RESUMO
The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl3) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl3 -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration.
Assuntos
Cloreto de Alumínio/toxicidade , Benzodiazepinas/farmacologia , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Niacina/análogos & derivados , Cloreto de Alumínio/antagonistas & inibidores , Animais , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Niacina/farmacologia , Teste de Campo Aberto/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Wistar , Teste de Desempenho do Rota-RodRESUMO
Oxidative stress and mitochondrial dysfunction are two pathophysiological factors often associated with the neurodegenerative process involved in Parkinson's disease (PD). The aim of this study was to investigate the effects of a novel hybrid molecule, named JM-20, in different in vitro and in vivo models of PD induced by rotenone. To perform in vitro studies, SHSY-5Y cells were exposed to rotenone and/or treated with JM-20. To perform in vivo studies male Wistar rats were intoxicated with rotenone (2.5 mg/kg) via intraperitoneal injection and/or treated with JM-20 (40 mg/kg) administered via oral (for 25 days, both treatment). Rats were evaluated for global motor activity by measurement of locomotor activity. In addition, the effects on mortality, general behavior and redox parameters were also investigated. JM-20 protected SHSY-5Y cells against rotenone-induced cytotoxicity, evidenced by a significant diminution of cell death. In in vivo studies, JM-20 prevented rotenone-induced vertical exploration and locomotion frequency reductions, moreover prevented body weight loss and mortality induced by rotenone. It also improved the redox state of rotenone-exposured animals by increasing superoxide dismutase and catalase activities, total tissue-SH levels and decreasing malondialdehyde concentrations. Finally, JM-20 inhibited spontaneous mitochondrial swelling and membrane potential dissipation in isolated rats brain mitochondria. These results demonstrate that JM-20 is a potential neuroprotective agent against rotenone-induced damage in both in vitro and in vivo models, resulting in reduced neuronal oxidative injury and protection of mitochondria from impairment.
Assuntos
Benzodiazepinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Niacina/análogos & derivados , Rotenona/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , Niacina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages. METHODS: The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined. RESULTS: The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions. CONCLUSIONS: The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory deï¬cits associated with AD in humans.
Assuntos
Benzodiazepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Memória/efeitos dos fármacos , Niacina/análogos & derivados , Nootrópicos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/farmacologia , Distribuição Aleatória , Ratos Wistar , EscopolaminaRESUMO
Objetivo: desarrollar una formulación de cisplatino a una concentración de 1 mg/mL, estableciendo el procedimiento de preparación de la solución, para ser administrada por vía parenteral, con buena estabilidad física, química, biológica y microbiológica. Métodos: se prepararon variantes en dos formulaciones de cisplatino: una solución con tampón de acetato y otra sin el empleo de solución tampón, a las cuales se les siguió su estabilidad física y química durante 3 meses. En las formulaciones se empleó materia prima de la firma IMPEX SA, con una potencia de 99,74 por ciento , según certificado de análisis del fabricante. Se realizaron tres lotes a escala piloto de cisplatino 10 mg en bulbos 10 R ámbar y tres lotes de cisplatino 50 mg en bulbos 50 H ámbar, empleándose una dosis de 1 mg/mL. Se usaron excipientes que le confieren isotonía y estabilidad a la formulación con ácido clorhídrico 0,1 N y como vehículo, agua para inyección. Por cromatografía líquida de alta resolución se evaluó la estabilidad para determinar la fecha de vencimiento del medicamento. Por métodos biológicos se determinó la ausencia de pirógenos y por métodos microbiológicos, la esterilidad. Resultados: en ambas formulaciones no hubo diferencias en los resultados físicos y químicos, por lo que se realizó el escalado industrial con la segunda formulación. Durante 12 meses el cisplatino 10 y 50 mg soluciones presentó buena estabilidad físico-química, comportándose sus concentraciones entre 90,0 y 105,0 por ciento y el pH entre 3,5-6,5 a temperatura ambiente. Conclusiones: Las formulaciones de cisplatino 10 y 50 mg presentan las especificaciones de calidad físico-químicas, microbiológicas y biológicas informadas por 12 meses a temperatura ambiente. Este medicamento al cumplir con todos los parámetros de calidad, está registrado en el órgano regulador cubano para ser utilizado con seguridad en pacientes
