Cilastatin (MK0791)
(Synonyms: 西司他丁; MK0791) 目录号 : GC32162
An inhibitor of dipeptidase (dehydropeptidase I)
Cas No.:82009-34-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cilastatin is an inhibitor of dipeptidase (dehydropeptidase I), a renal dipeptidase.1 It inhibits human renal dipeptidase (Ki = 0.7 μM), porcine dipeptidase (IC50 = 0.11 μM), and bacterial metallo-β-lactamase CphA from A. hydrophila (IC50 = 178 μM).1,2,3 Cilastatin (200 μg/ml) protects primary porcine renal proximal tubular epithelial cells from nephrotoxicity and apoptosis induced by vancomycin .4 In a mouse model of systemic infection, cilastatin in combination with imipenem protects mice from S. aureus, E. coli, and P. aeruginosa infection.5 Cilastatin was designed to inhibit renal metabolism of imipenem and prolong its half-life.2 Formulations containing cilastatin in combination with imipenem have been used to treat susceptible bacterial infections.
1.Campbell, B.J., Forrester, L.J., Zahler, W.L., et al.Beta-lactamase activity of purified and partially characterized human renal dipeptidaseJ. Biol. Chem.259(23)14586-14590(1984) 2.Kahan, F.M., Kropp, H., Sundelof, J.G., et al.Thienamycin: Development of imipenen-cilastatinJ. Antimicrob. Chemother.12(Suppl. D)1-35(1983) 3.Keynan, S., Hooper, N.M., Felici, A., et al.The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-β-lactamase enzyme CphAAntimicrob. Agents Chemother.39(7)1629-1631(1995) 4.Humanes, B., Jado, J.C., Cama?o, S., et al.Protective effects of cilastatin against vancomycin-induced nephrotoxicityBiomed Res. Int.704382(2015) 5.Petersen, P.J., Jacobus, N.V., Weiss, W.J., et al.In vitro and in vivo activities of LJC10,627, a new carbapenem with stability to dehydropeptidase IAntimicrob. Agents Chemother.35(1)203-207(1991)
| Cas No. | 82009-34-5 | SDF | |
| 别名 | 西司他丁; MK0791 | ||
| Canonical SMILES | O=C(O)/C(NC([C@@H]1C(C)(C)C1)=O)=C/CCCCSC[C@H](N)C(O)=O | ||
| 分子式 | C16H26N2O5S | 分子量 | 358.45 |
| 溶解度 | DMSO : 15 mg/mL (41.85 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7898 mL | 13.9489 mL | 27.8979 mL |
| 5 mM | 0.558 mL | 2.7898 mL | 5.5796 mL |
| 10 mM | 0.279 mL | 1.3949 mL | 2.7898 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Imipenem/Cilastatin/Relebactam: A Review in Gram-Negative Bacterial Infections
Drugs 2021 Feb;81(3):377-388.PMID:33630278DOI:10.1007/s40265-021-01471-8.
Imipenem/Cilastatin/relebactam (Recarbrioℿ is an intravenously administered combination of the carbapenem imipenem, the renal dehydropeptidase-I inhibitor Cilastatin, and the novel β-lactamase inhibitor relebactam. Relebactam is a potent inhibitor of class A and class C β-lactamases, conferring imipenem activity against many imipenem-nonsusceptible strains. Imipenem/Cilastatin/relebactam is approved in the USA and EU for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) in adults and other gram-negative infections, including complicated urinary tract infections (cUTIs) [including pyelonephritis] and complicated intra-abdominal infections (cIAIs), in adults with limited or no alternative treatment options. In pivotal phase II and III trials, imipenem/Cilastatin/relebactam was noninferior to piperacillin/tazobactam in patients with HABP/VABP and to imipenem/Cilastatin in patients with cUTIs and cIAIs. It was also effective in imipenem-nonsusceptible infections. Imipenem/Cilastatin/relebactam was generally well tolerated, with a safety profile consistent with that of imipenem/Cilastatin. Available evidence indicates that imipenem/Cilastatin/relebactam is an effective and generally well tolerated option for gram-negative infections in adults, including critically ill and/or high-risk patients, and a potential therapy for infections caused by carbapenem-resistant pathogens.
A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study)
Clin Infect Dis 2021 Dec 6;73(11):e4539-e4548.PMID:32785589DOI:10.1093/cid/ciaa803.
Background: Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/Cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). Methods: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/Cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population. Results: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/Cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≿5, 24.7% moderate/severe renal impairment, 42.9% were ≿5 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/Cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/Cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/Cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. Conclusions: Imipenem/Cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. Clinical trials registration: NCT02493764.
Imipenem/Cilastatin/relebactam: A new carbapenem β-lactamase inhibitor combination
Am J Health Syst Pharm 2021 Mar 31;78(8):674-683.PMID:33580649DOI:10.1093/ajhp/zxab012.
Purpose: The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, efficacy, safety, and current regulatory status of imipenem/Cilastatin/relebactam are reviewed. Summary: Imipenem/Cilastatin/relebactam is a newly approved anti-infective combination of a well-established β-lactam and a new β-lactamase inhibitor for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intra-abdominal infections (cIAIs) caused by susceptible gram-negative bacteria in patients 18 years of age or older with limited or no alternative treatment options. The antibiotic is also indicated for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The antibiotic is active in vitro against a wide range of pathogens, including multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales (CRE) such as Klebsiella pneumoniae carbapenemase. The addition of relebactam does not restore the activity of imipenem against metallo-β-lactamase (MBL)-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. Two phase 3 clinical trials of imipenem/Cilastatin/relebactam were conducted. In the RESTORE-IMI 1 trial, the efficacy and safety of imipenem/Cilastatin/relebactam was found to be comparable to that of imipenem/Cilastatin plus colistin for the treatment of infections caused by imipenem-nonsusceptible gram-negative bacteria in patients with HABP/VABP, cUTIs, and cIAIs, with a significantly lower incidence of nephrotoxicity reported with the new antibiotic. The RESTORE-IMI 2 trial demonstrated the noninferiority of imipenem/Cilastatin/relebactam to piperacillin/tazobactam for the treatment of HABP/VABP. Commonly reported adverse events in clinical trials included anemia, elevated liver enzymes, electrolyte imbalances, nausea, vomiting, diarrhea, headache, fever, phlebitis and/or infusion-site reactions, and hypertension. Conclusion: Imipenem/Cilastatin/relebactam is a new β-lactam/β-lactamase inhibitor combination with activity against MDR gram-negative bacteria, including many CRE but excluding MBL-producing Enterobacterales and carbapenem-resistant Acinetobacter baumannii. It is approved for the treatment of cUTIs, cIAIs, and HABP/VABP.
The risk of seizures among the carbapenems: a meta-analysis
J Antimicrob Chemother 2014 Aug;69(8):2043-55.PMID:24744302DOI:10.1093/jac/dku111.
Objectives: A consensus exists among clinicians that imipenem/Cilastatin is the most epileptogenic carbapenem, despite inconsistencies in the literature. Methods: We conducted a meta-analysis of all randomized controlled trials comparing carbapenems with each other or with non-carbapenem antibiotics to assess the risk of seizures for imipenem, meropenem, ertapenem and doripenem. Results: In the risk difference (RD) analysis, there were increased patients with seizure (2 per 1000 persons, 95% CI 0.001, 0.004) among recipients of carbapenems versus non-carbapenem antibiotics. This difference was largely attributed to imipenem as its use was associated with an additional 4 patients per 1000 with seizure (95% CI 0.002, 0.007) compared with non-carbapenem antibiotics, whereas none of the other carbapenems was associated with increased seizure. Similarly, in the pooled OR analysis, carbapenems were associated with a significant increase in the risk of seizures relative to non-carbapenem comparator antibiotics (OR 1.87, 95% CI 1.35, 2.59). The ORs for risk of seizures from imipenem, meropenem, ertapenem and doripenem compared with other antibiotics were 3.50 (95% CI 2.23, 5.49), 1.04 (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74) and 0.44 (95% CI 0.13, 1.53), respectively. In studies directly comparing imipenem and meropenem, there was no difference in epileptogenicity in either RD or pooled OR analyses. Conclusions: The absolute risk of seizures with carbapenems was low, albeit higher than with non-carbapenem antibiotics. Although imipenem was more epileptogenic than non-carbapenem antibiotics, there was no statistically significant difference in the imipenem versus meropenem head-to-head comparison.
Cilastatin as a protective agent against drug-induced nephrotoxicity: a literature review
Expert Opin Drug Saf 2020 Aug;19(8):999-1010.PMID:32666842DOI:10.1080/14740338.2020.1796967.
Introduction: Cilastatin, a dehydropeptidase I inhibitor, has been used alongside imipenem, a broad spectrum antibiotic, in order to reduce its renal metabolism, consequently increasing its urinary recovery and effectiveness for many years. However, this measure could be useful in preventing imipenem-induced renal damage and decreasing the number of nephrotoxicity reports with imipenem. In this review, the authors gathered all available studies focusing on Cilastatin use as a nephroprotective agent, beside well-known nephrotoxic medications like vancomycin, cisplatin, cyclosporine, or tacrolimus. Areas covered: PubMed, Scopus, Google Scholar, and Medline databases were searched using key words like 'Cilastatin,' 'nephroprotective,' 'nephroprotection,' 'vancomycin,' 'nephrotoxicity,' 'cisplatin,' 'cyclosporine,' 'tacrolimus,' and 'prevention' with varying combinations. All relevant animal and human studies up to the date of publication were included. Expert opinion: It seems that Cilastatin could potentially be effective against drug-induced nephrotoxicity via mechanisms such as reducing reactive oxygen species (ROS) production, apoptosis, P-glycoprotein suppression, and morphological changes of renal cells. Nearly all the in vitro, in vivo and human studies have supported this hypothesis. Though since Cilastatin protective effect has not extensively been researched in humans, its efficacy and widespread use with other nephrotoxic agents is yet to be defined in large well-designed human studies.