RESUMO
A natural product, pseurotin A inhibits IgE production in vitro. Wide variety of chemical modification of pseurotin A was performed. Structure-activity relationship studies of pseurotin analogues elucidated that 10-deoxypseurotin A strongly inhibits IgE production with IC(50) of 0.066 microM. An immunosuppressive activity of another natural product, synerazol was also found.
Assuntos
Imunoglobulina E/biossíntese , Imunossupressores/química , Pirrolidinonas/síntese química , Animais , Imunoglobulina E/metabolismo , Imunossupressores/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Pirrolidinonas/antagonistas & inibidores , Pirrolidinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The clinical efficacy of combination therapy comprising a long acting beta(2)-agonist (LABA) and corticosteroid is widely recognized for the treatment of adult asthma. Here we examine the effect of salmeterol xinafoate (SX) and fluticasone propionate (FP) alone and in combination on the immunological activation of human cultured mast cells (HCMC)in vitro. METHODS: HCMC were passively sensitized with IgE antibody and then activated by challenging with anti-IgE antibody. The effect of drugs on the activation of mast cells was examined by measuring the amount of released chemical mediators (histamine, leukotrienes (LT) and prostaglandin D(2) (PGD(2))) and granulocyte macrophage colony stimulating factor (GM-CSF). RESULTS: The release of each chemical mediator was inhibited by 10-9-10-8M SX but not by 10-10-10-7M FP. The production of GM-CSF was inhibited by a concentration of 10-8M in both drugs and the inhibition was augmented by combined treatment with 10-11M of each drug. CONCLUSIONS: The immunological release of chemical mediators (histamine, LT, PGD(2)) from HCMC was inhibited by SX but not by FP. SX and FP inhibited the production of GM-CSF by HCMC and both drug showed synergistic inhibition in the production of GM-CSF.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacologia , Albuterol/análogos & derivados , Androstadienos/farmacologia , Antiasmáticos/farmacologia , Anti-Inflamatórios/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Liberação de Histamina/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Albuterol/administração & dosagem , Albuterol/farmacologia , Androstadienos/administração & dosagem , Antiasmáticos/administração & dosagem , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Fluticasona , Humanos , Imunoglobulina E/imunologia , Leucotrienos/metabolismo , Mastócitos/metabolismo , Prostaglandina D2/metabolismo , Xinafoato de SalmeterolRESUMO
The effects of a newly synthesized compound, 6-acetoamido-1-acetyl-1-indazole (TAS-3-124), on autoimmune diseases were studied. We used animal models of collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats to evaluate the efficacy of TAS-3-124. TAS-3-124 at doses of 100 and 300 mg/kg p.o. inhibited the development of CIA, decreasing the swelling of fore- and hind-limbs and bone destruction in knee joints. This agent also suppressed the delayed type hypersensitivity reaction (DTH) against type II collagen. These effects were confirmed by histopathological examination and measurement of the expression of mRNA of proinflammatory cytokines in the knee joint. In addition, TAS-3-124 at a dose of 300 mg/kg inhibited the development of EAE and the DTH to myelin basic protein (MBP) in rats. Moreover, TAS-3-124 inhibited the production of proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 but not T cell derived cytokines in mice. These demonstrate the efficacy of TAS-3-124 against experimental autoimmune disease, probably due to the suppression of the production of proinflammatory cytokines in the pathological lesion.
Assuntos
Acetamidas/uso terapêutico , Artrite Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Indazóis/uso terapêutico , Animais , Sequência de Bases , Citocinas/biossíntese , Primers do DNA , Feminino , Hipersensibilidade Tardia , Masculino , Camundongos , RatosRESUMO
MX-68 is a newly synthesized antifolate, which is a derivative of methotrexate (MTX). In this paper, the effect of MX-68 on allergic airway responses in mice and guinea-pigs was studied. In the first experiment, antigen-induced airway inflammation and airway hyperresponsiveness (AHR) to acetylcholine in mice were examined and compared with the effects of classical antifolate methotrexate and prednisolone. Mice were sensitized with ovalbumin as an antigen and challenged with ovalbumin inhalation three times. After the last inhalation, AHR and airway inflammation were observed. An increase in Th2 cytokines (IL-4 and IL-5) and a decrease in a Th1 cytokine (IFN-gamma) in the bronchoalveolar lavage fluid (BALF), as well as an elevation of the immunoglobulin level in serum, were observed in sensitized mice. Oral administration of MX-68 had no effect on changes of body weight, but prednisolone reduced body weight during the experiment. The antigen-induced AHR and increases in the number of eosinophils and lymphocytes in BALF were significantly inhibited by MX-68. MX-68 interfered with the elevation of IL-4 and IL-5 levels in BALF, but had no effect on the decrease in IFN-gamma. Moreover, MX-68 significantly inhibited the elevation of serum IgE and IgG levels. In the guinea-pig model for bronchial asthma, biphasic increases in airway resistance (immediate asthmatic response, IAR, and late asthmatic response, LAR), as well as accumulated inflammatory cells in BALF, were observed after repeated antigen challenge. These asthmatic responses and inflammatory signs were significantly decreased by administration of MX-68. These results suggest that MX-68 obviously has an anti-inflammatory effect in an animal model of asthma and would be useful clinically for the treatment of bronchial asthma.