Cilastatin, a new therapeutic promise for acute kidney injury.

Acute kidney injury is a devasting clinical syndrome resulting from multiple causes, characterized by an abrupt deterioration of kidney function for which there is no pharmacologic treatment. Cilastatin has demonstrated direct nephroprotective effects in acute kidney injury and now is shown to be effective to specifically target therapeutically loaded nanoparticles to the proximal tubule to treat acute kidney injury.

Development of a Short-Term Embolic Agent Based on Cilastatin for Articular Microvessels.

Background and Objectives: This study aimed to develop an embolic agent with short-term embolic effects using cilastatin as the basic material. Materials and Methods: The particle size distribution of 25 mg cilastatin-based short-term embolic agents was evaluated microscopically under three different mixing conditions. A total of thirty-six healthy male Sprague Dawley rats were divided into four groups. Each group of six rats was injected once into the tail artery with 0.4 mL each of (A) Cilastatin + D-Mannitol Mixture, (B) Iohexol, (C) Prepenem, and (D) embolization promoter (EGgel). Results: A visual inspection of the tail appearance of rats in each group was performed at 0, 3, 7, 15, and 21 days. At weeks 1 and 3, three rats per group were euthanized, and histopathological analyses were performed on the specimens obtained from each group. No significant differences were observed on day 7, but mild inflammation was observed in Group (D) on day 15. Histopathological inflammation scoring of tail central artery embolization was performed using a six-point scale (from 0 = absent to 5 = marked inflammation). Three groups were formed consisting of six male New Zealand white rabbits each: control, positive control, and test groups. The control group received an Iohexol injection (rabbits: 0.8 mL). The positive control and experimental groups were injected with prepenem and cilastatin/D-mannitol compound, respectively (0.8 mL), and vascular angiography was performed. The order of occlusion progression after embolization was as follows: test group, positive control group, and control group. Conclusions: We developed a cilastatin/D-mannitol compound that exhibits characteristics of short-term embolization by utilizing the pharmacokinetic properties of cilastatin and the crystalline material D-mannitol. We evaluated its particle size distribution microscopically, conducted histopathological evaluation including inflammation via animal experiments, and assessed the embolization effect.

A randomized non-inferiority study comparing imipenem/cilastatin/relebactam with standard-of-care Gram-negative coverage in cancer patients with febrile neutropenia.

BACKGROUND: Antibiotic overuse leads to the emergence of antibiotic resistance that threatens immunocompromised cancer patients. Infections caused by MDR Gram-negative pathogens are difficult to treat and associated with high mortality. Hence, empirical therapy with standard-of-care (SOC) antibiotics could be suboptimal in these vulnerable patients. New antibiotics covering potential resistant pathogens may be considered. METHODS: We conducted a randomized non-inferiority study comparing safety and efficacy of imipenem/cilastatin/relebactam (IPM/REL), a ß-lactam/ß-lactamase inhibitor combination, with SOC antibiotics (cefepime, piperacillin/tazobactam or meropenem) in cancer patients with febrile neutropenia. Patients received at least 48 h of IV antibiotics and were assessed at end-of-IV (EOIV) therapy, test of cure (TOC; Days 21-28), and late follow-up (LFU; Days 35-42). RESULTS: A total of 100 patients were enrolled (49 IPM/REL and 50 SOC). Demographics and rates of documented microbiological infections were similar in both groups. In the SOC arm, 86% of antibiotics consisted of cefepime. Patients on IPM/REL had a higher favourable clinical response at EOIV than those on SOC (90% versus 74%; P = 0.042); however, responses were similar at TOC and LFU. Microbiological eradication was comparable at all three timepoints. Study drug-related adverse events and adverse events leading to drug discontinuation were similar in both groups, with no study drug-related mortality. CONCLUSIONS: Our results suggest that compared with SOC antibiotics, predominantly cefepime, IPM/REL for empirical coverage of febrile neutropenia in cancer patients is generally safe and could be associated with a better clinical outcome at EOIV. The current SOC consisting mainly of agents that do not cover for ESBL-producing and carbapenem-resistant Enterobacterales bacteria should be reconsidered.

Combining ulinastatin with TIENAM improves the outcome of sepsis induced by cecal ligation and puncture in mice by reducing inflammation and regulating immune responses.

Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2+ Treg cells and increasing CD8+ T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment.

An elderly male with septic arthritis and bacteremia.

Rhodococcus hoagii is a gram positive actinomycete found in horses and cattle. Humans can be infected by ingestion or inhalation through contaminated food or soil. The organism usually infects immunosuppressed hosts with pneumonia being the common presentation. We present a case of an 89 years old, apparently immunocompetent host presenting with fever, encephalopathy and arthritis who grew Rhodococcus hoagii in blood and synovial fluid, The patient responded well to a combination of vancomycin, azithromycin and imipenem-cilastatin. Our case demonstrates that extra-pulmonary manifestations such as septic arthritis and bacteremia can be seen in immune competent hosts.

Real-world evaluation of imipenem/cilastatin/relebactam across US medical centres.

We assessed 160 patients who received imipenem/cilastatin/relebactam for ≥2 days. At treatment initiation, the median Charlson Comorbidity Index was 5, 45% were in the intensive care unit, and 19% required vasopressor support. The in-hospital mortality rate was 24%. These data advance our understanding of real-world indications and outcomes of imipenem/cilastatin/relebactam use.

Cilastatin as a Potential Anti-Inflammatory and Neuroprotective Treatment in the Management of Glaucoma.

Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.

Therapeutic drug monitoring of imipenem/cilastatin and meropenem in critically ill adult patients.

OBJECTIVES: To investigate the factors influencing imipenem/cilastatin (IMI) and meropenem (MEM) concentrations in critically ill adult patients and the role of these concentrations in the clinical outcome. METHODS: Plasma trough concentrations of IMI and MEM were detected by high-performance liquid chromatography. A target value of 100%-time above MIC was used for the drugs. RESULTS: A total of 186 patients were included, with 87 receiving IMI and 99 receiving MEM. The percentages of patients reaching the target IMI and MEM concentrations were 44.8% and 38.4%, respectively. The proportions of patients infected with drug-resistant bacteria were 57.5% and 69.7% in the IMI group and MEM group, respectively. In the multivariate analysis, the risk factors for an IMI concentration that did not reach the target were infection with drug-resistant bacteria, and those for MEM were infection with drug-resistant bacteria, estimated glomerular filtration rate, and diabetes mellitus. A total of 47.1% of patients had good outcomes in the IMI cohort, and 38.1% of patients had good outcomes in the MEM cohort. The duration of mechanical ventilation and IMI concentration were associated with ICU stay in patients in the IMI cohort, while MEM concentration and severe pneumonia affected the clinical outcome of patients in the MEM cohort. CONCLUSION: Infection with drug-resistant bacteria is an important factor influencing whether IMI and MEM concentrations reach the target. Furthermore, IMI and MEM concentrations are associated with the clinical outcome, and elevated doses of IMI and MEM should be given to patients who are infected with drug-resistant bacteria.

Legal Performance-enhancing Drugs Alter Course and Treatment of Rhabdomyolysis-induced Acute Kidney Injury.

INTRODUCTION: Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown. Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment. MATERIALS AND METHODS: In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort, cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours. RESULTS: Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect. Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI. CONCLUSIONS: Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.

Beneficial herb-drug interaction of rhein in Jinhongtang and Imipenem/Cilastatin mediated by organic anion transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. AIM OF THE STUDY: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). MATERIALS AND METHODS: A mouse model of sepsis induced by Staphylococcus aureus (S. aureus) was used to evaluate the pharmacodynamic interaction in vivo. In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. RESULTS: Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus. However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CLr of Imipenem was reduced by 58.5%, while its half-life (t1/2) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC50 values of 0.08 ± 0.01 µM (OAT1) and 2.86 ± 0.28 µM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. CONCLUSION: Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs. Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.

A Retrospective Comparison of the Efficacy of Embolization with Imipenem/Cilastatin and Microspheres in the Management of Chronic Shoulder Pain.

PURPOSE: To compare the efficacy of embolization with imipenem/cilastatin and microspheres in chronic shoulder pain. METHODS: This retrospective study included 29 patients who underwent embolization for chronic shoulder pain between June 2017 and March 2022 with calibrated MSs from 100 to 250 µm or IMP/CS. The main objective was the clinical success evaluated by the Minimum Clinically Important Difference (MCID) at 3 months after the procedure, validated if the patient responded yes to 2 questions: (1) Is the pain less severe than before the procedure? (2) Are you satisfied with the procedure? The decrease in visual analogue pain scale scores and the safety of the procedure were evaluated. RESULTS: Embolization was achieved in all patients. In the MS group, 4/15 patients (26.7%) experienced clinical success at 3 months according to MCID versus 10/14 patients (71.4%) in the IMP/CS group (p = 0.02). The mean VAS decreases were respectively - 28.6% ± 34.6 in the MS group and - 36.8% ± 27.8 in the IMP/CS group at 1 month (p = 0.50), - 29.9% ± 29.0 and - 39.6% ± 23.0 at 3 months (p = 0.33) and - 30.6% ± 32.8 and - 46.6% ± 28.4 at 6 months after the procedure (p = 0.26). Eleven patients (73.3%) in the MS group and 3 patients (21.4%) in the IMP/CS group had complications (p = 0.01). Among them, 2/15 patients (13.3%) had transient skin ischaemia in the MS group. CONCLUSION: Embolization with IMP/CS may be more effective and safer than MSs in the management of chronic shoulder pain.

Cost-effectiveness of imipenem/cilastatin/relebactam for hospital-acquired and ventilator-associated bacterial pneumonia.

Aim: This study evaluates the cost-effectiveness of imipenem/cilastatin/relebactam (IMI/REL) for treating hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in an 'early adjustment prescribing scenario'. Methods: An economic model was constructed to compare two strategies: continuation of empiric piperacillin/tazobactam (PIP/TAZ) versus early adjustment to IMI/REL. A decision tree was used to depict the hospitalization period, and a Markov model used to capture long-term outcomes. Results: IMI/REL generated more quality-adjusted life years than PIP/TAZ, at an increased cost per patient. The incremental cost-effectiveness ratio of $17,529 per QALY is below the typical US willingness-to-pay threshold. Conclusion: IMI/REL may represent a cost-effective treatment for payers and a valuable option for clinicians, when considered alongside patient risk factors, local epidemiology, and susceptibility data.

Megalin blockade with cilastatin ameliorates multiple wasp sting-induced acute kidney injury in rats.

Cilastatin has been shown to prevent various drug-induced nephrotoxicities and confer renoprotection in a mouse model of glycerol-mediated rhabdomyolysis-induced acute kidney injury (AKI). The present study aimed to investigate whether cilastatin attenuates wasp sting-induced AKI in rats. Male Wistar rats were divided into the control, cilastatin, AKI, and AKI + cilastatin groups. Nephrotoxicity was assessed using renal function, rhabdomyolysis (creatine kinase, CK) and intravascular hemolysis (lactate dehydrogenase, LDH) markers, and histological changes. In addition, tubular injury biomarkers, apoptosis, oxidative stress markers, complement C3 expression, and urine and blood myoglobin levels were examined. Compared with the control or cilastatin group, the AKI group showed significant histological damage, increased levels of CK, LDH, and creatinine, and increased mRNA expression of tubular injury biomarkers. Cilastatin ameliorated wasp venom-induced kidney injury by attenuating oxidative stress and apoptosis. Cilastatin also reduced C3 expression in the renal tubular cells. In addition, cilastatin reduced serum myoglobin levels and increased urine myoglobin concentrations. Therefore, megalin blockade with cilastatin attenuates wasp venom-induced AKI owing to its antioxidative and antiapoptotic properties.

FKBP51, AmotL2 and IQGAP1 Involvement in Cilastatin Prevention of Cisplatin-Induced Tubular Nephrotoxicity in Rats.

The immunophilin FKBP51, the angiomotin AmotL2, and the scaffoldin IQGAP1 are overexpressed in many types of cancer, with the highest increase in leucocytes from patients undergoing oxaliplatin chemotherapy. Inflammation is involved in the pathogenesis of nephrotoxicity induced by platinum analogs. Cilastatin prevents renal damage caused by cisplatin. This functional and confocal microscopy study shows the renal focal-segmental expression of TNFα after cisplatin administration in rats, predominantly of tubular localization and mostly prevented by co-administration of cilastatin. FKBP51, AmotL2 and IQGAP1 protein expression increases slightly with cilastatin administration and to a much higher extent with cisplatin, in a cellular- and subcellular-specific manner. Kidney tubule cells expressing FKBP51 show either very low or no expression of TNFα, while cells expressing TNFα have low levels of FKBP51. AmotL2 and TNFα seem to colocalize and their expression is increased in tubular cells. IQGAP1 fluorescence increases with cilastatin, cisplatin and joint cilastatin-cisplatin treatment, and does not correlate with TNFα expression or localization. These data suggest a role for FKBP51, AmotL2 and IQGAP1 in cisplatin toxicity in kidney tubules and in the protective effect of cilastatin through inhibition of dehydropeptidase-I.

New evidence in severe pneumonia: imipenem/ cilastatin/relebactam.

Imipenem combined with beta-lactamase inhibitor relebactam (IMI/REL) has an extensive bactericidal activity against Gram-negative pathogens producing class A or class C beta-lactamases, not active against class B and class D. The phase 3 clinical trial (RESTORE-IMI-2), double-blind, randomized, evaluated IMI/REL vs. piperacillin-tazobactam (PIP/TAZ) for treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), demonstrated non-inferiority at all-cause mortality at 28 days (15.9% vs 21.3%), favorable clinical response at 7-14 days end of treatment (61% vs 59.8%) and with minor serious adverse effects (26.7% vs 32%). IMI/REL is a therapeutic option in HAP and VAP at approved dosage imipenem 500 mg, cilastatin 500 mg and relebactam 250 mg once every 6h, by an IV infusion over 30 min.

Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital-acquired/ventilator-associated bacterial pneumonia.

In the phase III RESTORE-IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all-cause mortality at day 28 and favorable clinical response at the early follow-up visit in adult participants with gram-negative hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE-IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end-stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 µg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice.

BACKGROUND: Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of AKI and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate CKD. Development of specific pharmacologic therapy is desirable because supportive care is nearly impossible in austere environments. Myoglobin, the principal cause of rhabdomyolysis-related AKI, undergoes megalin-mediated endocytosis in proximal tubule cells, a process that specifically injures these cells. METHODS: To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL/6 mice and mice (14-32 weeks old) with proximal tubule-specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation. RESULTS: Inducible proximal tubule-specific deletion of megalin was highly protective in this mouse model of rhabdomyolysis-induced AKI. The megalin knockout mice demonstrated preserved GFR, reduced proximal tubule injury (as indicated by kidney injury molecule-1), and reduced renal apoptosis 24 hours after injury. These effects were accompanied by increased urinary myoglobin clearance. Unlike littermate controls, the megalin-deficient mice also did not develop progressive GFR decline and persistent new proteinuria. Administration of the pharmacologic megalin inhibitor cilastatin to wild-type mice recapitulated the renoprotective effects of megalin deletion. This cilastatin-mediated renoprotective effect was dependent on megalin. Cilastatin administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by megalin deletion. CONCLUSIONS: We conclude that megalin plays a critical role in rhabdomyolysis-induced AKI, and megalin interference and inhibition ameliorate rhabdomyolysis-induced AKI. Further investigation of megalin inhibition may inform translational investigation of a novel potential therapy.

