Cilastatin sodium

Imipenem/cilastatin sodium (IPM/CS) as an embolic agent for transcatheter arterial embolisation: a preliminary clinical study of gastrointestinal bleeding from neoplasms.[Pubmed:23961409]

Springerplus. 2013 Jul 26;2:344.

PURPOSE: To evaluate the feasibility and usefulness of imipenem/Cilastatin sodium (IPM/CS) as an embolic agent for intestinal bleeding from neoplasms. MATERIALS AND METHODS: Seven patients who underwent 11 transarterial embolisations (TAEs) using IPM/CS as an embolic material for duodenal or small/large intestinal tumour bleeding from January 2004 to December 2011 were retrospectively evaluated. A mixture of IPM/CS and contrast medium was introduced through the microcatheter positioned at the feeding artery to the tumour until extravasation disappeared or stasis of blood flow to the tumour staining was observed. RESULTS: Haemostasis was obtained in all patients. Therefore, the technical success rate was 100%. Rebleeding was observed in four patients. All of them underwent repeat TAE using IPM/CS, and haemostasis was obtained successfully. No complication was identified following laboratory and clinical examinations. No haemorrhagic death occurred. Haemorrhagic parameters, including blood haemoglobin and the amount of blood transfusion, improved after TAE. CONCLUSION: The safety, feasibility, and effectiveness of TAE using IPM/CS as an embolic material for intestinal bleeding from neoplasms were suggested by this study. The mild embolic effect of IPM/CS may be adequate for oozing from tumours. Although rebleeding may occur after embolotherapy using IPM/CS, repeat embolisation is effective as treatment for rebleeding.

[Domestic imipenem cilastatin sodium for the treatment of severe aspiration pneumonia, a curative effect observation].[Pubmed:23040783]

Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012 Oct;24(10):628-31.

OBJECTIVE: To evaluate the efficacy and safety of domestic imipenem Cilastatin sodium for the treatments of severe aspiration pneumonia. METHODS: A randomize, open, parallel-controlled trial was conducted. Sixty-eight patients with severe aspiration pneumonia were divided into trial group (n=36) and control group (n=32) by random distribution method. The application of trial group domestic imipenem Cilastatin sodium was 1.0 g intravenous drip, every 6-8 hours for 7-14 days. The control group application with imported injection imipenem Cilastatin sodium was 1.0 g intravenous drip, every 6-8 hours for 7-14 days. The highest daily temperature (T), heart rate (HR), breathing rate (RR), pulse blood oxygen saturation (SpO(2)), blood oxygen partial pressure (PaO(2)), inhaled oxygen concentration (FiO(2)), oxygenation index (PaO(2)/FiO(2)), airway peak pressure (Paw), minute ventilation (MV) and white blood count (WBC), pro calcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP) index before and 1, 3, 7 days after treatment, and liver and kidney function, chest X-rays, and sputum cultures of drug sensitive test were conducted. And the effectiveness and safety were determined according to the standards. RESULTS: After treatment indexes of the two groups were obviously improved, i. e. T, HR, RR, Paw, MV, the WBC, PCT, CRP were gradually declined, PaO(2)/FiO(2) was gradually raised. There were statistical significance before and 3 days after treatment in the trial and the control group [T: 37.35+/-0.91 centigrade vs. 38.43+/-1.06 centigrade, 37.28+/-0.88 centigrade vs. 38.35+/-1.11 centigrade; HR: 90.25+/-10.60 bpm vs. 118.94+/-15.46 bpm, 89.31+/-11.17 bpm vs. 124.34+/-17.87 bpm; RR: 25.14+/-3.17 bpm vs. 32.28+/-4.49 bpm, 24.81+/-2.43 bpm vs. 33.13+/-4.17 bpm; Paw: 23.03+/-3.04 cm H(2)O vs. 33.22+/-4.59 cm H(2)O, 22.75+/-3.22 cm H(2)O vs. 33.63+/-4.79 cm H(2)O; MV: 8.67+/-1.26 L/min vs. 11.80+/-2.01 L/min, 8.88+/-1.45 L/min vs. 13.21+/-2.90 L/min; WBC: 11.26+/-1.96 x10(9)/L vs. 14.57+/-3.10 x10(9)/L, 12.28+/-3.38 x10(9)/L vs. 15.25+/-4.93 x10(9)/L; PCT: 6.90+/-5.46 mug/L vs. 16.97+/-7.93 mug/L, 6.17+/-6.13 mug/L vs. 21.26+/-11.54 mug/L; CRP: 85.50+/-37.91 mg/L vs. 120.17+/-45.47 mg/L, 94.31+/-38.51 mg/L vs. 142.34+/-53.57 mg/L; PaO(2)/ FiO(2): 182.06+/-40.88 mm Hg vs. 98.67+/-20.62 mm Hg, 184.09+/-43.78 mm Hg vs. 96.22+/-22.59 mm Hg, all P<0.05]. There was no significant change in SpO(2) before and after treatment in two groups. And the total clinical effective rate in trial and control group were 83.4% and 81.2%, adverse reaction rate were 13.9% and 9.4%, bacterial removal rate were 90.3% and 87.0% respectively, and there was no significant difference between the two groups (all P>0.05). CONCLUSION: Domestic imipenem Cilastatin sodium can effectively control severe aspiration pneumonia, and it is safe and effective antibiotics.

