RESUMO
Phenothiazines inhibit antioxidant enzymes in trypanosomatids. However, potential interferences with host cell antioxidant defenses are central concerns in using these drugs to treat Trypanosoma cruzi-induced infectious myocarditis. Thus, the interaction of thioridazine (TDZ) with T. cruzi and cardiomyocytes antioxidant enzymes, and its impact on cardiomyocytes and cardiac infection was investigated in vitro and in vivo. Cardiomyocytes and trypomastigotes in culture, and mice treated with TDZ and benznidazole (Bz, reference antiparasitic drug) were submitted to microstructural, biochemical and molecular analyses. TDZ was more cytotoxic and less selective against T. cruzi than Bz in vitro. TDZ-pretreated cardiomyocytes developed increased infection rate, reactive oxygen species (ROS) production, lipid and protein oxidation; similar catalase (CAT) and superoxide dismutase (SOD) activity, and reduced glutathione's (peroxidase - GPx, S-transferase - GST, and reductase - GR) activity than infected untreated cells. TDZ attenuated trypanothione reductase activity in T. cruzi, and protein antioxidant capacity in cardiomyocytes, making these cells more susceptible to H2O2-based oxidative challenge. In vivo, TDZ potentiated heart parasitism, total ROS production, myocarditis, lipid and protein oxidation; as well as reduced GPx, GR, and GST activities compared to untreated mice. Benznidazole decreased heart parasitism, total ROS production, heart inflammation, lipid and protein oxidation in T. cruzi-infected mice. Our findings indicate that TDZ simultaneously interact with enzymatic antioxidant targets in cardiomyocytes and T. cruzi, potentiating the infection by inducing antioxidant fragility and increasing cardiomyocytes and heart susceptibility to parasitism, inflammation and oxidative damage.
Assuntos
Antioxidantes , Cardiomiopatia Chagásica , Miócitos Cardíacos , Espécies Reativas de Oxigênio , Tioridazina , Trypanosoma cruzi , Animais , Miócitos Cardíacos/parasitologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Trypanosoma cruzi/efeitos dos fármacos , Camundongos , Antioxidantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tioridazina/farmacologia , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Miocardite/parasitologia , Miocardite/tratamento farmacológico , Miocardite/metabolismo , Miocardite/patologia , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Masculino , Tripanossomicidas/farmacologia , Superóxido Dismutase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Doença de Chagas/metabolismo , Doença de Chagas/patologia , Catalase/metabolismo , Ratos , NADH NADPH Oxirredutases/metabolismoRESUMO
Crotamine is a cationic polypeptide composed by 42 amino acid residues with several pharmacological and biological properties, including the selective ability to enter and kill actively proliferating tumour cells, which led us to propose its use as a theranostic agent for cancer therapy. At the moment, the improvement of crotamine antitumoral efficacy by association with chemotherapeutic adjuvants is envisioned. In the present work, we evaluated the association of crotamine with the antitumoral adjuvant phenotiazine thioridazine (THD). In spite of the clear efficacy of these both compounds as anticancer agents in long-term in vivo treatment of animal model bearing implanted xenograph melanoma tumor, the expected mutual potentiation of the antitumor effects was not observed here. Moreover, this association revealed for the first time the influence of THD on crotamine ability to trigger the hind limb paralysis in mice, and this discovery may represent the first report suggesting the potential involvement of the CNS in the action of this snake polypeptide on the skeletal muscle paralysis, which was classically believed to be essentially limited to a direct action in peripheral tissues as the skeletal muscle. This is also supported by the observed ability of crotamine to potentiate the sedative effects of THD which action was consistently demonstrated to be based on its central action. The better characterization of crotamine properties in CNS may certainly bring important insights for the knowledge needed to pave the way toward the use of this molecule as a theranostic compound in human diseases as cancer.
