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Objective Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications, has rarely been evaluated. Therefore, we evaluated the efficacy of anti-influenza drugs against seasonal influenza in healthy young and middle-aged adults. Methods A systematic review and network meta-analysis were conducted. The Cochrane Central Register of Controlled Trials and Medical Literature Analysis and Retrieval System Online were searched for original articles reporting double-blind, randomized controlled trials published up to the end of July 2023. Clinical trials that tested the efficacy of anti-influenza drugs in young and middle-aged patients with seasonal influenza were also included. The primary outcome was time to fever alleviation. The efficacy and adverse effects of these treatments were estimated using a Bayesian hierarchical random-effects model and a Markov chain Monte Carlo simulation. Results In total, 24 articles with 34 treatments and 8,949 individuals were included. Oseltamivir (300 mg/day for 5 days) showed the largest reduction in time to fever alleviation by -19.1 [95% confidence interval (CI): -29.4, -10.7] h compared with a placebo. Baloxavir marboxil (40 mg/day) reduced the time to symptom alleviation by -28.2 (95% CI: -42.7, -13.7) h, and peramivir (300 mg/day) administered by intravenous infusion for 1 day reduced the time to resumption of usual activities by -43.5 (95% CI: -72.8, -14.2) h. Conclusion Several pharmaceutical treatments were able to reduce the recovery time for fever and symptom alleviation and resumption of usual activities in young and middle-aged adults with seasonal influenza without increasing the risk of complications.

Osteonecrosis of the jaw (ONJ) is a relatively rare side effect after prolonged use of bisphosphonates, which are drugs used to treat bone resorption in osteoporosis and certain cancers. This study introduces a novel ONJ model in rats by combining exposure to bisphosphonates, oral surgery, and bacterial inoculation. Potential ONJ preventive effects of polyguanidine (GuaDex) or antibiotics were evaluated. The study consisted of twenty-four male Wistar rats were divided into four groups. Groups 1 to 3 were given weekly doses of i.v. Zoledronic acid (ZA), four weeks before and two weeks after an osteotomy procedure on their left mandibular first molar. Group 4 was a negative control. Streptococcus gordonii bacteria were introduced into the osteotomy pulp chamber and via the food for seven days. On day eight, the rats were given different treatments. Group 1 was given a GuaDex injection into the osteotomy socket, Group 2 was given an intramuscular (i.m.) injection of clindamycin, Group 3 (positive control) was given an i.m. injection of saline, and Group 4 was given an i.m. injection of saline. Blood samples were taken two weeks after the osteotomy procedure, after which the rats were euthanized. Bone healing, bone mineral density, histology, and blood status were analyzed. The results showed that Group 1 (GuaDex) had no ONJ, extensive ongoing bone regeneration, active healing activity, vascularization, and no presence of bacteria. Group 2 (clindamycin) showed early stages of ONJ, avascular areas, and bacteria. Group 3 showed stages of ONJ, inflammatory infiltrates, defective healing, and bacterial presence, and Group 4 had normal healing activity and no bacterial presence. Conclusion: ZA treatment and bacterial inoculation after tooth extraction inhibited bone remodeling/healing and induced ONJ characteristic lesions in the rats. Only GuaDex apparently prevented ONJ development, stimulated bone remodeling, and provided an antimicrobial effect., Competing Interests: Declaration of competing interest The authors stated that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We are writing to you in response to the article published in BMC Nephrology titled "Dose of nafamostat mesylate during continuous kidney replacement therapy in critically ill patients: a two-centre observational study". The study provided valuable information on the use of nafamostat mesylate (NM) during continuous renal replacement therapy (CRRT) in critically ill patients. We noticed in this study that a higher dose of NM resulted in a decrease in ICU and hospital mortality. However, the underlying mechanism behind this phenomenon remains unclear. We believe exploring this further is warranted., (© 2024. The Author(s).)

Competing Interests: Declaration of competing interest None.

We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Camostat mesylate, an oral serine protease inhibitor, is a powerful TMPRSS2 inhibitor and has been reported as a possible antiviral treatment against COVID-19. Therefore, we aim to assess the safety and efficacy of camostat mesylate for COVID-19 treatment., Methods: A systematic review and meta-analysis synthesizing randomized controlled trials from PubMed, Scopus, Embase, Cochrane, Web of Science, clinical trials.gov, and medrxiv until June 2023. The outcomes were pooled using Mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes. The protocol is registered in PROSPERO with ID CRD42023439633., Results: Nine RCTs, including 1,623 patients, were included in this analysis. There was no difference between camostat mesylate and placebo in producing negative PCR test results at 1-7 days (RR: 0.76, 95% CI: [0.54, 1.06] P = 0.1), 8-14 days (RR: 1.02, 95% CI: [0.84, 1.23] P = 0.87), or 15-21 days (RR: 0.99, 95% CI: [0.82, 1.19] P = 0.90); clinical resolution of symptoms at 1-7 days (RR: 0.94 (95% CI: 0.58, 1.53) P = 0.81), 8-14 days (RR: 0.91, 95% CI: [0.74, 1.11] P = 0.33, ), or 15-21 days (RR: 0.77, 95% CI: [0.40, 1.51] P = 0.45); and time to symptom improvement (MD:-0.38 weeks (95% CI: [-1.42, 0.66] P = 0.47, I 2  = 85%)., Conclusion: Camostat mesylate did not improve clinical outcomes in patients with COVID-19, compared to placebo., (© 2024. The Author(s).)