Objective: to develop a cisplatin formulation at 1mg/mL concentration by setting the solution preparation procedure for parenteral administration, with good physical, chemical, biological and microbiological stability. Methods: two formulation variants of cisplatin: one solution with and the other without acetate buffer. Both were followed in terms of physical and chemical stability for 3 months. The formulations used raw material from IMPEX SA company, which has 99.74 percent power as certified by the manufacturer analysis. Three batches of 10mg cistoplatin at pilot scale in amber 10 R vials, 3 batches of 50 mg cisplatin in amber 50 H vials and the dose was 1mg/ml. Excipients were used to give isotony and stability to the formulation with 0.1 N chlorhydric acid and injection water for vehicle. The high performance liquid chromatography allowed evaluating the stability to determine the expiry date of the drug. The biological and microbiological methods determined lack of pyrogens and sterility respectively. Results: both formulations showed no differences in physical and chemical results, so the second formulation was used at industrial scale. During 12 months, 10 and 50 mg cisplatin solutions exhibited good physical and chemical stability, ranging its concentrations from 90,0 to 105,0 percent whereas pH was 3,5 to 6,5 at room temperature. Conclusions: 10 and 50mg cisplatin formulations have the physical-chemical, microbiological and biological specifications reported in 12 months at room temperature. Since this drug meets all the quality parameters, the Cuban regulatory agency registers it as a safe drug for patients
Assuntos
Cisplatino , CitostáticosRESUMO
Un tema de gran interés para la industria farmacéutica moderna lo constituye sin duda, la búsqueda de tecnologías para la obtención de formas farmacéuticas para la administración y transporte de citostáticos, antiinflamatorios, péptidos y hormonas, entre otros fármacos, que impliquen una reducción de su toxicidad o una liberación controlada del principio activo para lograr con ello un aumento de su eficacia. En el presente trabajo se estudió la influencia del flujo de líquido de alimentación, del flujo de aire de atomización y de secado, y se evaluaron diferentes características fisicoquímicas y morfológicas (tamaño, forma, porosidad y distribución de tamaño de partículas, eficiencia de encapsulación del principio activo) de microesferas de tramadol. Como resultado se obtuvo que es posible lograr microesferas con un tamaño de 18,93 ± 2,31 µm con forma esférica, una superficie no porosa, y se demostró mediante difractometría de rayos X la encapsulación del tramadol en el polímero
An interesting subject for pharmaceutical industry is the search of technologies to achieve pharmaceutical ways for administration and transportation of cytostatics, anti-inflammatories, peptides and hormones among other drugs implicating a reduction of its toxicity or a contolled releasing of active principle to increase its effectiveness. In present paper authors studied the influence of fluid flow in feeding, of atomization air and of driying; different physicochemical and morphological features (size, shape, porosity and distribution in the particles size, and the effectiveness of active principle encapsulation) of Tramadol's microspheres. As result, it was possible to achieve microspheres of 18,93 ± 2,31 µm with an spherical shape, a non-porous surface demostrating it by X-ray difractometry and Tramadol encapsulation in the polymer
Assuntos
Rhizophoraceae , Tecnologia FarmacêuticaRESUMO
El desarrollo tecnológico requiere de métodos analíticos confiables que permitan la cuantificación del fármaco en diferentes etapas de la investigación. El objetivo de este trabajo fue las validaciones prospectivas de 2 métodos analíticos, uno por UV-VIS y otro por cromatografía líquida de alta eficiencia, desarrolladas para el control del proceso de fabricación, de la calidad y para el estudio de estabilidad de ketamina. A las técnicas se le determinaron los parámetros de desempeño, especificidad, linealidad, exactitud, rango y precisión. Los resultados alcanzados permiten concluir que ambos métodos cumplen con los requisitos establecidos como aceptables para cada uno de los casos en el rango de concentraciones establecido. El método espectrofotométrico puede utilizarse en el control del proceso de producción y el control de calidad del producto terminado al igual que el método cromatográfico; el primero, es de elección para el control de proceso de fabricación por su sencillez y rapidez, y el segundo, para el estudio de estabilidad del producto por su elevada especificidad.