Assuntos
Antineoplásicos/uso terapêutico , Venenos de Crotalídeos/toxicidade , Extremidade Inferior , Paralisia/tratamento farmacológico , Tioridazina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Camundongos , Tioridazina/farmacologiaRESUMO
While thioridazine (Tio) inhibits the antioxidant defenses of Trypanosoma cruzi, the gold standard antitrypanosomal drug benznidazole (Bz) has potent anti-inflammatory and pro-oxidant properties. The combination of these drugs has never been tested to determine the effect on T. cruzi infection. Thus, we compared the impact of Tio and Bz, administered alone and in combination, on the development of skeletal myositis and liver inflammation in T. cruzi-infected mice. Swiss mice were randomized into six groups: uninfected untreated, infected untreated, treated with Tio (80 mg/kg) alone, Bz (50 or 100 mg/kg) alone, or a combination of Tio and Bz. Infected animals were inoculated with a virulent T. cruzi strain (Y) and treated by gavage for 20 days. Mice untreated or treated with Tio alone developed the most intense parasitemia, highest parasitic load, elevated IL-10, IL-17, IFN-γ, and TNF-α plasma levels, increased N-acetylglucosaminidase and myeloperoxidase activity in the liver and skeletal muscle, as well as severe myositis and liver inflammation (P < 0.05). All parameters were markedly attenuated in animals receiving Bz alone (P < 0.05). However, the co-administration of Tio impaired the response to Bz chemotherapy, causing a decrease in parasitological control (parasitemia and parasite load), skeletal muscle and liver inflammation, and increased microstructural damage, when compared to the group receiving Bz alone (P < 0.05). Altogether, our findings indicated that Tio aggravates systemic inflammation, skeletal myositis and hepatic inflammatory damage in T. cruzi-infected mice. By antagonizing the antiparasitic potential of Bz, Tio limits the anti-inflammatory, myoprotectant and hepatoprotective effects of the reference chemotherapy, aggravating the pathological remodeling of both organs. As the interaction of T. cruzi infection, Bz and Tio is potentially toxic to the liver, inducing inflammation and microvesicular steatosis; this drug combination represents a worrying pharmacological risk factor in Chagas disease.
Assuntos
Doença de Chagas/tratamento farmacológico , Miosite/patologia , Nitroimidazóis/farmacologia , Tioridazina/toxicidade , Tripanossomicidas/farmacologia , Acetilglucosaminidase/metabolismo , Animais , Doença de Chagas/sangue , Doença de Chagas/imunologia , Citocinas/sangue , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Glicogênio/metabolismo , Hepatite/metabolismo , Hepatite/patologia , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Miosite/tratamento farmacológico , NADH NADPH Oxirredutases/antagonistas & inibidores , Nitroimidazóis/uso terapêutico , Carga Parasitária , Parasitemia/tratamento farmacológico , Peroxidase/metabolismo , Tioridazina/uso terapêutico , Transaminases/metabolismo , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimentoRESUMO
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).
Assuntos
Humanos , Idoso , Arritmias Cardíacas/diagnóstico , Tioridazina/uso terapêutico , Doenças Cardiovasculares/diagnóstico , Arritmias Cardíacas/induzido quimicamente , Doenças Cardiovasculares/induzido quimicamente , Epidemiologia Descritiva , Estudos Longitudinais , Pessoas Mentalmente Doentes , Demência/diagnóstico , Demência/terapia , Eletrocardiografia/métodos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/terapiaRESUMO
Paracoccidioides brasiliensis is a thermodimorphic fungus associated with paracoccidioidomycosis (PCM), the most common systemic mycosis in Latin America. PCM treatment involves a long-term chemotherapeutic approach and relapses occur at an alarming frequency. Moreover, the emergence of strains with increased drug-resistance phenotypes puts constant pressure on the necessity to develop new alternatives to treat systemic mycoses. In this work, we show that the phenothiazine (PTZ) derivative thioridazine (TR) inhibits in vitro growth of P. brasiliensis yeasts at micromolar concentrations. We employed microarray hybridization to examine how TR affects gene expression in this fungus, identifying ~1800 genes that were modulated in response to this drug. Dataset evaluation showed that TR inhibits the expression of genes that control the onset of the cell wall integrity (CWI) response, hampering production of all major structural polysaccharides of the fungal cell wall (chitin, α-glucan and ß-glucan). Although TR and other PTZs have been shown to display antimicrobial activity by various mechanisms, inhibition of CWI signaling has not yet been reported for these drugs. Thus, TR may provide a novel approach to treat fungal infections by targeting cell wall biogenesis.
