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PubMed1977

Effect of piflutixol on turnover of catecholamines in mouse brain and rat corpus striatum.

Dopamine metabolism in vivo was studied after treatment with piflutixol (6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene) a novel thioxanthene derivative with potent neuroleptic properties and sedative effects. In mice piflutixol increased both noradrenaline (NA) and dopamine (DA) turnover rate measured as increased disappearance of 14C-amines formed from 14C-L-tyrosine. The ratio between the minimal effective doses for 14C-NA and 14C-DA disappearance was 2, which is of the same order of magnitude as obtained with cis(Z)-chlorprothixene, pimozide and chlorpromazine. After 14C-L-tyrosine the accumulation of 14C-dopamine was initially increased after which it decreased from day 4--5. These changes resemble those obtained after other neuroleptics and parallel the initial receptor blockade and the subsequent receptor supersensitivity found in pharmacological experiments (MOLLER NIELSEN et al. 1977). Piflutixol induced a rapid increase in both DOPAC and HVA with a maximal effect after 2--6 hours. After 2--3 days the levels had returned to normal. The doses of piflutixol which at 24 hours doubled the levels of DOPAC and HVA were found to be 0.055 and 0.021 mg/kg subcutaneously, respectively. It is concluded that piflutixol is a powerful and long lasting DA receptor blocking agent, which changes the synthesis and release of DA in a way similar to basic neuroleptics.

Animals↗

PubMed1982

Pharmacological specificity of conditioned avoidance response inhibition in rats: inhibition by neuroleptics and correlation to dopamine receptor blockade.

The inhibitory effect of 36 neuroleptic compounds on conditioned avoidance response (CAR) and unconditioned escape response (UER) has been studied in rats. All neuroleptics antagonized CAR in doses below those inhibiting UER and below those inducing catalepsy. Stereospecificity was shown in two cases. Significant correlation was found between CAR inhibitory and cataleptogenic potency. Also inhibition of amphetamine induced stereotypy, affinity to 3H-haloperidol binding sites in vitro and clinical potency was significantly correlated to CAR inhibition. CAR and UER inhibition induced by cis(Z)-flupentixol and haloperidol was attenuated by scopolamine, but was only weakly influenced by methysergide and prazosin. Among a wide range of other CNS active compounds tested, CAR was inhibited by alpha 1-adrenergic antagonists, benzodiazepines, a barbiturate, GABA agonists, morphine and a serotonin agonist, but in doses inducing other motor disturbances. It is concluded that CAR inhibition is a sensitive test for dopamine receptor antagonists. However, additional alpha-adrenergic activity found for some neuroleptics (e.g. clozapine, chlorprothixene) may contribute to the CAR inhibitory potency. Additional antimuscarinic activity of neuroleptics may moderately attenuate CAR inhibition whereas serotonin receptor blockade is of minor importance.

Animals↗

PubMed1989

Trimipramine and other antipsychotics inhibit Campylobacter pylori in vitro.

A series of conventional anti-ulcer drugs, tricyclic antidepressants and neuroleptics (and some CNS non-active isomers) were tested in vitro for possible inhibition of Campylobacter pylori. These bacteria are claimed to play an etiological role in peptic ulcer disease, at least in gastritis B. While cimetidine, famotidine, ranitidine and pirenzepine were inactive, all the antipsychotic agents and their isomeric derivatives were active to various degrees with IC50 of 26-59 microM. Of special interest is trimipramine (Surmontil) that has been demonstrated to be effective against duodenal ulcers in some trials. The activity of the non-neuroleptic stereo-isomers of clopenthixol and chlorprothixene may lead to investigation in patients with peptic ulcer disease of this kind of agents. However, a firm connection between the antimicrobial activity of these compounds, their possible anti-ulcer effect and the etiological role of Campylobacter pylori in peptic ulcer disease must first be established.

Anti-Ulcer Agents↗

PubMed1986

The antibacterial effect of selected phenothiazines and thioxanthenes on slow-growing mycobacteria.

The aim of the present investigation was to illustrate the antibacterial effect of various phenothiazine and thioxanthene derivatives on mycobacteria in vitro. It was demonstrated that clopenthixol is about twice as potent as chlorpromazine (CPZ) and levomepromazine-maleate is about half as potent as CPZ, measured by the inhibitory effect on the growth of the mycobacterial strains. Measured in the same way the stereoisomeric compounds of flupenthixol are shown to be more potent than the stereo-isomeric compounds of clopenthixol and chlorprothixen. The two last-named compounds are equal in potency. The stereo-isomeric analogs of the thioxanthene derivatives are equal in antibacterial potency against the slow-growing mycobacteria. The mycobacterial strains investigated show no difference in sensitivity between the cis (Z)--and and trans (E)--compounds of the thioxanthenes. It seems particularly promising that also the more resistant mycobacteria other than Mycobacterium tuberculosis, e.g. M. avium and M. intracellulare, are sensitive in the concentration range investigated. Considered as a whole, these results might be a stimulus to investigate the antimicrobial effect of the thioxanthenes in vivo.