Technological development requires of reliable and analytical methods to quantify drugs in different stages of research. Aim of present paper was the prospective validations of two analytical methods, one by UV-VIS, and the other by high performance liquid chromatography, developed to control of manufacture process, quality, and to study of Ketamine stability. Techniques included the following parameters: performance, specificity, linearity, accuracy, rank, and precision. Results achieved allow concluding that both methods fulfill the criteria established as fair to each of the cases in rank of concentrations stetted. Spectrophotometry method may be used in control of production process and in control of quality of end product just like the chromatography method, the first one, is the choice to control of manufacture process due to its simplicity and speed, and the second one, to study of product stability due to its high specificity.
Assuntos
Anestésicos Dissociativos/análise , Controle de Qualidade , Estudos de Validação como Assunto , Cromatografia Líquida de Alta Pressão/métodos , Espectrofotometria/métodosRESUMO
Se demostró la intercambiabilidad terapéutica mediante un estudio de bioequivalencia en 25 voluntarios sanos de una formulación cubana de carbamazepina de 200 mg con respecto al producto innovador (Tegretol®), en condiciones de administración a dosis única; el diseño experimental fue cruzado a doble ciegas y aleatorizado; el periodo de lavado fue de 15 días. Las extracciones para la obtención del plasma, se realizaron a las 0; 0,5; 1; 1,5; 2; 3; 4; 6; 8; 10; 12; 16; 20; 24; 48; 72; 96 y 120 h. Para el análisis se empleó un método analítico por cromatografía líquida de alta eficiencia, isocrático en fase reversa con detección ultravioleta. Se estimaron mediante técnicas no compartimentales los parámetros farmacocinéticos (AUC0-t, AUCt-¥, Cmax, Tmax y T1/2) representativos de la biodisponibilidad en magnitud y velocidad. Sobre la base de los resultados estadísticos, ambas formulaciones resultaron bioequivalentes.
It was possible to demonstrate the therapeutic interchange level by means of a bioequivalence study in 25 healthy volunteers of a Cuban formula of Carbamazepine(200 mg) according to the innovative product (Tegretol®) for a administration of unique dose; the experimental design was of crossed, double-blind and random type; washing period was of 15 days. Extractions for plasma obtaining were performed at 0, 0,5, 1, 1,5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 and 120 hours. In analysis we used an analytical method by high performance liquid chromatography, isocratic type in reverse phase with UV detection. By means of non-compartment techniques pharmacokinetic parameters (AUC0-t, AUC t-¥, Cmax, Tmax, and T½) were estimated, which are representative of bioavailability in magnitude and speed. On the base of statistical results, both formulae were bioequivalent.
Assuntos
Carbamazepina/administração & dosagem , Carbamazepina/análise , Cromatografia Líquida de Alta Pressão/métodosRESUMO
Los glicósidos cardiotónicos representan la combinación de una aglicona o genina con 3 moléculas de monosacáridos. Su actividad farmacológica reside en la aglicona, pero son sus unidades monoméricas (moléculas de glucosa) las que rigen la absorción, la penetrabilidad en la membrana celular, la persistencia de la acción cardíaca y la potencia del glicósido resultante. Se reporta el desarrollo del proceso tecnológico de la digoxina inyectable, para el tratamiento de insuficiencias cardíacas y arritmias supraventriculares, cuyos resultados han sido favorables y verificados por los requerimientos que establece la USP 23. Se comprobó por medio de los estudios de estabilidad que el producto tiene un tiempo de vida útil de 2 años, almacenado a temperatura ambiente. Se demostró que la toxicidad del glicósido en roedores (ratones) albinos hembras resultó estar en el entorno de 3,61-4,26 mg/kg de peso corporal