Assuntos
Proteínas Fúngicas/genética , Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Paracoccidioides/efeitos dos fármacos , Tioridazina/farmacologia , Parede Celular/efeitos dos fármacos , Parede Celular/genética , Polissacarídeos Fúngicos/biossíntese , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Paracoccidioides/genética , Paracoccidioidomicose/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacosRESUMO
The present study shows the factors that modulate the photodamage promoted by phenothiazines. Cytochrome c was irradiated with UV light for 120 min, over a pH range from 4.0 to 8.0, in the absence and in the presence of different concentrations of thioridazine (TR) and fluphenazine (FP). In the absence of phenothiazines, the maximal rate of a Soret band blue shift (nm/min) from 409 to 406 nm was obtained at pH 4.0 (0.028 nm/min). The presence of phenothiazines at the concentration range 10-25 µmol/L amplified and accelerated a cytochrome c blue shift (409 to 405 nm, at a rate = 0.041 nm/min). Above 25 µmol/L, crescent concentrations of phenothiazines contributed to cytochrome c protection with (maximal at 2500 µmol/L). Scanning electronic microscopy revealed the formation of nanostructures. The pH also influenced the effect of low phenothiazine concentrations on cytochrome c. Thus, the predominance of phenothiazine-promoted cytochrome c damage or protection depends on a balance of the following factors: the yield of photo-generated drug cation radicals, which is favored by acidic pH; the stability of the cation radicals, which is favored by the drug aggregation; and the cytochrome c structure, modulated by the pH.
Assuntos
Citocromos c/química , Citocromos c/metabolismo , Flufenazina/química , Flufenazina/farmacologia , Tioridazina/química , Tioridazina/farmacologia , Raios Ultravioleta , Animais , Relação Dose-Resposta a Droga , Radicais Livres/metabolismo , Concentração de Íons de Hidrogênio , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologiaRESUMO
OBJECTIVES: Current drug choices to treat extensively drug-resistant (XDR) tuberculosis (TB) are scarce; therefore, information on the safety, tolerability and efficacy of alternative regimens is of utmost importance. The aim of this study was to describe the management, drug adverse effects and outcome of alternative combined treatment in a series of XDR-TB patients. PATIENTS AND METHODS: A retrospective study was performed on 17 non-AIDS, pulmonary adult patients with XDR-TB admitted to a referral treatment centre for infectious diseases in Buenos Aires from 2002 through 2008. Drug susceptibility testing was performed under regular proficiency testing and confirmed at the national TB reference laboratory. RESULTS: Linezolid was included in the drug regimens of all patients; moxifloxacin and/or thioridazine were included in the regimens of 14 patients. Clinically tractable drug adverse effects were observed in nine patients, the most frequent being haematological disorders and neurotoxicity. In two patients, thioridazine was discontinued. Negative culture conversion was achieved in 15 patients, 11 completed treatment meeting cure criteria, 4 are still on follow-up with good evolution, 1 defaulted treatment and 1 was lost to follow-up. CONCLUSIONS: The combination of linezolid, moxifloxacin and thioridazine is recommended for compassionate use in specialized centres with expertise in the management of XDR-TB.
