No role for protease inhibitors as a mitigation strategy for postpancreatectomy acute pancreatitis (PPAP): Propensity score matching analysis.

BACKGROUND: While the use of protease inhibitor gabexate mesylate (GM) is still controversial in acute pancreatitis, it has never been tested for postpancreatectomy acute pancreatitis (PPAP). This study aims to assess the impact of GM on postoperative serum hyperamylasaemia (POH) or PPAP after pancreatoduodenectomy (PD). METHODS: Consecutive patients developing POH after PD between 2016 and 2021 were included. According to GM administration, patients were divided into GM-treated and control (CTR) groups. GM was administered from postoperative day 1-3 in POH patients who underwent surgery before 2017. A 2:1 propensity matching was used to minimize the risk of bias. RESULTS: Overall, 264 patients with POH were stratified in the GM (59 patients) and CTR (104 patients) cohorts, which showed balanced baseline characteristics after matching. No difference in postoperative complications was observed between the groups (all p > 0.05), except for PPAP occurrence, which was significantly higher in the GM group (37% vs. 22%, p = 0.037). A total of 45 patients (28%) evolved to PPAP. Comparing PPAP patients in the GM and CTR groups, no significant differences in POPF, relaparotomy, and mortality (all p > 0.09) were found. No difference in intravenous crystalloid administration was found in patients with PPAP, whether or not they developed major complications or pancreatic fistula (p > 0.05) CONCLUSION: Protease inhibitor seems ineffective in preventing a PPAP after PD once a POH has occurred. Further studies are needed to achieve benchmarks for treating PPAP and identify mitigation strategies to prevent the evolution of POH into additional morbidity.

Lineage of drug discovery research on fluorinated pyrimidines: chronicle of the achievements accomplished by Professor Setsuro Fujii.

Prof. Setsuro Fujii achieved significant results in the field of drug discovery research in Japan. He developed nine well-known drugs: FT, UFT, S-1 and FTD/TPI are anticancer drugs, while cetraxate hydrochloride, camostat mesilate, nafamostat mesilate, gabexate mesilate and pravastatin sodium are therapeutic drugs for various other diseases. He delivered hope to patients with various diseases across the world to improve their condition. Even now, drug discovery research based on Dr. Fujii's ideas is continuing.

Novel therapeutic compounds for prostate adenocarcinoma treatment: An analysis using bioinformatic approaches and the CMap database.

INTRODUCTION: Prostate adenocarcinoma is the most frequently diagnosed malignancy, particularly for people >70 years old. The main challenge in the treatment of advanced neoplasm is bone metastasis and therapeutic resistance for known oncology drugs. Novel treatment methods to prolong the survival time and improve the life quality of these specific patients are required. The present study attempted to screen potential therapeutic compounds for the tumor through bioinformatics approaches, in order to provide conceptual treatment for this malignant disease. METHODS: Differentially expressed genes were obtained from the Gene Expression Omnibus database and submitted into the Connectivity Map database for the detection of potentially associated compounds. Target genes were extracted from the search results. Functional annotation and pathway enrichment were performed for the confirmation. Survival analysis was used to measure potential therapeutic effects. RESULTS: It was revealed that 3 compounds (vanoxerine, tolnaftate, and gabexate) may help to prolong the disease-free survival time from tumor metastasis of patients with the tumor. A total of 6 genes [also-keto reductase family 1 member C3 (AKR1C3), collagen type III α 1 chain (COL3A1), lipoprotein lipase (LPL), glucuronidase, ß pseudogene 11 (GUSBP11), apolipoprotein E (APOE), and collagen type I α 1 chain (COL1A1)] were identified to be the potential therapeutic targets for the aforementioned compounds. CONCLUSION: In the present study, it was speculated that 3 compounds may function as the potential therapeutic drugs of bone metastatic prostate adenocarcinoma; however, further studies verifying vitro and in vivo are necessary.

Current pharmacological modalities for management of novel coronavirus disease 2019 (COVID-19) and the rationale for their utilization: A review.

SARS-CoV-2 has caused a pandemic which is putting strain on the health-care system and global economy. There is much pressure to develop both preventative and curative therapies for SARS-CoV-2 as there is no evidence to support therapies to improve outcomes in patients with SARS-CoV-2. Medications that inhibit certain steps of virus life cycle that are currently used to treat other illnesses such as Malaria, Ebola, HIV and Hepatitis C are being studied for use against SARS-CoV-2. To date, data is limited for medications that facilitate clinical improvement of COVID-19 infections.

