Caspofungin is an echinocandin antifungal agent, which is used to treat a variety of fungal infections. Its antifungal effect is through inhibition β- 1,3-d-glucan polymer [1].
Caspofungin on cell membrane perturbation was not parallel to the increase of cytosolic Ca2 + activity and was insensitive to the removal of Ca2 + from the extracellular space. In addition, caspofungin triggered the translocation of phosphatidylserine to the surface of erythrocytes without increasing the abundance of ceramide. Caspofungin induced lupus erythematosus without inducing oxidative stress, and the addition of antioxidant N-acetylcysteine did not significantly change the effect of caspofungin on cell membrane perturbation. Caspase activation, p38 kinase or activity of staurosporin sensitive kinases such as protein kinase C are not required for the action of caspofungin. Therefore, the perturbation of cell membrane induced by caspofungin has nothing to do with the increase of cytosolic Ca2+. Activity, oxidative stress, ceramide formation or the activity of p38 kinase and astrosporin sensitive kinase are all the main inducements of lupus erythematosus [2]. In contrast, in the presence of d4476, a casein kinase inhibitor, the effect of caspofungin on cell membrane perturbation was attenuated. Therefore, the effect of caspofungin on cell membrane perturbation may involve the activation of casein kinase. However, the effect of d4476 other than casein kinase inhibition cannot be excluded. Moreover, caspofungin significantly enhanced the translocation of phosphatidylserine even in the presence of d4476, indicating that a further mechanism was involved [3].
Caspofungin induces hemolysis. The physiological function of eryptosis is actually to clear defective red blood cells in the circulating blood before hemolysis [2]. If defective erythrocytes fail to enter erythrocytosis in time, hemolysis leads to the release of hemoglobin, which passes through the glomerular filter and precipitates in the acidic lumen of the renal tubules, blocking the nephron, which may lead to renal failure [4].
Caspofungin showed limited antifungal activity in vitro and had limited efficacy in this lung challenge model. The survival rate was not significantly prolonged in the group of mice receiving a dose of caspofungin of 4 or 8 mg / kg / day. Amphotericin B at 2 mg / kg QD completely prevented death during the study. In addition, although amphotericin B significantly reduced the fungal load in the lungs and spleens, the administration of a higher dose (10 mg / kg twice daily) of caspofungin only reduced the quantitative culture colony count by 0.5 log compared with that used in the survival experiment [5]. Although this effect may not have clinical significance, it does indicate that caspofungin has an effect on H Capsulatum has certain activity The poor efficacy was not caused by insufficient dose, because a single IP dose of 1 mg / kg to mice produced 3 µ G/ml and 0.3 µ G / ml of blood [6].
References:
[1] Song J C, Stevens D A. Caspofungin: pharmacodynamics, pharmacokinetics, clinical uses and treatment outcomes[J]. Critical reviews in microbiology, 2016, 42(5): 813-846.
[2] Lang E, Lang F. Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death[C]//Seminars in cell & developmental biology. Academic Press, 2015, 39: 35-42.
[3] Peter T, Bissinger R, Lang F. Stimulation of eryptosis by caspofungin[J]. Cellular Physiology and Biochemistry, 2016, 39(3): 939-949.
[4] Harrison H E, Bunting H, Ordway N K, et al. The pathogenesis of the renal injury produced in the dog by hemoglobin or methemoglobin[J]. The Journal of Experimental Medicine, 1947, 86(4): 339-356.
[5] Kohler S, Wheat L J, Connolly P, et al. Comparison of the echinocandin caspofungin with amphotericin B for treatment of histoplasmosis following pulmonary challenge in a murine model[J]. Antimicrobial agents and chemotherapy, 2000, 44(7): 1850-1854.
[6] Hajdu R, Thompson R, Sundelof J G, et al. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)[J]. Antimicrobial agents and chemotherapy, 1997, 41(11): 2339-2344.
卡泊芬净是一种棘白菌素类抗真菌剂,用于治疗多种真菌感染。其抗真菌作用是通过抑制β-1,3-d-葡聚糖聚合物[1]。
卡泊芬净对细胞膜的扰动与细胞溶质 Ca2 + 活性的增加不平行,并且对从细胞外空间去除 Ca2 + 不敏感。此外,卡泊芬净可触发磷脂酰丝氨酸向红细胞表面的转移,而不会增加神经酰胺的丰度。卡泊芬净在不诱导氧化应激的情况下诱导红斑狼疮,添加抗氧化剂N-乙酰半胱氨酸没有显着改变卡泊芬净对细胞膜扰动的影响。 Caspase 激活、p38 激酶或星形孢菌素敏感激酶（如蛋白激酶 C）的活性对于卡泊芬净的作用不是必需的。因此,卡泊芬净引起的细胞膜扰动与胞质Ca2+的增加无关。活性、氧化应激、神经酰胺形成或p38激酶和星形孢菌素敏感激酶的活性都是红斑狼疮[2]的主要诱因。相反,在存在酪蛋白激酶抑制剂 d4476 的情况下,卡泊芬净对细胞膜扰动的影响减弱。因此,卡泊芬净对细胞膜扰动的影响可能涉及酪蛋白激酶的激活。但是,不能排除d4476抑制酪蛋白激酶以外的作用。此外,即使在 d4476 存在的情况下,卡泊芬净也能显着增强磷脂酰丝氨酸的转运,表明涉及进一步的机制[3]。
卡泊芬净诱导溶血。红斑狼疮的生理功能实际上是在溶血前清除循环血液中有缺陷的红细胞[2]。如果有缺陷的红细胞不能及时进入红细胞增多症,溶血导致血红蛋白释放,血红蛋白通过肾小球滤器沉淀在肾小管的酸性腔内,阻塞肾单位,可能导致肾功能衰竭[4] ].
卡泊芬净在体外显示出有限的抗真菌活性,并且在这种肺部攻击模型中的疗效有限。在接受 4 或 8 mg/kg/天卡泊芬净剂量的小鼠组中,存活率没有显着延长。 2 mg / kg QD 的两性霉素 B 在研究期间完全防止了死亡。此外,尽管两性霉素 B 显着降低了肺和脾脏中的真菌负荷,但给予较高剂量（10 mg / kg,每天两次）的卡泊芬净与生存期相比仅使定量培养菌落计数减少 0.5 log实验[5]。虽然这种作用可能没有临床意义,但它确实表明卡泊芬净对 H Capsulatum 具有一定的活性。疗效不佳并不是由于剂量不足造成的,因为对小鼠单次 IP 剂量 1 mg/kg 产生 3 µ； g/ml 和 0.3 µ；克/毫升血液[6].