Abstract:
Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of Ca2+ release-activated Ca2+ (CRAC) channels has been proposed as a potential treatment, and currently, a novel selective CRAC channel inhibitor CM4620 (Auxora, CalciMedica) is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here, we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 n m, have been studied against necrosis induced by bile acids, palmitoleic acid, or l-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 n m and palmitoleic acid starting from 1 n m. Combining CM4620 and galactose (1 m m) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acid-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced edema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 m m) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.
摘要:
急性胰腺炎(AP)是一种威胁生命的炎症性疾病,没有特定的治疗方法。过度的细胞质Ca2+升高和细胞内ATP耗竭是AP起始的原因。抑制CRAC通道已被提出作为一种潜在的治疗方法,一种新型选择性CRAC通道抑制剂CM4620(AuxoraTM,CalciMedica),正在进行2b期人体试验。虽然CM4620有望成为AP的第一个有效治疗方法,它在动物模型中不能产生完全的保护。最近,另一种方法建议用天然碳水化合物半乳糖减少ATP消耗。在这里,我们已经研究了使用最小有效浓度的CM4620与半乳糖组合的可能性。CM4620的保护作用,在1-100nM的范围内,已经对胆汁酸引起的坏死进行了研究,棕榈油酸或L-天冬酰胺酶。CM4620从50nM开始显著防止胆汁酸或天冬酰胺酶诱导的坏死,和从InM开始的棕榈油酸。组合CM4620和半乳糖(ImM)显著降低坏死程度至接近对照水平。在棕榈油酸-酒精诱导的AP实验小鼠模型中,浓度为0.1mg/kg的CM4620可显著减少水肿,坏死,炎症,和总组织病理学评分。0.1mg/kgCM4620与半乳糖(100mM)的组合显着减少了进一步的坏死,炎症,和组织病理学评分。我们的数据表明,CM4620可以在比以前报道的浓度低得多的浓度下使用,减少潜在的副作用。CM4620与半乳糖的新型组合协同靶向AP的互补病理机制。