Transcatheter arterial embolization using imipenem/cilastatin sodium for tendinopathy and enthesopathy refractory to nonsurgical management.[Pubmed:23707086]

J Vasc Interv Radiol. 2013 Jun;24(6):787-92.

PURPOSE: To evaluate the feasibility and effects of transcatheter arterial embolization with imipenem/Cilastatin sodium (CS) to treat tendinopathy and enthesopathy that are refractory to traditional nonsurgical management. MATERIALS AND METHODS: Transcatheter arterial embolization with imipenem/CS as an embolic agent was performed in seven patients (five men; mean age, 51.7 y) with tendinopathy and enthesopathy (patellar tendinopathy, n = 1; rotator cuff tendinopathy, n = 2; plantar fasciitis, n = 1; lateral epicondylitis, n = 1; iliotibial band syndrome, n = 1; and Achilles insertion tendinopathy, n = 1). All patients had unrelenting pain at the site of tendinopathy and enthesopathy before the procedure. Technical success, adverse events, and changes in visual analog scale (VAS) scores were assessed. RESULTS: All procedures were technically successful, and no major adverse events developed. Compared with before the procedure, mean VAS scores were significantly decreased at 1 day, 1 week, and 1 and 4 months after the procedure (72.7 mm+/-9.9 vs 17.4 mm+/-18.5, 16.0 mm+/-18.1, 13.7 mm+/-7.3, and 9.7 mm+/-6.8, respectively; all P< .001). CONCLUSIONS: Transcatheter arterial embolization with imipenem/CS was feasible and effectively relieved unrelenting pain associated with tendinopathy and enthesopathy.

Spectrophotometric and chemometric methods for determination of imipenem, ciprofloxacin hydrochloride, dexamethasone sodium phosphate, paracetamol and cilastatin sodium in human urine.[Pubmed:26709018]

Spectrochim Acta A Mol Biomol Spectrosc. 2016 Mar 15;157:26-33.

New accurate, sensitive and selective spectrophotometric and chemometric methods were developed and subsequently validated for determination of Imipenem (IMP), ciprofloxacin hydrochloride (CIPRO), dexamethasone sodium phosphate (DEX), paracetamol (PAR) and Cilastatin sodium (CIL) in human urine. These methods include a new derivative ratio method, namely extended derivative ratio (EDR), principal component regression (PCR) and partial least-squares (PLS) methods. A novel EDR method was developed for the determination of these drugs, where each component in the mixture was determined by using a mixture of the other four components as divisor. Peak amplitudes were recorded at 293.0 nm, 284.0 nm, 276.0 nm, 257.0 nm and 221.0 nm within linear concentration ranges 3.00-45.00, 1.00-15.00, 4.00-40.00, 1.50-25.00 and 4.00-50.00 mug mL(-1) for IMP, CIPRO, DEX, PAR and CIL, respectively. PCR and PLS-2 models were established for simultaneous determination of the studied drugs in the range of 3.00-15.00, 1.00-13.00, 4.00-12.00, 1.50-9.50, and 4.00-12.00 mug mL(-1) for IMP, CIPRO, DEX, PAR and CIL, respectively, by using eighteen mixtures as calibration set and seven mixtures as validation set. The suggested methods were validated according to the International Conference of Harmonization (ICH) guidelines and the results revealed that they were accurate, precise and reproducible. The obtained results were statistically compared with those of the published methods and there was no significant difference.

