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At least 217 records · Page 12Linked to original sources
PubMed1986

The effect of calmodulin antagonists on the activation of RAW-264 macrophage-like cells for tumor cell killing.

The effects of several calmodulin antagonists on the activation of RAW-264 macrophage-like cells for tumor cell killing were investigated. At concentrations ranging from 5 X 10(-8) to 5 X 10(-7) M, calmidazolium, trifluoperazine, chlorprothixene, chlorpromazine and W-13 inhibited the development of cytolytic activity, evoked in RAW-264 by treatment with lymphokine and lipopolysaccharide, in a dose-dependent manner. Since the order of the potency of these drugs against the activation of RAW-264 cells was much the same as their ability to inhibit calmodulin-dependent phosphodiestherase activity: calmidazolium greater than trifluoperazine greater than chlorprothixene greater than chlorpromazine greater than W-13, and because W-12, a nonactive analog of W-13, failed to inhibit the process of activation, we believe that the development of cytolytic activity in RAW-264 cells may be dependent on calmodulin. At micromolar concentrations, calmodulin antagonists (except calmidazolium) enhanced the process of activation. The enhancement of cytolytic activity was neither the result of the toxicity of these drugs nor related to their effects on intracellular calcium. It was entirely dependent on the presence of stimulants but occurred independently from the stage of macrophage activation, and most likely was due to the nonspecific interference of these agents with calmodulin-independent processes.

Animals↗
PubMed1993

Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists.

Conformational analyses have been performed on several phenothiazine and thioxanthene dopamine antagonists using the MM2-87 program and parameter set. The compounds that were examined are thioridazine (2), methotrimeprazine (3), cis- and trans-chlorprothixene, and a piperidylidene derivative of chlorprothixene. In addition, (+)-2 and (-)-3 were determined by X-ray crystallography to have the R absolute configuration. The above compounds were superimposed onto loxapine, which was used as a template for the previously proposed dopamine D2 receptor ligand model. The conformational properties and receptor affinities of these compounds were found to be entirely consistent with the ligand model. For example, a conformer of (+)-R-2 that is consistent with the ligand model is lower in energy than a consistent conformer for (-)-S-2, which agrees with the higher D2 receptor affinity of the former. Similarly, in agreement with the much higher affinity of (-)-R-3 relative to (+)-S-3, only the former contains a low energy conformer consistent with the ligand model. The ligand model is also consistent with the greater potency of cis-thioxanthenes over the trans isomers. These results emphasize the importance of the correct orientation of the ammonium hydrogen for high affinity at the D2 receptor. The pharmacophore for D2 receptor ligands is compared with a recently proposed pharmacophore for D1 ligands.

Antipsychotic Agents↗
PubMed1978

Neuroleptic blockade of the effect of various neurotransmitter substances.

The antagonistic effect of neuroleptics to acetylcholine, histamine, 5-HT, and noradrenaline was examined in various in vivo and in vitro models. Piflutixol, a new potent thioxanthene neuroleptic, markedly antagonizes the effect of dopamine, noradrenaline, 5-HT and to some extent histamine, whereas the affinity for muscarinic receptors was rather weak. Clozapine and chlorprothixene on the other hand, have high affinity for muscarinic receptors and also antagonize the effect of histamine and 5-HT, whereas clozapine was a weak antagonist of noradrenaline and dopamine when compared to the effect of piflutixol. Chlorprothixene, however, also exhibits a rather good antagonism of noradrenaline and dopamine. Haloperidol proved to be weak in all models when compared with the other neuroleptics examined. Flupenthixol specifically antagonizes dopamine and noradrenaline, whereas fluphenazine was a more potent antagonist of dopamine than of the other transmitters. The data show, that neuroleptic compounds possess very different profiles with regard to interaction with various neurotransmitter substances. It is suggested, that the rather potent anti 5-HT and antihistamine effects observed for certain substances may contribute to the central effect of these drugs.

Animals↗
PubMed1979

Differential antagonism of antiavoidance, cataleptic and ptotic effects of neuroleptics by biperiden.

