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PubMed1982

Serum concentration and protein binding of thioridazine and its metabolites in patients with chronic alcoholism.

The blood chemistry and clinical pharmacokinetics of thioridazine and its metabolites, side-chain sulphoxide, side-chain sulphone and ring sulphoxide, were studied in 31 alcoholics and were compared with values in 17 thioridazine-treated controls without alcoholism. Pathological blood chemistry values, including abnormal liver function and protein concentrations, were common among the alcoholics. In relation to dosage, the majority had a low serum concentration of thioridazine and at a given concentration of thioridazine they had high serum concentrations of its metabolites. Positive intercorrelations were found between pathological liver function tests, prolonged serum half-life and increased serum concentration of thioridazine. The free fractions of thioridazine, side-chain sulphoxide and ring sulphoxide were significantly higher and those of the side-chain sulphone lower in the alcoholics than in the controls. The free fractions of side-chain and ring sulphoxide were significantly increased in patients with a low concentration of alpha 1-acid glycoprotein.

Adult↗
PubMed2000

Psychomotor effects of zaleplon and thioridazine coadministration.

OBJECTIVE: To assess the potential pharmacokinetic and pharmacodynamic interaction of zaleplon and thioridazine administered concomitantly in healthy volunteers. METHODS: A three-period, double-blind, randomized crossover study of the psychomotor effects of single oral doses of zaleplon 20 mg alone, thioridazine 50 mg alone, or the two drugs administered concomitantly was performed in 12 healthy subjects. Pharmacodynamic testing was performed before, and at 1, 2, 4, and 8 h after drug administration. Critical flicker fusion (CFF), tapping rate (TR), reaction time (RT) with dominant and nondominant hands, and digit symbol substitution test (DSST) were used to assess psychomotor performance. RESULTS: Pharmacokinetic results showed that coadministration of zaleplon and thioridazine did not alter the pharmacokinetic profile of either drug. In both CFF and TR tests, values for change from baseline with combined treatment were not significantly different from those with thioridazine at any time point, indicating no pharmacodynamic interaction. RT test values with coadministered treatment were significantly different from those with thioridazine alone at 1 h after administration, indicating additivity. Supra-additivity was observed in DSST results at 1, 2, and 4 h. There was no interaction at 8 h. CONCLUSION: The results of single-dose administration showed an additive pharmacodynamic interaction between zaleplon and thioridazine at 1 h in one of four tests and supra-additivity for 4 h in another test. This interaction is relatively short in duration due to the short half-life of zaleplon.

Acetamides↗
PubMed1984

Diltiazem-like effect of thioridazine on the dihydropyridine binding site of the calcium channel of rat myocardial membranes.

The phenothiazine thioridazine enhances the binding of [3H]-nitrendipine to cardiac membranes and antagonizes the inhibition of [3H]-nitrendipine binding by other classes of calcium channel blockers. These effects are similar to those of diltiazem. The increased binding of [3H]-nitrendipine in the presence of thioridazine or diltiazem is due to increased binding affinity rather than an increased number of binding sites. Increased affinity is due in part to a decrease in the dissociation rate of nitrendipine in the presence of either thioridazine or diltiazem. Thioridazine also reverses the blocking effect of tiapamil (a phenylalkylamine) on [3H]-nitrendipine binding to rat heart membranes, as does diltiazem, suggesting that thioridazine binds to the same site as diltiazem. Thioridazine may have calcium channel blocking effects in the high therapeutic and toxic dose ranges that could be responsible for some of its adverse cardiovascular effects.

Animals↗
PubMed1984

Thioridazine-5-sulfoxide cardiotoxicity in the isolated, perfused rat heart.

The potential cardiotoxicity of a racemic mixture of thioridazine-5-sulfoxide, an oxidative metabolite of thioridazine, was studied in the isolated, perfused rat heart. Thioridazine-5-sulfoxide (ring sulfoxide) was prepared by a new method in which a racemic mixture of the two diastereoisomeric forms of the compound was formed. Hearts from male Sprague-Dawley rats were perfused using a modified Langendorff preparation. Quinidine (31 microM) served as a positive control for the measurements of the electrocardiogram (ECG) and the heart rate. Thioridazine (13 microM) perfusion resulted in a variable heart rate and elevated S-T segment. Perfusate concentrations of the ring sulfoxide as low as 12 microM increased P-R and Q-T intervals, produced delays in A-V and ventricular conduction, premature ventricular contractions and ultimately A-V block. These findings suggest that thioridazine cardiotoxicity may be due in part to the actions of thioridazine ring sulfoxide.

