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PubMed1985

Effects of neuroleptics displaying antidepressant activity on behavior of rats in the forced swimming test.

Levomepromazine, thioridazine and cis-chlorprothixene, neuroleptics with antidepressant activity, trans-chlorprothixene, the therapeutically inactive isomer of chlorprothixene, clozapine, an atypical neuroleptic, and imipramine, a classical antidepressant, were studied in the forced swimming test in rats after single or chronic administration. Levomepromazine (1.5 mg/kg), clozapine (2.5 and 5.0 mg/kg) and imipramine (10 mg/kg) after single administration, 1 hr before the test, shortened the period of the immobility. After chronic administration only imipramine (10 mg/kg orally, twice daily, for 10 days) diminished the immobility. Levomepromazine, thioridazine, cis-chlorprothixene and trans-chlorprothixene (1.5 mg, orally, twice daily, for 10 days), 15-18 hr after the last dose did not influence the immobility, although the behavioral parameters in the open field test were not depressed. It is concluded that the forced swimming test is not a suitable pharmacological model for revealing antidepressant activities of certain neuroleptics that are useful in treating certain forms of human depression.

Animals↗

PubMed2002

Simultaneous LC determination of some antidepressants combined with neuroleptics.

A reversed-phase HPLC method with UV detection at 252 nm is presented for the simultaneous determination of some tricyclic antidepressants (amitriptyline, imipramine) and neuroleptics (chlorprothixene, thioridazine) in their quaternary mixtures. Sample analysis was performed on a bonded reversed phase C-18, 5 microm, 250 x 4.6 mm ID (Lichrospher 100RP-18) column using acetonitrile and 0.01 M aqueous solution of triethylamine (1:1) as the mobile phase at 0.9 ml/min. The pH was adjusted to 2.7 with concentrated phosphoric acid. The retention time was for imipramine, amitriptyline, chlorprothixene, and thioridazine 5.8, 6.5, 8.3, 10.8 min, respectively. The linearity was obeyed up to 15 ppm for imipramine and amitriptyline, 12 ppm for chlorprothixene and 10 ppm for thioridazine. The presented method also allows the determination of the mentioned drugs individually in their pharmaceutical preparations.

Amitriptyline↗

PubMed1989

[Significant CO2 retention in children after premedication with Dormicum and Thalamonal].

Whereas in adults the use of Innovar for premedication has been abolished, the combination of midazolam and Innovar is still recommended for the premedication of children. This combination may lead to an additional depressive effect on respiration. A prospective, randomized study was performed to evaluate the risk of ventilatory depression. In 36 infants capillary blood gas values were measured pre- and postmedication with either rectal midazolam (0.4 mg/kg) and i.m. Innovar (0.04 ml/kg) or after oral chlorprothixene (2.0 mg/kg). After chlorprothixen the blood gas values did not change, whereas after the combination of midazolam and Innovar pCO2 rose significantly from 35.5 to 43.0 mmHg. In 7 of 22 cases pCO2 reached values above 45 mmHg. This difference compared to the chlorprothixene group was significant (p less than 0.05). The pH fell significantly from 7.42 to 7.36 in the combination group. Clinical signs of respiratory depression could not be observed in this group. The combination of midazolam with Innovar is therefore not useful for premedication in infants and young children.

Analgesics↗

PubMed1979

Neurolepticlike actions of l-methadone: effect on mescaline-induced altered behavior and on tissue levels of mescaline in mice.

Mice were injected ip with either saline, l-methadone (2.5, 5, 20 mg/kg), perphenazine (1, 10, 15 mg/kg), or chlorprothixene (1.25, 2.5, 15 mg/kg) 30 min prior to mescaline-14C (25 mg/kg). Mescaline-induced behavioral changes such as agitation, excitement, slight increase in ventilation, and fright to sound stimuli were prevented by all doses of three drugs, and head-shaking, scratching, and locomotor-increasing effects by 5 and 20 mg/kg methadone and by all doses of both neuroleptics. Catalepticlike state and moderate to marked hypothermia induced by all doses of chlorprothixene, 10 and 15 mg/kg perphenazine, and 20 mg/kg methadone were not reversed by mescaline. Chlorprothixene (all doses), perphenazine (10, 15 mg/kg), and methadone (5, 20 mg/kg) caused marked retention of mescaline and its deaminated metabolite, 3, 4, 5-trimethoxyphenyl acetic acid in both brain and plasma. The fact that relatively higher doses of methadone than neuroleptics are needed to ensure effective antagonism to mescaline action tends to indicate a less specific interaction of the opiate with the neuroleptic/dopamine receptor proposed for central mescaline effects.

