RESUMO
Psoriasis is considered an immune-mediated inflammatory skin disorder that affects the quality of life of nearly four percent of the world population. Considering the side effects of existing therapeutic drugs and the urgent need for new drug development, we screened more than 250 traditional Chinese medicine compounds to identify drugs that significantly reduced the viability of human HaCaT keratinocytes, a psoriasis-related model cell line. Convallatoxin (CNT) was found to be a highly effective inhibitor of HaCaT cell viability. Subsequent mechanistic studies revealed that CNT induced HaCaT cell death by necroptosis rather than by apoptosis. CNT destroyed the membrane integrity of HaCaT cells, as detected by nuclear propidium iodide (PI) staining and lactate dehydrogenase (LDH) release. Additionally, the intercellular levels of adenosine triphosphate (ATP) were lower in HaCaT cells treated with CNT than in control HaCaT cells, and typical necroptosis-associated characteristics were observed by electron microscopy in cells treated with CNT. Furthermore, compared with control HaCaT cells, CNT-treated HaCaT cells produced more reactive oxygen species (ROS), but this effect was inhibited by the antioxidants N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and apocynin and the necroptosis inhibitor Nec-1. In addition, antioxidant treatment attenuated necroptotic cell death, suggesting that CNT-induced HaCaT necroptosis is mediated by oxidative stress. More importantly, CNT ameliorated skin lesions and inflammation in imiquimod (IMQ)- and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced psoriasis-like mouse models. In conclusion, our results demonstrate that CNT is cytotoxic against HaCaT cells in vitro and exerts antipsoriatic activities in two mouse models of psoriasis in vivo, making CNT a potential promising candidate drug for future research.
Assuntos
Queratinócitos/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Estrofantinas/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Células HaCaT , Humanos , Imiquimode/toxicidade , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases/metabolismo , Psoríase/patologia , Espécies Reativas de Oxigênio/metabolismo , Pele/patologia , Estrofantinas/uso terapêuticoRESUMO
The experiments with isolated rat atria isometrically contracting and those with simulated rat heart failure were performed to study the effects of the alpha-, beta-, and X-blocker cordarone on the pharmacodynamic effects of strophanthin. Cordarone was demonstrated to greatly decrease the toxicity of the cardiotonic in circulatory decompensation, without causing negative effects of cardiac inotropic function. Cordarone in combination with strophanthin slightly diminished the magnitude of the negative chronotropic effect of the cardiac glycoside and slowed down the rate of its cardiotonic effect.
Assuntos
Amiodarona/farmacologia , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Estrofantinas/farmacologia , Amiodarona/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Quimioterapia Combinada , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Rana ridibunda , Ratos , Ratos Wistar , Estrofantinas/uso terapêutico , Estrofantinas/toxicidade , Fatores de TempoRESUMO
By use of pentobarbital sodium to produce experimental congestive heart failure (CHF) in 40 rabbits, they were treated with xin-fu-ning IV (XFN IV), the plasma atrial natriuretic factor (ANF) levels and atrial tissue ANF levels of rabbits were measured. The results showed that XFN IV had elevated ANF levels of the rabbits with CHF. It showed that XFN IV could improve endocrine function of heart, and it also showed good curative effect on CHF.
Assuntos
Fator Natriurético Atrial/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Animais , Barbitúricos , Cardiotônicos/uso terapêutico , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Masculino , Coelhos , Estrofantinas/uso terapêuticoRESUMO
In rats with adrenaline-induced myocarditis conditionally therapeutic doses of strophanthin (2.7 mg/kg) and digoxin (0.89 mg/kg) were chosen according to performance of the test of swimming until the complete fatigue. The influence of drugs in these doses on enzymatic activity was evaluated by histochemical methods in heart of control and myocarditis rats. It was found out that both of cardiac glycosides decreased lactate dehydrogenase and membrane Na+, K+-ATPase activity and increased succinate dehydrogenase activity in rats with experimental myocarditis.