There is an urgent unmet need for more targeted and effective treatments for advanced epithelial ovarian cancer (EOC). The emergence of drug resistance is a particular challenge, but small molecule covalent inhibitors have promise for difficult targets and appear less prone to resistance. Michael acceptors are covalent inhibitors that form bonds with cysteines or other nucleophilic residues in the target protein. However, many are categorized as pan-assay interference compounds (PAINS) and considered unsuitable as drugs due to their tendency to react non-specifically. Targeting RPN13/ADRM1-mediated substrate recognition and deubiquitination by the proteasome 19S Regulatory Particle (RP) is a promising treatment strategy. Early candidate RPN13 inhibitors (iRPN13) produced a toxic accumulation of very high molecular weight polyubiquitinated substrates, resulting in therapeutic activity in mice bearing liquid or solid tumor models, including ovarian cancer; however, they were not drug-like (PAINS) because of their central piperidone core. Up284 instead has a central spiro-carbon ring. We hypothesized that adding a guanidine moiety to the central ring nitrogen of Up284 would produce a compound, RA475, with improved drug-like properties and therapeutic activity in murine models of ovarian cancer. RA475 produced a rapid accumulation of high molecular polyubiquitinated proteins in cancer cell lines associated with apoptosis, similar to Up284 although it was 3-fold less cytotoxic. RA475 competed binding of biotinylated Up284 to RPN13. RA475 shows improved solubility and distinct pharmacodynamic properties compared to Up284. Specifically, tetraubiquitin firefly luciferase expressed in leg muscle was stabilized in mice more effectively upon IP treatment with RA475 than with Up284. However, pharmacologic analysis showed that RA475 was more rapidly cleared from the circulation, and less orally available than Up284. RA475 shows reduced ability to cross the blood-brain barrier and in vitro inhibition of HERG. Treatment of mice with RA475 profoundly inhibited the intraperitoneal growth of the ID8-luciferase ovarian tumor model. Likewise, RA475 treatment of immunocompetent mice inhibited the growth of spontaneous genetically-engineered peritoneal tumor, as did weekly cisplatin dosing. The combination of RA475 and cisplatin significantly extended survival compared to individual treatments, consistent with synergistic cytotoxicity in vitro. In sum, RA475 is a promising candidate covalent RPN13i with potential utility for treatment of patients with advanced EOC in combination with cisplatin., Competing Interests: RA475 is described in the Johns Hopkins University technology C16365 - ANTI-CANCER “SPIROCYCLIC-GUANIDINE COMPOUNDS” AND USES THERE OF, provisional application filed on May 18, 2020 as U.S. Patent Application No. 63/026,268, inventors Roden RB and Anchoori RK. The study described in this publication utilized compounds manufactured by Up Therapeutics LLC (MTA A36130) and covered by US patent US20190365726 and application 17/154,306. Dr. Roden is a consultant to Up Therapeutics LLC and owns stock in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Anchoori is the founder of Up Therapeutics LLC and owns stock in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Michelle Rudek reports a relationship with Geminus Therapeutics, LLC, that includes co-founder, board membership, and equity or stocks. Michelle Rudek reports a relationship with GlaxoSmithKline that includes employment (spouse). This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Anchoori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Spinal cord injury (SCI) is a devastating condition for which effective clinical treatment is currently lacking. During the acute phase of SCI, myriad pathological changes give rise to subsequent secondary injury. The results of our previous studies indicated that treating rats post-SCI with nafamostat mesilate (NM) protected the blood-spinal cord barrier (BSCB) and exerted an antiapoptotic effect. However, the optimal dosage for mice with SCI and the underlying mechanisms potentially contributing to recovery, especially during the acute phase of SCI, have not been determined. In this study, we first determined the optimal dosage of NM for mice post-SCI (5 mg/kg/day). Subsequently, our RNA-seq findings revealed that NM has the potential to inhibit pyroptosis after SCI. These findings were further substantiated by subsequent Western blot (WB) and Immunofluorescence (IF) analyses in vivo. These results indicate that NM can alleviate NLRP3 (NOD-like receptor thermal protein domain associated protein 3)-mediated pyroptosis by modulating the NF-κB signaling pathway and reducing the protein expression levels of NIMA-related kinase 7 (NEK7) and cathepsin B (CTSB). In vitro experimental results supported our in vivo findings, revealing the effectiveness of NM in suppressing pyroptosis induced by adenosine triphosphate (ATP) and lipopolysaccharide (LPS) in BV2 cells. These results underscore the potential of NM to regulate NLRP3-mediated pyroptosis following SCI. Notably, compared with other synthetic compounds, NM exhibits greater versatility, suggesting that it is a promising clinical treatment option for SCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