Animals↗

PubMed1984

[Comparative clinical studies on parenteral and oral premedication in childhood with special regard to the volume and acidity of the gastric juice].

90 children of age between 1 and 10 years who were scheduled for adenotomy were randomized into 3 premedication-groups. Group 1 received no premedication, group 2 chlorprothixene 1 mg/kg i.m. and group 3 chlorprothixene 2 mg/kg orally. Prior to induction of anaesthesia 63.3% of the unpremedicated children were anxious or crying, in contrast to 23.3% of the children given oral or i.m. premedication. With respect to the reaction on venepuncture with a Butterfly G 23, there was no significant difference between the groups. The volume of gastric acid (median values) was 0.056 ml/kg in group 1, 0.063 ml/kg in group 2, and 0.068 ml/kg in group 3, with a pH of 2.0, 1.5 and 2.0 respectively. One hour after operation 44.8% of the children in group 1, 92.6% in group 2 and 84.6% in group 3 were calm or sleeping. Premedication definitively improves the pre- and postoperative management of children. We now recommend oral chlorprothixene for the premedication of children because the effect of this oral premedication is equivalent to i.m. application, and the oral route has no influence on the quantity or acidity of gastric contents.

Adenoids↗

PubMed1981

Pre- and postsynaptic alpha-adrenoceptor antagonism by neuroleptics in vivo.

Different types of neuroleptics were studied for pre- and postsynaptic alpha-adrenoceptor antagonism in pithed rats using the blood pressure effect of clonidine as a measure of postsynaptic alpha-adrenoceptor activation and the depression of the heart rate response to electrical stimulation as a measure of presynaptic alpha-adrenoceptor activation. Yohimbine (0.1 mg/kg) was more active at pre- than postsynaptic alpha-adrenoceptors while the reverse was found with prazosin (0.02-5 mg/kg). Phentolamine (1-5 mg/kg) on the other hand was very active at both receptors. Cocaine 1-5 mg/kg had no effect on these responses indicating that noradrenaline uptake inhibition presumably does not interfere with the revaluation of the alpha-adrenoceptor antagonistic effect of the neuroleptics. Melperone, haloperidol, thioridazine and flupenthixol (0.15 mg/kg) were more selective antagonists at postsynaptic alpha-adrenoceptors than prazosin. Clozapine, chlorprothixene showed preferential presynaptic (0.15 mg/kg) were antagonists at both types of receptors. Chlorprothixene showed preferential presynaptic alpha-antagonism of high potency. Chlorprothixene was the only neuroleptic drug which like phentolamine (1-5 mg/kg) gave complete presynaptic alpha-antagonism. These results indicate widely different selectivity of neuroleptics for pre- and postsynaptic alpha-adrenoceptors on peripheral sympathetic nerves. It is suggested that neuroleptics with presynaptic alpha-adrenoceptor antagonism may enhance the activity of Beta-adrenergic systems indirectly both in peripheral organs like the heart, and within the central nervous system.

Adrenergic alpha-Antagonists↗

PubMed2000

Effect of some psychotropic drugs and a barbiturate on mycoplasmas.

The inhibitory effect of selected membrane stabilisers on Mycoplasma pneumoniae, M. hominis and Ureaplasma urealyticum was investigated in vitro. The phenothiazine chlorpromazine (CPZ) and the barbiturate thiopental (Leopental(R)) as well as the stereo-isomeric thioxanthene derivatives; cis(Z)-clopenthixol (Zu-clopenthixol(R))/ trans (E)-clopenthixol and cis (Z)-chlorprothixen (Truxal(R))/trans(E)-chlorprothixen, all have antimycoplasmal effect in the range 3.9-312 mg/l, measured as growth inhibition. It was also demonstrated that the enzymatic functions of the different mycoplasma strains, such as breakdown of glucose, arginine and urea, were abolished by concentrations of CPZ that were sufficiently low to allow multiplication of the organisms. A similar effect was obtained with Leopental(R) although the mycoplasmas were generally only half as sensitive to this drug. Also M. gallisepticum and Acholeplasma laidlawii were inhibited by CPZ and Thiopental. The four thioxanthenes were all inhibitory to mycoplasmal growth and the effect was independent of their stereo-isomeric configuration. The clopenthixol stereoisomers, but not the chlorprothixene isomers, inhibited colour change at concentrations lower than those which inhibited growth. While enzyme activity may continue for some time in vitro when classic antibiotics have inhibited mycoplasmal growth, the reverse effect was observed with phenothiazines and thioxanthenes. The membrane stabilisers may be useful tools in the investigation of microbiological activity on the mycoplasma membrane. From these drugs, new 'antibiotics' might be developed with another action than that of the known antimycoplasmal drugs.

