TMPRSS2 inhibitors for the treatment of COVID-19 in adults: a systematic review and meta-analysis of randomized clinical trials of nafamostat and camostat mesylate.

BACKGROUND: Synthetic serine protease inhibitors block the cellular enzyme transmembrane protease serine 2, thus preventing SARS-CoV-2 cell entry. There are two relevant drugs in this class, namely, nafamostat (intravenous formulation) and camostat (oral formulation). OBJECTIVE: To determine whether transmembrane protease serine 2 inhibition with nafamostat or camostat is associated with a reduced risk of 30-day all-cause mortality in adults with COVID-19. DATA SOURCES: Scientific databases and clinical trial registry platforms. STUDY ELIGIBILITY CRITERIA, INTERVENTIONS, AND PARTICIPANTS: Preprints or published randomized clinical trials (RCTs) of nafamostat or camostat vs. usual care or placebo in adults requiring treatment for COVID-19. METHODS OF DATA SYNTHESIS AND RISK-OF-BIAS ASSESSMENT: The primary outcome of the meta-analysis was 30-day all-cause mortality. Secondary outcomes included time to recovery, adverse events, and serious adverse events. Risk of bias (RoB) was assessed using the revised Cochrane RoB 2 tool for individually randomized trials. Meta-analysis was conducted in the R package meta (v7.0-0) using inverse variance and random effects. Protocol registration number was INPLASY202320120. RESULTS: Twelve RCTs were included. Overall, the number of available patients was small (nafamostat = 387; camostat = 1061), the number of enrolled patients meeting the primary outcome was low (nafamostat = 12; camostat = 13), and heterogeneity was high. In hospitalized adults, we did not identify differences in 30-day all-cause mortality (risk ratio [95% CI]: 0.58 [0.19, 1.80], p 0.34; I2 = 0%; n = 6) and time to recovery (mean difference [95% CI]: 0.08 days [-0.74, 0.89], p 0.86; n = 2) between nafamostat vs. usual care; and for 30-day all-cause mortality (risk ratio [95% CI]: 0.99 [0.31, 3.18], p 0.99; n = 2) between camostat vs. placebo. CONCLUSION: The RCT evidence is inconclusive to determine whether there is a mortality reduction and safety with either nafamostat or camostat for the treatment of adults with COVID-19. There were high RoB, small sample size, and high heterogeneity between RCTs.

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.

Enteral administration of the protease inhibitor gabexate mesilate preserves vascular function in experimental trauma/hemorrhagic shock.

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10-10 to 10-5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC50: - 5.73 ± 0.25 vs. - 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC50: - 6.62 ± 0.21 vs. - 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.

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.

Mechanisms of NMDA receptor inhibition by nafamostat, gabexate and furamidine.

N-methyl-D-aspartate (NMDA) receptors are affected by many pharmaceuticals. In this work, we studied the action of the serine protease inhibitors nafamostat, gabexate and camostat, and an antiprotozoal compound, furamidine, on native NMDA receptors in rat hippocampal pyramidal neurons. Nafamostat, furamidine and gabexate inhibited these receptors with IC50 values of 0.20 ± 0.04, 0.64 ± 0.13 and 16 ± 3 µM, respectively, whereas camostat was ineffective. Nafamostat and furamidine showed voltage-dependent inhibition, while gabexate showed practically voltage-independent inhibition. Nafamostat and furamidine demonstrated tail currents, implying a 'foot-in-the-door' mechanism of action; gabexate did not demonstrate any signs of 'foot-in-the-door' or trapping channel block. Gabexate action was also not competitive, suggesting allosteric inhibition of NMDA receptors. Furamidine and nafamostat are structurally similar to the previously studied diminazene and all three demonstrated a 'foot-in-the-door' mechanism. They have a rather rigid, elongated structures and cannot fold into more compact forms. By contrast, the gabexate molecule can fold, but its folded structure differs drastically from that of typical NMDA receptor blockers, in agreement with its voltage-independent inhibition. These findings provide a better understanding of the structural determinants of NMDA receptor antagonism, while also supporting the potential clinical repurposing of these drugs as neuroprotectors for glaucoma and other neurodegenerative diseases.