Potential therapeutic targets and promising drugs for combating SARS-CoV-2.

As of April 9, 2020, a novel coronavirus (SARS-CoV-2) had caused 89,931 deaths and 1,503,900 confirmed cases worldwide, which indicates an increasingly severe and uncontrollable situation. Initially, little was known about the virus. As research continues, we now know the genome structure, epidemiological and clinical characteristics, and pathogenic mechanisms of SARS-CoV-2. Based on this knowledge, potential targets involved in the processes of virus pathogenesis need to be identified, and the discovery or development of drugs based on these potential targets is the most pressing need. Here, we have summarized the potential therapeutic targets involved in virus pathogenesis and discuss the advances, possibilities, and significance of drugs based on these targets for treating SARS-CoV-2. This review will facilitate the identification of potential targets and provide clues for drug development that can be translated into clinical applications for combating SARS-CoV-2.

Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies.

We evaluated clinical outcomes of disseminated intravascular coagulation (DIC) in patients with hematological malignancies treated with synthetic protease inhibitors (SPIs) and compared the effects of gabexate mesilate (FOY) and nafamostat mesilate (FUT). We retrospectively examined 127 patients [acute myeloid leukemia (n = 48), acute lymphoblastic leukemia (n = 25), and non-Hodgkin lymphoma (n = 54)] with DIC, who were diagnosed according to Japanese Ministry of Health, Labour and Welfare criteria and treated with SPIs [FOY (n = 55) and FUT (n = 72)] at our hospital from 2006 to 2015. The DIC resolution rates on days 7 and 14 were 42.6% and 62.4%, respectively. No significant differences were observed in DIC resolution rates between the FUT and FOY groups [40.3% vs. 45.5% (day 7), P = 0.586; 56.3% vs. 69.8% (day 14), P = 0.179, respectively]. Multivariate analysis revealed that response to chemotherapy was the only independent predictor of DIC resolution on days 7 and 14 (ORR 2.81, 95% CI 1.32-5.98, P = 0.007; ORR 2.51, 95% CI 1.12-5.65, P = 0.026). Resolution of DIC was correlated with improvement of background hematological malignancies, and no significant differences were observed between the two SPIs.

Anticoagulant Therapy for Disseminated Intravascular Coagulation After Gastrointestinal Surgery.

Many studies about anticoagulant therapy for disseminated intravascular coagulation (DIC) confused gastrointestinal surgery-related DIC with DIC unrelated to a prior operation. Furthermore, the potentially increased risk of bleeding by anticoagulants complicates their use. We carried out a systematic review to describe the efficacy and safety of anticoagulant agents for DIC after gastrointestinal surgery. Several studies have indicated that gabexate mesylate improves DIC score without increasing bleeding events, and that antithrombin is associated with lower mortality of DIC after gastrointestinal surgery. Recombinant thrombomodulin has been the most frequently analyzed anticoagulant agent in this field. DIC score and survival rate were better in patients treated with recombinant thrombomodulin, without increasing bleeding events. In conclusion, anticoagulant therapy may be effective and safe in DIC after gastrointestinal surgery.

Successful treatment of disseminated intravascular coagulation by recombinant human soluble thrombomodulin in patients with acute myeloid leukemia.

Disseminated intravascular coagulation (DIC) is a life-threatening condition that frequently occurs in patients with hematologic malignancies. Currently, recombinant human soluble thrombomodulin (rTM) is a therapeutic DIC drug that is manufactured and sold in Japan only. We evaluated the efficacy of rTM compared to that of gabexate mesilate (GM), which was previously used routinely for treating DIC in Japan, in patients with acute myeloid leukemia (AML). This retrospective study enrolled 43 AML patients, including 17 with acute promyelocytic leukemia (APL), that was complicated with DIC. DIC resolution rates in non-APL AML and rTM-treated APL patients were 68.4% and 81.8%, respectively. In non-APL AML patients, the duration of rTM administration was significantly shorter than that of GM (7 vs 11 days), suggesting that rTM could improve DIC earlier than GM, although rTM was used in patients with more severe DIC. Moreover, treatment with rTM significantly improved DIC score, fibrinogen, fibrin/fibrinogen degradation product (FDP), and prothrombin time (PT) ratio. Conversely, treatment with GM only improved the DIC score and FDP. In APL patients, the duration of rTM administration was also significantly shorter than that of GM. No severe side effects associated with the progression of bleeding were observed during rTM administration. These findings suggest that rTM is safe, and its anti-DIC effects are more prompt than GM for treating AML patients with DIC.

