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PubMedDate not supplied

Metabolism and disposition of trifluoperazine in the rat. I. A thin-layer chromatographic method for the measurement of trifluoperazine and its metabolites in rat tissues.

A method has been developed for quantitative measurement of trifluoperazine and its metabolites, 7-hydroxytrifluoperazine and desmethyltrifluoperazine, in rat organs. Trifluoperazine sulfoxide could also be assayed, but it proved to represent a very minor part only of total biotransformation products in tissues. Alkalinized tissue homogenates were extracted with di-isopropyl ether. Following removal of the bulk of lipids, the compounds to be quantitated were separated by thin-layer chromatography and measured by ultraviolet reflectance photometry on the plates. In recovery experiments, the method proved to possess a high reproducibility. The sensitivity limit for quantitative determination was about 0.1 nmol per extract, and the limit of detectability was 0.025-0.05 nmol. The applicability of the method was shown by analyzing the tissues of rats that had received 12.3 micronmol of trifluoperazine, ip, per kg.

Animals↗

PubMed1978

Specificity of the binding of trifluoperazine to the calcium-dependent activator of phosphodiesterase and to a series of other calcium-binding proteins.

Trifluoperazine inhibits the activation of phosphodiesterase by binding to the calcium-dependent activator. To determine further the specificity by which trifluoperazine binds to activator, we compared the binding of trifluoperazine to activator prepared from several species and tissues and to a number of other calcium-binding proteins devoid of activator activity. Trifluoperazine binds to activator prepared from human, bovine, rat and rabbit brain and from chick embryo fibroblasts. In each case, the binding of trifluoperazine to activator was qualitatively similar and related quantitatively to the ability of the preparation to activate phosphodiesterase. Of the other calcium-binding proteins examined, namely, troponin-C, S-100 protein, phospholipase A, phospholipase B and myosin light chain, only troponin-C displayed any significant calcium-specific binding of trifluoperazine. The binding to troponin-C, however, appeared to be different from the binding to activator; whereas the binding of trifluoperazine to actovator showed no cooperativity, the binding to troponin-C showed positive cooperatively. These results and earlier data showing that trifluoperazine fails to bind to a variety of other proteins, indicate that the binding of trifluoperazine to the calcium-dependent activator of phosphodiesterase is selective and suggest that this binding may explain some of the biochemical and pharmacological actions of this antipsychotic agent.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1992

Blockade by trifluoperazine of a Ca(2+)-activated K+ channel in rat hippocampal pyramidal neurons.

The effects of trifluoperazine, a phenothiazine derivative, on the large-conductance Ca(2+)-activated K+ channel (BKCa) in dissociated rat hippocampal pyramidal neurons were examined using the inside-out configuration of the patch-clamp technique. The BKCa was activated by 12.6 microM Ca2+ on the internal surface of the membrane patch. The single channel conductance of the BKCa was 244 +/- 17.5 pS (n = 10) in symmetrical solutions of 150 mM K+. Trifluoperazine, applied on the internal surface of the membrane, decreased the open probability of the channel without changing the single channel conductance. The reduction in the open probability was well described by a block of the open state of the channel in a simple sequential model. The apparent dissociation constant (KD) for the reduction was calculated to be 1.4 microM and the Hill coefficient 0.69 at +20 mV. The inhibition was voltage dependent, being more pronounced at depolarized voltages. The voltage dependence enabled us to estimate that the binding site for the agent in the channel lies about half way across the membrane electrical field. It is concluded that trifluoperazine blocks the open state of the BKCa, which is known to provide an outward current for repolarization and afterhyperpolarization of the neuronal action potential. This may result in a decrease in spike intervals during burst firing of neurons.

Action Potentials↗

PubMed1992

Antitubercular activity of trifluoperazine, a calmodulin antagonist.

Trifluoperazine, a calmodulin antagonist, completely inhibited the growth of mycobacteria. The minimum inhibitory concentrations in shake cultures in a synthetic medium containing 0.2% Tween 80 were 5 and 8 micrograms/ml, respectively, for the human pathogenic strain Mycobacterium tuberculosis H37Rv and M. tuberculosis resistant to isoniazid. When added to a growing culture of M. tuberculosis H37Rv on the 10th day (mid exponential phase), trifluoperazine 50 micrograms/ml further arrested growth of this organism. It is suggested that trifluoperazine or similar calmodulin antagonists might be useful as antitubercular drugs.