Efficacy of gabexate mesilate in preventing post endoscopic retrograde cholangiopancreatography pancreatitis: A meta-analysis of randomized clinical trials.

BACKGROUND/PURPOSE: The evidence provided by syntheses of the preventative effects of gabexate mesilate against pancreatitis among patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) is limited and highly heterogeneous. To enhance the understanding of this topic, this study aimed to provide overview of gabexate mesilate on preventing post ERCP pancreatitis (PEP) by synthesizing all relevant randomized controlled trials (RCTs). METHODS: We searched three databases for relevant RCTs. Two authors independently extracted data of pancreatitis incidence after ERCP, abdominal pain within 48 hours, and hyperamylasemia for quality assessment and meta-analysis. RESULTS: Thirteen RCTs with 3718 patients undergoing ERCP met the eligibility criteria and were included. The results revealed that the use of gabexate mesilate led to lower PEP (Peto odds ratio: 0.66, 95% confidence interval [CI]: 0.49 to 0.89), especially in the subgroup of gabexate mesilate infusion starting more than 30 min (Risk ratio: 0.45, 95% CI: 0.29 to 0.72). CONCLUSION: The present synthesis found that gabexate mesilate could be an option of prophylactic treatment of pancreatitis for patients undergoing ERCP, and reveals that it is favorable to administer it starting 30 min before the ERCP. This evidence may improve the clinical prevention of PEP.

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.

Comprehensive analysis of drugs to treat SARS­CoV­2 infection: Mechanistic insights into current COVID­19 therapies (Review).

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

Camostat Mesilate, Pancrelipase, and Rabeprazole Combination Therapy Improves Epigastric Pain in Early Chronic Pancreatitis and Functional Dyspepsia with Pancreatic Enzyme Abnormalities.

BACKGROUND/AIMS: The aims of the study are to clarify the pathophysiological differences among early chronic pancreatitis (ECP), functional dyspepsia with pancreatic (FD-P) enzyme abnormalities and FD patients and to determine whether camostat mesilate, pancrelipase, and rabeprazole triple therapy improve FD symptoms in the ECP patients and FD-P patients in cross-over way. METHODS: We enrolled 84 consecutive patients presenting with typical symptoms of FD patients (n = 42), ECP patients (n = 15), and FD-P patients (n = 27). Gastric emptying was assessed by the 13C-acetate breath test. ECP was diagnosed based on the criteria recommended by the Japan Pancreatic Association. RESULTS: The proportions of female in ECP patients and FD-P were significantly higher compared to that in FD patients. The early phase of gastric emptying in ECP and FD-P patients was significantly disturbed compared to that in FD patients. The primary outcome of this study is that 4 weeks of camostat mesilate, pancrelipase, and rabeprazole triple therapy significantly ameliorated epigastric pain in ECP patients compared to acotiamide and rabeprazole combination therapy. CONCLUSION: Although there were no significant differences in pathophysiology between ECP patients and FD-P patients, triple therapy can significantly ameliorate epigastric pain in ECP patients. Further studies will be needed to clarify why triple therapy can improve epigastric pain in ECP patients.

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.

Efficacy of Triple-Drug Therapy to Prevent Pancreatic Fistulas in Patients With High Drain Amylase Levels After Pancreaticoduodenectomy.

