyleneglycol (DOEG), a structural analogue of the diacyl moiety of PA and DAG, selectively inhibits the basal synthesis (0.59 +/- 0.15, P < 0.05) as well as the CPZ-induced rise (0.49 +/- 0.11, P < 0.02) of PI. These results suggest that CPZ-induced increase in the concentrations of PI and 1,2-DAG may interfere with signal-transduction pathways in the placenta of pregnant patients treated with CPZ. Furthermore, DOEG is able to antagonize the CPZ effect which directs lipid biosynthesis towards the formation of PI.

Reversal of chlorpromazine-induced avoidance depression by the N-methyl-D-aspartate antagonist, dizocilpine, in mice.

The non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 (dizocilpine) was tested, alone or in combination with chlorpromazine, in mice previously trained in the shuttlebox. The lowest doses of dizocilpine (0.02 and 0.04 mg kg-1) attenuated the disrupting action of the neuroleptic (1.5 mg kg-1) on avoidance-performance, while avoidance depression induced by 1.5 and 2 mg kg-1 chlorpromazine was completely or almost completely reversed by 0.08 mg kg-1 NMDA antagonist. The highest dose (0.16 mg kg-1) of dizocilpine did not ameliorate avoidance-performance of mice receiving 2 mg kg-1 chlorpromazine, perhaps because of ataxic effects produced by the drug combination, at these doses. The results support suggestions for a potential use of NMDA antagonists in the treatment of extrapyramidal side-effects of neuroleptics.

Effects of the novel thyrotropin-releasing hormone analogue Na -((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prol ina mide monohydrate on the central nervous system in mice and rats.

The central nervous system (CNS) effects of a novel thyrotropin-releasing hormone (TRH) analogue, JTP-2942 (Na-alpha- ((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-pro linamide monohydrate, CAS 131404-34-7) were investigated and compared with those of TRH. When administrated subcutaneously, JTP-2942 was about 80 times more potent than TRH in the antagonization of reserpine-induced hypothermia, and when administrated intravenously it was about 16 times more potent than TRH in the potentiation of flexor reflexes. Furthermore, oral administration of JTP-2942 was able to antagonize a chlorpromazine-induced reduction in locomotor activity, while TRH was far less effective. In tests on the recovery from pentobarbital-induced sleep and disturbance of consciousness induced by concussive head trauma, JTP-2942 was about 30 and 3 times more potent than TRH, respectively. Thus, JTP-2942 had a far stronger and more persistent action compared with TRH in regard to these effects. However, JTP-2942 had a 3-fold lower effect on thyroid stimulating hormone (TSH) release than TRH. These results suggest that the stimulatory effects of JTP-2942 are selective for the CNS and that this TRH analogue may be applicable to clinical use.

Inhibition of SV40 DNA replication in vitro by chlorpromazine.

We examined the inhibitory effect of chlorpromazine, a phenothiazine derivative, on SV40 DNA replication in a HeLa cell extract. The inhibition by chlorpromazine was reversed by cardiolipin, phosphatidylinositol, phosphatidylglycerol, and phosphatidylserine. Studies on a staged reaction showed that the pre-elongation step was sensitive to chlorpromazine: chlorpromazine-resistant DNA synthesis was observed when the drug was added after the pre-elongation step. Analysis of replication products by agarose gel electrophoresis revealed that some steps of DNA chain elongation and maturation of closed circular forms were also sensitive to this drug.

Neurotoxicity of chlorpromazine and modulation by amantadine as a function of mouse strain.

The separate and combined effects of successive administration of amantadine, 100 mg/kg, i.p., and chlorpromazine, 0.2 mg/kg, i.p., on motor activity and whole brain levels of certain biogenic amines and major metabolites were studied in four strains of mice. These were the albino ICR, the inbred BALB/C, C57BL/6 and the hybrid CDF-I mice. Amantadine produced a strain-dependent behavioral stimulation subsequent the fourth dose. This was apparent in ICR and C57BL/6 mouse strains and was followed by a behavioral depression phase occurring during the night in C57BL/6 mice which was antagonized by chlorpromazine. Administration of chlorpromazine alone affected only CDF-1 mouse mobility. Chlorpromazine reduced only ICR mouse brain dopamine without concomitant changes in major acid metabolites. Repeated administration of amantadine prior to chlorpromazine negated this effect. Chlorpromazine enhancement of BALB/C brain serotonin and 5-hydroxyindoleacetic acid was antagonised by pretreatment with amantadine. This antagonism was also evident in BALB/C mouse brain dihydroxyphenylacetic acid. The results suggest genotypic-dependent behavioral and cerebral effects by the drugs studied. The antagonism between amantadine and chlorpromazine on brain amines may explain the therapeutic efficacy of amantadine in modulating chlorpromazine-induced extrapyramidal disorders.