Antitubercular Agents↗

PubMed1976

A double-blind comparison of loxapine succinate and trifluoperazine in newly admitted schizophrenic patients.

A study was conducted evaluating the efficacy of loxapine succinate in newly admitted schizophrenic patients through a four-week double-blind comparison with trifluoperazine. Twenty-four patients received between 40 and 80 mg loxapine succinate daily and 19 patients received between 20 and 50 mg trifluoperazine daily. The two groups showed comparable significant improvement on the BPRS and CGI. The discharge and termination rates of the two groups were not significantly different and the incidence and severity of side effects, most frequently extrapyramidal signs, were similar in both groups. Loxapine succinate was judged to be an effective treatment for newly admitted schizophrenic patients.

Adolescent↗

PubMed1979

Effects of trifluoperazine, chlorpromazine, and haloperidol upon temporal information processing by schizophrenic patients.

Healthy controls, unmedicated, actively symptomatic schizophrenics, and similar patients undergoing treatment with either trifluoperazine, chlorpromazine, or haloperidol were studied with tests of temporal discrimination and measures of transmitted information shown previously to be sensitive to various kinds of brain dysfunction, including haloperidol effects in a nonpsychotic population. Variations in psychophysical method, cognitive load, discrimination complexity, and sense-mode conditions permitted representative sampling of the temporal processing. Untreated, actively psychotic patients showed no impairment of temporal processing while all three antipsychotic medications were associated with significant deficit; trifluoperazine and haloperidol produced the most deficit, with chlorpromazine in the middle between the higher potency drugs on the one hand and unmedicated patients and healthy controls on the other.

Adult↗

PubMed1976

A double-blind comparative trial of loxapine and trifluoperazine in acute and chronic schizophrenic patients.

A double-blind comparative trial of loxapine and trifluoperazine was carried out in 57 acute and chronic schizophrenic patients. In both groups of patients loxapine proved to be equivalent in its effects to trifluoperazine and there were suggestions it might be rather more effective in chronic patients. Side-effects were similar with the two drugs but anticholinergic effects, excitement, dizziness and faintness occurred rather more commonly with loxapine. Laboratory tests, urine analysis, cardiovascular and ophthalmological investigations showed no significant abnormalities.

Acute Disease↗

PubMed1975

Absorption, distribution and excretion of trifluoperazine in rats.

In rats receiving a low oral dose (0.35 mg/kg p.o.) of trifluoperazine (TFP), a potent neuroleptic phenothiazine, the parent drug distribution was separate from that of its metabolite trifluoperazine sulfoxide (TFP-SO). This was not seen after intraperitoneal administration (i.p.) of the same or high dose (5mg/kg). TFP-SO was not detected in the brain, wheras TFP was significantly associated with microsomes when its brain level was highest. Absorption, distribution, metabolism, and dose dependent excretion procedded rapidly with 97% of a dose recovered 24 hr after p.o. treatment, only 6% in the urine and the remainder in feces with 87% of this metabolized to compounds other than TFP-SO. TFP and its metabolites arrived in feces via two pathways, largely the bile plus another route. The excretion pattern was unchanges with other drugs or after treatment for 3 wk, although excretion differed on the first day after i.p. and p.o. administration.

Animals↗

PubMed1975

A double-blind comparison of loxitane--loxapine succinate and trifluoperazine hydrochloride in chronic schizophrenic patients.

Therapeutic efficacy and safety of loxapine succinate (LOX) and trifluoperazine hydrochloride were compared by means of a controlled, double-blind study involving 49 chronic schizophrenic inpatients. The data indicated that LOX in dosages ranging from 40 - 65 mg/day, (usually administered on a b.i.d. schedule) had demonstrable anti-psychotic activity in 14 of 25 chronic schizophrenic patients (56%), while TFP treatment in appropriate dosage showed a similar activity in 9 of 23 patients (39%). Both LOX and TFP displayed essentially the same profile and incidence of side effects. Clinical laboratory abnormalities were minor. On the basis of this study, and in comparison with trifluoperazine, it appears that loxapine is an efficacious and essentially safe medication, suitable for the treatment of chronic schizophrenia.

