RESUMO
Thioridazine is a phenothiazine drug which has previously been extensively used for its antipsychotic properties as it is associated with a low risk of extra-pyramidal side-effects. There is good evidence to suggest that, in common with other phenothiazine drugs, thioridazine has important anti-microbial activity and is a potential candidate for development as an anti-microbial drug against multi-resistant organisms, including drug-resistant strains of M. tuberculosis. The clinical pharmacology and toxicity profile of thioridazine are reviewed in this article and the implications for future drug development along with the patent are discussed.
Assuntos
Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Tioridazina/uso terapêutico , Animais , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Descoberta de Drogas , Quimioterapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Mycobacterium tuberculosis/patogenicidade , Patentes como Assunto , Medição de Risco , Fatores de Risco , Tioridazina/efeitos adversos , Tioridazina/farmacocinética , Resultado do TratamentoRESUMO
UNLABELLED: Reducing drug related deaths has been identified as a health priority by the Scottish Executive. AIMS: This study investigates the association between drug related deaths in the Lothian region and prior contact with hospital-based services in the Edinburgh Royal Infirmary. DESIGN/SETTING: Retrospective analysis of 90 drug related deaths in Lothian from 2003-2005. Hospital episodes within five years of death were identified by searching the electronic patient record system within the Edinburgh Royal Infirmary. FINDINGS: Seventy-five of the 90 drug related deaths occurred in the hospital catchment area. Forty five of these 75 deaths (60%) occurred in patients who had used hospital-based services in the previous five years. The median time from hospital contact to deaths was five months and median number of hospital attendances/admissions was three (range 1 - 26). CONCLUSION: Liaison between emergency departments, clinical toxicology services and community based drug addiction services is important to identify drug misusers at high risk. A hospital-based specialist nurse-led liaison service may be able to fulfil this role.
Assuntos
Hospitais/estatística & dados numéricos , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escócia/epidemiologiaRESUMO
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.
Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Sistema de Condução Cardíaco/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Tioridazina/efeitos adversos , Tioridazina/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Estudos Transversais , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Antagonistas de Dopamina/efeitos adversos , Antagonistas de Dopamina/sangue , Feminino , Variação Genética , Genótipo , Humanos , Modelos Lineares , Síndrome do QT Longo/sangue , Síndrome do QT Longo/fisiopatologia , Masculino , Mesoridazina/efeitos adversos , Mesoridazina/sangue , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Fatores de Risco , Esquizofrenia/tratamento farmacológico , Fatores Sexuais , Fumar/efeitos adversos , Tioridazina/administração & dosagem , Tioridazina/farmacocinética , População Branca/genéticaRESUMO
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.