Animals↗
PubMed1993

Artifacts in the analysis of thioridazine and other neuroleptics.

Although the sensitivity to light of thioridazine and its metabolites has been described, the problem does not seem to be widely acknowledged. Indeed, a survey of the literature shows that assays of these compounds under light-protected conditions have been performed only in a few of the numerous analytical studies on this drug. In the present study, thioridazine, its metabolites, and 18 other neuroleptics were tested for their sensitivity to light under conditions used for their analysis. The results show that light significantly affects the analysis of thioridazine and its metabolites. It readily causes the racemization of the isomeric pairs of thioridazine 5-sulphoxide and greatly decreases the concentration of thioridazine. This sensitivity to light varied with the medium used (most sensitive in acidic media) and also with the molecule (in order of decreasing sensitivity: thioridazine > mesoridazine > sulforidazine). Degradation in neutral or basic media was slow, with the exception of mesoridazine in a neutral medium. Twelve other phenothiazines tested, as well as chlorprotixene, a thioxanthene drug, were found to be sensitive to light in acidic media, whereas flupenthixol and zuclopenthixol (two thioxanthenes), clozapine, fluperlapine, and haloperidol (a butyrophenone) did not seem to be affected. In addition to being sensitive to light, some compounds may be readily oxidized by peroxide-containing solvents.

Antipsychotic Agents↗
PubMed1997

Clinical experience with risperidone, haloperidol, and thioridazine for dementia-associated behavioral disturbances.

The efficacy and safety of risperidone, haloperidol, and thioridazine for treating dementia-associated behavioral disturbances were evaluated in a retrospective study of 186 patients aged 65 years or older with DSM-III-R or DSM-IV diagnoses of Alzheimer's dementia, senile dementia NOS, or organic brain syndrome. Study patients were selected from the charts of 12,000 residents of 60 long-term-care facilities in New Jersey if they were treated with one of the three agents for behaviors dangerous to themselves or others. The 186 selected patients included 60 treated with risperidone (mean, 1 mg/day), 83 with haloperidol (mean, 2 mg/day), and 43 with thioridazine (mean, 33 mg/day). Target behaviors were violence (74 patients), shouting (31), delusions (26), paranoia (19), pacing (3), and mixed behaviors (33). Target behaviors improved in 94% of patients given risperidone, 65% given haloperidol, and 67% given thioridazine (p < .001). Treatment failures (treatment discontinued in patients because of side effects or no improvement) were more frequent in patients started on haloperidol (28) or thioridazine (15) than on risperidone (3). Extrapyramidal symptoms were reported in 7% of patients taking risperidone, 22% taking haloperidol, and 18% taking thioridazine. Safe, effective doses are readily achieved with risperidone but difficult to achieve with haloperidol or thioridazine because their effective doses often cause unacceptable side effects. These data are only suggestive because no guidelines exist for defining or measuring behavioral disturbances or for how they are affected by social, psychological, or environmental factors.

Aged↗
PubMed2002

Cardiotoxicity and prescription of thioridazine in New Zealand.

OBJECTIVE: To review the production of cardiac arrhythmia by thioridazine, and consider the role of government regulation in light of antipsychotic prescribing trends in New Zealand. METHODS: We conducted a focused literature review on psychotropic-induced cardiotoxicity, including mechanisms and incidence. In addition, we considered trends in antipsychotic prescription in New Zealand and decisions made by regulatory bodies in Australia, North America and the United Kingdom regarding restrictions on the prescription of thioridazine. RESULTS: In general, the cardiotoxicity of antipsychotics, including thioridazine, relates to the ability of these drugs to antagonize voltage-sensitive potassium channels, and thereby prolong the QT interval. This action can lead to malignant arrhythmias in a very small proportion (< < 1%) of patients; the risk may be increased by other drugs or factors which prolong QT or inhibit the metabolism of thioridazine. A review of prescription doses and volumes in New Zealand indicates that thioridazine is prescribed mainly in low doses by non-specialists, and its use has been waning significantly over the past 2 years. These trends predate recent publicity regarding cardiotoxicity. CONCLUSION: Recommendations regarding thioridazine use are presented. Although new patients should not receive this drug, existing patients benefiting from modest doses should not be denied access unless clear-cut risk factors for cardiotoxicity are evident.

