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The macrolide antibiotic erythromycin has been associated with QT interval prolongation and inhibition of the hERG-encoded channels responsible for the rapid delayed rectifier K + current I( Kr ). It has been suggested that low concentrations of erythromycin may have a protective effect against hERG block and associated drug-induced arrhythmia by reducing the affinity of the pore-binding site for high potency hERG inhibitors. This study aimed to explore further the notion of a potentially protective effect of erythromycin. Whole-cell patch-clamp experiments were performed in which hERG-expressing mammalian (Human Embryonic Kidney; HEK) cells were preincubated with low to moderate concentrations of erythromycin (3 or 30 µM) prior to whole-cell patch clamp recordings of hERG current (I hERG ) at 37°C. In contrast to a previous report, exposure to low concentrations of erythromycin did not reduce pharmacological sensitivity of hERG to the antipsychotic thioridazine and antihistamine terfenadine. The IC 50 value for I hERG tail inhibition by terfenadine was decreased by ~32-fold in the presence of 3 µM erythromycin (p < .05 vs. no preincubation). Sensitivity to thioridazine remained unchanged (p > .05 vs. no preincubation). The effects of low concentrations of erythromycin were investigated for a series of pore blocking drugs, and the results obtained were consistent with additive and/or synergistic effects. Experiments with the externally acting blocker BeKm-1 on WT hERG and a pore mutant (F656V) were used to explore the location of the binding site for erythromycin. Our data are inconsistent with the use of erythromycin for the management of drug-induced QT prolongation., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Objectives: To develop a thioridazine/moxifloxacin-based combination regimen for treatment of pulmonary infection due to Mycobacterium avium-intracellulare complex (MAC) that kills bacteria faster than the standard treatment regimen., Methods: Monocytes were infected with MAC and inoculated into the hollow-fibre system model for pulmonary MAC disease (HFS-MAC). We co-administered ethambutol plus azithromycin daily for 28 days, to achieve the same human concentration-time profiles that result from standard doses, in three HFS-MAC systems. Two experimental regimens consisted of thioridazine at an exposure associated with optimal kill, given intermittently on days 0, 3, 7 and 10. Regimen A consisted of thioridazine in combination with standard dose azithromycin for the entire study duration. Regimen B was thioridazine plus moxifloxacin at concentration-time profiles achieved by the standard daily dose administered for 14 days, followed by daily azithromycin. Each HFS-MAC was sampled for bacterial burden every 7 days., Results: The bacteria in the non-treated HFS-MAC grew at a rate of 0.11 ± 0.01 log10 cfu/mL/day. The azithromycin/ethambutol regimen decreased bacterial burden by 1.21 ± 0.74 log10 cfu/mL below baseline during the first 7 days, after which it failed. Regimen A killed 3.28 ± 0.32 log10 cfu/mL below baseline up to day 14, after which regrowth occurred once thioridazine treatment stopped. Regimen B killed bacteria to below the limits of detection in 7 days (≥5.0 log10 cfu/mL kill), with rebound in the azithromycin continuation phase., Conclusions: The thioridazine/moxifloxacin regimen demonstrated that rapid microbial kill could be achieved within 7 days. This is a proof of principle that short-course chemotherapy for pulmonary MAC is possible., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The present report describes extrapyramidal side effects (EPS) appearing after 32 months of exclusive treatment with clozapine at low dosages. This case evidences that long-term treatment with clozapine may be associated with EPS and suggests that, even if clozapine is considered the medication with the fewest EPS and it is often prescribed as an effective treatment for them, its use does not fully eliminate the risk of neurological side effects.

Lung cancer stem cells are a subpopulation of cells critical for lung cancer progression, metastasis, and drug resistance. Thioridazine, a classical neurological drug, has been reported with anticancer ability. However, whether thioridazine could inhibit lung cancer stem cells has never been studied. In our current work, we used different dosage of thioridazine to test its effect on lung cancer stem cells sphere formation. The response of lung cancer stem cells to chemotherapy drug with thioridazine treatment was measured. The cell cycle distribution of lung cancer stem cells after thioridazine treatment was detected. The in vivo inhibitory effect of thioridazine was also measured. We found that thioridazine could dramatically inhibit sphere formation of lung cancer stem cells. It sensitized the LCSCs to chemotherapeutic drugs 5-FU and cisplatin. Thioridazine altered the cell cycle distribution of LCSCs and decreased the proportion of G0 phase cells in lung cancer stem cells. Thioridazine inhibited lung cancer stem cells initiated tumors growth in vivo. This study showed that thioridazine could inhibit lung cancer stem cells in vitro and in vivo. It provides a potential drug for lung cancer therapy through targeting lung cancer stem cells.