Acción antifungica de clorpromacina, ketoconazol y cicloheximida sobre dos cepas de Pycnoporus cinnabarinus (Jacq. ex Fr.) Karst / Antifungic action chlorpromacine, ketoconazole and cycloheximide on two Pycnoporus cinnabarinus (Jacq. ex Fr.) Karst strains

El desarrollo de dos cepas de Pycnoporus cinnabarinus (Jacq. ex Fr.) Karts, fue inhibido durante 72 horas al agregar al medio de cultivo clorpromacina, ketoconazol o cicloheximida respectivamente. La cepa Pc 58 fue inhibida por 33 ug/ml de clorpromacina y la cepa Pc470.6 por 40 ug/ml. Cicloheximida inhibió el crecimiento de la cepa Pc58 a una concentración de 3 ug/ml y a la cepa Pc470.6 a 5 ug/ml. El agente más eficaz para inhibir el crecimiento de estas cepas de P. cinnabarinus fue el Ketoconazol, que actuó a concentraciones menores de 0,5 ug/ml en la cepa Pc58 y a 0,9 ug/ml en la cepa Pc470.6

Inhibition of chlorpromazine-induced catalepsy by the 5-HT-1A ligands pindolol and buspirone in mice.

Neuroleptics such as chlorpromazine and haloperidol are capable of inducing catalepsy in rodents. Non-selective 5-hydroxytryptamine (5-HT) antagonists such as methysergide reduce the cataleptic effect of haloperidol. The present study was designed to evaluate the participation of 5-HT-1A receptors in chlorpromazine-induced catalepsy in mice. Pindolol and buspirone, two putative 5-HT-1A receptor ligands, were used. Pretreatment with these drugs reduced the cataleptic effect of chlorpromazine. Clomipramine, a 5-HT neuronal uptake blocker, reversed the inhibitory effect of buspirone. Pretreatment with clomipramine alone caused a potentiation of neuroleptic-induced catalepsy. These results suggest that central 5-HT-1A receptors play an important role in neuroleptic-induced catalepsy in mice.

Inhibition of chlorpromazine-induced catalepsy by the 5-HT-1A ligands pindolol and Buspirone in mice

Neuroleptcs such as chlorpromazine and haloperidol are capable of inducing catalepsy in rodents. Non-selective 5-hydroxytryptamine (5-HT) antagonists such as methysergide reduce the cataleptic effect of haloperidol. The present study was designed to evaluate the particpation of 5-HT-1A receptors in chlorpromazine-induced catalepsy in mice. Pundolol and buspirone, two putative 5-HT-1A receptor ligands, were used. Pretreatment with these drugs reduced the cataleptic effect of chlorpromazine. Clomipramine, a 5-HT neuronal uptake blocker, reversed the inhibitory effect of buspirone. Pretreatment with clomipramine alone caused a potentiation of neuroleptic-induced catalepsy. These results suggest that central 5-HT-1A receptors play an important role in neuroleptic-induced catalepsy in mice

Anticholinergic-neuroleptic antagonism in terms of positive and negative symptoms of schizophrenia: implications for psychobiological subtyping.

In three studies of comparable design, 47 schizophrenics received anticholinergic anti-Parkinsonism (AP) medications for two to four weeks along the course of neuroleptic treatment. Clinical ratings during the AP phase were contrasted against the preceding and following two-week periods on neuroleptic alone, and these changes were analysed for a total of 27 psychopathology dimensions and for clusters of seven positive and seven negative symptoms. Schizophrenics overall exhibited significant exacerbation of total psychopathology, and positive but not negative symptoms. Only those with a predominantly positive syndrome when drug-free were susceptible to AP therapeutic reversal. However, other subgroup analyses revealed worsening of total psychopathology and positive symptoms among catatonic, schizophreniform, chronic, and good outcome cases, but negative symptoms alone were significantly increased among paranoids. The results were not supportive of a positive-negative dichotomy of schizophrenia, but instead suggested a tripartite model: a distinct paranoid group and a division of the non-paranoids into a positive and a negative type.

Efecto de la cloropromacina sobre la reacción injerto contra huésped / Effect of chlorpromazine on graft versus host reaction

Efecto de la cloropromacina sobre la reacción injerto contra huésped. Se estudió el efecto de la cloropromacina (CL) sobre la reacción injerto contra huésped (r.I.c.H.) producida por la inyección de células parentales inmunocompetentes al híbrido F1, valorada mediante el índice esplénico (I.E.). Se pudo demostrar que la CL inhibió la r.I.c.H. en las dos dosis de células estudiadas, tanto cuando el tratamiento se realizó sobre los animales donantes como sobre el huésped. El efecto de la CL sobre la r.I.c.H. se antogonizí parcialmente con alfa bromocriptina. La inyección de prolactina (PR) al huésped produjo un efecto similar a la CL cuantitativamente menor. Estas drogas no modificaron la estructuras linfática ni el i.E. de los híbridos F1 no inoculados con células linfáticas. El tratamiento con CL a animales donantes previamente inmunizados inhibió la capacidad de las células inmunocompetentes para producir la r.I.c.H. en híbridos F1. Este efecto de la CL fue cuantitativamente mucho menor cuando el tratamiento se realizó a animales donantes sin inmunización previa. La CL y la PR incubadas "in vitro" con células linfáticas no modificaron la capacidad de los linfocitos para producir r.I.c.H. Se postula que la CL inhibe la r.I.c.H. en parte por elevar los niveles plasmáticos de PR y que su efecto y el de la PR se producen solamente en los clonos linfocitarios en expansión, estimulados por los antígenos de histocompatibilidad (AU)

