Nagao Koichi, Akabane Hirotomo, Masuda Taisei, Komai Masato, Tanaka Hiroyuki, Nagai Hiroichi
Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
J Pharm Pharmacol. 2004 Feb;56(2):187-96. doi: 10.1211/0022357022548.
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.
MX - 68是一种新合成的抗叶酸剂，它是甲氨蝶呤（MTX）的衍生物。本文研究了MX - 68对小鼠和豚鼠过敏性气道反应的影响。在第一个实验中，检测了抗原诱导的小鼠气道炎症和对乙酰胆碱的气道高反应性（AHR），并与经典抗叶酸剂甲氨蝶呤和泼尼松龙的作用进行了比较。用卵清蛋白作为抗原使小鼠致敏，并通过吸入卵清蛋白进行三次激发。最后一次吸入后，观察AHR和气道炎症。在致敏小鼠的支气管肺泡灌洗液（BALF）中观察到Th2细胞因子（IL - 4和IL - 5）增加，Th1细胞因子（IFN - γ）减少，以及血清中免疫球蛋白水平升高。口服MX - 68对体重变化没有影响，但泼尼松龙在实验期间使体重减轻。MX - 68显著抑制了抗原诱导的AHR以及BALF中嗜酸性粒细胞和淋巴细胞数量的增加。MX - 68干扰了BALF中IL - 4和IL - 5水平的升高，但对IFN - γ的降低没有影响。此外，MX - 68显著抑制了血清IgE和IgG水平的升高。在豚鼠支气管哮喘模型中，重复抗原激发后观察到气道阻力的双相增加（速发型哮喘反应，IAR，和迟发型哮喘反应，LAR）以及BALF中炎症细胞的积聚。给予MX - 68后，这些哮喘反应和炎症体征显著减轻。这些结果表明，MX - 68在哮喘动物模型中具有明显的抗炎作用，在临床上可用于治疗支气管哮喘。