BACKGROUNDS: Prior studies have suggested that drain amylase level is a predictive marker for developing pancreatic fistulas (PFs) after pancreaticoduodenectomy (PD). However, means of preventing PF after discovering high drain amylase levels have not been previously established. The purpose of this study was to evaluate the efficacy of a combination drug therapy (using three drugs; gabexate mesilate, octreotide, and carbapenem antibiotics, named as triple-drug therapy [TDT]) regimen in preventing PF for patients with high drain amylase levels on postoperative day (POD) 1 after PD. MATERIALS AND METHODS: We divided the 183 patients who underwent PD into two groups in accordance with their enrollment in the study: for those enrolled early in the study (early period), TDT was not administered to patients with high drain amylase level; however, for those enrolled later in the study (late period), TDT was administered if drain amylase levels were over 10,000 IU/L on POD 1. We retrospectively compared the incidence of PF between the two groups. RESULTS: Incidences of PFs were statistically, significantly prevented in the late group (early 17% versus late 6%; P = 0.01). For patients with low levels of drain amylase (<10,000 IU/L), the PF ratio was equivalent between two groups (early 8% versus late 5%; P = 0.56); however, PFs in patients with high drain amylase levels in the late period group were dramatically prevented by TDT administration (early 89% versus late 11%; P < 0.001). CONCLUSIONS: TDT may be a promising therapy to prevent PFs in patients with high drain amylase levels after PD.

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.

Impact of continuous regional arterial infusion in the treatment of acute necrotizing pancreatitis: analysis of a national administrative database.

BACKGROUND: Although continuous regional arterial infusion (CRAI) of protease inhibitors and broad antibiotics has been suggested as one of the therapeutic option for patients with acute necrotic pancreatitis (ANP), the effectiveness has not been well-corroborated in clinical studies. METHODS: We conducted a retrospective cohort study using a Japanese national administrative database. Severe acute pancreatitis patients with a poorly enhanced pancreas region (i.e., definitive or clinically suspected ANP) were identified and dichotomized according to whether CRAI was performed. We compared the outcomes of in-hospital mortality, surgical interventions, hospital-free days, and healthcare costs between groups adjusted by the well-validated case-mix adjustment model using a multivariate mixed-effect regression analysis and a propensity score matching analysis. RESULTS: Of 243,312 acute pancreatitis patients, 702 eligible patients were identified, of these 339 patients underwent CRAI. The case-mix adjustment model established had good predictability for in-hospital mortality with an area under the receiver operating characteristics curve of 0.87. CRAI was significantly associated with reduced in-hospital mortality [14.5% in the CRAI group vs. 18.2% in the non-CRAI group, adjusted odds ratio (95% confidence interval; CI) = 0.60 (0.36-0.97)]. Significant associations were not observed for the frequency of surgical interventions and mean hospital-free days; however, significantly higher healthcare costs were observed in the CRAI group. Results of the propensity score matching analysis did not alter these results. CONCLUSIONS: Analysis of a nationwide large-scale database suggested that CRAI was significantly associated with reduced in-hospital mortality for patients with ANP. Further randomized controlled trials are warranted.

Immediate-type allergic and protease-mediated reactions are involved in scratching behaviour induced by topical application of Dermatophagoides farinae extract in NC/Nga mice.

Atopic dermatitis (AD)-like dermatitis can be induced by repeated topical application of an ointment containing Dermatophagoides farinae body (Dfb) extract in NC/Nga mice. This AD-like murine model also exhibits a biphasic increase in the number of scratching behaviour after topical application of Dfb ointment. In this study, we investigated the possible mechanisms underlying the scratching behaviour in each phase. An increase in the content of mast cell-derived mediators such as histamine and 5-hydroxytryptamine in the lesional skin and increased vascular permeability were observed in the early phase after the Dfb ointment application. Chlorpheniramine (H1 receptor antagonist) and cromoglycate (mast cell stabilizer) reduced the scratching behaviour in the early phase but not that in the later phase. Furthermore, the content of various endogenous pruritogens such as interleukin-31 and thymic stromal lymphopoietin in the lesional skin was increased 1 or 24 hours after the Dfb ointment application. Elevated expression of proteinase-activated receptor-2 (PAR-2) was also observed in the epidermis. Finally, gabexate (serine protease inhibitor) reduced the scratching behaviour in both phases, and anti-PAR2 antibody also showed a tendency to reduce both scratching behaviours. These findings suggest that immediate-type allergic reactions caused by mast cell degranulation and PAR-2 activation by proteases are involved in the scratching behaviour in this AD-like model.