Anti-Bacterial Agents↗

PubMed1991

Effect of selected neuroleptic agents and stereo-isomeric analogues on virus and eukaryotic cells.

Chlorpromazine, cis(Z)-chlorprothixene (Truxal), and the non-neuroleptic trans(E)-chlorprothixene and trans(E)-flupenthixol were studied in vitro for possible antiviral effect on Herpes simplex virus 2 and for toxic effect on human diploid fibroblasts. Based on an enzyme-linked immunosorbent assay (ELISA) antiviral activity was demonstrated for all the compounds in the concentration range 0.39 micrograms/ml-25 micrograms/ml. A cell-toxic effect was shown in the higher concentration range for all the compounds except cis(Z)-chlorprothixene. A cell-stimulatory effect was also detected at the lower concentration range (about 3.13 micrograms/ml) for all compounds. Thus both cell stimulation and antiviral effect can be found for the same agent within the same concentration range. The results point to the possibility of creating different antiviral drugs--which would also include a cell-stimulatory activity--among psychopharmacological drugs and their stereoisomeric analogues.

Antipsychotic Agents↗

PubMed1984

Phenothiazines and structurally related compounds as inhibitors of adenosylmethionine decarboxylase: effects on the purified enzyme.

The effects of chlorpromazine, imipramine, thioridazine, chlorprothixene, amitriptyline, desipramine and triflupromazine on adenosylmethionine decarboxylase purified from rat liver have been studied. The compounds caused competitive inhibition of the enzyme at 10(-5) - 10(-3) M concentrations. For chlorprothixene and triflupromazine the inhibition was linear, while the other drugs showed increasing, nonlinear inhibition at higher concentrations. Apparent Ki's for the compounds were between 6.8 X 10(-5) M (for chlorprothixene) and 6.4 X 10(-4) M (for desipramine). Inhibition of 50% under optimal assay conditions was achieved between drug concentrations of 1.3 X 10(-4) M (thioridazine) and 1.3 X 10(-3) M (imipramine).

Adenosylmethionine Decarboxylase↗

PubMed1964

GASTROINTESTINAL DISTURBANCES ASSOCIATED WITH WITHDRAWAL OF ATARACTIC DRUGS.

The psychological effects of abrupt withdrawal of ataractic drugs have been studied by others. Physical symptoms also occur under such circumstances and include abdominal pain, nausea and vomiting. Forty patients were divided into four groups of 10, each group receiving one of the following drugs: chlorpromazine, thioridazine, perphenazine or chlorprothixene. This medication was then suddenly withdrawn. In each of the chlorpromazine and thioridazine groups, three patients had gastrointestinal symptoms within 48 hours, lasting one to eight days. One patient on chlorprothixene, 450 mg. daily, experienced symptoms for six days. Perphenazine withdrawal produced no such symptoms. Thioridazine has little antiemetic action but perphenazine is prescribed for vomiting; hence it seems unlikely that the reported symptoms are due to a rebound action on the vomiting centre.These findings are relevant to the situation of withdrawal of ataractics prior to administration of anesthetics and to drug studies involving cross-over from an active compound to a placebo. The increasing use of ataractics suggests that this additional diagnostic possibility should be considered in the presence of obscure gastrointestinal symptoms.

Chlorpromazine↗

PubMed1986

Colorimetric determination of thioxanthenes with tetracyanoethylene.

A simple and rapid colorimetric method for the quantitative determination of the thioxanthene derivatives, chlorprothixene, tiotixene and metixene has been performed either in their pure form or in tablets. The procedure is based upon the formation of charge transfer complexes with the pi-acceptor tetracyanoethylene. The spectra of the complex show maxima at 415, 410 and 390 nm with a high apparent molar absorptivity which facilitates the determination of 5-100 micrograms X ml-1 of the studied compounds. The mean recoveries are 100.1 +/- 1.4%, 99.8 +/- 0.8% and 100.2 +/- 1.1% for chlorprothixene, tiotixene and metixene, respectively. This procedure is applied to determine these drugs in certain formulations and the results compare favourably to compendial methods.