Assuntos
Digoxina/uso terapêutico , Coração/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Miocardite/tratamento farmacológico , Miocárdio/enzimologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Estrofantinas/uso terapêutico , Succinato Desidrogenase/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos , Epinefrina , Masculino , Miocardite/induzido quimicamente , Miocardite/enzimologia , Esforço Físico/efeitos dos fármacos , RatosRESUMO
In experiments on rabbits it was established that strophanthin (0.05 mg/kg) administered to animals with cardiac insufficiency due to a severe overloading of the heart function by occlusion of the diaphragmatic portion of the aorta by 4/5 of its diameter improved the contractile activity and relaxing properties of the left ventricle. This effect is however transient (up to 15-30 minutes) with the subsequent reduction of its characteristic indices, the development of symptoms of intoxication and not infrequently death of animals. alpha-tocopherol administered before the pathology reproduction (10 mg/kg, 3 days) increases the period of myocardial compensation and when given in combination with strophanthin significantly potentiates the cardiac effect of glycoside manifesting by an increase of the strength and rate of contraction and intensity of diastolic relaxation of the myocardium, prolongs the animal's life.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Estrofantinas/uso terapêutico , Vitamina E/uso terapêutico , Doença Aguda , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Quimioterapia Combinada , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Masculino , CoelhosRESUMO
Experiments on intact dogs and animals with an early stage of experimental cardiopulmonary insufficiency due to chronic pneumonia were made to study the action of strophanthine on the hemodynamics of the left and right ventricles and pressure in the pulmonary artery. Administration of the glycoside to animals with cardiopulmonary insufficiency increased the contractility of the right ventricle and the intensity of diastolic relaxation of both ventricles. Strophanthine was revealed to exert the prevailing effect on the cardiodynamics of the right ventricle both in intact dogs and in animals with experimentally induced pathology. Strophanthine increased pressure in the pulmonary artery, promoting the overload of the right ventricle to a less degree than convallotoxin.
Assuntos
Coração/efeitos dos fármacos , Doença Cardiopulmonar/tratamento farmacológico , Estrofantinas/uso terapêutico , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Masculino , Contração Miocárdica/efeitos dos fármacos , Doença Cardiopulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacosRESUMO
The effects of strophathin in a dose of 0.15 mg/kg bw were investigated under alpha- and beta-adrenergic blockade by the methods of thermodilution and circulation registration in the pool of the occluded coronary artery in anesthetized dogs. It was determined that strophanthin increased the blood supply of the myocardial ischemic centres, the minute heart volume, and systemic arterial pressure and decreased the general peripheral vascular resistance. The alpha-adrenoblocker, phentolamine (0.025 mg/kg intravenously) decreased the strophanthin stimulant effect on the collateral coronary blood stream and heart activity without changing its chronotropic and vasopressive action. The beta-adrenoreceptor blockade induced by obsidan (0.5 mg/kg) made no changes in the pattern of the glycoside cardiovascular effects and diminished its chronotropic action.
Assuntos
Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/tratamento farmacológico , Coração/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos/efeitos dos fármacos , Estrofantinas/uso terapêutico , Doença Aguda , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Fentolamina/farmacologia , Propranolol/farmacologiaRESUMO
It was shown in experiments on rats with experimental ischemic myocardial infarction that strophanthin inhibits free-radical lipid peroxidation, decreases (in mean and little doses) the ectopic activity of the myocardium, eliminates tachyarrhythmias arising in the presence of coronary occlusion, delays the appearance on the ECG of changes characteristic for acute myocardial infarction. In mean doses, strophanthin decreases the macrosize of the zone of infarction. It is recommended that strophanthin K (in mean and little doses) be included in a combined therapy of myocardial infarction.