Triple-drug therapy to prevent pancreatic fistula after pancreatectomy in a rat model.

BACKGROUND: Pancreatic fistula (PF) is one of post-operative complications in pancreatic surgery, but there is no consensus about the optimal treatment for PF. Our group has established a rat model of PF, and we conducted the present investigation to determine the efficacy of the triple-drug therapy (somatostatin analogue, gabexate mesilate, and imipenem/cilastatin) against PF using our rat model. METHODS: In the PF rat model, the triple-drug therapy was administered to the treated (T) group (n = 4), and we compared the results with those of a control (C) group (n = 4). The rats were sacrificed on postoperative day 3 (POD 3) and the levels of amylase and lipase in serum and ascites were measured. The intra-abdominal adhesion was scored. Each pancreas was evaluated pathologically, and inflammation was scored. RESULTS: The ascitic amylase levels on POD 3 were 1982 (1738-2249) IU/L in the C group and significantly lower at 136 (101-198) IU/L in the T group (p = 0.02). The ascitic lipase levels on POD 3 were 406 (265-478) U/L in the C group and significantly lower at 13 (7-17) U/L in the T group (p = 0.02). The intra-abdominal adhesion score on POD 3 was 2 (1-2) in the C group and significantly lower at 0 (0-1) in the T group (p = 0.02). The histological evaluation showed that the average of pancreatic inflammatory score was 8.5 (8-9) in the C group and significantly milder at 5 (5-7) in the T group (p = 0.01). CONCLUSION: Our findings suggest that the triple-drug therapy could be useful as a treatment for PF in clinical settings.

Effect of Somatostatin, Ulinastatin and Gabexate on the Treatment of Severe Acute Pancreatitis.

OBJECTIVE: The objective of this study is to evaluate the efficacy of somatostatin, ulinastatin and gabexate for the treatment of severe acute pancreatitis. MATERIALS AND METHODS: A total of 492 patients with severe acute pancreatitis were assigned randomly into the following 4 groups: (1) somatostatin; (2) somatostatin + ulinastatin; (3) somatostatin + gabexate and (4) somatostatin + ulinastatin + gabexate. Acute physiology and chronic health evaluation II scores; clinical parameters including time of abdominal pain and distention extinct; recovering to normality of heart rate and respiration rate; amylase and blood glucose; ratios of efficacy; multiple organ dysfunction syndrome (MODS); mortality; complication; levels of endotoxin; tumor necrosis factor alpha; interleukin-6 (IL-6), IL-8 and IL-10 and side effects were analyzed. RESULTS: Acute physiology and chronic health evaluation II scores, time of abdominal pain extinct and distention extinct, time of recovering to normality of heart rate, time of recovering to normality of respiration rate and time of recovering to normality of amylase and blood glucose were significantly decreased in the somatostatin + ulinastatin, the somatostatin + gabexate and the somatostatin + ulinastatin + gabexate subgroups compared with the somatostatin subgroup. Ratios of efficacy were significantly improved, whereas ratios of MODS, mortality and complication were significantly decreased in the somatostatin + ulinastatin and the somatostatin + ulinastatin + gabexate subgroups compared with the somatostatin subgroup. Tumor necrosis factor alpha, IL-6 and IL-8 levels on the fourth day after treatment showed significant decrease in the somatostatin + ulinastatin, the somatostatin + gabexate and the somatostatin + ulinastatin + gabexate subgroups compared with the somatostatin subgroup. The IL-10 levels on the fourth day were significantly improved in the somatostatin + ulinastatin, the somatostatin + gabexate and the somatostatin + ulinastatin + gabexate subgroups compared with the somatostatin subgroup. CONCLUSIONS: Somatostatin is effective for the treatment of acute pancreatitis, ulinastatin demonstrates improvement in therapeutic benefits and gabexate can relieve the clinical symptoms and shorten the course of disease but cannot improve the effective ratio or decrease MODS, mortality and complication.