Adult↗

PubMed1978

A twelve month comparison of penfluridol and trifluoperazine in chronic schizophrenic outpatients.

This investigation is a 52-week double-blind study comparing the efficacy and safety of penfluridol and trifluoperazine in 25 chronic schizophrenic outpatients. Penfluridol was administered once weekly and trifluoperazine daily. Measurements were made at baseline, various fixed intervals during the study period and termination. The data reveals that both agents were similarly effective in maintaining control of the symptoms of chronic schizophrenic patients at a level commensurate with or better than that provided by their previous medication. Besides being effective, medications were also well tolerated. The side effects were characteristic of marketed neuroleptics. Akathisia was more common with penfluridol but readily controlled with anti-parkinsonian medication. Other side effects were similar in severity and occurrence between study-drug groups. Both agents had low autonomic liability, and neither agent was depressogenic.

Adult↗

PubMed1977

Thiothixene and trifluoperazine in acutely disturbed schizophrenic patients.

In acutely disturbed newly admitted patients at Neuropsychiatric Unit, Karachi, the efficacy of thiothixene is not significantly different as compared to trifluoperazine. In trifluoperazine group also all the target symptoms improved while 'depressive mood' and 'suspiciousness' did not change significantly. In thiothixene group significant improvement was noticed on all the target symptoms except 'tension' and 'depressive mood'. The ethnic or genetic make up of the patient population was concluded to be the reason for non-effectiveness of thisthixene on effective psychopathology in acute schizophrenia. The extra-pyramidal side effects were clinically more pronounced in thiothixene group.

Acute Disease↗

PubMed1976

Electrochemical evidence for interaction between chlorpromazine hydrochloride and trifluoperazine hydrochloride and the flavin coenzymes.

Polarographic and chronopotentiometric methods were applied to study the effects of the phenothiazine tranquilizers chlorpromazine hydrochloride and trifluoperazine hydrochloride on the electrochemical behavior of the flavin coenzymes flavin mononucleotide and flavin adenine dinucleotide. The effects of the drugs were measured mainly by decreases in the diffusion currents, id, developed in the polarographic experiments and by a similar decrease in the chronopotentiometric constant, ior1/2, in the chronopotentiometric experiments when the coenzymes were reduced in the presence of the added drugs. The observed interference with the redox properties of the coenzymes could conceivably be related to the reported ability of the drugs to inhibit respiration and produce their tranquilizing effect.

Chlorpromazine↗

PubMed1992

Protective effect of trifluoperazine on the mitochondrial damage induced by Ca2+ plus prooxidants.

Isolated rat liver mitochondria undergo extensive swelling and disruption of membrane potential when they accumulate Ca2+ in the presence of a prooxidant such as diamide or t-butylhydroperoxide. The phenothiazinic drug trifluoperazine, at concentrations (15-35 microM) which do not inhibit respiration or the influx of Ca2+ into mitochondria, significantly protected mitochondria against the deleterious effects of Ca2+ plus a prooxidant. In contrast, at concentrations higher than 100 microM the drug potentiated these deleterious effects of Ca2+ and prooxidants and had a damaging effect per se on the inner mitochondrial membrane. It is proposed that the protection conferred by the drug is mediated by changes in membrane protein structure that decrease the production of protein thiol cross-linkings which occur when mitochondria accumulate calcium under oxidant stress conditions.

Animals↗

PubMed1992

Phenothiazines inhibit acetylcholinesterase by concentration-dependent-type kinetics. A study with trifluoperazine and perphenazine.

The properties of perphenazine (PPZ) and trifluoperazine (TFP) as fluorescent dyes were exploited to calculate their critical micellar concentrations. The relative fluorescence quantum yield of the two amphiphiles was dependent on their concentration, abruptly decreasing above 30-40 microM PPZ and 20-30 microM TFP. Evidence is presented that this phenomenon is driven by the formation of non-fluorescent drug aggregates. The type of inhibition kinetics displayed by PPZ and TFP on human erythrocyte acetylcholinesterase (AChE) was also dependent on drug concentration, turning from non-competitive to a "mixed" inhibition type at concentrations at which PPZ and TFP were demonstrated to undergo micelle formation. Results support the notion that phenothiazines may interact with AChE both as monomers and micellar aggregates, producing different inhibitory effects.