Assuntos
Acetamidas/administração & dosagem , Antituberculosos/administração & dosagem , Compostos Aza/administração & dosagem , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Oxazolidinonas/administração & dosagem , Quinolinas/administração & dosagem , Tioridazina/administração & dosagem , Acetamidas/efeitos adversos , Adulto , Antituberculosos/efeitos adversos , Argentina , Compostos Aza/efeitos adversos , Ensaios de Uso Compassivo/métodos , Farmacorresistência Bacteriana Múltipla , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Feminino , Fluoroquinolonas , Humanos , Linezolida , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Oxazolidinonas/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , Tioridazina/efeitos adversos , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologiaRESUMO
Thioridazine (TDZ) has been shown to have in vitro activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis, to promote the killing of intracellular MDR and XDR strains and to cure the mouse of antibiotic-susceptible and -resistant pulmonary tuberculosis (TB) infections. Recently, TDZ was used to cure 10 of 12 XDR-TB patients in Buenos Aires, Argentina. At the time of writing, it is being used for the therapy of non-antibiotic-responsive terminal XDR-TB patients in Mumbai, India, on the basis of compassionate therapy and although it is too early to determine a cure, the patients have improved appetite, weight gain, are afebrile and free of night sweats, and their radiological picture shows great improvement. Because XDR-TB is essentially a terminal disease in many areas of the world and no new effective agents have yet to yield successful clinical trials, global clinical trials for the therapy of XDR-TB are urgently required.
Assuntos
Antituberculosos/uso terapêutico , Ensaios Clínicos como Assunto , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tioridazina/uso terapêutico , Animais , Antituberculosos/farmacologia , Argentina , Humanos , Índia , Camundongos , Tioridazina/farmacologiaRESUMO
The purpose of this study was to develop a method for the stereoselective analysis of thioridazine-2-sulfoxide (THD-2-SO) and thioridazine-5-sulfoxide (THD-5-SO) in culture medium and to study the biotransformation of rac-thioridazine (THD) by some endophytic fungi. The simultaneous resolution of THD-2-SO and THD-5-SO diastereoisomers was performed on a CHIRALPAK AS column using a mobile phase of hexane:ethanol:methanol (92:6:2, v/v/v)+0.5% diethylamine; UV detection was carried out at 262 nm. Diethyl ether was used as extractor solvent. The validated method was used to evaluate the biotransformation of THD by 12 endophytic fungi isolated from Tithonia diversifolia, Viguiera arenaria and Viguiera robusta. Among the 12 fungi evaluated, 4 of them deserve prominence for presenting an evidenced stereoselective biotransformation potential: Phomopsis sp. (TD2) presented greater mono-2-sulfoxidation to the form (S)-(SE) (12.1%); Glomerella cingulata (VA1) presented greater mono-5-sulfoxidation to the forms (S)-(SE)+(R)-(FE) (10.5%); Diaporthe phaseolorum (VR4) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(FE) (84.4% and 82.5%, respectively) and Aspergillus fumigatus (VR12) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(SE) (31.5% and 34.4%, respectively).
Assuntos
Antipsicóticos/isolamento & purificação , Asteraceae/microbiologia , Cromatografia Líquida de Alta Pressão/métodos , Fungos/metabolismo , Tioridazina/análogos & derivados , Tioridazina/isolamento & purificação , Amilose/análogos & derivados , Amilose/química , Antipsicóticos/química , Antipsicóticos/metabolismo , Aspergillus fumigatus/isolamento & purificação , Aspergillus fumigatus/metabolismo , Biotransformação , Soluções Tampão , Carbamatos/química , Cromatografia Líquida de Alta Pressão/normas , Meios de Cultura/química , Dietilaminas/química , Etanol/química , Éter/química , Fungos/isolamento & purificação , Hexanos/química , Metanol/química , Phyllachorales/isolamento & purificação , Phyllachorales/metabolismo , Reprodutibilidade dos Testes , Solventes/química , Espectrofotometria Ultravioleta , Estereoisomerismo , Tioridazina/química , Tioridazina/metabolismoRESUMO
The stereoselective kinetic biotransformation of thioridazine, a phenothiazine neuroleptic drug, by endophytic fungi was investigated. In general, the sulfur of lateral chain (position 2) or the sulfur of phenothiazinic ring (position 5) were oxidated yielding the major human metabolites thioridazine-2-sulfoxide and thioridazine-5-sulfoxide. The quantity of metabolites biosynthesized varied among the 12 endophytic fungi evaluated. However, mono-2-sulfoxidation occurred in higher ratio and frequency. Among the 12 fungi evaluated, 4 of them deserve prominence for presenting an evidenced stereoselective biotransformation: Phomopsis sp. (TD2), Glomerella cingulata (VA1), Diaporthe phaseolorum (VR4), and Aspergillus fumigatus (VR12). Both enantiomers of thioridazine were consumed by the fungi; however, the 2-sulfoxidation yielded preferentially the R configuration at the sulfur atom.