Thioridazine as an antipsychotic agent was extensively used to treat various psychotic disorders, e.g. schizophrenia. However, the therapy with this drug can induce serious side effects such as extrapyramidal symptoms or ocular and skin disorders, which mechanisms are still not fully established. To gain inside the molecular mechanisms underlying thioridazine toxicity, we examined the effect of this drug on cell viability, antioxidant defence system as well as melanogenesis in normal human melanocytes. It was demonstrated that thioridazine induces concentration-dependent loss in cell viability. The value of EC50 was calculated to be 2.24 μM. To study the effect of thioridazine on antioxidant defence system in melanocytes, the level of hydrogen peroxide and the activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were determined. The drug in concentrations of 0.1, 0.25, 1.0 and 2.5 μM caused changes in cellular antioxidant defence system indicating the induction of oxidative stress. It was also shown that the analysed neuroleptic in concentrations of 1.0 and 2.5 μM significantly inhibited melanogenesis. The observed changes in cell viability, antioxidant defence system and melanization in normal human melanocytes after thioridazine treatment may explain an important role of reactive oxygen species as well as melanin in mechanisms involved in this drug side effects directed on pigmented tissues.

Objective: Thioridazine is a first-generation antipsychotic drug that was withdrawn from the market worldwide in 2005. The outcome of clinically stable schizophrenia patients who used thioridazine before market withdrawal was evaluated., Methods: Nationwide registers in Finland were utilized to study thioridazine use, hospitalization rate and length of hospital stay., Results: Although thioridazine use continued to diminish year after year, the hospitalization rate remained constant until the withdrawal year of 2005, when the percentage of patients hospitalized for schizophrenia doubled., Conclusion: The market withdrawal of thioridazine predisposed many stable patients towards psychotic relapses. In order to minimize this kind of risk, an overall risk-benefit assessment and a clear-cut plan for the replacement of an antipsychotic should be established before market withdrawal., (Copyright © 2012 John Wiley & Sons, Ltd.)

Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobial drugs. Within this pharmacological class we selected thioridazine, which is most efficacious and least toxic, when used as an antipsychotic drug. We tested thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible (-4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01). Thioridazine may represent an effective compound for treatment of susceptible and multidrug-resistant tuberculosis. The phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs.

Purpose: Progression of metabolic illness in a patient with schizophrenia who was stabilized on an atypical antipsychotic is described using a case study framework. Risks and benefits of staying on current treatment versus switching to another agent and switching strategies are described., Conclusions: Switching an antipsychotic with more favorable side effects may improve metabolic parameters if other weight loss strategies have failed. Switching or stopping medications too quickly may exacerbate psychiatric symptoms. There is little evidence to support which is the best switching strategy., Practice Implications: The psychiatric mental health nurse practitioner carries a significant responsibility of discussing risks and benefits of switching and closely monitoring the patient during a switch of medications. Ensuring that the patient decides and agrees upon the treatment plan will improve the overall outcome.

We compared the effects of single doses of thioridazine and mesoridazine on the heart rate-corrected QT (QTc) interval in healthy adult volunteers. QTc intervals and plasma concentrations of thioridazine, mesoridazine, and metabolites were measured after single oral doses of thioridazine hydrochloride 50 mg, mesoridazine besylate 50 mg, or placebo in a double-blind, crossover study. Mean maximum increases in the QTc interval following thioridazine (37.3+/-4.1 ms, P=0.023) and mesoridazine (46.6+/-7.4 ms, P=0.021) were similar and significantly greater than following placebo (12.9+/-8.1 ms). The area under the effect-time curve over 8 h following drug administration was similar between the two drugs (129.3+/-22.1 vs 148.3+/-43.0 ms h). In conclusion, thioridazine and mesoridazine are associated with similar effects on the QTc interval.