Targeting mast cells in gastric cancer with special reference to bone metastases.

Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases.

Comparison of recombinant human thrombomodulin and gabexate mesylate for treatment of disseminated intravascular coagulation (DIC) with sepsis following emergent gastrointestinal surgery: a retrospective study.

PURPOSE: Recombinant thrombomodulin (rTM) has been available in Japan since 2008, but there is concern about its association with postoperative hemorrhage. The efficacy and safety of rTM were examined in patients with disseminated intravascular coagulation (DIC) caused by a septic condition after gastrointestinal surgery. METHODS: Forty-two patients were emergently admitted to the intensive care unit after emergent gastrointestinal surgery in Kyushu University Hospital from May 2008 to April 2013. Of these patients, 22 had DIC (defined as an acute DIC score ≥ 4). All but three patients received treatment with gabexate mesylate (GM) (n = 9) or rTM (n = 10). The causes of sepsis were peritonitis with colorectal perforation, anastomotic leakage, and intestinal necrosis. Acute DIC score, sepsis-related organ failure assessment score, platelet count, and a variety of biochemical parameters were compared between rTM and GM recipients after treatment administration. RESULTS: There were no significant differences between the groups for any parameter except C-reactive protein levels. The CRP level tended to be lower in the rTM group than in the GM group. Acute DIC score in the rTM group resolved significantly earlier than that in the GM group. No patient stopped the administration of rTM because of postoperative bleeding. CONCLUSION: rTM may be an effective therapeutic drug for the treatment of septic patients with DIC following emergent gastrointestinal surgery.

[Acute pancreatitis in pediatric age: our experience in 52 cases]. / Pancreatite acuta in età pediatrica: nostra esperienza su 52 casi.

AIM: The aim of this study was to report our experience about clinical presentation and management in children with mild and sever acute pancreatitis (PA). METHODS: At the onset of clinical manifestations the following laboratory and instrumental tests were performed to all patients: abdominal ultrasonography, measurement of blood amylase and lipase and PCR; preventive antibiotic therapy, gabexate mesylate and proton pump inhibitors were also administrated to all patients. During the follow-up CT and dosage amylase and lipase in blood were performed. RESULTS: Results summarize data of 52 patients with suspected diagnosis of acute pancreatitis admitted to our hospital within 24 h of symptoms (from January 2008 to December 2011). Age ranged between 4-18 years, and the study included 30 females and 22 males. According to Santorini Consensus Conference, 40 patients were defined having a mild and 12 a severe pancreatitis. All patients with mild PA underwent a medical and/or surgical treatment (endoscopic retrograde cholangiopancreatography, laparoscopic cholecystectomy); there were 2 fatalities between patients with severe PA and 2 cases of pancreatic pseudocyst treated with guided CT drainage and therapy with octreotide. All patients had abdominal pain but the location, severity and duration of pain were extremely variable. Blood dosage of amylase was altered in 83% of cases and of lipase in 100%. Ultrasonography showed abnormalities in 89% of the patients and TC showed alterations of pancreatic parenchyma in 100% of the cases when performed at 48 h. CONCLUSION: In absence of randomized controlled studies, systematic review or guidelines for diagnosis and management of PA in pediatric age we used our experiences on adult patients, aware of this approach limitation.

The effect of serine protease inhibitors on airway inflammation in a chronic allergen-induced asthma mouse model.

Serine protease inhibitors reportedly attenuated airway inflammation and had antioxidant in multiorgan. However, the effects of the serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on a long-term challenged mouse model of chronic asthma are unclear. BALB/c mice (6 mice/group) were intratracheally inoculated with five doses of Dermatophagoides pteronyssinus (Der p; 50 µL, 1 mg/mL) at one-week intervals. Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), or UTI (10,000 U/kg) were, respectively, injected intraperitoneally into these mice. Control mice received sterile PBS. At 3 days after the last challenge, mice were sacrificed to assess airway hyperresponsiveness (AHR), remodeling, and inflammation; lung histological features; and cytokine expression profiles. Compared with untreated controls, mice treated with FUT, FOY, and UTI had decreased AHR and goblet cell hyperplasia, decreased eosinophil and neutrophil infiltration, decreased Der p-induced IL-4 levels in serum and IL-5, IL-6, IL-13, and IL-17 levels in bronchoalveolar lavage fluid, and inhibited nuclear factor (NF)-κB activity in lung tissues. The serine protease inhibitors FUT, FOY, and UTI have potential therapeutic benefits for treating asthma by downregulating Th2 cytokines and Th17 cell function and inhibiting NF-κB activation in lung tissue.

