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Caspofungin Sale

(Synonyms: 卡泊芬苷; MK-0991; L-743872) 目录号 : GC17230

An echinocandin-type antifungal

Caspofungin Chemical Structure

Cas No.:162808-62-0

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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

Red blood cells

Preparation Method

To test the involvement of kinases, erythrocytes were exposed to caspofungin and casein kinase inhibitor d4476, p38 kinase inhibitor SB203580 (or a combination of protein kinase C inhibitors) for 48 hours staurosporin (. The involvement of oxidative stress was tested by adding antioxidant N-acetylcysteine, and the involvement of caspase was tested by adding pan caspase inhibitor zVAD).

Reaction Conditions

30 - 60 µg/ml for 48h

Applications

Before measurement, red blood cells were incubated in Ringer's solution with or without caspofungin (30 - 60 µ g / ml) for 48 hours. Caspofungin significantly reduced red blood cell forward scattering at each tested caspofungin concentration. In addition, caspofungin (≥ 45 µ g / ml) significantly increased the percentage of reduced red blood cells and significantly decreased the percentage of swollen red blood cells at each tested caspofungin concentration.

Animal experiment [2]:

Animal models

Female ICR mice

Preparation Method

In the transient inhibition model, caspofungin and AMB were tested at twice the increased dose of 0.03 to 1.0 mg / kg body weight, injected intraperitoneally once a day (QD) for 14 days. There were 10 mice in each treatment group.In the chronic inhibition model, caspofungin and AMB were tested at doses of 0.25, 0.5 and 1.0 mg / kg IP, QD for 7 days. In the first two chronic inhibition studies, there were 10 mice in each group, while in the third study, there were 50 mice in each group.In both models, infected and sham treated control mice received sterile distilled water, and incidence rate and mortality were recorded daily for 28 days.

Dosage form

0.125 mg/kg

Applications

Caspofungin at a concentration of ≥ 0.125 mg / kg / dose significantly prolonged the survival time of infected mice. Treatment with 0.5 and 1.0 mg / kg / dose of caspofungin resulted in 70% and 90% survival, respectively.

References:

[1]. Peter T, Bissinger R, Lang F. Stimulation of eryptosis by caspofungin[J]. Cellular Physiology and Biochemistry, 2016, 39(3): 939-949.
[2]. Abruzzo G K, Gill C J, Flattery A M, et al. Efficacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice[J]. Antimicrobial Agents and Chemotherapy, 2000, 44(9): 2310-2318.

产品描述

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].

Chemical Properties

Cas No. 162808-62-0 SDF
别名 卡泊芬苷; MK-0991; L-743872
化学名 (2R,6S,11R,12R,14aS,15S,20S,23S,25aS)-20-((R)-3-amino-1-hydroxypropyl)-12-((2-aminoethyl)amino)-23-((1S,2S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl)-9-(11,13-dimethyl-2-oxopentadecyl)-2,11,15-trihydroxy-6-((R)-1-hydroxyethyl)hexadecahydro-1H-dipyrrolo[2,1-
Canonical SMILES O=C([C@@H]1C[C@@H](O)CN1C([C@@H](NC(C2CC(CCCCCCCCC(C)CC(CC)C)=O)=O)[C@@H](C)O)=O)N[C@@H]([C@H](O)[C@@H](O)C3=CC=C(O)C=C3)C(N[C@@H]([C@H](O)CCN)C(N4CC[C@H](O)[C@H]4C(N[C@@H](NCCN)[C@H](O)C2)=O)=O)=O
分子式 C53H89N9O15 分子量 1092.33
溶解度 ≥ 48.1mg/mL in DMSO 储存条件 Store at -20°C,protect from light
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Research Update

Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial

Clin Infect Dis2019 May 30;68(12):1981-1989.PMID: 30289478DOI: 10.1093/cid/ciy827

Background: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. Methods: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ¡ݱ dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. Results: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. Conclusions: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. Clinical trials registration: NCT00413218.

Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial

JAMA2019 Nov 5;322(17):1673-1681.PMID: 31688884DOI: 10.1001/jama.2019.15702

Importance: Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds.
Objective: To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy.
Design, setting, and participants: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018).
Interventions: Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle.
Main outcomes and measures: The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival.
Results: The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole).
Conclusions and relevance: Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility.
Trial registration: ClinicalTrials.gov Identifier: NCT01307579.

Caspofungin: a review of its characteristics, activity, and use in intensive care units

Expert Rev Anti Infect Ther2020 Dec;18(12):1213-1220.PMID: 32662712DOI: 10.1080/14787210.2020.1794817

Introduction: Candidemia is the fourth frequent reason of healthcare-related bloodstream infections in critically ill patients. For initial management of (suspected) invasive candidiasis in critically ill patients, usage of an echinocandin, e.g. caspofungin, has been recommended.
Areas covered: In this study, characteristics of caspofungin and its use in intensive care unit (ICU) patients are reviewed based on an electronic search using PubMed and Google scholar.
Expert opinion: Caspofungin is a semisynthetic derivative from pneumocandin B and the first member of the echinocandins that was approved by the U.S. Food and Drug Administration (FDA) to fight fungal infection. Caspofungin inhibits the enzyme ¦¨1,3)-D-glucan synthase of the fungal cell wall resulted in inhibition of the synthesis of ¦¨1,3)-D-glucan. For critically ill patients, inter- and intraindividual variations affect the caspofungin concentration. The incidence rates and densities of candidemia in surgical ICUs may be higher than medical ICUs resulting in a higher burden of candidemia in surgical ICUs. However, the mortality rate in surgical ICU patients with candidemia is higher than that medical ICU patients due to differences in their underlying conditions.

Rezafungin Versus Caspofungin in a Phase 2, Randomized, Double-blind Study for the Treatment of Candidemia and Invasive Candidiasis: The STRIVE Trial

Clin Infect Dis2021 Dec 6;73(11):e3647-e3655.PMID: 32955088DOI: 10.1093/cid/ciaa1380

Background: Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC).
Methods: Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ¡ܴ weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up.
Results: Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. In total, 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS.
Conclusions: RZF was safe and efficacious in the treatment of candidemia and/or IC.
Clinical trials registration: NCT02734862.

Caspofungin: an overview

Expert Rev Anti Infect Ther2005 Oct;3(5):697-705.PMID: 16207161DOI: 10.1586/14787210.3.5.697

The echinocandins are a novel class of antifungal agents that have come into use over the past 10 years. The mechanism of action of these lipopeptide agents is via noncompetitive inhibition of the synthesis of 1,3-beta-glucans, which are fungal cell wall constituents. All agents of this class are only available in an intravenous formulation. The first approved agent of this class was caspofungin (Cancidas). Caspofungin is a therapeutic option for patients with candidal esophagitis and deep-seated candidal infections, and is an alternative therapy for Aspergillus infections, especially in the salvage setting. In addition, it is a therapeutic option for the empiric therapy of febrile neutropenia. The usefulness of this agent in treating less common fungal infections has been cited in anecdotal reports. One major limitation of this drug is the lack of an oral formulation. Caspofungin may be considered as a component of combination antifungal regimens. Caspofungin represents a significant advance in the care of patients with serious fungal infections.