Chlorprothixene↗

PubMed1985

Tetracyclic pyridazines as potential psychopharmacological agents.

Since the Z isomer of chlorprothixene (1) is far more active than its E counterpart, it was of interest to develop a stereoselective synthesis for this class of compounds. Insertion of a benzenesulfonamido group at the peri position of a chlorprothixene precursor did affect the stereochemistry of side-chain olefin formation, but after hydrolysis attempted removal of the resulting amine led to a Widman-Stoermer cyclization to afford the corresponding tetracyclic pyridazine-containing compound (4). Since this material displayed encouraging activity in neurotransmitter uptake inhibition studies, compounds in which the sulfur bridge was replaced with an ethano bridge similar to that found in imipramine (8) and with sulfur removed (7) were also prepared. These, together with the corresponding peri amino compounds (3, 5, and 6), were tested as neurotransmitter-uptake The two bridged arylamines 3 and 6 displayed potent and selective inhibition of norepinephrine uptake both when tested in vitro and after in vivo administration. The pyridazine-containing compounds exhibited reasonable activity in vitro, but the activity was lost when they were administered in vivo. None of the compounds displayed significant ability to interfere with spiroperidol binding.

Animals↗

PubMed1978

Relation of albinism and drugs to the visual evoked potential of the mouse.

The individual and combined influences of pentobarbital and chlorprothixene on the early components of the cortical visual evoked potential (VEP) were examined in the C57BL/6 mouse. Pentobarbital produced a large increase in latency, and chlorprothixene resulted in a smaller latency increase. When these agents were combined, their effects on the VEP latency were antagonistic. The effects of pentobarbital on VEP amplitude varied as a function of flash intensity, and this barbiturate anesthetic also produced qualitative VEP waveform changes. When the congenic albino (c/c) C57BL/6 was compared with the black (+/+) C57BL/6 mouse; pentobarbital anesthesia produced a decrease of latency with increasing stimulus intensity only in the c/c genotype, whereas VEP amplitudes were similarly affected by pentobarbital in both genotypes.

Albinism↗

PubMed1964

SOME ACTIONS OF CENTRALLY ACTIVE AND OTHER DRUGS ON THE TRANSMISSION OF SINGLE NERVE IMPULSES THROUGH THE ISOLATED SUPERIOR CERVICAL GANGLION PREPARATION OF THE RABBIT.

The effect of some centrally-active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis-isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a "facilitating" action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.

Action Potentials↗

PubMed1999

Effect of some psychotropic drugs on the activated macrophage-induced luminol-dependent chemiluminescence.

The effect of some psychotropic drugs on the activity of macrophages to produce superoxide radicals during phagocytosis was tested. Three-cyclic antidepressants, imipramine and amitriptyline, and the thioxanthene neuroleptic, chlorprothixene, were studied. The superoxide production was measured by luminol-dependent chemiluminescence. The drugs were investigated in the concentration range of 10(-7)-10(-4) mol/l. It was seen that all tested drugs caused a concentration-dependent decrease of the luminol-dependent chemiluminescence. The inhibitory effect of imipramine and amitriptyline on the macrophage superoxide production was moderate, while the effect of chlorprothixene was significantly stronger (a decrease more than 100 times that of macrophage chemiluminescence). Essentially, the luminol-dependent chemiluminescence reflects the level of superoxide radicals in the system. Therefore, the effect of drugs may be due to the possible activity for scavenging superoxide. In additional experiments with different systems of generations of O2- and different methods of registration, this possibility was discarded. Therefore, the effect of the drugs on the luminol-dependent chemiluminescence seems to be due to drug-induced decrease of the ability of activated macrophages to produce superoxide radicals.

Amitriptyline↗

PubMed1997

Phototoxic properties of neuroleptic drugs.