Assuntos
Ascomicetos/metabolismo , Aspergillus fumigatus/metabolismo , Tioridazina/metabolismo , Biotransformação , Phyllachorales/metabolismo , Estereoisomerismo , Tioridazina/químicaRESUMO
Mice infected with Trypanosoma cruzi Tulahuen strain or SGO-Z12 isolate were treated at 180 days post infection (p.i.) (i.e. chronic phase) with benznidazole (for 30 days) or thioridazine (for 12 days). Both drugs produced a decrease in electrocardiographic alterations, fewer modifications in the affinity and density of cardiac beta-receptors, and few isolated areas of fibrosis in the heart, whereas untreated mice presented areas of necrosis and fibre fragmentation 350 days p.i. (P<0.01). Survival in treated mice was 100% for benznidazole and 88% for thioridazine, independent of the parasite strain; survival for untreated mice was 30% and 40% for Tulahuen strain and SGO-Z12 isolate, respectively (P<0.01). No cardiotoxic effects of thioridazine were detected at the dose and treatment schedule used. These results show the benefit of treatment in the chronic phase of Chagas disease and that thioridazine should be considered as a promising agent for the treatment of Chagas disease.
Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tioridazina/uso terapêutico , Tripanossomicidas/uso terapêutico , Animais , Doença Crônica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Eletrocardiografia , Camundongos , Nitroimidazóis/farmacologia , Tioridazina/farmacologia , Tripanossomicidas/farmacologiaRESUMO
In this work the interaction of Hydroxyzine, Promethazine and Thioridazine with Langmuir films of dipalmitoylphosphatidylcholine (dpPC) and dipalmitoylphosphatidic acid (dpPA), is studied. Temporal variations in lateral surface pressure (pi) were measured at different initial pi (pi(i)), subphase pH and drug-concentration. Drugs with the smallest (PRO) and largest (HYD) molecular size exhibited the lowest adsorption (k(a)) and the highest desorption (k(d)) rate constant values, respectively. The affinity binding constants (K(b)) obtained in monolayers followed the same profile (K(b,PRO) < K(b,HYD) < K(b,THI)) of the egg-PC/water partition coefficients (P) determined in bilayers. The drug concentration required to reach the half-maximal Deltapi at pi(i) = 14 mN/m (K(0.5)), was very sensitive to pH. The maximal increment in pi upon drug incorporation into the monolayer (deltapi(max)) will depend on the phospholipid collapse pressure (pi(c)), the monolayers's compressibility and drug's size, shape and charge. The higher pi(c) of dpPC lead to higher pi(cut-off) values (maximal pi allowing drug penetration), if compared with dpPA. In dpPC and dpPA pi(cut-off) decreased as a function of the molecular size of the uncharged drugs. In dpPA, protonated drugs became electrostatically trapped at the monolayer surface hence drug penetration, monolayer deformation and pi increase were impaired and the correlation between pi(cut-off) and drug molecular size was lost.
