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PubMedDate not supplied

Cis-flupentixol metabolites in rat plasma and bile. The first proof of glutathione conjugation at the exocyclic double bond.

The plasma and biliary metabolites of cis-flupentixol (cis-FPT) were studied after ip administration to rats. Cis-FPT sulfoxide was found to be the major phase-I metabolite in plasma and bile. Five biliary metabolites were isolated by gradient elution HPLC and characterized by various spectroscopic methods: F1, 1'-S-glutathionyl-10,1'-dihydroFPT sulfoxide; F2, cis-FPT sulfoxide sulfate; F3, 8-O-(or 7-O) glucuronyl-cis-FPT; F4, cis-FPT sulfoxide; and F5, cis-FPT glucuronide. A novel non-enzymatic addition of glutathione (GSH) onto the exocyclic double bond was demonstrated to occur for the first time with not only flupentixol and certain of its metabolites, but also with other psychotropic drugs with a tricyclic nucleus and an exocyclic double bond. Specifically, these nonenzymatic additions of GSH were observed with cis-FPT, trans-FPT, cis-FPT sulfoxide, cis-, trans-dealkylFPT, cis-FPT N-oxide, cis-chlorprothixene, cis-thiothixene, and cyclobenzaprine. Among them, cis-FPT sulfoxide showed the most potent adduct formation activity, and the product was characterized to be identical with the in vivo metabolite F1 of cis-FPT.

Animals↗
PubMed1990

[The effect of changing the association properties of psychopharmaceuticals in colloidal solutions on their liberation. 4. The effect of chemical structure as well as environmental conditions on the elevation of critical micelle formation concentration and reduction of micelle weight with hydrotropic material].

As shown by 8 different tri- and tetracyclic psychiatric drugs the authors demonstrated that the rate of desaggregation is markedly influenced by the chemical structure of drugs. In presence of 0.1 mol/l nicotinamide the cmc increased between 1.3 times for Maprotiline-HCl and 3.5 times for Chlorprothixene-HCl in acetate buffer pH 5.0; I = 0.154. Investigations about influences on the micellar weights showed for Flupenthixol-di HCl, Clomipramine-HCl and Melitracen-HCl decreases of 21.5, 16.1 and 14.0 per cent conferred by addition of 0.3 mol/l nicotinamide. There was a good correlation to the increase of the cmc. Different hydrotropic substances may show great differences of influence on the micellar weights and the cmc respectively. The micellar weight of Flupenthixoldi HCl for example reduces for about 17 per cent by concentrations of 0.2 mol/l nicotinamide or 1 mol/l propandiol-1.2, but the cmc increases to the 3.6- and 1.4fold value.

Chemistry, Pharmaceutical↗
PubMed1989

[Lithium in the prevention of affective disorders: 20 years' experience].

Long term preventive lithium administration results are referred to with the manifestation of a full effect in 23% affective illness-related patients. In 70% of patients, the occurrence of side-effects including those initial ones was stated in no but 40% patients in the course of long term lithium-prophylaxis. This fact testifies about the decrease in number of side-effects during the treatment with lithium. Most frequent side-effects were tremors and diarrhea. No serious renal complications were observed, except the onsets of tardive dyskinesis in on patient after the combined administration of chlorprothixene, amitriptyline and lithium. In three patients, the distant relapses were observed without discontinuation of therapy after the 10-year-lasted successful lithium-prophylaxis. In accord to the long term experience, the authors estimate 0.4 mmol/l lithemia level to be the minimal effective one. They believe the lithium is a reliable thymoprophylactic agent, though in accord with them the other substances with larger therapeutic spectrum are to be searched as well as predictors of an effective lithium-prophylaxis.

Affective Disorders, Psychotic↗
PubMed1988

Tardive dyskinesia. Pathophysiological mechanisms and clinical trials.

Recent observations from human and animal studies indicate that the traditional dopamine supersensitivity theory in tardive dyskinesia (TD) is insufficient. Instead, a new hypothesis is proposed: TD may be due to an increased D-1 receptor function or an increased ratio between D-1/D-2 receptor functions in the brain, maybe associated with a diminished activity in certain striatofugal GABA neurons. This hypothesis is based on experiments with selective D-1 and D-2 drugs in rodents and monkeys, but has not yet been tested clinically due to lack of D-1 agonists and antagonists for human use. In a Nordic multicenter study, various neuroleptics (haloperidol, perphenazine, chlorprothixene) were given to 33 elderly psychiatric patients with TD. The main result of this study was the demonstration of 1) an inverse relationship between parkinsonism and TD, and 2) an inconsistent response to withdrawal of various neuroleptics. Following withdrawal, 38% of the patients had a TD aggravation, 27% a TD reduction, and 35% no TD change, all compared with the TD level before the neuroleptic test period and independent of the neuroleptic given. This observation speaks against the dopamine hypersensitivity theory and is more in accordance with the new hypothesis proposed above. The GABA part of the TD hypothesis has been tested with different GABA agonists such as gamma-acetylenic GABA, gamma-vinyl GABA and THIP, but most studies suggest that the therapeutic effect of these drugs in TD is limited and maybe secondary to parkinsonism and sedation. Clinicians are eagerly awaiting new GABA agonists with selective affinity to subgroups of GABA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