BACKGROUND: Photo-induced eruptions are well-known adverse effects of some neuroleptic drugs, particularly chlorpromazine. OBJECTIVE: By a photohemolysis test we assessed in vitro the phototoxic properties of 12 phenothiazines (chlorpromazine, dixyrazine, fluphenazine, levomepromazine, perazine, perphenazine, promazine, promethazine, prothipendyl, thioridazine, trifluoperazine, triflupromazine) and 5 thioxanthenes (chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol). METHODS: Human erythrocytes from 3 donors were incubated with the compounds and irradiated with light sources rich in UVA or UVB, respectively. Doses were up to 100 J/cm2 UVA or up to 1,600 mJ/cm2 UVB. Photo-induced hemolysis was calculated as percentage of complete hemolysis. RESULTS: Photo-induced hemolysis >10% due to radiation rich in UVA was found with chlorpromazine (maximal median: 98%), dixyrazine (100%), fluphenazine (84%), perazine (100%), perphenazine (100%), promazine (16%), promethazine (25%), prothipendyl (96%), trifluoperazine (100%), triflupromazine (76%), chlorprothixene (100%) and thiothixene (31%). UVB-rich radiation induced hemolysis only with chlorpromazine (73%), dixyrazine (45%) and perazine (60%). CONCLUSION: Most neuroleptics are strongly phototoxic in vitro indicating a potential risk for photo-induced reactions also to occur in patients treated with these drugs.

Antipsychotic Agents↗

PubMed2003

Separation of (Z)- and (E)-isomers of thioxanthene and dibenz[b,e]oxepin derivatives with calixarenes and resorcinarenes as additives in nonaqueous capillary electrophoresis.

Five acidic calix[4]arenes with carboxylic or sulfonic groups at either the upper or lower rim of the cavity and one resorc[4]arene were investigated to separate three thioxanthenes (flupentixol, clopenthixol, chlorprothixene) and a dibenz[b,e]oxepin derivative (doxepin) with cis-/trans-isomerism by nonaqueous capillary electrophoresis (NACE). Partial filling of the capillary with the UV-absorbing selectors led to a low detection limit and an advantageous signal-to-noise ratio (S/N). A sufficient electrophoretic mobility of the calixarenes towards the anode was necessary to outweigh the oppositely directed electroosmotic flow (EOF). This depended from the functional groups, the dissociation and the hydrodynamic radius of the cyclophanes. In contrast, the resorcinarene was useable only by addition of sodium dodecyl sulfate (SDS) because only the complex of the two selectors had an anodic apparent electrophoretic mobility. p-Sulfonyl-calix[4]arene (ss-a1) was the most capable selector for all E/Z-isomers with maximal alpha-values ranging from 1.056 for doxepin to 1.224 for chlorprothixene. This was due to the sufficient migration in reversed direction to the EOF even at low pH* values of 3.0. Otherwise, electrostatic as well as hydrophobic interactions with the positively charged isomers seem to contribute to a superior recognition. Increasing the concentration up to 15 mM ss-a1 and using acidic media (pH* 5.0) led to high separation efficiency. Changing the organic solvent provides a powerful tool to improve selectivity with N,N-dimethylformamide-methanol (DMF-MeOH)-mixtures for thioxanthenes. Further electrophoretic parameters were optimized, such as the concentration of the electrolytes, the addition of SDS, the kind of electrolytes and the voltage. Distinct differences in selectivities were found between the derivatives with thioxanthene and dibenzo[b,e]oxepin ring system, respectively. Further, the different basic side chain was responsible for the different selectivity at higher pH* values. In contrast, the substitution at position 2 of the thioxanthenes played a secondary role. Based on the studies of single parameters a method for a simultaneous separation of the four pairs of isomers within 13 min was developed.

Calixarenes↗

PubMed1976

Inhibition of conditional avoidance response by neuroleptics upon repeated administration.

Development of tolerance to neuroleptic compounds tested in the conditional avoidance model was investigated. Since tolerance may manifest itself by a diminished potency and/or a shortened duration of effect, the complete time course of effect was registered in these experiments. Rats were pretreated approximately 2 weeks with daily oral doses of chlorprothixene (20 mg/kg), flupenthixol (10 mg/kg), fluphenazine (2.5 mg/kg), or haloperidol (10 mg/kg) or twice a week with piflutixol (0.31 mg/kg). Three days after withdrawal chlorprothixene and flupenthixon caused a slightly but significantly weaker inhibition of avoidance performance in rats pretreated with the respective compounds and compared with non-pretreated rats, the duration of effect was shortened. Six dasy after withdrawal of piflutixol the duration of effect of a dose of piflutixol causing maximum inhibition was significantly shortened, while no homologous tolerance could be demonstrated in fluphenazine-pretreated rats. Cross tolerance was found after haloperidol-pretreatment when the rats were tested with fluphenazine 6 days after withdrawal. Homologous piflutixol tolerance could be shown 4 weeks after withdrawal. These results indicate that it is possible to demonstrate a slight tolerance to the effect of neuroleptic compounds when these are tested in conditional avoidance experiments. The cause of this tolerance is discussed.

Animals↗