RESUMO
Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.
RESUMO
The aim of this work was to study effects of ketotifen fumarate (KF) on prevention of tissue damage in testes of rats with experimental autoimmune orchitis (EAO) and on the contralateral testis in a model of prolonged testicular cord torsion (TCT). Rats with EAO or TCT were injected intraperitoneally once daily with KF or saline solution (vehicle group). Incidence and severity of testicular damage were evaluated by histopathology using an EAO score or a Johnsen score. Mast cells (MC) were identified by histochemistry and quantified. In EAO model, KF significantly reduced severity of histopathological testicular damage compared to rats in the vehicle group. KF also reduced the number of testicular MC compared to vehicle group. Similarly, in TCT model, multifocal damage of the contralateral testis was observed 30 days after testicular torsion characterized by sloughing of the germinal epithelium, seminiferous tubule atrophy, and interstitial edema. Focal signs of inflammation and fibrosis of seminiferous tubular walls were also observed. In contrast, sections of contralateral testis of rats injected with KF and killed 30 days after surgery showed normal histological features. A significant decrease in the number of MC was observed in rats treated with KF compared to untreated animals. In conclusion, we demonstrated that treatment with KF reduced testicular inflammatory process and MC infiltrates in both EAO and TCT models. The results suggest a promising treatment for infertile male patients with testicular pathologies associated with inflammation and germ cell loss.
Assuntos
Doenças Autoimunes/patologia , Epididimite/patologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Cetotifeno/farmacologia , Mastócitos/efeitos dos fármacos , Orquite/patologia , Torção do Cordão Espermático/patologia , Testículo/efeitos dos fármacos , Animais , Doenças Autoimunes/imunologia , Contagem de Células , Epididimo/efeitos dos fármacos , Epididimo/imunologia , Epididimo/patologia , Epididimite/imunologia , Hipersensibilidade Tardia , Imunidade Celular/efeitos dos fármacos , Masculino , Mastócitos/imunologia , Mastócitos/patologia , Orquite/imunologia , Ratos , Índice de Gravidade de Doença , Torção do Cordão Espermático/imunologia , Testículo/imunologia , Testículo/patologia , VacinaçãoRESUMO
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG35-55 and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Cetotifeno/administração & dosagem , Estabilizadores de Mastócitos/administração & dosagem , Mastócitos/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Mastócitos/imunologia , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologiaRESUMO
The purpose of the present study was to investigate the interaction between ketotifen fumarate and anhydrous theophylline in aqueous media of various pH (1.2 and 6.8). Using Job's continuous-variation analysis and Ardon's spectrophotomeric measurement methods, the values of the stability constants of theophylline with ketotifen were determined at a fixed temperature (37 ºC) at various pH. The stability constants, ranging between 5.66 and 9.92, were derived from Ardon's plot, indicating that comparatively stable complexes had formed as a result of an interaction between the drugs. However, following the interaction of theophylline with ketotifen, stability constants were <1 at gastric pH (1.2) and intestinal pH (6.8). Concurrent administration of ketotifen and theophylline could result in the formation of a stable complex and this is likely to reduce the therapeutic activities of both drugs.
O objetivo do presente estudo foi investigar a interação entre o fumarato de cetotifeno e a teofilina anidra em meios aquosos com vários pH (1,2 e 6,8). Utilizando a análise da variação contínua de Job e os métodos de medida espectrofotométrica de Ardon, os valores das constantes de estabilidade da teofilina com o cetotifeno foram determinados em temperatura fixa (37 oC) em vários pH. As constantes de estabilidade, variando entre 5,66 e 9,92 derivaram-se a partir do delineamento de Ardon, indicando, comparativamente, que complexos estáveis se formaram como resultado da interação entre os fármacos. Entretanto, seguindo a interação da teofilina com o cetotifeno, as constantes de estabilidade foram <1, em pH gástrico (1,2) e intestinal (8,8). A administração concomitante de cetotifeno e teofilina poderia resultar na formação de complexo estável, o que reduz a atividade terapêutica de ambos os fármacos.