The interaction between neuroleptics and an anticholinergic, biperiden, in the antiavoidance, catalepsy and ptosis tests was investigated in mice for the purpose of predicting the extrapyramidal side-effects of neuroleptics. The cataleptic effect of most neuroleptics used was antagonized to some extent by biperiden, while the ptotic effect was hardly influenced. The antiavoidance effect of haloperidol, trifluperidol and perphenazine was markedly antagonized and that of chlorpromazine moderately. However, the effect of thioridazine, chlorprothixene, levomepromazine and clozapine was little antagonized. In neuropharmacological tests, haloperidol, trifluperidol and perphenazine exhibited a selective antidopaminergic activity, while chlorprothixene, levomepromazine and clozapine showed antidopaminergic, antiadrenergic and also anticholinergic activities when similar doses were given. These results indicate that biperiden antagonism may be marked in the tests related to the extrapyramidal symptoms and in drugs liable to induce extrapyramidal side effects, however, there would be little or no antagonism in drugs possessing the anticholinergic property and eliciting few extrapyramidal side-effects.

Animals↗
PubMed1975

Rate-dependent Effects of drugs. II. effects of some major tranquilizers on multiple fixed-ratio, fixed-interval schedule performance.

The effects of promazine, chlorpromazine, triflupromazine, prochlorperazine, trifluoperazine, perphenazine, fluphenazine, haloperidol, benzquinamide, tetrabenazine and chlorprothixene were determined on the rate of conditioned key pecking of pigeons under a multiple fixed-ratio 30, fixed-interval 5-minute schedule of food presentation. Chlorpromazine, prochlorperazine, perphenazine, chlorprothixene and tetrabenazine decreased responding relatively more within the fixed-interval component than within the fixed-ratio component and also produced rate-dependent effects within the fixed interval component, increasing the low rates of responding early in the fixed-interval but decreasing the high rates of responding in the terminal parts of the fixed interval. Triflupromazine, trifluoperazine, fluphenazine and haloperidol also decreased responding relatively more within the fixed-interval component than within the fixed-ratio component, but did not produce rate-dependent effects within the fixed-interval component. Both low and high rates of responding within the fixed interval were decreased only by these four drugs and they produced small and inconsistent decreases in the quarter-life values. Promazine and benzquinamide decreased responding relatively more within the fixed-ratio component than within the fixed-interval component and also produced rate-dependent effects within the fixed-interval component. There was a structure-activity relationship between the chemical group on the benzene ring of the phenothiazine nucleus and the rate-dependent effect on responding within the fixed-interval component. Phenothiazines with a hydrogen or chlorine group on the benzene ring produced a rate-dependent effect on responding within the fixed interval, while phenothiazines with a trifluoromethyl group on the benzene ring did not produce a rate-dependent effect on responding within the fixed interval.

Animals↗
PubMed1964

A COMPARISON OF IMIPRAMINE, CHLORPROMAZINE AND RELATED DRUGS IN VARIOUS TESTS INVOLVING AUTONOMIC FUNCTIONS AND ANTAGONISM OF RESERPINE.

Seven structurally-related compounds consisting of three antidepressant drugs (imipramine, desmethylimipramine and amitriptyline), three tranquillizing agents (promazine, chlorpromazine and chlorprothixene) and a hybrid, desmethylpromazine, have been examined in a series of tests involving autonomic functions and antagonism of reserpine. Activities of the compounds in antagonizing reserpine-induced ptosis in rabbits and prolongation of alcohol hypnosis in mice give good correlation with their clinical actions, whilst their activities in augmenting excitation of rats by amphetamine and yohimbine toxicity in mice, and in reversing reserpine-induced bradycardia in rats offer further evidence for drug-induced sensitization to adrenergic or tryptaminic mechanisms, which is not however specific for antidepressant agents. No evidence has been obtained to indicate that a central parasympatholytic action is an important component of the antidepressant activity of imipramine and related drugs.

Alcoholic Intoxication↗
PubMed1996

MRI examination and monitoring of pediatric patients under sedation.

From April 1992 to May 1994, 780 patients aged from 1 day to 8 years were examined. Sedation of these patients was conducted by giving chlorprothixene orally and, in some cases, chloral hydrate had to be added. The patients were monitored with a pulse oxymeter. Investigations could begin after 50 -120 min. In 710 patients (91%) the first attempt to perform the examination was successful; 70 patients required one or two further attempts. Only two of the 780 patients (0.5%) showed evidence of respiratory depression. The total number of pediatric MRI examinations performed in 1 year is almost 1000. In the hands of an experienced pediatric radiologist these examinations can be performed entirely without anesthesia.

Child↗
PubMed1991

Role of calcium channels in effects of antidepressant drugs on responsiveness to pain.