[Induction of hepatic tyrosine transaminase in rats by phenothiazine derivatives and analogs].

We have showed induction of tyrosine-alpha-ketoglutarate transaminase in hepatic cytosol of Rats (Wistar strain) five hours after intraperitoneal administration of tricyclic compounds (phenothiazine, iminodibenzyl, thioxanthene, thiophenylpyridylamin, dibenzocycloheptadiene, dibenzoxepin derivatives). Chemical structure of these molecules is very important: sulfur atom (phenothiazine, thioxanthene), some substituants like chlorine (chlorpromazine, chlorprothixene) and 2'-dimethylaminopropyl chain (promethazine) increase this inductive effect.

Animals↗
PubMed1988

Antiplasmid activity of tricyclic compounds.

Three representative groups of tricyclic psychopharmacons were shown to have antiplasmid activity. The first group, e.g., comprises promazine, chlorpromazine, promethazine, levo- and dextromepromazine, thioridazine, diethazine, thiethylperazine. There are two heteroatoms (S and N) in the ring system of these compounds. In the second group, which includes desipramine, imipramine, however, there is only one heteroatom N, or S in chlorprothixene, chlorpenthixols and in the third group amitriptyline, maprotiline contain no heteroatoms. The medical significance of plasmid elimination by tricyclic psychopharmacons and related compounds in vitro is that this opens up a new perspective in the struggle against bacterial resistance to antibiotics. This approach utilizes the beneficial side-effect of the plasmid curing ability of these psychopharmacons, and may serve as a guideline for drug design in the future, to develop related substances which are potent in eliminating the drug resistance-carrying plasmids of bacteria, but which have no other pharmacological effects. Here we propose a new mechanism for plasmid curing by tricyclic drugs.

Antidepressive Agents, Tricyclic↗
PubMed1988

[Malignant hyperthermia in Austria. III. Anesthesia in susceptible patients].

Anesthesia in patients susceptible to malignant hyperthermia (MH) is generally considered to be very risky, although - with one notable exception - there are no prospective studies about anesthetic management in a large number of such patients. The prophylactic use of dantrolene has been recommended in MH patients, although there is no strong evidence supporting this - despite the fact that dantrolene may have serious side effects. We therefore decided to report the results of our own anesthetic technique for MH patients, as our technique does not include the prophylactic use of dantrolene. From 1981 to 1988, 19 operations on 16 MH-susceptible patients were performed. Patients 1-4 were pediatric survivors of an MH episode, where MH susceptibility was confirmed by muscle biopsy and in vitro contracture tests in at least one parent; patients 5-7 were survivors of an MH crisis, and they later underwent diagnostic muscle biopsies themselves; all other patients (nos. 8-16) were relatives of MH survivors with positive in vitro contracture tests. Diazepam, pentobarbital, pethidine, and chlorprothixene were used for premedication; no prophylactic dantrolene was given. Anesthesia was induced by thiopentone and was continued by nitrous oxide/oxygen, fentanyl, and droperidol; alcuronium, atracurium, and vecuronium were administered as necessary. Pyridostigmine, atropine, and naloxone were used if appropriate. New or disposable tubings were used for ventilation, and the vaporizers were removed from the anesthesia machines. ECG and body temperature were recorded in all patients; blood pressure was monitored invasively if indicated; end tidal CO2 was monitored whenever possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

The influence of neuroleptics on the behavioural effect of 5-hydroxytryptophan.

The antagonism of neuroleptics of various groups (chlorpromazine, chlorprothixene, clopenthixol, clozapine, flupenthixol, fluphenazine, haloperidol, levomepromazine, mepazine, perazine, perphenazine, pimozide, prochlorperazine, promazine, spiperone, thiopromazine, thioridazine, trifluperazine, trifluperidol, triflupromazine) towards L-5-hydroxytryptophan (5-HTP) was assessed on the basis of inhibition of characteristic head-twitches. ED50 was assayed in mice and rats. The results indicate that all investigated neuroleptics inhibit the action of 5-HTP and their ED50 values are, as a rule, lower than the values of ED50 for catalepsy. That action is for the majority of neuroleptics more pronounced in mice than in rats. The present paper disucsses possible serotonergic, dopaminergic and also noradrenergic mechanism of action of neuroleptics in the 5-HTP test.