Anti-Bacterial Agents↗

PubMed2006

Searching for new antimalarial therapeutics amongst known drugs.

The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high-throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.

Animals↗

PubMed1977

The interaction between clonidine and various neuroleptic agents and some benzodiazepine tranquillizers.

The central hypotensive action of clonidine, infused into the vertebral artery of chloralose-anaesthetized cats was antagonized by several phenothiazine-neuroleptics (chlorpromazine, promazine, promethazine, thiethylperazine, thioridazine), by chlorprothixene and to a limited extent by haloperidol administered via the same route. Pimozide and some benzodiazepines (chlordiazepoxide, diazepam and flurazepam) hardly influenced the central hypotensive response to clonidine. The antagonism between clonidine and the psychotropic drugs is probably associated with central alpha-adrenoceptors, clonidine being the agonist and the neuroleptic agents the antagonists at these receptors. Virtually the same type of antagonism was observed in conscious, spontaneously hypertensive rats where both clonidine and the neuroleptic drugs were injected intravenously. The phenothiazines and also piperoxane effectively diminished the centrally induced hypotensive response to clonidine, whereas the initial pressor effect to clonidine was not reduced.

Anesthesia↗

PubMed1979

A high performance liquid chromatographic assay of cis- and trans- isomers of tricyclic neuroleptic drugs.

Tricyclic neuroleptics based upon the thioxanthene nucleus exhibit geometrical isomerism and the major pharmacological activity resides in the Z-component. An h.p.l.c. procedure which enables the separation detection and quantification of these isomers is described. The method is applicable to the analysis of flupenthixol, clopenthixol, chlorprothixene, doxepin and dothiepin. Measurement of the isomer-ratios in various samples of flupenthixol has shown that small batch to batch variations are apparent. The determination of the isomer-ratio in formulations has been shown to rely upon the complete extraction of the medicament. This is due to the differential release of the components from the tablet matrix with the cis-isomer being favoured. There is little difference observed between the adsorption isotherms of the two components (onto charcoal) but in competition experiments differential adsorption may be demonstrated. This has clear implications for the pharmacokinetics of these drugs.

Antipsychotic Agents↗

PubMed1980

The photochemical stability of cis- and trans-isomers of tricyclic neuroleptic drugs.

The irradiation of the tranquillizers flupenthixol, clopenthixol and chlorprothixene has been found to induce rapid cis-trans isomerization. The composition of the photosatitionary mixture is not that of the batch drug and hence this process may affect the activity. Further decomposition to a thioxanthone derivative occurs rapidly in the presence of air. Exclusion of oxygen, however, does not prevent further degradation and a slower secondary isomerization is observed on prolonged irradiation. Doxepin and dothiepin also undergo analogous reactions but the isomerizations are much slower and the oxidative degradation yields many products.

Antidepressive Agents, Tricyclic↗

PubMed1981

Stimulus-secretion coupling in exocrine pancreas; possible role of calmodulin.

Many calcium-mediated effects in mammalian cells may be activated by calcium-calmodulin stimulated enzymes. These effects are inhibited by various antidepressant drugs which bind to and inactivate calmodulin. In the current study, calmodulin was identified by affinity chromatography and gel electrophoresis in the cytoplasm of dispersed rat pancreatic acinar cells. Its role in enzyme secretion was assessed by evaluating the effects of various antidepressants drugs on the enzyme secretory process. Chlorpromazine, trifluoperazine, thioridazine, chlorprothixene and amitriptyline inhibited amylase secretion stimulated by carbachol, A-23187, and cholecystokinin-pancreozymin but not that elicited by dibutyryl cyclic AMP secretin or vasoactive intestinal peptide (VIP). Haloperidol, sulpiride, phenobarbital, and ethanol were without effect on secretagogue-stimulated enzyme release. Only those agents which blocked secretion also inhibited 45Ca release stimulated by carbachol from isotope preloaded cells. The data suggest that calmodulin may have a functional role in pancreatic enzyme secretion.

Amylases↗

PubMed1981

Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents.