The effect of acute and chronic treatment with three antidepressant drugs on the cortical L-type calcium channel (measured as [3H]nitrendipine binding sites) and on the responsiveness to pain (assessed in the hot-plate test) was tested on the Wistar rat. Acute administration of antidepressants did not affect the characteristics of calcium channels and did not significantly prolong the hot-plate latency. However, a combination of antidepressants with nifedipine brought about analgesia. Chronic administration of imipramine did not significantly affect the characteristics of calcium channels but produced a moderate analgesic effect. In contrast, chronic administration of citalopram and chlorprothixene increased the density of [3H]nitrendipine binding sites and induced hyperalgesia, which was nullified by acute administration of nifedipine. The results confirm that calcium channels may be involved in analgesia and hyperalgesia and indicate that chronic treatment with some antidepressant may induce an increase in the density of cortical calcium channels.

Animals↗
PubMed1983

Membrane effects of phenothiazines in yeasts. I. Stimulation of calcium and potassium fluxes.

Application of trifluoperazine (10-50 microM) to suspensions of the yeast Saccharomyces cerevisiae induces the following effects. (1) A marked increase in the initial rate of 45Ca2+ influx into the cells, accompanied by an increase in the cellular content of calcium. This stimulation in 45Ca2+ influx (10-20-fold) is observed only in the presence of a metabolic substrate and is completely inhibited by LaCl3. The dose-response curves of the cellular accumulation of 45Ca2+ are of a bell shape, indicating a biphasic response. The concentration of the drug yielding maximal accumulation depends on the density of the cells in the suspensions. The results indicate that the stimulation of 45Ca2+ influx is mediated by an energy-dependent carrier-mediated process and not by the increase in the passive membrane permeability to Ca2+. (2) Efflux of K+ from the cells is induced. Removal of metabolic substrate abolishes the effect at concentrations of up to 35 microM and reduces it at higher concentrations. Addition of high concentrations of cations (K+, Na+, Mg2+) to the medium abolishes the stimulation of both K+ efflux and Ca2+ influx. Chloropromazine, thioridazine and chlorprothixene display similar effects, but at higher concentrations. The results are discussed in terms of two possible alternative mechanisms; (1) calmodulin-independent effects of trifluoperazine on cell membranes, or (2) inhibition of some calmodulin-dependent processes by low concentrations of trifluoperazine.

Antipsychotic Agents↗
PubMed1979

The effect on sister-chromatid exchanges of drugs and dyes by intercalation and photoactivation.

Intercalating dyes (acridine orange, proflavin and methylene blue) and drugs (chlorpromazine, promazine and chlorprothixene) were tested for their ability to induce sister-chromatid exchanges (SCEs) with and without photoactivation by visible light. Whereas in the dark all substances tested increased the frequency of SCEs, a superimposed effect of visible light on SCE formation was observed for the acridines proflavin and acridine orange, but not for the pheneothiazine derivatives methylene blue and chlorpromazine. These results are discussed in connection with the known mutagenic effects of these substances and with the factors that may be involved in SCE formation induced by intercalating molecules in the absence and presence of visible light.

Acridines↗
PubMed1985

Antidepressants and endogenous opioid peptide systems.

The influence of antidepressants on the brain and pituitary content of immunoreactive beta-endorphin (ir-beta E) and dynorphin (ir-DYN) was studied in rats. Chronic administration of the first and second generation antidepressants imipramine, citalopram and rolipram, and of the antidepressant neuroleptics levomepromazine and chlorprothixene elevated the level of ir-beta E in the hypothalamus. Imipramine and levomepromazine also increased the level of ir-DYN in this tissue. Imipramine administered chronically potentiated stress-induced as well as morphine analgesia. The results obtained suggest that chronic antidepressants enhance the brain opioid system activity and increase the sensitivity of opiate receptors.

Animals↗
PubMed2002

Separation of cis- and trans-isomers of thioxanthene and dibenz[b,e]oxepin derivatives on calixarene- and resorcinarene-bonded high-performance liquid chromatography stationary phases.

The chromatographic behavior of six calix[n]arene phases (n=4, 6, 8) and one calix[4]resorcinarene phase is described for the separation of cis- and trans-isomers of three thioxanthene (flupentixol, clopenthixol, chlorprothixene) and one benz[b,e]oxepin derivative (doxepin). The influences of two different organic modifiers (MeOH, MeCN) for the separation of the isomers on every column are described. Different selectivities of the stationary phases exist as a function of the ring size of the calixarenes and their substitution at the "upper rim" with p-tert.-butyl groups. Furthermore, the influence of free phenol groups on the resorcinarene phase is discussed. Relations between structural elements of the analytes and the retention behavior on the stationary phases are found. The selectivity of the calixarene and resorcinarene stationary phases is compared with a RP-C18 phase containing the same base silica. Advantages of the resorcinarene as well as of the calixarene columns exist for the separation of cis- and trans-isomers of three compounds dependent from the substitution in position 2 of the thioxanthenes, respectively the kind of the basic side chain of all substances.