The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined. In 97 patients, dose-corrected plasma concentrations (C/Ds) of thioridazine and metabolites were correlated with age but not sex or CYP2C19 genotype. Patients with no functional CYP2D6 alleles (n=9) had significantly higher C/D for thioridazine (P=0.017) and the ring sulfoxide metabolite and a significantly higher thioridazine/mesoridazine ratio compared with those with >/=1 functional CYP2D6 allele (n=82). Smokers had significantly lower C/D for thioridazine, mesoridazine, and sulforidazine and significantly lower thioridazine/ring sulfoxide ratios than non-smokers. QTc interval was not significantly affected by CYP2D6 or CYP2C19 genotypes. Plasma concentrations of thioridazine are influenced by age, smoking, and CYP2D6 genotype, but CYP2D6 genotype does not appear to influence on-treatment QTc interval.

Objectives: To explore the odds ratios (ORs) of death associated with antipsychotic (AP) medications dispensed to elderly subjects., Method: Subjects were veterans and war widows 65 years and older dispensed an AP drug in 2001 in NSW or ACT. For all subjects, dispensing records for AP medication, benzodiazepines, lithium, carbamazepine, sodium valproate and antidepressant medication were extracted and combined with age, gender and date of death. A study date was allocated, either the date of death or a random date from 1.5.01 to 31.12.01. Subjects dispensed an AP in 2001, but not dispensed an AP or other psychotropic medication in the 120 days prior to their study date, formed a reference group. Psychotropic dispensing in the 120 days prior to the study date was analysed using nested logistic regression models to produce ORs of death associated with various AP drugs. The ORs for risperidone, olanzapine and pericyazine were compared. Haloperidol ORs were established for those dispensed the drug 0-30 days prior to study date or 31-120 days prior to the study date., Results: The ORs associated with haloperidol, olanzapine, risperidone, pericyazine, thioridazine and chlorpromazine were significant when compared with the reference group. Odds ratios for all three haloperidol periods were significant when compared with olanzapine, risperidone and pericyazine 120 day ORs. Although there was a trend favouring olanzapine when compared with risperidone, the difference in the ORs failed to reach significance (p=0.066)., Conclusions: Haloperidol is associated with significantly higher mortality rates than other AP medication but it is not clear whether this represents drug toxicity or the medical conditions for which it was dispensed. There was no evidence that the conventional AP pericyazine was associated with a higher mortality rate than olanzapine or risperidone.

Antipsychotic drugs are classified as typical and atypical based on extrapyramidal effects. However, since the frontal cortex is one of the most important regions for antipsychotic actions, this study attempted to classify antipsychotic drugs based on gene expression in the frontal cortex. Chlorpromazine and thioridazine were selected as typical antipsychotics, and olanzapine and quetiapine as atypical antipsychotics. Since these drugs have similar chemical structures, the effect of the basic structure on gene expression can be eliminated. Cluster analysis of microarray experiments separated 4-drug-administered mice into chlorpromazine-quetiapine and thioridazine-olanzapine groups. This classification scheme is different from that which is based on criteria currently used to group the typical and atypical drugs and suggests that antipsychotic drugs can be further separated into multiple groups.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine, perazine 10, chlorpromazine, haloperidol 0.3, risperidone 0.1, sertindole 0.05), in the absence of the neuroleptics in vitro. Some of the neuroleptics added in vitro to control liver microsomes decreased the activity of CYP2C6. Sertindole and levomepromazine (Ki = 25 and 31 microM, respectively) were the most potent inhibitors of the rat CYP2C6 among the drugs studied. Their effects were more pronounced than those of the other phenothiazines tested: thioridazine and chlorpromazine (Ki = 88 and 91 microM, respectively), promazine and perazine (Ki = 322 and 341 microM, respectively), risperidone (Ki = 414 microM) or haloperidol (Ki = 606 microM). The investigated neuroleptics--when given to rats in vivo for one day or two weeks--did not produce any indirect effect on CYP2C6 via other mechanisms, except for levomepromazine, which increased the activity of the enzyme after 24-h exposure. Therefore, the direct inhibitory effect of levomepromazine on CYP2C6 may be attenuated by an indirect mechanism at the beginning of the neuroleptic therapy. In summary, the obtained results show direct inhibitory effects of some phenothiazine neuroleptics and sertindole on the activity of CYP2C6 in vitro in rat liver microsomes. Considering relatively high pharmacological doses and therapeutic concentrations of phenothiazines, it seems that the inhibitory effect of levomepromazine (and other phenothiazines with Ki values below 100 microM) found in vitro may be of physiological and pharmacological importance in vivo.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2A measured as a rate of testosterone 7alpha-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine, perazine 10, chlorpromazine, haloperidol 0.3, risperidone 0.1, sertindole 0.05), in the absence of the neuroleptics in vitro. Most of the neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2A. Chlorpromazine (Ki = 11 microM) was the most potent inhibitor of the rat CYP2A among the studied drugs, whose effect was more pronounced than that of the other tested phenothiazines (Ki = 41-83 microM), haloperidol (Ki = 190 microM) or sertindole (Ki = 78 microM). Risperidone was not active in this respect. The investigated neuroleptics when given to rats in vivo for one day or two weeks--did not produce any indirect inhibitory effect on CYP2A via other mechanisms. The obtained results show direct inhibitory effects of phenothiazine neuroleptics on the activity of CYP2A in rat liver, which may be of physiological importance for the metabolism of testosterone, considering simultaneous inhibition of CYP2C11 and CYP3A by those drugs.