Efecto de la cloropromacina sobre la reacción injerto contra huésped / Effect of chlorpromazine on graft versus host reaction

Efecto de la cloropromacina sobre la reacción injerto contra huésped. Se estudió el efecto de la cloropromacina (CL) sobre la reacción injerto contra huésped (r.I.c.H.) producida por la inyección de células parentales inmunocompetentes al híbrido F1, valorada mediante el índice esplénico (I.E.). Se pudo demostrar que la CL inhibió la r.I.c.H. en las dos dosis de células estudiadas, tanto cuando el tratamiento se realizó sobre los animales donantes como sobre el huésped. El efecto de la CL sobre la r.I.c.H. se antogonizí parcialmente con alfa bromocriptina. La inyección de prolactina (PR) al huésped produjo un efecto similar a la CL cuantitativamente menor. Estas drogas no modificaron la estructuras linfática ni el i.E. de los híbridos F1 no inoculados con células linfáticas. El tratamiento con CL a animales donantes previamente inmunizados inhibió la capacidad de las células inmunocompetentes para producir la r.I.c.H. en híbridos F1. Este efecto de la CL fue cuantitativamente mucho menor cuando el tratamiento se realizó a animales donantes sin inmunización previa. La CL y la PR incubadas "in vitro" con células linfáticas no modificaron la capacidad de los linfocitos para producir r.I.c.H. Se postula que la CL inhibe la r.I.c.H. en parte por elevar los niveles plasmáticos de PR y que su efecto y el de la PR se producen solamente en los clonos linfocitarios en expansión, estimulados por los antígenos de histocompatibilidad

[Effect of chlorpromazine on the graft versus host reaction]. / Effecto de la cloropromacina sobre la reacción injerto contra huesped.

The effect of chlorpromazine (CLZ) on the graft vs. host reaction (G.vs.H.r.) induced by the injection of parental immunocompetent cells to F1 hybrids was studied. Rats of one parental strain were immunized with 3 X 10(7) splenic nucleated cells from the other parental strain. The injection of 3 X 10(6) and 6 X 10(6) nucleated cells obtained from the spleen of these previously immunized rats to 21-day-old F1 hybrids induced a typical G.vs.H.r. The degree of the G.vs. H.r. was estimated 10 days after the injection of the parental cells by the splenic index (S.I.) and histological studies of the spleen. The administration of CLZ (30 mg/kg/day i.p. during 10 days) either to the donor or to the host inhibited the G. vs.H.r. The effect of CLZ was partially antagonized by the simultaneous administration of Bromocriptine (10 mg/kg/day i.p.) to F1 hybrids. An effect similar, although quantitatively smaller to that of CLZ was caused by the injection of Prolactin (Pro) 100 I.U./kg/day, i.p. to F1 hybrids. None of these drugs modified neither the lymphatic structure nor the S.I. of hybrids not inoculated with lymphoid cells. The rectification of the functions number of injected cells vs. S.I. allowed us to apply the statistical method of covariance to the different treatments used and to establish the degree of significance of the modifications produced by the drugs. In contrast to the profound inhibition of the G.vs.H.r. obtained when CLZ was administered to previously immunized donors, the effect of this drug was minor if the treatment was performed in nonimmunized donors. Splenic cells obtained from rats previously immunized with the other parental strain were incubated in vitro during two hours with different concentrations of CLZ (10(-6), 10(-5) and 10(-4) M) or Pro (15,30,50,75,100,200 and 500 ng/ml). This treatment did not modify the capacity of these cells to induce G.vs.H.r. when injected into F1 hybrids. We postulate that the inhibitory action of CLZ on the G.vs.H.reaction is mediated, at least in part, by the capacity of this drug to increase the plasmatic levels of PRO. The effect of CLZ and PRO is observed mainly in lymphoid clones in expansion because of the stimulation by histocompatibility antigens.

Toad (Bufo paracnemius) mast cell degranulation by compound 48/80 and by chlorpromazine: a non-lytic process.

Toad mast cells are degranulated by compound 48/80 and by chlorpromazine. The former was effective at rather high (100 micrograms/ml) and the latter at low (0.1 mM) concentrations. Toad mast cell degranulation induced by these drugs was characterized by cytoplasmic granule dissolution without cell lysis. The metabolic inhibitor, dinitrophenol, blocked the degranulation induced by both agents. Glucose reversed the inhibition of compound 48/80-induced degranulation. The results indicate that toad mast cell degranulation by compound 48/80 and by chlorpromazine is a non-lytic process.