Inhibition of brush border dipeptidase with cilastatin reduces toxic accumulation of cyclosporin A in kidney proximal tubule epithelial cells.[Pubmed:15252165]

Nephrol Dial Transplant. 2004 Oct;19(10):2445-55.

BACKGROUND: Cilastatin reduces nephrotoxicity associated with cyclosporin A (CyA) in solid organ and bone marrow transplantation. This appears to be unrelated to changes in renal haemodynamics or CyA metabolism. How cilastatin induces this protection is unclear, but it could result from changes on accumulation of CyA proximal cells. METHODS: We investigated the effects of cilastatin on primary cultures of pig kidney proximal tubule epithelial cells (PTECs) treated with CyA and FK506. Cell membrane fluidity and membrane-bound cholesterol-rich raft (MBCR) distribution were evaluated by fluorescence microscopy, and CyA transport by radioimmunoassay. Changes in CyA- and FK506-induced apoptosis were also evaluated by electron and light microscopy, flow cytometry, and detection of cytoplasmic nucleosones by enzyme-linked immuosorbent assay. RESULTS: CyA caused a dose-dependent reduction of cell membrane fluidity, which was prevented by pre-treating PTECs with cilastatin. Cilastatin also inhibited CyA transport across membranes and reduced recovery of CyA in mitochondria and membrane-bound fractions from cilastatin-treated PTECs. This effect was not related to an altered distribution of MBCRs, which are essential for CyA transport. Cilastatin protected against CyA- and FK506-induced apoptosis. CONCLUSIONS: Prevention of CyA-induced reduction of cell membrane fluidity and inhibition of CyA transport are features of cilastatin's direct effects on PTECs. Unaltered distribution of MBCRs in the presence of cilastatin suggests that cilastatin binding to raft-bound dipeptidases, rather than MBCR modifications, causes interference with CyA transport. These results provide additional insight into the mechanisms and scope of cilastatin nephroprotection.

A continuous fluorometric assay for leukotriene D4 hydrolase.[Pubmed:10075814]

Anal Biochem. 1999 Mar 15;268(2):245-51.

A fluorogenic substrate for assay of leukotriene D4 hydrolase (LTDase; EC 3.4.13.19) has been prepared and evaluated, using enzyme purified from porcine kidney. The compound is based on internal quenching of the synthetic, fluorescent amino acid d, l-2-amino-3-(7-methoxy-4-coumaryl)propanoic acid (d,l-Amp) by a 2, 4-dinitrophenyl (DNP) group. The compound is epsilon-DNP-l-Lys-d-Amp which incorporates the D-isomer of Amp to exploit the unique ability among mammalian peptidases for LTDase to hydrolyze peptides containing a d-amino acid in the C-terminal position. epsilon-DNP-l-Lys-d-Amp was found to be an excellent substrate for LTDase, with Km value of 370 microoffUnder the conditions of assay, the substrate was without noticeable quenching effect on the fluorescence of the product (d-Amp) liberated by the action of LTDase. Using porcine kidney microvillar membranes, which contain a battery of peptidases, the specific inhibitor of LTDase, cilastatin, completely inhibited the breakdown of epsilon-DNP-l-Lys-d-Amp, indicating that the substrate is selective for LTDase.

Inhibition of the mammalian beta-lactamase renal dipeptidase (dehydropeptidase-I) by (Z)-2-(acylamino)-3-substituted-propenoic acids.[Pubmed:3495664]

J Med Chem. 1987 Jun;30(6):1074-90.

The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract. A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo. Many of the compounds were prepared in one step from an alpha-keto acid and a primary amide. The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl. With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 microM and a range of pharmacokinetic properties. By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer. The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.