Objectives: To examine the effects of anti-psychotic medications on cardiovascular parameters in overdose. Specifically, to examine dose-response relationships for thioridazine and chlorpromazine., Methods: A retrospective study of case records of patients presenting to the Edinburgh poisons treatment unit over 3 years (2000-2002). Information--including that on stated dose ingested, ECG parameters, and pulse and blood pressure--was extracted from case notes., Results: A total of 224 chlorpromazine, 96 thioridazine and 99 patients ingesting other anti-psychotics were evaluated. Full data on all aspects, both dose and cardiovascular change, was available in 96 chlorpromazine, 36 thioridazine and 27 of the other anti-psychotic cases. For thioridazine, there was a significant dose-response relationship for increasing heart rate and increasing QTc but not other cardiovascular changes. For chlorpromazine, there was no dose-response relationship for ECG changes, but there was a significant dose-response relationship for increasing heart rate and reduction in mean blood pressure., Conclusions: We have confirmed a relationship between increasing dose of thioridazine and prolongation of QTc in overdose patients. No such change was observed with chlorpromazine. Both of these agents are reported to cause QT prolongation, but this study suggests that the nature of these effects is different for each agent. Poisoned patients may offer ways of exploring in more detail, and at a larger dose range, the effects of potentially cardiotoxic drugs in humans.

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.

Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.

Background: The impact of the withdrawal of long-term antipsychotic medication prescribed to adults with intellectual disabilities on behavioural functioning has been investigated using a real-time direct observation methodology. Previous authors have reported a significant post-reduction difference in engagement in activity between the successful drug reduction and control groups., Method: In the present study, sequential analysis of the relationship between staff:resident interaction and behavioural engagement was used to give a more precise measure of the extent to which user responsiveness is affected by drug withdrawal. Responsiveness was measured by calculating the likelihood of engagement occurring given the occurrence of staff interaction. This likelihood was represented by the statistic Yule's Q-value., Results: High Yule's Q-value results pre- and post-baseline were found, indicating that clients were highly responsive to staff interaction. However, Yule's Q-value did not significantly increase following drug withdrawal., Conclusion: The present study provides no evidence of greater responsiveness following the withdrawal of psychotropic medication.

Some atypical antipsychotic drugs appear to improve cognitive function in schizophrenia and since acetylcholine (ACh) is of importance in cognition, we used in vivo microdialysis to examine the effects of antipsychotics administered acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine produced robust increases in ACh up to 1500% and 500%, respectively. The neuroleptics haloperidol, thioridazine, and chlorpromazine, as well as the atypical antipsychotics risperidone and ziprasidone produced modest increases in ACh by about 50-100%. Since most atypical antipsychotics affect a variety of monoaminergic receptors, we examined whether selective ligands for some of these receptors affect hippocampal ACh. Antagonists for the 5-HT(2A) (MDL 100,907), the 5-HT(2C) (SB 242,084), the 5-HT(6) (Ro 04-6790), the D(2) (raclopride) receptors, and the alpha(1)-adrenoceptors (prazosin) modestly increased ACh by about 50%. The 5-HT(1A) agonist R-(+)-8-OH-DPAT and the alpha(2)-adrenoceptor antagonist yohimbine significantly increased ACh by about 100% and 50%, respectively. Thus, olanzapine and clozapine increased ACh to a greater extent than other tested antipsychotics, explaining perhaps their purported beneficial effect in cognitive function in schizophrenia. It appears that selective activity at each of the monoaminergic receptors studied is not the sole mechanism underlying the olanzapine and clozapine induced increases in hippocampal ACh.