5-Hydroxytryptophan↗
PubMed1978

Pharmacological studies on CS-430, a new psychotropic agent.

10-Bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one (CS-430) is a new psychotropic drug and has the following properties. The compound showed sleep-inducing effect at both 0.2 and 5 mg/kg (p.o.) in cynomolgus monkeys or at 3 mg/kg (p.o.) in rats. CS-430 showed selective conflict attenuating in rats or anticonvulsant effects in mice. Furthermore, CS-430 blocked non-discriminated (Sidman) avoidance response without severe impairment of the motor function but not discriminated (shuttle-box) avoidance response in rats. CS-430 also blocked selectively electroshock-induced fighting behavior of mice but not isolation-induced fighting behavior of mice and muricidal behavior induced by ablation of the olfactory bulbs. In addition, CS-430 produced specific potentiation of chlorprothixene-induced sleep and particular potentiation of thiopental sleep in mice. These effects of CS-430 were similar to those of nitrazepam, but differed from those of phenobarbital. The effect of CS-430 on the motor function was roughly 1/2 as potent as that of nitrazepam in the various tests.

Animals↗
PubMed1979

Elimination of F'lac plasmid by different psychotropic drugs and some related compounds.

Desipramine, trimipramine, protriptyline, noxiptyline, promazine, trimeprazine, triflupromazine and chlorprothixene methoiodide eliminated the F'lac plasmid of Escherichia coli, while thiazinanum, toluidine blue, lidocaine and procaine were ineffective in this respect. The plasmid eliminating action of the drug ceased in the presence of 0.05 M magnesium sulphate. Methylene blue did not inhibit plasmid elimination by the psychotropic drugs, and in presence of the dye even lidocaine and procaine became effective. Based on plasmid elimination in the presence of methylene blue and on the selective effects of the lon- mutant, the plasmid eliminating mechanism of psychotropic drugs seems to differ from that of acridine orange.

Animals↗
PubMed1980

In vitro antisecretory effects of trifluoperazine and other neuroleptics in rabbit and human small intestine.

The inhibitory effects of several neuroleptic agents on intestinal secretion were examined in vitro by measuring short-circuit current, net Cl flux, and cyclic nucleotide concentration, In rabbit ileal mu cosa, trifluoperazine (0.2-0.5 mM) did not significantly alter basal transport rates, but partially inhibited responses to the following secretagogues: theophylline, 8-Br-cAMP, VIP, dimethyl-PGE2 and heat-stable Escherichia coli enterotoxin (a cGMP agonist). Trifluoperazine completely inhibited the response to Ca ionophore A23187. In human small intestinal mucosa, trifluoperazine (0.1-0.5 mM) inhibited electrical responses to VIP and theophylline almost completely. The inhibitory action of trifluoperazine was manifest only on serosal addition. Trifluoperazine did not significantly alter cAMP or cGMP concentrations either under basal conditions or in the presence of secretagogues. It also did not diminish the electrical response to luminally added D-glucose. Three other neuroleptics were tested and found to have antisecretory action; the order of potencies were trifluoperazine greater than chlorpromazine greater than haloperidol greater chlorprothixene. Since all four agents are potent inhibitors of calcium-dependent regulator in bovine brain, this ubiquitous protein may also be the target for their antisecretory action in intestine.

16,16-Dimethylprostaglandin E2↗
PubMed1982

Assessment of alpha-2 adrenergic antagonists on the central nervous system using reticular contraction in sheep as a model.

In contrast to others species, the activity of ruminant forestomach (reticulum) is under the control of the central nervous system. Xylazine, a potent alpha-2 agonist, was shown to inhibit reticular activity. The potential usefulness of this physiological response to evaluate drugs acting on central adrenoreceptors was assessed. In conscious sheep, reticular activity was recorded either by electromyographic or manometric techniques. It was demonstrated that xylazine inhibited reticular contraction in a dose-dependent manner. This inhibition, which displayed limited intra- and intersubject variation, was related to a central action of xylazine because vagal stimulation was able to elicit reticular contraction. The so-called specific alpha-2 antagonists (tolazoline and yohimbine) or nonspecific (phentolamine) antagonists reduced xylazine inhibition. In contrast, the so-called alpha-1 antagonists (chlorpromazine, chlorprothixene, nicergoline, prazosin and thymoxamine) were without effect. Schild plots for the antagonists tolazoline and yohimbine in competition with xylazine were linear and had slopes that were not significantly different from unity, indicating competitive antagonism. These results suggest that reticular contractions, a discrete and periodic phenomenon of central origin easily recorded in conscious sheep, could be a useful physiological model to assess the effect of drugs on the adrenoreceptors of the central nervous system.