Assuntos
Peróxidos Lipídicos/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Estrofantinas/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Radicais Livres , Masculino , Infarto do Miocárdio/tratamento farmacológico , Oxirredução/efeitos dos fármacos , Ratos , Fatores de TempoRESUMO
It was established in acute experiments on dogs with the anterior interventricular branch of the left coronary artery ligated in the middle third that isoptin increases essentially the blood flow and oxygen tension in the focus of acute myocardial ischemia, increases the cardiac stroke and minute volumes, and reduces the total peripheral vascular resistance. Strophanthin removes the favourable effect of isoptin on collateral coronary circulation and contractile myocardial activity and increases the total peripheral vascular resistance.
Assuntos
Circulação Colateral/efeitos dos fármacos , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Estrofantinas/uso terapêutico , Verapamil/uso terapêutico , Doença Aguda , Animais , Doença das Coronárias/fisiopatologia , Cães , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Feminino , MasculinoRESUMO
The effect of convallotoxin on hemodynamics of the right and left ventricles and pressure in the pulmonary artery was studied in intact dogs and in surgical stenosis of the pulmonary trunk. In intact anesthetized dogs, convallotoxin produced changes in hemodynamics that were more pronounced in the right than in the left ventricle (decreased intraventricular pressure, increased dp/dtmax and dp/dtmin). Administration of convallotoxin ton dogs one month after pulmonary trunk stenosis without episodes of congestive heart failure did not improve the cardiohemodynamics.
Assuntos
Coração/efeitos dos fármacos , Estenose da Valva Pulmonar/tratamento farmacológico , Estrofantinas/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Ventrículos do Coração/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Fatores de TempoRESUMO
In isadrin-induced myocarditis, the rat heart shows an increase in the activity of acid phosphatase, glucose-6-phosphate dehydrogenase. The heart weight also rises, whereas ATPase activity and magnesium content fall. Under these conditions strophanthin produces a marked decrease in acid phosphatase activity, stimulates the activity of glucoso-6-phosphate dehydrogenase, and demonstrates a tendency to increasing the activity of ATP-splitting enzymes, to reducing the activity of ATP-synthetase, and to the recovery of the magnesium content. Mefenamic acid and dexamethasone also decrease the activity of acid phosphatase but this decrease is less pronounced as compared with that induced by strophanthin. They exhibit the same tendency to the inhibition of glucoso-6-phosphate dehydrogenase. Mefenamic acid affects the remaining parameters similarly to strophanthin, while dexamethasone inhibits them.
Assuntos
Dexametasona/uso terapêutico , Coração/efeitos dos fármacos , Ácido Mefenâmico/uso terapêutico , Miocardite/tratamento farmacológico , Estrofantinas/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Magnésio/metabolismo , Masculino , Miocardite/metabolismo , RatosRESUMO
In experiments in nembutal anesthetized dogs the authors studied the dependence between the antifibrillation activity of propranolol, which was appraised according to the value of the ventricular fibrillation thresholds and the rate of spontaneous fibrillation after occlusion of the coronary artery, and the cardiodepressive and hypotensive action of this agent. It is shown that it is possible in principle to preserve the antifibrillation activity of propranolol infused intravenously in a dose of 1 mg/kg for correcting its cardiodepressive and hypotensive effect in combined intravenous infusion of 0.02 mg/kg corglycon. It is concluded that there is no dependence between antifibrillation activity and the cardiodepressive and hypotensive effects of propranolol.
Assuntos
Antiarrítmicos , Anti-Hipertensivos , Infarto do Miocárdio/tratamento farmacológico , Propranolol/uso terapêutico , Fibrilação Ventricular/tratamento farmacológico , Animais , Glicosídeos Cardíacos/uso terapêutico , Depressão Química , Cães , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Contração Miocárdica/efeitos dos fármacos , Estrofantinas/uso terapêuticoRESUMO
In rabbits and rats potassium glutaminate elicits antiarrhythmic effect in experimental arrhythmias induced by intravenous injection of strophanthine and calcium chloride, normalizes the content of electrolytes (potassium, sodium, calcium, magnesium) in the myocardium and blood of animals after they are injected strophanthine.