Acetylcholinesterase↗

PubMed1976

Effect of prolonged trifluoperazine, imipramine and haloperidol administration on serum cholesterol. An experimental study in rabbits.

As a result of prolonged intragastric administration of trifluoperazine (TFZ) and imipramine in rabbits, a significant rise in serum cholesterol was observed after 4, 8 and 12 weeks. Haloperidol was ineffective. Hypercholesterolemia produced by TFZ was not associated with increased estriol excretion in urine. Histochemical examination of aorta of TFZ-treated animals showed positive 'Schultz's reaction' for cholesterol, suggesting a possible causal relationship between TFZ-induced hypercholesterolemia and atherogenesis.

Animals↗

PubMed1978

Indications for the use of tranylcypromine and trifluoperazine (Parstelin).

Thirty-two patients were treated with the combination of tranylcypromine and trifluoperazine (Parstelin). The patients fell into 3 clinical groups, namely, endogenous depression (7 patients), neurotic depressive reaction (10 patients) and phobic anxiety with some depressive features (15 patients). Satisfactory response was found in 10 out of the 15 patients with phobic symptoms. The response in the other 2 groups was not significant. Side effects were troublesome in the neurotic depressive reaction group. In the phobic group the symptoms of the patients who responded were inclined to recur when the treatment was discontinued. It is considered that it is a useful preparation in the treatment of some phobic patients, but one must expect that the patients are likely to have to remain on the drug for long periods of time.

Adult↗

PubMed1978

Kinetics of [3H]trifluoperazine in bile fistula rats.

1. Anaesthetized male rats with a bile fistula received 12-3 micron mol/kg [9-3H]tri-fluoperazine into the tail vein, and the biliary excretion of total radioactivity, unchanged drug and phenolic glucuronides was followed for 8 h. 2. About half of the administered radioactivity apeared in bile within 8 h;80% of the biliary metabolites were unextractable even after beta-glucuronidasearylsulphatase hydrolysis; about 10% were glucuronides of 7-hydroxytrifluoperazine and its N-demethylated analogue; approx. 0-6% of the excreted radioactivity was unchanged drug. 3. A more rapid excretion, but a similar metabolite pattern, was observed when the drug was administered into the portal vein and bile was collected for 2 h. 4. Rats pre-treated with trifluoperazine per os for 3 weeks and then given the radioactive dose into the tail vein excreted increased quantities of the demethylated phenol glucuronide, while the other metabolities remained unchanged.

Animals↗

PubMedDate not supplied

Metabolism and disposition of trifluoperazine in the rat. II. Kinetics after oral and intravenous administration in acutely and chronically treated animals.

Male rats received 12.3 micronmol of trifluoperazine (CF3-PER) per kg orally or into the tail vein, and the kinetics of the drug and of its metabolites, 7-hydroxytrifluoperazine and desmethyltrifluoperazine, were followed from 0.5 to 8 hr after dosage. Brain, liver, lung, kidney, and plasma were analyzed by a thin-layer chromatographic method. Following iv injection, the levels of CF3-PER were much higher in brain, lung, kidney, and plasma obtained from the aorta than following oral administration, whereas the metabolite concentrations were very similar after administration by the two routes. However, CF3-PER concentrations in liver did not depend upon the route of administration. In conjunction with this fact, the poor availability of CF3-PER in the central compartment and extrahepatic tissues following oral dosage points to a pronounced first-pass effect. When CF3-PER plasma levels were measured in the portal vein of orally treated rats, the amount of drug absorbed unchanged from the intestine could be demonstrated to be 91% of the dose. A high liver extraction (about 80%) was demonstrated in vivo by sampling hepatic venous blood. Pretreatment of rats with SKF 525-A led to an impaired CF3-PER elimination and to an increase in the liver/plasma ratio. This showed that the liver extraction was due to rapid biotransformation. Orally dosed rats exhibited significantly higher levels of CF3-PER and of its demethylation product in brain, lung, and kidney when they had been pretreated for 3 weeks with 12.3 micronmol of CF3-PER per kg daily po. One and 4 hr after iv injection of 12.3 micronmol of 3H-CF3-PER per kg, total radioactivity in brain equalled the sum of the specifically analyzed compounds, whereas in lung and kidney the tritium quantity was up to 2-fold, and in liver and plasma up to 4-fold the sum of CF3-PER and its two main metabolites.

Administration, Oral↗