Antipsychotic agents which are considered to depressive to the central nervous system (CNS) but free of dependence liability were used in combination with barbiturates or tranquilizers to study the physical dependence liability in the so-enhanced CNS depression. In the study of physical dependence formation, when CNS depression was maintained in an enhanced stage during the continuous application of the drug combinations, the withdrawal convulsions were enhanced in both frequency and severity. In the crossphysical dependence study, two-drug combinations, i.e., phenobarbital (PhB)-chloropromazine (CPZ), PhB-diphenhydramine (DPH) and nitrazepam-chlorprothixene, and 3-drug combinations (i.e., PhB-CPZ-promethazine and PhB-CPZ-DPH were evaluated. The 2-drug combinations suppressed some of the withdrawal signs, but those at high dosages showed a tendency to aggravate the signs. The 3-drug combinations differed from the 2-drug combinations in that the suppression of withdrawal signs was synergistically enhanced and the barbital withdrawal signs were weak. In conclusion, when CNS depression with PhB was enhanced with combinations of dependence liability-free drugs the drug combinations enhanced withdrawal convulsions both in frequency and severity. The sedation enhanced by the combinations did not always parallel the suppression of barbital withdrawal.

Animals↗

PubMed1984

Studies on the muscle relaxation effects of ethyl loflazepate (CM6912) and evaluation as an anti-anxiety drug.

A new anti-anxiety drug, CM6912 (ethyl loflazepate, ethyl 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepine-3- carboxylate), was investigated for its effects on the alpha- and gamma-motor systems and on the cooperative muscular motions and for its interactions with other CNS drugs. The results obtained are as follows: Muscular discharges (EMG) induced by decerebrate rigidity were unaffected by 10 mg/kg (p.o.) of CM6912, but the amplitudes of the EMG were reduced by 50% for 3 hr by 30 mg/kg of CM6912 at 30 min after administration. Diazepam (10 mg/kg) also decreased the amplitudes of the EMG even at 5 min after administration, indicating that diazepam had a stronger than CM6912. Both monosynaptic spinal reflex (MSR) and polysynaptic spinal reflex (PSR) were unaffected by CM6912 (100 mg/kg). Dorsal root reflex potential was slightly enhanced by CM6912 (100 mg/kg), but not at a dose of 30 mg/kg. Diazepam (10 mg/kg) did not decrease MSR, but slightly reduced PSR. Dorsal root reflex potential was almost doubled by diazepam. The frequency of spontaneous discharges of Gla spindle afferent fiber of the extensor muscle of the hindlimb of anesthetized cats was unchanged by 10 mg/kg CM6912, but was suppressed by diazepam at the same dose while at a dose of 30 mg/kg, it was reduced mildly by CM6912, and markedly by diazepam. ED50 values for the antagonistic action on bemegride-induced convulsions were 0.30 mg/kg for CM6912 and 0.49 mg/kg for diazepam at 1 hr after administration, and they were 0.30 mg/kg and 0.67 mg/kg for CM6912 and diazepam, respectively, at 4 hr. The potentiating action of CM6912 on chlorprothixene-induced anesthesia was far weaker than that of diazepam. The suppressive potency of CM6912 on the adaptability to the rotarod was about half that of diazepam, and the muscle relaxant action of CM6912, examined by the inclined board test and the hanging test, was found to be similar to that of diazepam. These results suggest that CM6912 is less potent than diazepam in reducing muscular tone and in inducing sleep, while it has a stronger and longer-lasting anti-anxietic activity than diazepam.

Adaptation, Psychological↗

PubMedDate not supplied

Effect of some psychotropic drugs on luminol-dependent chemiluminescence induced by O2-, *OH, HOCl.

We studied antioxidant activity of six neuroleptics (chlorpromazine, levomepromazine, promethazine, trifluoperazine and thioridazine) and two antidepressants (imipramine and amitriptyline) in the range of concentration of 10(-7)-10(-4) M. We applied luminol-dependent chemiluminescence to test the ability of these drugs to scavenge the biologically relevant oxygen-derived species: hydroxyl radical, superoxide radical, hypochlorous acid in vitro. We found that the phenothiazines were powerful scavengers of hydroxyl and superoxide radicals. Chlorprothixene, amitriptyline and imipramine had no scavenge activity to the superoxide radical. All drugs showed a moderate scavenger effect on hypochloric anion.

Antidepressive Agents↗

PubMed1975

The toxicity of thioxanthene neuroleptics to isolated rat liver cells.

