Disease relevance of thioridazine

• This report describes a case of thioridazine-induced torsade de pointes that was successfully managed with isoproterenol infusion after therapy with other agents was unsuccessful [1].
• Letter: Acute hypotension from thioridazine [2].
• Thioridazine caused weight gain, blood pressure decreases, and ECG changes [3].
• A sixth case of reversible total heart block associated with thioridazine is presented giving further evidence that the deaths from overdose probably resulted from drug cardiotoxicity [4].
• Letter: Water intoxication and thioridazine [5].

Psychiatry related information on thioridazine

• In contrast, thioridazine administration was associated with appetite increase and enuresis [6].
• This study compared the therapeutic efficacy of thioridazine, loxapine, and a placebo in the treatment of behavioral disturbances in nursing home patients with dementia [7].
• Increased scratching responses and locomotor activity induced by mescaline were antagonized by all doses of CPZ and thioridazine; at higher doses, both CPZ (7.5, 15 mg/kg) and thioridazine (45 mg/kg) induced cataleptic-like condition and marked hypothermia [8].
• Finger tremor increased, and some psychologic tests were impaired by thioridazine; other psychologic tests, the auditory-evoked response, and palmar skin conductance were unaffected and showed no relationship to drug or prolactin levels [9].
• Whereas patients failed to respond to chlorpromazine 1800 mg/day, response to mesoridazine 400 mg/day and to thioridazine 800 mg/day was established on all Brief Psychiatric Rating Scale factors except for anxiety-depression [10].

High impact information on thioridazine

• Increased rate of accumulation of the drugs by thioridazine, trifluoperazine, and chlorpromazine was most prominent in the resistant KB-ChR-24 cells than in KB cells [11].
• Thioridazine: a radiation enhancer in advanced cervical cancer [12]?
• Relative prolactin-stimulating potency in humans of chlorpromazine, thioridazine, trifluoperazine, butaperazine, and haloperidol correlated well with their relative clinical potencies [13].
• The effects of three pharmacological treatments, methylphenidate hydrochloride, thioridazine hydrochloride, a methylphenidate/thioridazine combination, and placebo were studied in outpatient hyperkinetic children rated hyperactive both in school and at home or clinic [6].
• Although numerous mechanisms of action of pimozide and thioridazine have been identified, both drugs are calmodulin antagonists at drug concentrations that inhibit breast cancer cell growth in vitro [14].

Chemical compound and disease context of thioridazine

• Water intoxication and thioridazine (Mellaril) [15].
• The use of dopamine antagonists such as thioridazine in patients with prolactinoma may interfere with bromocriptine's action, resulting in potentially serious complications [16].
• The authors postulate that two types of combined lithium-neuroleptic toxicity occur: a neuroleptic malignant extrapyramidal syndrome and a lithium toxicity that occurs in combination with phenothiazines, primarily thioridazine [17].
• Several agents recently recommended for this condition, dimethyl aminoethanol, clozapine, and thioridazine, failed to modify the dyskinesia [18].
• Haloperidol versus thioridazine in the treatment of behavioral symptoms in senile dementia of the Alzheimer's type: preliminary findings [19].

Biological context of thioridazine

• Sensitization to thioridazine through sexual intercourse [20].
• A marked deterioration of his visual fields was noted after 3 months' therapy with both drugs, and this abnormality resolved five days after the thioridazine was stopped [16].
• Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype [21].
• Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO [22].
• 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 [23].

Anatomical context of thioridazine

• Thioridazine also antagonized potassium-induced, calcium-dependent contractions of rat vas deferens, with similar potency [24].
• 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 [23].
• The pH value in lysosomes was 5.28 in thioridazine-treated HeLa cells, while that in untreated cells was 5.15 [25].
• Cerebrospinal fluid probenecid and 5-hydroxyindoleacetic acid declined significantly during treatment with thioridazine [26].
• Ca2+ transport by the synaptosomal plasma membrane Ca2+-ATPase and the effect of thioridazine [27].

Associations of thioridazine with other chemical compounds

• It is concluded that thioridazine is a potent dopamine antagonist in the tuberoinfundibular system, and it is suggested that this system's regulation of prolactin secretion may provide a useful method for studying antipsychotic drug effects in man [28].
• BACKGROUND: Ongoing regimens of haloperidol, thioridazine, and lorazepam are commonly administered to manage behavior problems in nursing home residents [29].
• Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO [22].
• Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators [21].
• The effects of thioridazine (TDZ) on serum phenobarbital (PB) and phenytoin (PHT) were studied in mentally retarded persons [30].

Gene context of thioridazine

• The role of certain drug metabolizing enzymes in cardiotoxicity, such as CYP2D6 for thioridazine, has been suggested [31].
• Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%) [32].
• 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) [32].
• Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance [33].
• Typical antipsychotics haloperidol, thioridazine and chlorpromazine non-selectively inhibited [(14)C]glycine uptake mediated by GlyT1a and GlyT2 with potency of 9-21 microM [34].

Analytical, diagnostic and therapeutic context of thioridazine

• Concentrations of thioridazine and metabolites in serum were measured by HPLC [21].
• Thioridazine and the neuroleptic radioreceptor assay [23].
• METHODS: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo [35].
• Quantitative evaluation of visual evoked potentials (VEPs) revealed an increase in latencies and decrease in amplitudes during thioridazine treatment [36].
• The Percoll gradient centrifugation pattern showed that thioridazine delayed both the appearance of [125I]EGF in lysosomes and the disappearance of [125I]EGF from the lysosomes [25].

References