Assuntos
Técnicas In Vitro/métodos , Cetotifeno/análise , Teofilina/análise , Reatividade-EstabilidadeRESUMO
El colirio de ketotifeno se indica para aliviar los signos y síntomas de las conjuntivitis alérgicas, por ser este un potente antihistamínico H1 que muestra cierta capacidad para inhibir la liberación de histamina y otros mediadores en mastocitos. El objetivo del presente trabajo consistió en realizar el desarrollo tecnológico del colirio de ketotifeno 0,025 por ciento, de producción nacional teniendo en cuenta que es un medicamento muy utilizado en la Operación Milagro, en la cual participa la República de Cuba, para lo que se hace un diseño y los estudios de preformulación. Se estudió ademàs, las especificaciones de calidad de la formulación seleccionada, la estabilidad del producto y el tiempo de vigencia de este. Se realizó el estudio de estabilidad acelerado y por vida de estante, para lo cual se emplearon 3 lotes del producto a escala piloto. El colirio resultó estable física, química y microbiológicamente envasado en frascos de polietileno de baja densidad, por espacio de 12 meses a temperatura ambiente.
The Ketotifen eyedrops is prescribed to relieve the signs and symptoms of allergic conjunctivitis due to it is a powerful H1 antihistaminic with certain ability to inhibit the histamine release and other mediators in the case of mast cells. The aim of present paper was to perform the technological development of 0,025 percent eyedrops Ketotifen of national production considering that it is a drug very used in the Operación Milagro with participation of the Republic of Cuba and with its own design and the pre-formula. Also, we studied the selected formula specifications, the product stability and its expiry date. An accelerated stability study was conducted and by shelf life using 3 batches of pilot scale product. The eyedrops was physically, chemically and microbiologically stable when it is bottling in low-density polyethylene flasks during 12 months at room temperature.
Assuntos
Estabilidade de Medicamentos , Soluções Oftálmicas/normasRESUMO
OBJETIVO: O objetivo desse estudo foi comparar as soluções oftálmicas de fumarato de cetotifeno 0,025 por cento e de cloridrato de olopatadina 0,1 por cento em pacientes portadores de ceratoconjuntivite primaveril. MÉTODOS: Avaliação realizada em um único centro, simples-cega, comparando-se paralelamente cetotifeno e olopatadina. As medicações foram avaliadas em 4 momentos (dias 1, 7, 14 e 21) por meio de tabelas de graduações padronizadas. A freqüência de eventos adversos foi a principal variável de segurança. RESULTADOS: Na avaliação da evolução do prurido ocular, ardor, lacrimejamento, hiperemia conjuntival, secreção e fotofobia observou-se que o uso tópico do cetotifeno proporcionou melhora significante deste sintoma em relação a olopatadina (p>0,05). Observou-se que a partir do 7° dia de tratamento os pacientes em uso da olopatadina tinham menos ardor, em relação aos que fizeram uso do cetotifeno, mas após o 21° dia essa relação inverteu. Na comparação da sensação de corpo estranho, papilas e pontos de Horner-Trantas evidenciou-se equivalência sem significância estatística. CONCLUSÃO: Concluímos que ambas são drogas equivalentes e atuaram de forma eficaz e segura na remissão dos sintomas relacionados à conjuntivite alérgica primaveril. Houve diferença a favor do cetotifeno (p<0,05) na melhora do prurido, lacrimejamento, hiperemia conjuntival, presença de secreção e fotofobia.