Calixarenes↗
PubMed1976

Novel analogs of tricyclic psychopharmacological agents.

The synthesis of several novel analogs of amitriptyline and chlorprothixene, in a number of which the position of the side-chain nitrogen atom rigidly fixed with respect to the tricyclic nucleus, is described. The compounds were evaluated for antidepressant-like activity in the Dopa and serotonin interaction tests and for potential antipsychotic activity in the methamphetamine interaction test. 5-(3-Dimethylaminocyclohex-1-enyl)-5H-dibenzo[a,d]cycloheptene (12) was about equipotent with imipramine in the Dopa and methamphetamine tests, and 3-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-spiro-6'-3'-methyl-3'-azabicyclo[3.1.0]hexane (23) also displayed marked activity in the same tests. Prototype compounds for other ring systems, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene tropane (16) and 5-(3-dimethylaminocycloheptylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (18), were less active.

Amitriptyline↗
PubMed1998

Combined treatment of schizophrenic psychoses with haloperidol and valproate.

In accordance with a previous study of adjuvant effects of the anticonvulsant carbamazepine (CBZ) on the neuroleptic treatment of schizophrenic psychoses, the effects of valproate (VPA) were tested in a randomly assigned double-blind, placebo-controlled study. Apart from a (statistically nonsignificant) psychopathological deterioration following discontinuation of VPA while on continuous neuroleptic mediation after four weeks and a statistically significant effect on "hostile belligerence", no overall therapeutic effects of the combination of haloperidol (HPD) with VPA were observed under controlled conditions. Unlike the results with CBZ, concomitant use of VPA led to an even higher consumption of haloperidol and biperiden and to a higher rate of extrapyramidal symptoms compared with the corresponding placebo group, although these differences did not attain statistical significance. In regard to use of the sedative neuroleptic chlorprothixene, there was a trend toward lower doses in the VPA group than in the placebo group. From these results, adjuvant effects like those of carbamazepine in the neuroleptic treatment of schizophrenic psychoses could not be confirmed for valproate in the present study. However, the trend toward lower doses of sedative medication and observed effects on "hostile belligerence" may indicate sedative and/or antimanic properties of valproate which have recently been demonstrated in several controlled studies.

Adult↗
PubMed1995

[Polytrauma and malignant neuroleptic syndrome. Case presentation with diagnostic problems].

The neuroleptic malignant syndrome (NMS) is a rare but potentially fatal reaction associated with neuroleptic drugs. The role of an acute reduction in brain dopamine activity in the development of NMS is commonly accepted as underlying pathogenesis. The diagnosis is maintained by the classic findings of extrapyramidal signs, hyperthermia and autonomic dysfunction. Treatment consists primarily of early recognition and discontinuation of triggering drugs. We report on a young patient with an acute paranoid schizophrenia who suffered a severe polytrauma due to a jump from 10 m height initiated by acoustic hallucinations. The patient received haloperidol for psychotic symptoms in a dose of up to 65 mg/d and chlorprothixene. NMS developed during the second week after the polytrauma. Discontinuation of neuroleptic therapy was followed by complete recovery. The report underlines problems of diagnosis due to the ambiguity of the diagnostic criteria of neuroleptic malignant syndrome in the presence of polytrauma.

Adult↗
PubMed1990

Anticonvulsants as adjuncts for the neuroleptic treatment of schizophrenic psychoses: a clinical study with beclamide.

A recent study showed an adjuvant effect of carbamazepine in the neuroleptic treatment of acute schizophrenic psychoses. Since beclamide (beta-chlorpropionamide) was reported to reduce the neuroleptic doses required, the combination haloperidol-beclamide was tested using a double-blind, placebo-controlled study in 23 inpatients with an acute schizophrenic psychosis. In both groups patients received haloperidol and either beclamide or placebo. Every 7 d the treating psychiatrist could increase the haloperidol dose by 3 mg per day if clinically necessary. Chlorprothixene and biperiden were on hand as additional medication. After 28 d beclamide or placebo were discontinued under a constant dose of haloperidol and a final rating with the Inpatient Multidimensional Rating Scale, Brief Psychiatric Rating Scale, and Extrapyramidal Symptom Scale was carried out. Without reaching statistical significance, the beclamide group needed a lower dose of neuroleptic medication, showed fewer side effects and a more pronounced psychopathological improvement.

Anticonvulsants↗