A series of thioxanthenes was tested for cytotoxicity to isolated rat hepatocytes, as measured by the loss of an intracellular enzyme (GOT) to the surrounding medium. The relative order of potency was found to be: SKF 10812 greater than cis- = trans-chlorprothixene = N-756A greater than cis- = trans-flupenthixol greater than xanthiol greater than methixene = cis- = trans-clopenthixol = N-716 greater than N-710. The presence of an unsaturated exocyclic bond increased the apparent toxicity as did the presence of a substituent (trifluoromethyl, chlorine, bromine) at the two position of the tricyclic nucleus. The trifluoromethyl substituted thioxanthenes were three to four times more potent than their halogenated analogs, but there were no differences in potency among the halogenated (chlorine or bromine) thioxanthenes. Compounds which had a dimethylaminopropylidene side chain were five to six times stronger in causing enzyme leakage than were their analog which had a hydroxyethylpiperazinylpropylidene side chain. Although only the cis-isomers of each compound are highly active neuroleptics, both isomers were equipotent at causing the efflux of GOT from rat hepatocytes.

Animals↗

PubMedDate not supplied

[Influence of antidepressants on the convulsive action of corazole and strychnine].

The influence of 10 antidepressants on an experimentally induced convulsive syndrome in mice was studied. It was found that, as concerns their ability to have an effect on DL50 of metrasol, the depressants may be classified into drugs protecting mice against the action of metrasol (melipramine, amitryptiline, chlorprothixen and phthoracizine), those potentiating the effect of metrasol (insidon, phrenolon, iproniazide, nuredal) and drugs producing no essential effect on DL50 of metrasol (desipramine, sonapax). All of the above drugs had an effect of decreasing the mean lethal dose of strychnine.

Animals↗

PubMed1976

Classification of psychoactive drugs by visually evoked potentials in rabbits by means of multiple discriminant analysis. A possible way of predicting the clinical efficacy of new psychoactive drugs.

The influence of representatives of various groups of antipsychotic drugs on the visually evoked potential (EP) was investigated with the aid of a modified recording and evaluation technique for the rabbit EEG from cortical and subcortical structures. The starting point was the hypothesis that changes in the EP in animal experiments caused by representative members of these "substance groups" (neuroleptics with predominantly antipsychotic or predominantly sedative effect, and antidepressants with predominantly mood-brightening or predominantly sedative main components) make predictions of the clinical efficacy of "unknown" substances possible on the basis of clinical therapeutic principles of classification. Experiments were carried out with haloperidol and fluphenazine, chlorpromazine, amitriptyline and doxepin, and with imipramine and clomipramine, as representatives of these classes of substances. The hypothesis was checked by attempts to assign amitriptyline and chlorprothixene in varying dosage, haloperidol, benzperidol and mianserine to appropriate classes. As classification and assignment procedure we used stepwise multiple discriminant analysis (SWDA) according to our modification of the BMD 0 7 M Program. The purpose of the latter program, and its applicability to our studies, are described and discussed. It was found 1. that with EP data from animal experiments it is possible to classify various groups of psychoactive drugs on the basis of clinical therapeutic findings, using SWDA; 2. that assignment of "unknown" compounds can be based on this classification; 3. that hence with some caution predictions of the clinical effect of newly developed substances may be made on the basis of findings in animal experiments. The EP variables which contain most information for making up the separation formula and hence are of special importance, are investigated with respect to their possible neurophysiological evidential value, and their significance is discussed. It was found that the EP from the visual cortex are of particular significance for the separation of groups in the form presented here.

Animals↗

PubMed1997

[A systematic screening and identification method for 29 central nervous system drugs in body fluid by high performance capillary electrophoresis].