Preconditioning with gabexate is superior to inosine for ameliorating acute renal ischemia-reperfusion injury in rats.

OBJECTIVE: The objective of this study was to compare the protease inhibitor gabexate with widely used inosine for reducing renal ischemia-reperfusion injury. METHOD: A total of 48 rats were divided into 4 groups of 12 and administered gabexate, inosine, normal saline (NS), or nothing by injection through the vena dorsalis of the penis. Then all rats were subjected to right nephrectomy and 30-minute warm ischemia of the left kidney. At 24 and 48 hours after reperfusion, blood samples were collected from the inferior vena cava and serum creatinine (SCr) was assayed. Left kidney tissue was homogenized and used to assay malondialdehyde (MDA) and superoxide dismutase (SOD). The tissue was also analyzed using hematoxylin-eosin (HE) staining, TUNEL staining, and NF-κB immunohistochemistry. RESULTS: SCr level decreased after reperfusion more in the gabexate group than in the other groups. Reperfused kidney tissue in the gabexate group showed lower MDA levels but higher SOD activity than did tissue in the inosine and saline groups, as well as lower pathology scores based on HE staining, lower necrosis index, and lower levels of NF-κB expression (all P < .05). Tissue in the inosine and saline groups showed similar necrosis index and NF-κB expression (P > .05). CONCLUSION: Preconditioning with gabexate is superior to preconditioning with inosine for ameliorating rat renal ischemia-reperfusion injury. Future studies are needed to verify the effects of gabexate in the clinic, especially for kidney transplantation.

The antifibrotic effect of a serine protease inhibitor in the kidney.

Interstitial fibrosis is a final common pathway for the progression of chronic kidney diseases. Activated fibroblasts have an extremely important role in the progression of renal fibrosis, and transforming growth factor (TGF)-ß1 is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-ß1 signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-ß1 markedly increased the phosphorylation of TGF-ß type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1, in renal fibroblasts (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, 8-wk-old male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) and were concurrently treated with a slow-release pellet of CM or vehicle for 14 days. Protocol 2 was similar to protocol 1 except that CM was administered 7 days after UUO. CM substantially improved renal fibrosis as determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and Smad2/3 and the levels of α-SMA, CTGF, promatrix metalloproteinase-2, and matrix metalloproteinase-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These antifibrotic effects of CM were also observed in protocol 2. Our present results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of TGF-ß1 signaling.

Gabexate mesylate as treatment in the course of ANCA-negative microscopic polyangiitis.

Patients with small vessel vasculitis present fluctuating antineutrophil cytoplasmic antibodies (ANCA) levels to the point that positive ANCA may be missed even if only up to 10% of patients with microscopic polyangiitis (MPA) are ANCA-negative. The first-line treatment of MPA is the association of steroids and cyclophosphamide, especially in the presence of a rapidly progressive glomerulonephritis. Plasmapheresis, intravenous immunoglobulins, and tumor necrosis factor inhibitors have been proposed as alternative to standard therapy. Disseminated intravascular coagulation (DIC) is a possible event in the course of small vessel vasculitis. Gabexate mesylate is a protease inhibitor able to suppress endothelial cell injury, and it may be administered to treat DIC related to different diseases. In ANCA-associated vasculitis, cytokines play a key role in promoting endothelial damage. DIC-related thrombocytopenia may be misinterpreted as drug-induced because of the immunosuppressive properties of cyclophosphamide. Two cases of ANCA-positive MPA associated with DIC and treated with gabexate are reported in the literature with improvement of both hematological disorder and renal function. Our patient presented a rapidly progressive glomerulonephritis, and the renal biopsy showed MPA, in the absence of ANCA. After two weeks of steroid treatment, our patient developed a DIC. This case represents the first report of ANCA-negative MPA managed with gabexate, which showed improvement of coagulation disorders and kidney function. In conclusion, the anti-inflammatory properties of gabexate could be helpful in MPA at increased bleeding risk when immunosuppressive treatment is contraindicated, even in ANCA-negative vasculitis.

Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations.

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted.