Fatal anaphylaxis Due to Nafamostat Mesylate During Hemodialysis.
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ABSTRACT:
SUBMITTER: Kim JH
PROVIDER: S-EPMC7984943 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Fatal anaphylaxis Due to Nafamostat Mesylate During Hemodialysis.
Kim Joo Hee JH Park Ji Young JY Jang Seung Hun SH Kim Jwa Kyung JK Song Young Rim YR Lee Hyung Seok HS Kim Sung Gyun SG
Allergy, asthma & immunology research 20210501 3
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| S-EPMC11252668 | biostudies-literature
Project description:BackgroundUnfractionated heparin sodium and nafamostat mesylate have long been used as anticoagulants in continuous kidney replacement therapy (CKRT) where citrate is unavailable. This study aimed to determine whether heparin or nafamostat mesylate used during CKRT was associated with a longer filter life.MethodsIn this single-centre observational study, we included adult patients who required CKRT and used heparin or nafamostat mesylate for their first CKRT in the intensive care unit from September 1, 2013, to December 31, 2020. The primary outcome was filter life (from the start to the end of using the first filter). We used propensity score matching to adjust for the imbalance in patients' characteristics and laboratory data at the start of CKRT and compared the outcomes between the two groups. We also performed restricted mean survival time analysis to compare the filter survival times.ResultsWe included 286 patients, 157 patients on heparin and 129 patients on nafamostat mesylate. After propensity score matching, the mean filter life with heparin was 1.58 days (N = 91, Standard deviation [SD], 1.52) and with nafamostat mesylate was 1.06 days (N = 91, SD, 0.94, p = 0.006). Multivariable regression analysis adjusted for confounding factors supported that heparin was associated with a longer filter life compared with nafamostat mesylate (regression coefficient, days, 0.52 [95% CI, 0.15, 0.89]). The between group difference of the restricted mean filter survival time in the matched cohort was 0.29 (95% CI, 0.07-0.50, p = 0.008).ConclusionCompared to nafamostat mesylate, heparin was associated with one-third to one-half a day longer filter life.Trial registrationNot applicable.
| S-EPMC9840945 | biostudies-literature
Project description:IntroductionFor hemodialysis patients at high risk of bleeding, a regional anticoagulant can be used, such as citrate or nafamostat mesylate (NM). The objective of this study was to evaluate NM as an alternative to citrate for anticoagulation in hemodialysis patients at high risk of bleeding.MethodsThis retrospective single-center study included consecutive patients in our dialysis center treated with either citrate or NM anticoagulation for hemodialysis from January 2022 to December 2023.The primary outcome was major clotting, defined as premature dialysis due to extracorporeal circuit clotting. The secondary outcome was the incidence of a major bleeding episode during or after hemodialysis.ResultsIn total, 651hemodialysis sessions were performed in 196 patients and were compared (289 citrate and 362 NM anticoagulation). A lower number of premature dialysis due to clotting occurred in the NM sessions compared to citrate sessions (0.84% vs.5.19%, p = 0.001). NM was associated with a lower risk of major clotting compared with citrate during treatment (OR:0.063; CI: 0.008-0.475; p = 0.007). Regarding second outcome, no more major bleeding events related to NM occurred compared to citrate.ConclusionAmong hemodialysis patients with high risk of bleeding, anticoagulation with NM, compared with citrate anticoagulation, provided relatively better efficacy, with no bleeding increment. NM is a valid alternative to citrate for hemodialysis patients at high risk of bleeding.
| S-EPMC11849013 | biostudies-literature
Project description:BackgroundSpinal cord injury (SCI) leads to severe physical disability and sensory dysfunction. Neurotropin (NTP) has been used clinically to alleviate neuropathic pain, while nafamostat mesylate (NM) used clinical on pancreatitis patients through inhibiting synthetic serine protease. Our previous studies showed that NTP and NM were able to repair SCI. However, the underlying mechanism has not been fully explored after treatment with these 2 different drugs.MethodsThe drugs NTP and NM were administered on a contusion SCI Wistar rat model. Cytokine array analysis was performed to describe the changes of 67 proteins after acute SCI. Hierarchical clustering and volcano plot analysis were conducted to clarify protein change profiles. The differently expressed proteins related to biological processes were analyzed by functional protein association networks, Gene Ontology and pathway analysis. Flow cytometric analysis was detected to reflect the activation of immune system after drug intervention, while withdrawal threshold and BBB score were detected to evaluated the mechanical allodynia and functional recovery after SCI.ResultsHGF, β-NGF, and activin were the 3 most upregulated proteins, while the receptor for RAGE, IL-1α, and TNF-α were the 3 most downregulated proteins after NTP treatment. Adiponectin, decorin and CTACK were the 3 most upregulated proteins, while RAGE, IL-1α, and IL-1β were the 3 most downregulated proteins in the NM group. Number of lymphocytes was decreased while BBB score was increased both in NTP and NM group. But only NTP could improve mechanical pain threshold after SCI.ConclusionsThe PI3K-Akt, Jak-STAT signaling pathway and apoptosis might participate in SCI restoration by NTP, while the MAPK and NOD-like receptor signaling pathway may participated in repairing SCI with NM. We concluded that NTP regulated the microenvironment via a neuroprotective effect and inhibition of inflammation to repair SCI, while NM healed SCI through an anti-inflammatory effect. Both NTP and NM could down-regulate the activation of immune system and improve the functional recovery while only NTP could improve the pathological neuralgia after SCI. Elucidating the molecular mechanisms of these 2 clinical drugs indicates that they their expected to be effective clinical treatment for SCI.
| S-EPMC8039678 | biostudies-literature
Project description:BackgroundNafamostat mesylate (nafamostat, NM) is an FDA-approved serine protease inhibitor that exerts anti-neuroinflammation and neuroprotective effects following rat spinal cord injury (SCI). However, clinical translation of nafamostat has been limited by an unclear administration time window and mechanism of action.MethodsTime to first dose of nafamostat administration was tested on rats after contusive SCI. The optimal time window of nafamostat was screened by evaluating hindlimb locomotion and electrophysiology. As nafamostat is a serine protease inhibitor known to target thrombin, we used argatroban (Arg), a thrombin-specific inhibitor, as a positive control in the time window experiments. Western blot and immunofluorescence of thrombin expression level and its enzymatic activity were assayed at different time points, as well its receptor, the protease activated receptor 1 (PAR1) and downstream protein matrix metalloproteinase-9 (MMP9). Blood-spinal cord barrier (BSCB) permeability leakage indicator Evans Blue and fibrinogen were analyzed along these time points. The infiltration of peripheral inflammatory cell was observed by immunofluorescence.ResultsThe optimal administration time window of nafamostat was 2-12 h post-injury. Argatroban, the thrombin-specific inhibitor, had a similar pattern. Thrombin expression peaked at 12 h and returned to normal level at 7 days post-SCI. PAR1, the thrombin receptor, and MMP9 were significantly upregulated after SCI. The most significant increase of thrombin expression was detected in vascular endothelial cells (ECs). Nafamostat and argatroban significantly downregulated thrombin and MMP9 expression as well as thrombin activity in the spinal cord. Nafamostat inhibited thrombin enrichment in endothelial cells. Nafamostat administration at 2-12 h after SCI inhibited the leakage of Evans Blue in the epicenter and upregulated tight junction proteins (TJPs) expression. Nafamostat administration 8 h post-SCI effectively inhibited the infiltration of peripheral macrophages and neutrophils to the injury site.ConclusionsOur study provides preclinical information of nafamostat about the administration time window of 2-12 h post-injury in contusive SCI. We revealed that nafamostat functions through inhibiting the thrombin-mediated BSCB breakdown and subsequent peripheral immune cells infiltration.
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Project description:The search for clinically effective antivirals against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is ongoing. Repurposing of drugs licensed for non-coronavirus disease 2019 (COVID-19) indications has been extensively investigated in laboratory models and in clinical studies with mixed results. Nafamostat mesylate (nafamostat) is a drug licensed in Japan and Korea for indications including acute pancreatitis and disseminated intravascular coagulation. It is available only for continuous intravenous infusion. In vitro human lung cell line studies with nafamostat demonstrate high antiviral potency against SARS-CoV-2 (half maximal inhibitory concentration [IC50] of 0.0022 µM [compared to remdesivir 1.3 µM]), ostensibly via inhibition of the cellular enzyme transmembrane protease serine 2 (TMPRSS2) preventing viral entry into human cells. In addition, the established antithrombotic activity is hypothesised to be advantageous given thrombosis-associated sequelae of COVID-19. Clinical reports to date are limited, but indicate a potential benefit of nafamostat in patients with moderate to severe COVID-19. In this review, we will explore the pre-clinical, pharmacokinetic and clinical outcome data presently available for nafamostat as a treatment for COVID-19. The recruitment to ongoing clinical trials is a priority to provide more robust data on the safety and efficacy of nafamostat as a treatment for COVID-19.
| S-EPMC9425784 | biostudies-literature
Project description:Critical illnesses associated with coronavirus disease 2019 (COVID-19) are attributable to a hypercoagulable status. There is limited knowledge regarding the dynamic changes in coagulation factors among COVID-19 patients on nafamostat mesylate, a potential therapeutic anticoagulant for COVID-19. First, we retrospectively conducted a cluster analysis based on clinical characteristics on admission to identify latent subgroups among fifteen patients with COVID-19 on nafamostat mesylate at the University of Tokyo Hospital, Japan, between April 6 and May 31, 2020. Next, we delineated the characteristics of all patients as well as COVID-19-patient subgroups and compared dynamic changes in coagulation factors among each subgroup. The subsequent dynamic changes in fibrinogen and D-dimer levels were presented graphically. All COVID-19 patients were classified into three subgroups: clusters A, B, and C, representing low, intermediate, and high risk of poor outcomes, respectively. All patients were alive 30 days from symptom onset. No patient in cluster A required mechanical ventilation; however, all patients in cluster C required mechanical ventilation, and half of them were treated with venovenous extracorporeal membrane oxygenation. All patients in cluster A maintained low D-dimer levels, but some critical patients in clusters B and C showed dynamic changes in fibrinogen and D-dimer levels. Although the potential of nafamostat mesylate needs to be evaluated in randomized clinical trials, admission characteristics of patients with COVID-19 could predict subsequent coagulopathy.
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Project description:Breast cancer is common worldwide, and the estrogen receptor-positive subtype accounts for approximately 70% of breast cancer in women. Tamoxifen and fulvestrant are drugs currently used for endocrinal therapy. Breast cancer exhibiting endocrine resistance can undergo metastasis and lead to the death of breast cancer patients. Drug repurposing is an active area of research in clinical medicine. We found that nafamostat mesylate, clinically used for patients with pancreatitis and disseminated intravascular coagulation, acts as an anti-cancer drug for endocrine-resistant estrogen receptor-positive breast cancer (ERPBC). Epigenetic repression of CDK4 and CDK6 by nafamostat mesylate induced apoptosis and suppressed the metastasis of ERPBC through the deacetylation of Histone 3 Lysine 27. A combination of nafamostat mesylate and CDK4/6 inhibitor synergistically overcame endocrine resistance in ERPBC. Nafamostat mesylate might be an essential adjuvant or alternative drug for the treatment of endocrine-resistant ERPBC due to the low cost-efficiency of the CDK4/6 inhibitor.
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Project description:Nafamostat mesylate is a serine protease inhibitor used in the treatment of acute pancreatitis. The impurities in nafamostat mesylate, the active pharmaceutical ingredient (API), were profiled via high performance liquid chromatography tandem ion trap coupled with time-of-flight mass spectrometer (HPLC-IT-TOF/MS). The chromatography was performed on an ACE-3 C18 column (200 mm × 4.6 mm, 3 μm) using methanol and 0.1% formic acid in purified water as mobile phase at a flow rate of 1.0 mL/min. The ions were detected by IT-TOF/MS with a full-scan mass analysis from m/z 100 to 800. In total, eleven impurities were detected in nafamostat mesylate API. The impurity profile was estimated based on the HPLC-IT-TOF/MS data, including accurate masses, MSn fingerprints of fragmentation pathways and a series of double-charged ions. Finally, seven impurities were identified and reported for the first time. The results will provide technical support for the quality control and clinical safety of nafamostat mesylate.
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