Embolic Characteristics of Imipenem-Cilastatin Particles in Vitro and in Vivo: Implications for Transarterial Embolization in Joint Arthropathies.

PURPOSE: To elucidate in vitro and in vivo characteristics and embolic properties of imipenem-cilastatin (IPM-CS) compared with hydrogel microspheres. MATERIALS AND METHODS: Particle size distribution was microscopically evaluated with 3 samples of 50 mg IPM-CS suspensions in each of 6 conditions by a mixture of contrast volume: 500 or 1000 µL and vortex mixing time: 5, 10, or 30 s. Time-dependent changes up to 3 h post-mixing were also evaluated. Fifteen male Sprague-Dawley rats (460.2 ± 5.0 g) underwent unilateral renal artery embolization using IPM-CS (n = 11) or hydrogel microspheres (n = 4). Follow-up angiography 48 h after embolization and histological evaluation, including acute tubular necrosis (ATN) and inflammation, were scored using a 5-point scale (from 0 = normal to 4 = severe). RESULTS: Over 91% of IPM-CS particles were <40 µm under all in vitro conditions. With the increased contrast volume, the average particle size also increased (mean ± standard deviation: 11.6 ± 13.9 vs 16.7 ± 18.2 µm for 500 and 1000 µL iodinated contrast, P < .001); however, the impact of the mixing/elapsed time were limited. At 48 h after embolization, all cases in the IPM-CS groups (11/11) showed major to complete recanalization versus no recanalization with hydrogel microspheres (0/4) (P < .001). The following are the median ATN and inflammation grades in the cortex (ventral/dorsal) and medulla (ventral/dorsal) in both groups: IPM-CS, ATN in cortex (2/4) and medulla (1/1), inflammation in cortex (0/0) and medulla (0/0); hydrogel microspheres, ATN in cortex (4/4) and medulla (3/2), inflammation in cortex (1/1) and medulla (1/1). CONCLUSIONS: IPM-CS suspension generated particles that were predominantly smaller than 40 µm and with unique short-term embolic effects, leaving predominantly peripheral ischemic changes.

Effect of Cilastatin on Cisplatin-Induced Nephrotoxicity in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy.

Cisplatin is one of the most widely used chemotherapeutic agents in oncology, although its nephrotoxicity limits application and dosage. We present the results of a clinical study on prophylaxis of cisplatin-induced nephrotoxicity in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC-cisplatin). Prophylaxis was with imipenem/cilastatin. Cilastatin is a selective inhibitor of renal dehydropeptidase I in the proximal renal tubule cells that can reduce the nephrotoxicity of cisplatin. Unfortunately, cilastatin is not currently marketed alone, and can only be administered in combination with imipenem. The study has a retrospective part that serves as a control (n = 99 patients receiving standard surgical prophylaxis) and a prospective part with imipenem/cilastatin prophylaxis corresponding to the study group (n = 85 patients). In both groups, we collected specific data on preoperative risk factors of renal damage, fluid management, hemodynamic control, and urine volume during surgery (including the hyperthermic chemotherapy perfusion), as well as data on hemodynamic and renal function during the first seven days after surgery. The main finding of the study is that cilastatin may exert a nephroprotective effect in patients with peritoneal carcinomatosis undergoing cytoreduction and hyperthermic intraperitoneal cisplatin perfusion. Creatinine values remained lower than in the control group (ANOVA test, p = 0.037). This translates into easier management of these patients in the postoperative period, with significantly shorter intensive care unit (ICU) and hospital stay.