Antipsychotic Agents↗
PubMedDate not supplied

Thioridazine and its metabolites in post mortem blood, including two stereoisomeric ring sulfoxides.

Thioridazine and metabolites were determined by a selective HPLC technique in blood from five post-mortem cases; two deaths attributed to drug overdose and three deaths due to natural causes or trauma. Additionally, total thioridazine-like compounds were determined in these blood samples and liver specimens by a nonspecific fluorometric technique. Blood concentrations were: thioridazine, 0.78-8.85 mg/L; mesoridazine, 0.52-26.8 mg/L; and sulforidazine, 0.00-0.87 mg/L. Thioridazine-5-sulfoxide stereoisomeric DL,LD, and DD,LL pair concentrations ranged from 0.02-0.56 and 0.03-0.83 mg/L, respectively. Thioridazine metabolite profiles were not helpful in differentiating therapeutic administration from severe overdose. Liver appears to be the specimen of choice in the assessment of thioridazine overdose.

Adult↗
PubMed1999

A combined biochemical and cytogenetic study of thioridazine-induced damage to nucleic acids.

In this work the biochemical effects of thioridazine, a commonly used phenothiazine, have been studied upon native double- and single-stranded DNA and also upon a supercoiled plasmid. The results indicate that thioridazine causes damage and scissions to these nucleic acids but only at concentrations much higher than the one used in our cytogenetic experiments and that the damage seems to depend on the concentrations used. Furthermore, we studied the action of thioridazine alone or in combination with caffeine and/or melphalan upon human lymphocytes in vitro. Thioridazine and caffeine (a well-known inhibitor of cellular repair mechanisms) were shown to act synergistically to potentiate the cytogenetic effect of melphalan on human lymphocytes. It is suggested that thioridazine alone or in combination with caffeine may exert its synergistic effect on melphalan cytotoxicity to cultured human lymphocytes not only indirectly, i.e. as a strong calmodulin inhibitor by facilitating the intracellular retention of melphalan, but also directly by reaction with nucleic acids and by causing scissions in and damage to them. Therefore, thioridazine (as chlorpromazine) has some potential as an adjuvant chemotherapeutic agent for the treatment of human cancer.

Caffeine↗
PubMed1997

Life-threatening dysrhythmias in severe thioridazine poisoning treated with physostigmine and transient atrial pacing.

OBJECTIVES: To describe clinical, electrocardiographic, and blood chemistry findings in a case of high-dosage thioridazine self-poisoning, focusing on the cellular mechanisms of the cardiovascular toxicity. DESIGN: Case report and literature review. SETTING: Intensive care unit (ICU) of a district hospital in Germany. PATIENT: A 68-yr-old male patient admitted to the ICU for treatment of a severe thioridazine intoxication. INTERVENTIONS: Prevention of absorption (gastric lavage), mechanical ventilation, fluids, alkalinization, catecholamines, drugs (physostigmine, neostigmine), direct current cardioversion/defibrillation, and transient pacemaker (atrial stimulation). MEASUREMENTS AND MAIN RESULTS: Central nervous, cardiovascular, and gastrointestinal systems indicated the adverse side effects of thioridazine intoxication over a period of 9 days. During high toxic thioridazine plasma concentrations (6061 to 6480 ng/mL), a life-threatening crisis occurred due to malignant ventricular arrhythmias followed by bradycardia (e.g., sinus node arrest). The electrocardiogram showed delays in all parts of the conduction system of the heart, including prolonged repolarization for several days, which disappeared completely when thioridazine plasma concentrations were within the therapeutic range. CONCLUSIONS: An individual therapeutic approach is needed in cases of thioridazine overdose. The primary aim is to stabilize the cardiac rhythm and the circulation.