The effects of haloperidol, risperidone, and thioridazine on the pharmacokinetics and side-effect profile of quetiapine were investigated in 36 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a single-center, two-period, multiple-dose, open-label, randomized trial. Over a one-to two-week period, quetiapine doses were escalated to 300 mg twice daily (bid). Patients were then treated for at least 7 days at the target quetiapine dose and subsequently entered into the combination therapy period, receiving haloperidol (7.5 mg, bid), risperidone (3 mg, bid), or thioridazine (200 mg, bid) for 8.5 days (after 3 days of dose escalation). Key assessments included the pharmacokinetics of quetiapine at steady state (area under the curve within a dosing interval [AUCtSS], maximum [CmaxSS], and minimum [CminSS] observed plasma concentrations, and oral clearance [Cl/f]), as well as the UKU Side Effect Rating Scale scores and safety evaluations. Neither risperidone nor haloperidol had significant effects on quetiapine pharmacokinetics. However, thioridazine produced statistically significant changes, decreasing the least squares means values of the AUCtSS, CmaxSS, and CminSS by 40%, 47%, and 31%, respectively, and increasing Cl/f by 68%. Increases in the following adverse events were noted during coadministration: somnolence (risperidone), insomnia and dry mouth (all three coadministered therapies), and dizziness (thioridazine). UKU side effect items that became worse in >or= 25% of patients during each coadministration period included sedation and increased sleep duration. Results of laboratory tests, electrocardiograms, and vital sign measurements revealed few clinically important changes. Clinical stability can be maintained with good tolerability during the transition from quetiapine monotherapy to periods of coadministration with haloperidol, risperidone, or thioridazine. Coadministration of either haloperidol or risperidone did not have any important effects on the steady-state pharmacokinetics of quetiapine. Thioridazine significantly increased the oral clearance of quetiapine. Increased doses of quetiapine may be necessary to control psychotic symptoms when thioridazine is coadministered with quetiapine.

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.

Background: Ongoing regimens of haloperidol, thioridazine, and lorazepam are commonly administered to manage behavior problems in nursing home residents. Nevertheless, there is controversy over whether periodic drug withdrawal should be attempted when those medications are prescribed. This study addressed that issue by examining the effects of discontinuing treatment with haloperidol, thioridazine, and lorazepam among residents of a large suburban nursing home., Methods: In a double-blind, crossover study, half of 58 nursing home residents (43 women and 15 men with a mean age of 86 years) continued to take the psychotropic medication they had been prescribed, whereas the other half were tapered to placebo. After 6 weeks of taking placebo or original drug, patients were tapered to the reverse schedule and remained on it for 6 weeks. Assessments included informant ratings by the nursing staff who completed the Brief Psychiatric Rating Scale and the Cohen-Mansfield Agitation Inventory., Results: Analyses comparing residents taking placebo to those taking medication after completion of the first phase showed no impact of drug therapy discontinuation on their behavior. Similarly, using the crossover design to compare residents' behaviors while taking placebo vs. taking drugs, withdrawal of medication had no impact on Cohen-Mansfield Agitation Inventory or Brief Psychiatric Rating Scale scores., Conclusions: Results of this work suggest that longterm use of haloperidol, thioridazine, and lorazepam in nursing homes to manage agitation should be closely monitored for their efficacy. Furthermore, routine attempts at drug withdrawal should be considered for most residents taking psychotropic medication.

Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (O: six males and eight females, aged 65-77 years) took part in a randomized double-blind three-period crossover study in which they received by mouth single doses of thioridazine (Y: 50 mg; O: 25 mg) remoxipride (Y: 100 mg; O: 50 mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9 h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was made for dose, there was little indication of any difference in degree of CNS depression between the two age groups. Haemodynamic measures showed orthostatic reductions in blood pressure with thioridazine which were particularly marked in the older group, who also showed lower compensatory increases in pulse rate. These results indicate potential problems with orthostatic hypotension with thioridazine in older patients. CNS depression may also be a problem, especially in patients with compromised cholinergic function.

The aim of the present study was to assess the influence of carbamazepine on the pharmacokinetics of the two phenothiazine neuroleptics thioridazine and perazine in rats. The obtained results are compared with the results of analogical experiments concerning promazine. Thioridazine or perazine (10 mg/kg i.p.) were administered twice a day for two weeks alone or jointly with carbamazepine (15 mg/kg i.p. during the 1st week, and 20 mg/kg i.p. during the 2nd week of treatment). Concentrations of the neuroleptics and their main metabolites in the plasma and brain were measured at 30 min, 6 and 12 h after the last dose of the drugs. Carbamazepine decreased the concentrations of thioridazine and its metabolites (especially mesoridazine and sulforidazine) in plasma at 30 min and 6 h after the last dose of the drugs. Similar changes in the concentrations of thioridazine and its metabolites were observed at 6 h in the brain. Carbamazepine did not significantly influence the pharmacokinetics of perazine. In vitro studies with liver microsomes of control rats revealed that carbamazepine added to the incubation mixture inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its N-demethylation or sulfoxidation by carbamazepine was observed. Neither carbamazepine nor the neuroleptics, administered separately or jointly for two weeks, significantly influenced the concentrations of cytochromes P-450 and b-5 in the liver. Carbamazepine++ given chronically decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine-treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced. In conclusion, carbamazepine given jointly with thioridazine or promazine at pharmacological doses to rats accelerates the metabolism of the neuroleptics, which is not the case with perazine. The observed induction proceeds by metabolic pathways other than N-demethylation or sulfoxidation. The different effect of carbamazepine on the N-demethylation of thioridazine and perazine in liver microsomes of control and carbamazepine-treated rats implicates that the two reactions are not catalyzed by the same enzyme. Such an induction of neuroleptic metabolism by carbamazepine in patients may worsen psychotic symptoms.

To understand the interaction of lithium (Li+) with a coadministered drug in both the blood and the brain, we have treated rats with either Li+ alone or Li+ and a codrug. In this paper we address the important problem of quantitation of intra and extracellular Li+ ion contents in blood by the 7Li-NMR technique and the use of a shift reagent (SR). Although Li+ can be studied by atomic absorption techniques, these techniques involve tedious separation of intra- and extracellular components prior to chemical analysis. Magnetic resonance studies on rat blood, in the dose range of 0.5 to 10 meq/kg, indicate that the intracellular red blood cell Li+ predominates in the lower dose range of 0.5-1.0 meq/kg. As the lithium dose increases, a significantly larger amount of Li+ accumulates in the extracellular volume. Our studies on a number of animals at various doses of LiCl indicate that 7Li-NMR of blood samples provide a reliable, noninvasive quantification of red blood cell and plasma Li+ concentrations. The NMR method was further used to study the effect of coadministered drugs such as thioridazine on the intra- and extracellular Li+ concentration of RBCs.

This study was aimed at investigation of the pharmacokinetics of thioridazine and its metabolites after a single and repeated administrations. Male Wistar rats received thioridazine as a single dose (10 mg/kg i.p.) or they were treated chronically with the neuroleptic (10 mg/kg i.p., twice a day for two weeks). Plasma and brain concentrations of thioridazine and its metabolites (N-desmethylthioridazine, mesoridazine, sulforidazine, and the ring sulfoxide) were determined using the HPLC method. The obtained data showed that sulfoxidation in position 2 of the thiomethyl substituent and in the thiazine ring are main metabolic pathways of thioridazine, and showed that, in contrast to humans, in the rat N-desmethylthioridazine is formed in appreciable amount. The biotransformation of thioridazine was rather fast yielding plasma peak concentrations of metabolites lower than that of the parent compound. The maximum concentrations of thioridazine and its metabolites in the brain appeared later than in plasma. The peak concentrations and AUC values of thioridazine and its metabolites were higher in the brain than in plasma and this corresponded well with their longer half-lives in the brain as compared to plasma. The drug was not taken up by the brain as efficiently as other phenothiazines. Chronic treatment with thioridazine produced significant increases (with the exception of thioridazine ring sulfoxide) in the plasma concentrations of the parent compound and its metabolites which was accompanied with the prolongation of their plasma half-lives. The observed plasma levels of thioridazine were within 'therapeutic range' while the concentrations of its metabolites were relatively lower as compared to those observed in psychiatric patients. The increased plasma concentrations of thioridazine and its metabolites observed in plasma after chronic treatment were not followed by parallel changes in the brain.

Bromperidol is a close structural analog of haloperidol. The authors studied the effects of levomepromazine and thioridazine, which are frequently added to other neuroleptics as sedatives, on plasma concentrations of bromperidol and its reduced metabolite. The subjects were 26 inpatients with schizophrenia receiving bromperidol, 12 to 24 mg/day, for 1 to 19 weeks. In 10 cases, 50 mg levomepromazine per day and in nine cases, 50 mg thioridazine per day were coadministered for 1 week. In seven cases, both drugs were coadministered with > or = 2-week intervals. Plasma concentrations of bromperidol and reduced bromperidol were measured by a high-performance liquid chromatographic method. Levomepromazine (n = 17) significantly (p < 0.001) increased plasma concentrations of bromperidol (7.3 +/- 4.1 versus 10.2 +/- 4.8 ng/ml) and reduced bromperidol (1.8 +/- 1.4 versus 4.5 +/- 3.3 ng/ml). Thioridazine (n = 16) did not significantly change plasma concentrations of bromperidol (9.1 +/- 5.7 versus 8.6 +/- 5.5 ng/ml), while those of reduced bromperidol could not be measured because of interfering peaks. The current study suggests that levomepromazine, but not thioridazine, increases plasma concentrations of bromperidol and reduced bromperidol by inhibiting the metabolism of these compounds.

A case is presented in which toxic concentrations of imipramine (Tofranil) resulted from the co-administration of low-dose thioridazine (Mellaril). This probably occurred in an individual with genetically reduced capacity for oxidative drug metabolism, specifically via thioridazine's interference with the hepatic cytochrome P450IID6 isoenzyme (CYP2D6). In addition, coelution of thioridazine and its metabolites resulted in false elevations of imipramine and desipramine as measured by a common high-performance liquid chromatography (HPLC) method (cyanopropyl column). In contrast, an enzyme immunoassay (Abbott TDxFLx) and a second reference HPLC method (silica column) accurately resolved the analytes. This combination of psychiatric drugs is not uncommon in the pediatric population and is one of which both clinicians and laboratorians need to be aware. To the author's knowledge, this is the first report of interferences of thioridazine with both the metabolism and measurement of imipramine in a pediatric patient.

Objective: As previous single case reports have indicated that acute poisoning with thioridazine can be potentially dangerous, an investigation was undertaken to find out whether the risk of severe poisoning in adults and children can be judged from the amount of the drug that has been taken., Patients and Methods: In a case-control study 202 medical notes of 202 patients were analysed (141 adults, aged 16-82 years; 61 children, aged 0.3-15 years) in which thioridazine was the only potentially harmful substance taken, the precise amount swallowed was known and the drug was the certain or probable cause of the signs. 30 children were excluded from the study, because their body weight was not known., Results: Mild thioridazine poisoning was characterized by somnolence, tremor, ataxia and dysarthria. The severity of the poisoning and the degree of disorder of consciousness correlated significantly with the amount of thioridazine taken. Severe intoxication with coma and ventricular arrhythmias was observed at a dose of 2 g and more. While the disorder of consciousness completely regressed in the first 24 hours, in a few of the patients the cardiac arrhythmias persisted for up to 28 hours after the drug intake. Charcoal administration seemed to influence the course favourably., Conclusion: Prolonged, intensive care supervision and treatment are essential if more than 2 g thioridazine have been swallowed. In addition to standard treatment with gastric lavage charcoal should be given as early as possible to limit absorption.

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. 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. 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. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

In a naturalistic study of 23 severely and profoundly mentally retarded adult male patients undergoing slow "diagnostic" neuroleptic taper, it was determined that at least 60% could eventually be managed without psychoactive medication. However, many of these demonstrated a remarkably long, but nonetheless transient, period of worsening. This suggests that behavioral deterioration during drug reduction trials does not always indicate a need for chronic neuroleptic maintenance since these behaviors may return to baseline without pharmacological intervention. On the other hand, 40% demonstrated persistent (> 2 years) behavioral worsening. Those individuals who demonstrated persistent deterioration had been generally well controlled on neuroleptics, were somewhat older, and were receiving a higher baseline dose. Most of these persistently worsened subjects currently require some type of psychoactive medication (although only two have been returned to neuroleptics).

Difficulties in developing techniques to measure plasma levels of neuroleptic drugs have included the presence of metabolites, as well as cross-reactivity not only between these metabolites and the parent compound but between drugs (e.g., a phenothiazine and a tricyclic). Although newer techniques have minimized some of these problems, interpretation of published data must also recognize such design limitations as variable dose, small sample size, etc. The literature is reviewed on the relationship between therapeutic response and plasma levels of chlorpromazine, thioridazine, thiothixene, fluphenazine, butaperazine, and haloperidol. It is suggested that additional studies, carefully designed, on dosage and plasma levels could help in achieving the lowest possible therapeutic dosage and thus in minimizing side effects.

The efficacy of oral concentrate in the rapid tranquilization of 159 acutely disturbed patients in a psychiatric emergency service was evaluated. Patients were randomly assigned to 1 of 10 treatment groups: 7 oral groups and 3 comparison intramuscular groups. Although intramuscular medication produced a faster response, concentrate also proved to be effective for rapid tranquilization. Side effects were benign and minimal. Age, sex, race, and diagnosis had no effect on outcome. The use of concentrate as a paradigm for treating acutely psychotic patients is discussed.

Results of investigations concerning the correlation between plasma concentrations and clinical effect of neuroleptics and antidepressives are summarised. In the case of neuroleptics there is in general no relationship between clinical parameters of activity and plasma concentration. For antidepressives there is, in most cases, a correlation between side-effects and plasma concentrations. Whether the therapeutic effect is dependent on the plasma concentration or not, is however open to some doubt. The practical value of plasma concentration estimations during therapy with the above mentioned drugs is therefore limited. Inadequate efficacy and/or poor tolerance can occasionally be explained by estimating plasma concentrations which alone, however, scarcely allow one to make prophecies. In determination of the optimal individual dosage must continue to be an empirical process based on clinical observations and experience.

The authors studied high-potency versus low-potency neuroleptic dosing practices for 110 Boston-area psychiatric inpatients and compared the findings with the dosing practices reported in surveys of nearly 16,000 Veterans Administration patients. Mean chlorpromazine equivalent doses for the most common agents correlated strongly in both samples. Although frequencies of lower doses of both types of agents were similar, doses of potent drugs above the daily equivalent of 1 g of chlorpromazine accounted for more than 40% of prescriptions. The mean chlorpromazine-equivalent dose of popular potent agents (haloperidol or fluphenazine) was 3.54 times as high as that of popular low-potency agents (chlorpromazine or thioridazine). Potent agents are commonly used in mania and schizophrenia, often in relatively high doses, which may carry an excess of risk over unproven added benefit.

The antipsychotic effect of alpha-methyltyrosine (alpha-MT) in combination with thioridazine was investigated by means of rating scales for "social behaviour" and "mental symptoms". The clinical effect was also evaluated in relation to the serum concentrations of alpha-MT and thioridazine and to the increase in prolactin secretion in response to the interaction with hypothalamic dopaminergic mechanisms. The interactions between the serum levels of alpha-MT and those of the transmitter precursors phenylalanine and tyrosine were analysed. The results confirmed the ability of alpha-MT (2 g/day) to potentiate the antipsychotic effect of thioridazine, whereby the dose of neuroleptic drug required to control psychotic symptoms may be markedly reduced. None of the four patients who completed the trial showed side effects that could be ascribed to alpha-MT. The antipsychotic effect of thioridazine, alone or in combination with alpha-MT, correlated well with the prolactin response in the individual patient. No important interference with serum phenylalanine or tyrosine levels was noted during treatment with alpha-MT.