A systematic screening method has been developed for the detection of 29 central nervous system (CNS) drugs in human plasma, urine and gastric juice by high performance capillary electrophoresis (HPCE). The first step is sample preparation. The patient's or normal human plasma (0.5 ml) spiked with CNS drugs was extracted with 2 x 4 ml dichloromethane, while 2 ml of patient's or spiked urine was extracted with 2 x 6 ml chloroform. The combined extract from plasma or urine was evaporated to dryness in a rotation evaporator at 35 degrees C. The residue was dissolved in 100 microliters methanol and subsequently 400 microliters of redistilled water was added. The patient gastric juice (3 ml) was centrifuged at 2,000 r.min-1 for 5 min. The supernatant was filtered through 0.45 micron microporous membrane for injection onto capillary columns. The second step was to perform CZE separation in acidic buffer composed of 30 mmol.L-1(NH4)3PO4(pH 2.50) and 10% acetonitrile (condition A). Most of the benzodiazepines (diazepam, nitrazepam, chlordiazepoxide, flurazepam, extazolam, alprazolam) and methaqualone were baseline separated and detected at 5-13 min, while thiodiphenylamines showed group peaks at 3-5 min and barbiturates migrate with electroosmotic fluid (EOF) together. The third step is to separate the drugs in basic buffer constituted of 70 mmol.L-1 Na2HPO4(pH 8.60) and 30% acetonitrile (condition B). The thiodiphenylamines and some other basic drugs could be well separated, which include thihexyphenidyl, imipramine, amitriptyline, diphenhydramine, chlorpromazine, doxepin, chlorprothixene, promethazine and flurazepam, while the rest of the CNS drugs did not interfere with the separation. The last step was to separate the drugs by micellar electrokinetic chromatography (MEKC) in such a buffer as 70 mmol.L-1 SDS plus 15 mmol.L-1 Na2HPO4 (pH 7.55) and 5% methanol (condition C). Barbiturates (barbital, phenobarbital, methylphenobarbital, amobarbital, thiopental, pentobarbital, secobarbital) and some hydrophobic drugs (glutethimide, alprazolam, clonazepam, carbamazepine, trifluoperazine, oxazepam) could be well separated. These drugs might be identified by both the relative migration time (rtm = tdrug/tEOF) and the ratios of peak heights (rh) monitored at different wavelength, since the ratios are characteristic of the spectrum of a drug. This method has been used in several real clinical samples of intoxication. For example, perphenazine and doxepin were detected in the gastric juice and phenobarbital in blood and gastric juice of an intoxicated patient.

Central Nervous System Agents↗

PubMed1992

A spin probe study of the effects of chlorpromazine and its derivatives on lipid-protein interactions in synaptosomal membranes.

The electron spin resonance spectra of 16-doxyl stearic acid (16-SA) incorporated into synaptosomes mostly showed a fluid lipid component and a minor motionally-restricted component (MRC) of the molar fraction of 10-20%, measured at 0 degree C. At 10 mmol/l concentration, thioridazine (TRZ), chlorpromazine (CPZ), chlorprothixene (CPT), perphenazine (PFZ) and levopromazine (LPZ) raised the MRC molar fraction in the synaptosomes to 100, 92, 65, 41 and 39%, respectively (as detected by the spin probe at 0 degrees C). At 4% concentration, TRZ, CPZ, CPT, PFZ, and LPZ the respective MRC percentages were 100, 75, 41, 24 and 17%. In synaptosomal membranes, AMRC splitting values of MRC, induced by TRZ and CPZ, were similar to those of the probe in human serum albumin. MRC induced by CPZ and TRZ was constant (+/- 15%) within the temperature range from 0 to 30 degrees C. At drug/lipid ratios > or = 2 : 1, TRZ and CPZ formed rigid complexes with total lipids isolated from the rat brain. The complexes melted upon increasing the temperature of the samples over 10-20 degrees C. The drugs decreased the lipid concentrations in synaptosomes in the order of potency TRZ > CPZ > CPT > PFZ > or = LPZ; this was similar to their effect on MRC increase. The drugs tested increased the membrane dynamics/disordering, and their potency fairly correlated with their MRC increasing effects. It is supposed that the drug-induced 16-SA probe MRC increase in synaptosomes was a result of mainly decreased lipid/protein ratio in the synaptosomal membranes, which in turn probably is connected with perturbation of lipid-protein interactions and/or membrane proteins. The perturbation of lipid-protein interactions and/or membrane proteins may be connected with the drug perturbation effect on the bulk lipid membrane part.

Animals↗

PubMed1992

[Toxic polyneuropathies].

Toxic factors may have damaging effects on the peripheral nerves at different sites: on the axon, on the myelin sheath, on the cell bodies and on the vasa nervorum. The toxic neuropathies can be divided up into polyneuropathies induced by drugs, by industrial, environmental and stimulant poisons. Mostly symmetrical sensory symptoms and signs are the first disturbances, often followed by symmetrical motor pareses. Some polyneuropathies induced by amiodarone, benzene, lead, cimetidine, chloroquine, dapsone, gentamycin, gold, imipramine, hexacarbons, nialamide, penicillin, triorthocresylphosphate and vincristine are primarily dominated by motory losses. Polyneuropathies induced by amitriptyline, ethylene, oxide, lead, chlorprothixene, heroin, hydralazine, methaqualone, nialamide and penicillin show an asymmetrical distribution pattern of the neural losses. In some types of toxic polyneuropathies the cranial nerves and the autonomic nerves are particularly involved. The clinical symptomatology of the most important types of toxic neuropathies are described shortly. The best therapy is, of course, termination of exposure to the toxic substance concerned.

Diagnosis, Differential↗