Aged↗
PubMed1992

Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.

The metabolism of most tricyclic antidepressants and some phenothiazine neuroleptics is under the genetic control of hepatic cytochrome P-450IID6, which also regulates the metabolism of dextromethorphan. This study investigated the effect of treatment with amitriptyline or thioridazine on testing for genetically regulated efficiency of the metabolism of dextromethorphan and mephenytoin. One group of 33 patients was treated with 150 mg amitriptyline a day (the AMI group); 25 other patients received a daily dose of thioridazine, either 200 mg (200-THD group; n = 7) or 400 mg (400-THD group; n = 18). Before and after 10 days of this treatment, all patients were tested with 25 mg dextromethorphan and 100 mg mephenytoin to determine their pharmacogenetic status with respect to their hepatic drug oxidizing systems (cytochrome P-450IID6 and P-450 MP). Two patients were poor metabolizers (PMs) of dextromethorphan and three of mephenytoin. Treatment with either psychotropic drug was without significant effect on the metabolism of mephenytoin, but both amitriptyline and thioridazine increased significantly the metabolic ratio of dextromethorphan/dextrorphan. Thioridazine had the effect of changing the pharmacogenetic status of 15 efficient metabolizers of dextromethorphan to poor metabolizers; amitriptyline did not have such an effect. There was no significant correlation between day-11 plasma levels of thioridazine, mesoridazine, or sulforidazine and the metabolism of dextromethorphan, but there was a correlation between the metabolism of dextromethorphan and plasma levels of amitriptyline and nortriptyline. Amitriptyline (p less than 0.05), but not thioridazine, decreases the ratio of conjugated/total dextrorphan in urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

The effect of lovastatin and thioridazine on the degradation of cocaine in human serum in vitro.

The effect of lovastatin and thioridazine on the degradation of cocaine in human serum was studied by incubating therapeutic and toxic concentrations of either drug with cocaine in human serum at 37 degrees C. Without these other drugs, cocaine concentrations decreased by an average of 88% in 120 minutes. Lovastatin at all concentrations studied showed a negligible effect on the degradation of cocaine in human serum and did not alter the pseudocholinesterase activity of the serum. In contrast, in the presence of a therapeutic concentration of thioridazine, cocaine concentrations decreased by only 71% during this period of time, and, with a toxic concentration of thioridazine, cocaine concentrations decreased by only 55%. Thioridazine suppressed the pseudocholinesterase activity of human serum by up to 19% during the 120-minute incubation period, and this effect was more pronounced at higher thioridazine concentrations. These findings suggest that thioridazine may prolong the serum half-life of cocaine by inhibiting the pseudocholinesterase-mediated catabolism of cocaine to ecgonine methyl ester. This may be important in cocaine users who are treated with phenothiazines and other structurally similar drugs. They also may be of interest in cocaine-abusing patients who are treated with phenothiazines for schizophrenic disorders.

Butyrylcholinesterase↗
PubMed2004

Comparative cardiac safety of low-dose thioridazine and low-dose haloperidol.

AIM: To compare the rate of ventricular arrhythmia, sudden death and unexplained or unattended death among users of thioridazine and haloperidol. METHODS: Observational cohort study of thioridazine and haloperidol users in the UK General Practice Research Database (GPRD) using data from 1987 through 29 June 2000. Patients were followed for 30 days following each study prescription. The event of interest was a diagnosis of ventricular arrhythmia, sudden death, or unexplained or unattended death. Cox regression was used to calculate rate ratios (RRs) and 95% confidence intervals (CIs), to examine potential confounding factors, and to examine dose-response relationships. RESULTS: Use of thioridazine and haloperidol in the GPRD was primarily in older patients, at low dose (median daily dose 31 mg thioridazine, 1.8 mg haloperidol). There was no association between thioridazine use and the rate of ventricular arrhythmia, sudden death, and unexplained or unattended death (adjusted RR 0.9, 95% CI 0.7, 1.1). The rate did not appear to increase with dose for either drug over the range observed. CONCLUSIONS: These results suggest that low-dose thioridazine and haloperidol have similar cardiac safety.