Assuntos
1,2-Dipalmitoilfosfatidilcolina/metabolismo , Hidroxizina/metabolismo , Ácidos Fosfatídicos/metabolismo , Prometazina/metabolismo , Tioridazina/metabolismo , 1,2-Dipalmitoilfosfatidilcolina/química , Ar , Hidroxizina/química , Bicamadas Lipídicas , Ácidos Fosfatídicos/química , Prometazina/química , Propriedades de Superfície , Tioridazina/química , ÁguaRESUMO
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
Assuntos
Ratos , Animais , Masculino , Fenotiazinas/efeitos adversos , Fígado , Flufenazina/efeitos da radiação , Mitocôndrias/efeitos da radiação , Ratos Wistar , Tioridazina/efeitos da radiação , Trifluoperazina/efeitos da radiação , Antipsicóticos , Estresse Oxidativo/efeitos da radiação , FotoquímicaRESUMO
Thioridazine (THD) is a phenothiazine neuroleptic drug used for the treatment of psychiatric disorders. After oral administration THD is extensively biotransformed to thioridazine 2-sulfone (THD 2-SO(2)), thioridazine 5-sulfoxide (THD 5-SO) and thioridazine 2-sulfoxide (THD 2-SO). THD 2-SO and THD 5-SO have two chiral centres and therefore exist as two diastereoisomeric pairs. The degradation and epimerization of THD 2-SO in human plasma, buffer and methanolic solutions were studied using an enantioselective HPLC method. The samples were prepared by liquid-liquid extraction with diethyl ether and the chiral resolution of the enantiomers was carried out on a Chiralpak AD column using a mobile phase consisting of hexane:ethanol:2-propanol (90:7:3, v/v/v) containing 0.2% diethylamine. The method was validated and used to study the degradation and epimerization under different conditions of incubation. Our results showed that both enantiomers were stable at varying temperatures, pH and ionic strengths; however, solubility problems were observed, mainly at pH 8.5. The influence of light on stability was studied using methanolic solutions and degradation and epimerization of the THD 2-SO enantiomers were observed under UV light of 366 and 254nm, respectively.
Assuntos
Sulfóxidos/sangue , Sulfóxidos/química , Tioridazina/análogos & derivados , Tioridazina/sangue , Humanos , Conformação Molecular , Tioridazina/metabolismoRESUMO
Trypanosoma cruzi trypanothione reductase is an enzyme that has been identified as a potential target for chemotherapy. Thioridazine inhibits it and prevented cardiopathy in mice infected with T. cruzi Tulahuen strain. As not all T. cruzi strains respond to treatment in the same way, an isolate from a chronic patient (SGO Z12) was used; parasitaemias were studied along with, survival, serology, electrocardiography, histology and cardiac beta receptor function. Parasitaemia in thioridazine (80 mg/(kg day) for 3 days) treated mice was less and lasted for a shorter period (P < 0.01), there were reduced electrocardiographic and histological alterations and significantly improved survival (80% of non-treated died). Treated mice had lower receptor affinity and higher density as a compensatory mechanism, modifying the course of T. cruzi infection (SGO Z12 isolate) and preventing the consequent cardiopathy.
Assuntos
Cardiomiopatia Chagásica/prevenção & controle , Doença de Chagas/complicações , Doença de Chagas/tratamento farmacológico , Tioridazina/farmacologia , Tioridazina/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Anticorpos Antiprotozoários/sangue , Modelos Animais de Doenças , Eletrocardiografia , Masculino , Camundongos , Miocárdio/patologia , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/efeitos dos fármacos , Parasitemia , Análise de Sobrevida , Tripanossomicidas/farmacologiaRESUMO
We present two methods for the enantioselective analysis of thioridazine (THD) and thioridazine 2-sulfone (THD 2-SO(2)) in human plasma based on liquid-liquid extraction with diethyl ether and chiral resolution of the enantiomers on Chiralpak AD and Chiralcel OD-H columns, respectively. After validation, the methods were used to study the degradation and racemization of both drug and metabolite. Our results showed that both enantiomers of THD and THD 2-SO(2) were stable at varying temperatures, pH, and ionic strengths; however, solubility problems for THD and THD 2-SO(2) enantiomers were observed, mainly at pH 8.5. The influence of light on the stability of the THD and THD 2-SO(2) enantiomers was also studied. Degradation of the THD enantiomers was observed under UV light (254 and 366 nm) while THD 2-SO(2) enantiomers were stable at these wavelengths and also when exposed to visible light.
Assuntos
Tioridazina/análogos & derivados , Tioridazina/sangue , Tioridazina/química , Antipsicóticos/sangue , Antipsicóticos/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Conformação Molecular , Soluções , EstereoisomerismoRESUMO
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.