Adrenergic alpha-Antagonists↗
PubMed1984

[Pharmacological studies of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivatives (450191-S) (I). Behavioral analysis].

The behavioral effects of 450191-S and its metabolites were investigated in mice, rats, cats and rhesus monkeys, and they were compared with those of related benzodiazepines (BDZ) such as diazepam and nitrazepam. Oral administration of 450191-S consistently caused sedation without excitability in mice and rats, and it was only 1/2 to 1/266 as potent as the BDZ in producing motor incoordination as assessed by traction, rotarod performance and inclined screen tests in mice, induced much less ataxia in cats and monkeys, and inhibited respiration in anesthetized cats. The locomotor activities of mice and rats measured by Animex and the open field test were not affected by 450191-S, but rearing and preening decreased with 450191-S as with the BDZ. 450191-S was equipotent with nitrazepam and 2 to 6 times more potent than diazepam and estazolam in potentiating chlorprothixene-induced hypnosis and thiopental-Na-induced anesthesia. These effects were not different with successive 14-day administration of 450191-S. Anti-pentylenetetrazol, picrotoxin and bicuculline convulsions of 450191-S had the same potency as nitrazepam, but caused much less anti-electroshock convulsion than the BDZ. 450191-S had potent antianxiety activity as observed by anti-aggressive and anti-conflict activities and had almost the same effect as diazepam on operant behavior. The metabolites M-1, M-2, M-A and M-3 showed approximately the same potency as 450191-S in inducing anesthetic potentiation and antianxiety activity, but they were much more potent in causing disturbance of the somatic functions. These results indicate that 450191-S possesses inhibitory effects on the central nervous system, including a potent sleep-inducing effect, and is characterized by markedly weak muscle relaxant activity and motor incoordination.

Aggression↗
PubMed1980

[Psycopharmacological and general pharmacological studies of 7-chloro-1-cyclopropylmethyl-1, 3-dihydro-5-(2-fluorophenyl)-2H-1, 4-benzodiazepin-2-one (KB-509) (author's transl)].

KB-509, a new derivative of benzodiazepines, increased locomotor activities of mice in doses of 8-32 mg/kg (p.o.) and a decrease occurred with higher doses. This drug was 3-6 and 1-2 times more potent than diazepam (DZP) and nitrazepam (NZP), respectively, in anticonvulsant (anti-pentylenetetrazol, bemegride, strychnine) activities, antiaggressive activity and potentiation of chlorprothixene-induced hypnosis in mice. On the other hand, KB-509 possessed similar potency to DZP and NZP in muscle relaxant activity in mice and inhibition of flexor in cats, and was markedly weaker than DZP and NZP in causing a loss of righting reflex in mice. In the spontaneous EEG activity, KB-509 induced a drowsy pattern and slightly inhibited arousal response to EEG in rabbits, as did DZP. In particular, KB-509 was more potent than DZP in suppressing the amygdala afterdischarge and had a longer duration of action. KB-509 and DZP slightly depressed body temperature, the cardio-respiratory system and the gastrointestinal tract in high doses. Potentiation of spontaneous motility of the uterus and increase of urine excretion were also observed with high doses. In conclusion, KB-509 is superior to both DZP and NZP in the ratio of anticonvulsant and/or taming activities and muscle relaxant activity, and has a weak central depressant activity.

Animals↗
PubMed1997

Determination of fluoxetine in human plasma using reserved phase HPLC.

A rapid, simple, accurate method for the determination of fluoxetine in human plasma is presented. Liquid-liquid extraction of fluoxetine was carried out using diethyl ether. Chlorprothixene was applied as an internal standard. The samples were chromatographed on a LiChrosorb RP-18 (10 microns) column and the mobile phase was acetonitrile/phosphate buffer pH 2.70 (9:1). The detection was carried at 254 nm. A linear quantitative response curve was generated over a concentration range of 100-600 ng/ml. Overall extraction efficiency of the extraction procedure was found to be 86 to 91% with a correlation coefficient of 0.992.

Antidepressive Agents, Second-Generation↗