Importancia de las arritmias cardiacas inducidas por tioridazina en las edades geriátricas / Importance of the heart arrhythmias induced by thioridazine in geriatric ages

RESUMEN Introducción: la discapacidad mental, íntimamente relacionada con el incremento de la expectativa de vida, se considera uno de los problemas más graves que hay que enfrentar en la centuria recién iniciada. Esto trae consigo el aumento de la prescripción de agentes anti psicóticos, como la tioridazina, lo que tiende a convertirse en un problema de salud al causar arritmias y en ocasiones fatales. Aún no se conoce en qué grado estas alteraciones son responsables de algunas muertes súbitas ocurridas en personas que tomaban estos medicamentos. Objetivo: identificar cuáles son las alteraciones clínicas y electrocardiográficas en los pacientes que usan la tioridazina, como droga de elección en los trastornos psiquiátricos. Materiales y métodos: se realizó un estudio descriptivo, a los ancianos atendidos en el Servicio de Geriatría que ingieran tioridazina, en cualquier dosis. Durante al período de marzo del año 2017 hasta marzo del 2018. Resultados: predominaron los ancianos del sexo femenino y comprendido en las edades 60 y 74 años, con nivel de escolaridad secundario, lo que se correlacionó con la doble función de la mujer en la sociedad actual, y el elevado nivel de escolaridad de la ciudadanía cubana. Predominaron antecedentes de hipertensión arterial y diabetes, al igual las palpitaciones en relación a un aumento de los bloqueos del has de his, observados en los electrocardiogramas. No se presentaron fallecidos. Conclusiones: deben utilizarse dosis bajas del medicamento, por corto tiempo y bajo supervisión electrocardiográfica (AU).

ABSTRACT Introduction: mental incapacity, tightly related to the life expectancy increase, is considered one of the most serious problems to afford in the current century. It brings about the increase of the prescription of anti-psychotic agents, like thioridazine, tending to become a health problem because of causing arrhythmias that are occasionally life-threatening. It is still unknown in what level these alterations are responsible for several sudden deaths in persons who took these drugs. Objective: to identify which are the clinical and electrocardiographic alterations in patients using thioridazine as drug of choice in psychiatric disorders. Materials and methods: a descriptive study was carried out in all patients who attended the Geriatric Service taking thioridazine in any doses during the period from March 2017 to March 2018. Results: female elder people aged 60-74 years predominated, with secondary school scholarship, finding a relationship with the double function of women in the current society, and the high level of scholarship among Cuban citizen. Arterial hypertension and diabetes antecedents predominated, and also palpitations related to the increase of His bundle blockade observed in electrocardiograms. There were no deaths. Conclusions: low doses of the drug should be used for a short time and under electrocardiographic supervision (AU).

Association between Thioridazine Use and Cancer Risk in Adult Patients with Schizophrenia-A Population-Based Study

OBJECTIVE: Several cell line studies have demonstrated thioridazine’s anticancer, multidrug resistance-reversing and apoptosis-inducing properties in various tumors. We conducted this nationwide population-based study to investigate the association between thioridazine use and cancer risk among adult patients with schizophrenia. METHODS: Based on the Psychiatric Inpatient Medical Claim of the National Health Insurance Research Database of Taiwan, a total of 185,689 insured psychiatric patients during 2000 to 2005 were identified. After excluding patients with prior history of schizophrenia, only 42,273 newly diagnosed patients were included. Among them, 1,631 patients ever receiving thioridazine for more than 30 days within 6 months were selected and paired with 6,256 randomly selected non-thioridazine controls. These patients were traced till 2012/12/31 to see if they have any malignancy. RESULTS: The incidence rates of hypertension and cerebrovascular disease were higher among cases than among matched controls. The incidence of hyperlipidemia, coronary artery disease and chronic pulmonary disease did not differ between the two groups. By using Cox proportional hazard model for cancer incidence, the crude hazard ratio was significantly higher in age, hypertension, hyperlipidemia, cerebrovascular disease, coronary artery disease and chronic pulmornary disease. However, after adjusting for other covariates, only age and hypertension remained significant. Thioridazine use in adult patients with schizophrenia had no significant association with cancer. CONCLUSION: Despite our finding that thioridazine use had no prevention in cancer in adult patients with schizophrenia. Based on the biological activity, thioridazine is a potential anticancer drug and further investigation in human with cancer is warranted.

Mechanism of thioridazine-induced apoptosis of human colorectal cancer SW480 cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the effect of thioridazine on the proliferation and apoptosis of human colorectal cancer SW480 cells.</p><p><b>METHODS</b>SW480 cells were treated with different concentrations of thioridazine, and MTT assay was used to evaluate the cell inhibition rate. Hoechst 33342 staining was performed to demonstrate the cell morphology changes. Flow cytometry was used to determine the cell apoptosis and cell cycle changes. RT-qPCR was used to detect PDCD4, c-MYC, BCL2, CCND1, CASPASE3, PARP1, CDK4 and EIF4A mRNA expressions, and Western blotting was employed to assay AKT, p-AKT, and PDCD4 protein expression levels.</p><p><b>RESULTS</b>MTT results showed that thioridazine inhibits the proliferation of SW480 cells. SW480 cells treated with thioridazine presented with such typical features of apoptosis of karyopyknosis, chromatin condensation and nuclear fragmentation. Flow cytometry showed that thioridazine was a cell cycle-specific drug and caused cell cycle arrest at G(1)/G(0) phase and an increased cell apoptosis rate. Thioridazine treatment of the cells resulted in up-regulated PDCD4 mRNA expression and down-regulated mRNA expressions of CCND1, CDK4, c-MYC, BCL2, CASPASE3, PARP1 and EIF4A, increased PDCD4 protein expression and reduced p-AKT protein expression.</p><p><b>CONCLUSION</b>Thioridazine inhibits the proliferation and induces apoptosis of SW480 cells by up-regulating PDCD4 and inhibiting PI3K/Akt pathway.</p>

Comparison of efficacy of thioridazine with clonidine acting through different mechanisms in acute opioid abstinence syndrome

To compare the efficacy, safety and tolerability of thioridazine with clonidine in patients with Acute opioid Abstinence Syndrome. This single blind comparative clinical trial was carried out at Department of Pharmacology, Basic Medical Sciences Institute [BMSI], Jinnah Postgraduate Medical Center [JPMC], Karachi. Fifty two addicts were selected randomly and were grouped into, group-A to received thioridazine 100 mg/day and group -B to received clonidine 150mcg/day. All participants completed the treatment program and stayed in hospital for ten days. The efficacy safety and tolerability of thioridazine was scant, while clonidine showed statistically significant turn down in the objective signs of acute opioid abstinence syndrome. Clonidine had more powerful effects than thioridazine. While treating the withdrawal signs of opioid abstinence syndrome may possibly pointed out that over activation of norepinephrine is a major factor contributes to the commencement of opioid abstinence syndrome

Comparative study of verapamil and thioridazine in acute opioid abstinence syndrome

To determine the effectiveness of verapamil and thioridazine in the treatment of acute opioid withdrawal syndrome in patients with chronic dependence on opioids. The study was conducted at Psychological Medicine Ward, Civil Hospital Karachi and Arshi Hospital, Naseerabad, F.B. area Karachi. A total of forty [40] patients were admitted for ten [10] days in hospital. No treatment was given during the first two days of admission after abrupt termination of opioid to observe the acute opioid withdrawal signs and symptoms. Patients were divided into 2 groups. Each group comprising of 20 opiate addicts. One group was given verapamil orally in a 40mg dose thrice daily and the other group was given thioridazine orally in a 10mg dose thrice daily from day 3 to day 9 of admission. The intensity of sign and symptoms were recorded by using subjective and objective opiate withdrawal questionnaire. Urine analysis for opioids was done on day 1, 5 and 10 of admission. Verapamil in comparison to thioridazine significantly decreased admission. Urine analyses for opioids were positive on day 01 while zero on day 10. Verapamil in comparison to Thioridazine was found to be safe and effective for the treatment of signs and symptoms of acute opioid withdrawal in in-door patients without any significant side effect

Effect of chemosensitizers on minimum inhibitory concentrations of fluconazole in candida albicans

To evaluate the effect of chemosensitizers on the in vitro activity of fluconazole against Candida albicans strains. Using Clinical Laboratory Standard Institute method, antifungal activity of fluconazole was determined alone and in combination with 16 chemosensitizers that included verapamil, reserpine, quinine, quinidine, gemfibrozil, lansoprazole, tamoxifen, diltiazem, desipramine, nicardipine, cyclosporine, chlorpromazine, prochlorperazine, promethazine, thioridazine, and trifluoperazine. Further studies were done using double combinations of selected chemosensitizers with fluconazole [28 combinations]. For testing combinations, half of the minimum inhibitory concentration [MIC] of each agent was selected in order to avoid the effect of the drug alone. One reference strain [ATCC90028] and one clinical isolate of C. albicans were used for testing the in vitro activity. Broth dilution method was used to determine the MICs of fluconazole and chemosensitizers. Of the 16 chemosensitizers tested, 3 exhibited in vitro activity by increasing fluconazole susceptibility to 7-fold. The MICs of the reference strain and clinical isolate for fluconazole were 5.5 and 0.55 MU g/ml, respectively, and these were reduced to 0.76 MU g/ml by gemfibrozil, 0.83 MU g/ml by quinine, and 0.76 MU g/ml by chlorpromazine in the reference strain, with MIC reduction to 0.08 MU g/ml by all three chemosensitizers in the clinical isolate. Some double combinations reduced the MIC of fluconazole to 10- to 100-fold, even when the chemosensitizers were not effective alone. The most effective double combinations were those of chlorpromazine with either reserpine or nicardipine

Antipsychotic Drugs and Sudden Death

Sudden, unexpected death may occur in apparently healthy individuals. Its occurrence in psychiatric patients has raised the concern that the use of psychotropics, especially antipsychotics, may be associated with an increased risk of sudden death. This concern is maintained even though not all psychiatric patients who have succumbed to sudden death have been on psychotropics. Early reports presented the concern that the use of chlorpromazine and thioridazine were associated with sudden death. More recently, the focus shifted to the more potent agents. Indeed, the FDA Advisory Committee discussed the possibility of a connection between sudden death and haloperidol. No decision could be reached by the FDA Committee because of the enormous complexity of the problem. Nonetheless, since sudden death continues to catastrophically complicate the course of some patients, the scope of this review is to further investigate the relationship between antipsychotic agents and sudden death

Photo-oxidative damage to isolated rat liver mitochondria induced by phenothiazines

Photosensitization is a well-known side-effect of phenothiazines that could involve photochemically promoted oxidative damage to mitochondria, leading to the impairment of metabolic functions and apoptosis. In this work, for the first time, we investigated the effects of photoexcited thioridazine (TR), trifluoperazine (TFP) and fluphenazine (FP) on isolated rat liver mitochondria. Under UV irradiation, the presence of these phenothiazines led to a dose-dependent lack of the respiratory control ratio. These effects were not accompanied by significant swelling and oxidation of protein thiol groups but were accompanied by lipid peroxidation. Lycopene and sorbate, well-known quenchers of singlet oxygen and triplet species, respectively, were ineffective at protecting mitochondrial lipids against the damage promoted by the excited phenothiazines, suggesting that photochemically-produced cation radicals were the pro-oxidant species. Corroborating this proposal, butylated hydroxytoluene (BHT) completely inhibited the lipid peroxidation induced by UV irradiation in the presence of phenothiazines. These novel results make a significant contribution to the understanding of the photochemical properties of phenothiazines in biological systems

A Case of Significant Arrhythmia Caused by Thioridazine Poisoning

A 51-year-old woman with schizophrenia and depression brought to our emergency room after thioridazine overdose. Her mental state was semicomatous. The initial electrocardiogram showed bradycardia, atrial premature contractions, prolonged PR interval, wide QRS complexes and U waves. She was admitted to the intensive care unit. Continuous electrocardiographic monitoring and artificial ventilation was performed. The treatment included fluids hydration, administration of inotropic agents, alkalization and replacement of electrolytes. On day 2, torsades de pointes on the electrocardiogram was occurred. The rhythms were resolved with isoproterenol infusion. Her hemodynamic state became stable. On day 6, electrocardiographic finding was normalized. She was recovered without any neurologic or cardiac complications. Herein, a rare case is reported, with the review of the literature.

Mania e gravidez: implicações para o tratamento farmacológico e proposta de manejo / Mania and pregnancy: issues related to pharmacologic treatment and management proposal

O tratamento de doenças psiquiátricas na gravidez é complexo, implicando decisões clínicas difíceis, sem contar-se com dados da literatura que embasem aplamente estas decisões. O transtorno afetivo bipolar é comum em mulheres em idade fértil, e há alto risco de ocorrência de manifestações clínicas na gravidez e no período pós-parto. Os autores revisam o conhecimento atual sobre o uso de psicotrópicos para episódio maníaco na gravidez e o efeito no desenvolvimento fetal e da criança. Enfatizam que, hoje, o uso de psicotrópicos na gravidez é apropriado em muitas situações clínicas, mas nenhuma decisão é completamente isenta de risco. Também apresentam uma proposta de manejo da doença em relação ao uso de psicotrópicos na gravidez, para pacientes com transtorno bipolar, e para aquelas que desejam engravidar.

Dosal Root Ganglionectomy for a Post-Herpetic Neuralgia: Case Report

We report a case of thoracic post-herpetic neuralgia which was improved by dorsal root ganglionectomy. The patient had failed to obtain adequate pain relief from conservative therapy such as carbamazepine, amitriptyline, thioridazine, gabapentin, and transcutaneous lidocaine infiltration. Thoracic dorsal root ganglionectomy from T5 to T7 on left side was performed and satisfactory pain relief without significant postoperative neurologic deficit was achieved. Although dorsal root entry zone operation for refractory pain was the most commonly performed procedure in past, dorsal root ganglionectomy is an alternative anatomically and technically safe procedure for the pain in the thoracic lesion. The clinical feature, operative technique and clinical result are presented with review of the literatures.

Clinical Experience of Clozapine Discontinuation: Comparison between Sulpiride and Thioridazine Switch Group / 대한정신약물학회지

OBJECTIVE: Several reports have found that withdrawal symptoms of clozapine are more severe and common than that of the typical antipsychotics. The objective of this study was to report the clinical experiences of relatively rapid withdrawal of clozapine in the patients with schizophrenia at the end of over a year clinical trial of clozapine. METHODS: Twenty-three patients with schizophrenia who had been administered clozapine were withdrawn from clozapine by tapering it over 1-2 weeks, depending on clozapine maintenance dose and subsequently switched to sulpiride or thioridazine randomly. Patients were assessed using PANSS, CGI, and Sympson-Augus Rating Scale on the first, third, and last day of clozapine tapering as well as on the first, second, and fourth week of sulpiride or thioridazine. RESULTS: Fifteen of the 23 patients (65%) relapsed: 5 patients relapsed during the clozapine tapering period and 10 patients relapsed during the switching period to sulpiride or thioridazine. Six of the 9 patients (67%) in the sulpiride switch group relapsed and 4 of the 10 patients (40%) in the thioridazine switch group relapsed. The withdrawal symptoms of clozapine appear faster with a higher relapse rate than the typical antipsychotic drugs. CONCLUSIONS: Our data suggests that if at all possible clozapine should not be discontinued and for patients who need to be switched to a different antipsychotics for a specific reason, at least 2 weeks of clozapine tapering are recommended. The possibility of cross tapering with another drug should also be considered.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país