Assuntos
Cetotifeno , Melanose , Método Duplo-Cego , Famotidina , Humanos , Melanose/tratamento farmacológicoRESUMO
BACKGROUND: Ketotifen is a second-generation noncompetitive H1-antihistamine and mast-cell stabilizer. It is commonly used to treat or prevent allergic conjunctivitis, asthma, chronic urticaria, anaphylaxis, mast-cell, and other allergic-type disorders. However, it has never been studied in aspirin-exacerbated respiratory disease (AERD), an aggressive phenotype of chronic rhinosinusitis with nasal polyps, where the mast cell plays a prominent role its pathogenesis. METHODS: Human sinonasal epithelial cells were grown at an air-liquid interface (ALI). Ketotifen powder was dissolved in saline to make 4 test solutions at 1.04, 2.08, 10.4, and 20.8 µg/mL. Control (saline) or ketotifen solution was added apically to ALI cultures from tissue of 5 unique patients, and ciliary beat frequency (CBF) changes were recorded. Lactate dehydrogenase was measured at 24 and 48 hours to estimate long-term cellular toxicity. RESULTS: Apical application of ketotifen at all concentrations was neither ciliotoxic nor ciliostimulatory, with no change in CBF over a period of 15 minutes after application. Cellular toxicity for all concentrations at 24 and 48 hours after application was <3% and <7%, respectively, that of lysed cultures. CONCLUSION: Topical application of ketotifen to an in vitro model of sinonasal epithelium is safe, as evaluated by CBF and lactate dehydrogenase. Ketotifen is neither ciliotoxic nor ciliostimulatory, and no long-term cellular toxicity was observed. Ketotifen may have promise as a topical nasal rinse in the treatment of AERD.
Assuntos
Antialérgicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Cetotifeno/farmacologia , Administração Tópica , Células Cultivadas , Cílios/efeitos dos fármacos , Cílios/fisiologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Humanos , L-Lactato Desidrogenase/metabolismo , Irrigação TerapêuticaRESUMO
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
Tityus serrulatus venom (Tsv)-induced pulmonary edema can occur in severe envenomation and the mechanisms involved are not completely understood. Therefore, we studied the effect of pharmacological modulation of the mast cell activation and the histamine antagonism on airways edema (investigated by Evans blue dye extravasation) and measured 5-hydroxytryptamine (5-HT) concentration in bronchoalveolar lavage fluid (BALF) in rats envenomed by Tsv. Additionally, the in vitro effect of Tsv on mast cells was studied using histological method and 5-HT release from mesenteric and peritoneal mast cells. We found that i.v. injection of Tsv increase vascular permeability in trachea, upper and lower bronchi and in lung parenchyma. This was not affected by ketotifen, a mast cell "stabilizer," or by pretreatment with pyrilamine (histamine H1 receptor antagonist). Moreover, 5-HT was not found in BALF of envenomed rats. In vitro experiments showed that Tsv did not induce mast cell degranulation nor release of 5-HT by mesenteric or peritoneal mast cells, in sharp contrast to preparations challenged by a mast cell activator, compound 48/80. In conclusion, our results show that Tsv causes strong edema in rat airways which is independent of mast cell activation and show that mast cells are not directly activated by Tsv.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Mordeduras e Picadas de Insetos/patologia , Mastócitos/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Venenos de Escorpião/toxicidade , Animais , Líquido da Lavagem Broncoalveolar/citologia , Degranulação Celular/efeitos dos fármacos , Azul Evans , Indicadores e Reagentes , Mordeduras e Picadas de Insetos/fisiopatologia , Cetotifeno/farmacologia , Masculino , Mastócitos/fisiologia , Pirilamina/farmacologia , Ratos , Ratos Wistar , Sistema Respiratório/irrigação sanguínea , EscorpiõesRESUMO
From cultures of thermophilic soil fungus Humicola grisea var thermoidea, a δ-lactam derivative (3-(2-(4-hydroxyphenyl)-2-oxoethyl)-5,6-dihydropyridin-2(1H)-one) that displayed anti-allergic activity was isolated, which was predicted by in silico computational chemistry approaches. The in vitro anti-allergic activity was investigated by ß-hexosaminidase release assay in rat basophilic leukaemia RBL-2H3 cells. The δ-lactam derivative exhibited similar anti-allergic activity (IC(50) = 18.7 ± 6.7 µM) in comparison with ketotifen fumarate (IC(50) = 15.0 ± 1.3 µM) and stronger anti-allergic activity than azelastine (IC(50) = 32.0 µM). Also, the MTT cytotoxicity assay with RBL-2H3 cells showed that δ-lactam does not display cytotoxicity at concentrations lower than 50 µM. This study suggests that the δ-lactam derivative has the potential to be used as a lead compound in the development of anti-allergic drugs for clinical use in humans.
Assuntos
Antialérgicos/química , Antialérgicos/farmacologia , Ascomicetos/química , Lactamas/química , Piridonas/química , Piridonas/farmacologia , Animais , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Concentração Inibidora 50 , Cetotifeno/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ftalazinas/farmacologia , Ratos , Microbiologia do Solo , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
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
OBJECTIVE: To compare the efficacy of olopatadine 0.1 % and ketotifen 0.025 % ophthalmic solutions in the treatment of allergic conjunctivitis. METHODS: Forty patients with allergic conjunctivitis were included in the study, they were randomized in two groups: G-I (n = 20) olopatadine 0.1 % and G-II (n = 20) ketotifen 0.025 %, both receiving one drop every 12 hours. We evaluated itching, burning, tearing, redness and chemosis previously and 30 minutes, one, two and four week after. RESULTS: Age G-I was 19.7 +/- 6.7 years; G-II, 21.05 +/- 8.3 years. When evaluating itching, olopatadine had a significant improvement at 30 minutes and after one week (p < 0.05). In the following weeks, the results were similar in both groups. Olopatadine showed significant improvement in burning at 30 minutes, one and two week (p < 0.05). Tearing significantly decreased at 30 minutes with olopatadine (p < 0.05). There was no difference in redness or chemosis improvement in both groups. CONCLUSIONS: In this study, olopatadine 0.1 % was more effective than topical ketotifen 0.025 % in improving itching, tearing and burning in allergic conjunctivitis patients.
Assuntos
Antialérgicos/uso terapêutico , Conjuntivite Alérgica/tratamento farmacológico , Dibenzoxepinas/uso terapêutico , Cetotifeno/uso terapêutico , Feminino , Humanos , Masculino , Cloridrato de Olopatadina , Adulto JovemRESUMO
This is a case report of a woman of 38 years old, studied and analyzed at the service of allergy and immunology with clinical manifestations of allergic rhinitis; studies of laboratory, cabinet and intradermal test were made to corroborate this diagnosis and the treatment with specific hyposensitization, oral antihistaminines and inhaled steroids was started. Two years later the patient referred urinary retention without important antecedents, so, a peripheral anticholinergic syndrome (PAS) was suspected, a urodynamic test study was carried out consisting in a uroflujometry, static and dynamic urethral profile, cystometry, flow pressure study and electromyography, which diagnosed low urinary obstruction (functional) and vesical sphincter pseudodysfunction, demonstrating the PAS associated with oral antihistamines.