PURPOSE: To compare the topical use of 0.025 percent ketotifen fumarate and 0.1 percent olopatadine hydrochloride in the treatment of patients with vernal keratoconjunctivitis. METHODS: A study performed in one center, simple masked, parallel-group compared ketotifen and olopatadine. These patients were evaluated on four visits during the treatment (days 1, 7, 14 and 21), defined by ratings scores. Adverse events were the main variable of safety rating. RESULTS: On evaluating ocular itching, burning, tearing, conjunctival hyperemia, mucous discharge and photophobia, the ketotifen group showed a significant improvement of total signs and symptoms (p<0.05). Between the baseline and the 2nd visit, treatment with olopatadine resulted in decreased burning, but after the 4th visit, ketotifen was slightly better. Sand sensation, papillae and Horner-Trantas dots were not significantly different in both groups. CONCLUSION: Both drugs were efficient and safe relieving the main symptoms and signs of vernal keratoconjunctivitis. Between the same timepoints, there was a significant difference in favor of ketotifen-treated patients (p<0.05), showing improvement of itching, tearing, conjunctival hyperemia, mucous discharge and photophobia.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Antialérgicos/efeitos adversos , Conjuntivite Alérgica/tratamento farmacológico , Dibenzoxepinas/efeitos adversos , Oftalmopatias/etiologia , Cetotifeno/efeitos adversos , Administração Tópica , Antialérgicos/uso terapêutico , Distribuição de Qui-Quadrado , Dibenzoxepinas/uso terapêutico , Cetotifeno/uso terapêutico , Soluções Oftálmicas , Prurido/etiologia , Estações do Ano , Método Simples-Cego , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Lágrimas/efeitos dos fármacosRESUMO
Se presentan los resultados de un estudio doble ciego, al azar, que compara los efectos de la nifedipina, una dihidropiridina antagonista del calcio, de amplia utilizacion cardiovascular, con los del Ketotifeno y los de un placebo; cada uno de ellos fue administrado por via oral cada 12 horas, durante 4 meses, a un grupo de 20 ninos mayores de 5 anos con asma alergica de una evolucion minima de 2 anos; el estudio se llevo a cabo en el Servicio de Alergias del Hospital Universitario San Vicente de Paul, de Medellin, Colombia, entre Julio de 1984 y Diciembre de 1986. La nifedipina produjo disminucion de la frecuecnia de las crisis en 17 pacientes (85%) y de su intensidad y duracion en 16 (80%); en esta misma proporcion (80%) se disminuyo el consumo de broncodilatadores; 18 pacientes (90%) informaron efectos beneficos de la nifedipina y la mejoria, evaluada por el medico, se hallo en 14 (70%). No hubo con la nifedipina modificaciones del pulso ni de la presion arterial ni, tampoco de 14 pruebas de funcion pulmonar; los efectos secundarios fueron minimos y autolimitados. Los resultados obtenidos con la nifedipina fueron estadisticamente semejantes a los de ketotifeno y los de ambos significativamente superiores a los logrados con el placebo(p<0.05)En conclusion: la nifedipina podria ser una alternativa en le manejo del asma alergica infantil leve o moderada, dado su comportamiento similar al del ketotifeno que es de eficacia reconocida en este campo; en un futuro los antagonistas del calcio pueden llegar a ser el tratamiento de elección del paciente asmatico si..
Between July 1984 and December 1986 a double blind randomized study was conducted at the Allergy Clinic of the Hospital Universitario San Vicente de Paúl, Medellín, Colombia, in order to compare the effects of Nifedipine, Ketotifen and placebo on allergic asthma in children; each drug and the placebo were administered orally every 12 hours for a period of 4 months to a group of 20 children. The objective was to evaluate the usefulness of Nifedipine In the prophylactic management of allergic asthma in this population and to compare it with Ketotifen, a provenly efficacious drug, and placebo. AII patients were older than 5 years and had suffered the disease for more than 2 years. Nifedipine treated patients showed a reduction in the frequency of their asthmatic crisis (17 patients; 85%) and in their intensity and duration (16 patients; 80%); a similar reduction was observed In the need for bronchodilators; 18 patients (90%) reported beneficial effects with this drug and medical evaluation confirmed Improvement In 14 (70%). These results resembled those obtained with Ketotifen and both were statistically superior to placebo (p<0.05). Pulmonary function tests, pulse rate and blood pressure did not show any significant changes. Secondary effects were minimal and self-Limited. It is concluded that Nifedipine can be an alternative drug for the treatment of mild to moderate allergic asthma in children. If calcium antagonists with higher affinity for the respiratory tract and better blocking effects are synthesized they might become the elective therapeutic choice for these patients