Adolescent↗
PubMed2005

Characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine.

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.

Animals↗
PubMed1985

Phenolic metabolites of thioridazine in man.

After oral administration of thioridazine or mesoridazine to man, faecal extracts contained mainly unconjugated 7-hydroxy-thioridazine and its demethylated analogue, together with some 3-hydroxy-thioridazine, and 7-hydroxy derivatives of sulphoridazine and desmethyl sulphoridazine. In contrast, urine contained free 7-hydroxy-mesoridazine, and no free 7-hydroxy-thioridazine was detectable. Conjugates of all these phenols were also found. After oral sulphoridazine administration (thioridazine side-chain sulphone), urine contained mainly 7-hydroxy-sulphoridazine and faeces both 7-hydroxy-sulphoridazine and its desmethyl analogue. Sulphoridazine metabolism is therefore much simpler than that of thioridazine. This different elimination pattern in faeces and urine may be due to reduction of sulphoxides but not sulphones by intestinal bacteria.

Administration, Oral↗
PubMed1976

The influence of cystamine on pharmacokinetics and pharmacodynamics of thioridazine.

A study on the influence of cystamine on the kinetics and dynamics of the action of thioridazine has been carried out. Higher levels of this drug in the blood and lower levels in the brain tissue than those in unpremedicated rats were determined. Half-life of thioridazine underwent shortening from 2-55 hr to 1-05 hr. Excretion of thioridazine with bile was not significantly affected by premedication with cystamine. beta-Glucuronidase activity, after an initial drop on the first day following premedication, increased to levels higher than the control values. The dynamics of the action of the thioridazine were little affected. The cataleptic action of thioridazine was enhanced on the first day after premedication with cystamine. Thioridazine depressed exploratory activity in rats more significantly only during the first three days after cystamine premedication.

Animals↗
PubMedDate not supplied

Interaction of thioridazine with ocular melanin in vitro.

The aim of this study was to examine in vitro the binding capacity of thioridazine to natural melanin isolated from pig eyes and to synthetic DOPA-melanin. The amount of drug bound to melanin was determined by the use of the UV spectrophotometric method. Studies on the kinetics of thioridazine-melanin complex formation showed that the amount of drug bound to melanin increases with increasing initial drug concentration and the prolongation or incubation time, allowed to attain equilibrium state after about 24 hours. Binding parameters, i.e., the number of independent binding sites and the association constants were determined on the basis of Scatchard plots. For thioridazine-ocular melanin and thioridazine-DOPA-melanin complexes two classes of binding sites were found with the association constants K1 approximately 2 x 10(4) M(-1) and K2 approximately 9 x 10(2) M(-1). For ocular and synthetic melanin complexes with thioridazine no significant differences in the values of binding parameters were found. The demonstrated ability of thioridazine to interact with melanin in vitro is discussed in relation to this drug ocular toxicity in vivo.

Animals↗
PubMed1984

Thioridazine and the neuroleptic radioreceptor assay.

When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in the same sample by measuring the actual concentrations of parent drug and active metabolites and multiplying these values by the relative potency of each compound. The present report demonstrates that in the NRRA for thioridazine or its active metabolites, the normal displacement of [3H]-spiperone from striatal membranes by thioridazine is altered in the presence of sera. The inclusion of serum (50 microliter/ml) distorts the sigmoidal displacement curves, such the resulting log-logit (or Hill) slope is markedly decreased. Similar serum-induced changes in the log-logit slope are seen for two active metabolites of thioridazine, but not for chlorpromazine or haloperidol. As a consequence, when one of these latter drugs is used as a standard, the NRRA substantially underestimates the actual NLA (chlorpromazine equivalents) values for patients treated with thioridazine. Moreover, because of differences in the magnitude of the effect with serum from different individuals, it is not possible to control completely for this effect. Thus, these data reconcile discrepancies that have been reported for data from the NRRA versus that from direct analytical measurements, and demonstrate that the use of the NRRA as a quantitative tool in the clinical pharmacology of thioridazine may lead to erroneous estimations of active drug and metabolites in the blood.

Animals↗