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; I 2  = 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., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells., Methods: We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life., Trials Registration: jRCT2021220012 registered on 17 June 2022., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kobayakawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Nafamostat mesylate, a synthetic serine protease inhibitor, has been shown to have antiviral activity against SARS-CoV-2 and anticoagulant properties that may be beneficial in the treatment of COVID-19. We conducted a meta-analysis to evaluate the effectiveness and safety of nafamostat mesylate for the treatment of COVID-19. PubMed, Embase, Cochrane Library, Scopus, Web of Science, medRxiv, and bioRxiv were searched up to July 2023 for studies comparing the outcomes of nafamostat mesylate treatment and no nafamostat mesylate treatment in patients with COVID-19. Mortality, disease progression, and adverse events were analyzed. Six studies involving 16,195 patients were included in the analysis. Meta-analysis revealed no significant difference in mortality (odds ratio [OR]: 0.88, 95% CI: 0.20-3.75, P = 0.86) or disease progression (OR: 2.76, 95% CI: 0.31-24.68, P = 0.36) between groups. However, nafamostat mesylate was associated with an increased risk of hyperkalemia (OR: 7.15, 95% CI: 2.66-19.24, P < 0.0001). Nafamostat mesylate did not improve mortality or morbidity in hospitalized patients with COVID-19. The risk of hyperkalemia is a serious concern that requires monitoring and preventive measures. Further research in different COVID-19 populations is required.

Continuous renal replacement therapy (CRRT) is often disrupted due to various factors, such as patient-related issues, vascular access complications, treatment plans, and medical staff factors. This unexpected interruption is referred to as non-selective filter stoppage and can result in additional treatment expenses. This study conducted a retrospectively analyzed 501 CRRT filters used in 62 patients with severe burns, lifespan and therapeutic effect of all filters were mainly analyzed, used logistic regression analysis was performed to identify risk factors associated with non-selective cessation filters. Out of 493 filters, 279 cases received heparin (56.60%), the median lifespan of the filter was 14.08 h (25th, 75th quantile: 7.30, 21.50); 128 cases were treated with nafamostat mesylate (26.00%), and the median lifespan of the filter was 16.42 h (10.49, 22.76); 86 cases were treated with sodium citrate (17.40%), and the median lifespan of the filter was 31.06 h (19.25, 48.75). In addition, significant differences were observed in the electrolyte index, renal function index, and procalcitonin levels before and after treatment with a single filter (P < .001). Multivariate logistic regression showed that the risk of non-selective cessation of sodium citrate anticoagulants was lower than that of heparin anticoagulation. Overall, CRRT is progressively becoming more prevalent in the treatment of patients with severe burns. The lifespan of individual filters and total patient treatment duration showed a consistent upward trend. The filter's lifespan was notably greater during sodium citrate anticoagulation when compared to nafamostat mesylate and heparin, meanwhile notably reducing the risk of non-selective cessation. Therefore, we recommend sodium citrate for anticoagulation in patients without any contraindications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Burn Association.)

Cancer-targeted nanotechnology has a new trend in the design and preparation of new materials with functions for imaging and therapeutic applications simultaneously. As a new type of carbon nanomaterial, the inherent core-shell structured carbon dots (CDs) can be designed to provide a modular nanoplatform for integration of bioimaging and therapeutic capabilities. Here, core-shell structured CDs are designed and synthesized from levofloxacin and arginine and named Arg-CDs, in which levofloxacin-derived chromophores with up-conversion fluorescence are densely packed into the carbon core while guanidine groups are located on the shell, providing nitric oxide (NO) for photodynamic therapy of tumors. Moreover, the chromophores in the carbon core irradiated by visible LED light generate large amounts of reactive oxygen species (ROSs) that will oxidize the guanidine groups located on the shell of the Arg-CDs and further increase the NO releasing capacity remarkably. The as-synthesized Arg-CDs show excellent biocompatibility, bright up-conversion fluorescence, and a light-controlled ROS & NO releasing ability, which can be a potential light-modulated nanoplatform to integrate bioimaging and therapeutic functionalities.

Pancreatitis is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). As the management of pancreatitis is limited, clinical approaches focus on the prevention of post-ERCP pancreatitis (PEP). In theory, the serine protease inhibitor nafamostat can reduce circulating inflammatory mediators in pancreatitis. We aimed to investigate the effect of nafamostat in the prevention of PEP in this systematic review and meta-analysis. The protocol for this review was registered in PROSPERO (CRD42022367988). We systematically searched 5 databases without any filters on September 26, 2022. The eligible population was adult patients undergoing ERCP. We compared the PEP preventive effect of nafamostat to placebo. The main outcome was the occurrence of PEP. We calculated the pooled odds ratios (ORs), mean differences, and corresponding 95% confidence intervals (95% CIs) and multilevel model. The risk of bias was assessed using the Rob2 tool. Seven randomized controlled trials involving 2,962 patients were eligible for inclusion. Nafamostat reduced the overall incidence rate of PEP (20 mg, OR: 0.50, 95% CI: 0.30-0.82 and 50 mg, OR: 0.48, 95% CI: 0.24-0.96). However, the occurrence of mild PEP was significantly reduced only in the subgroup receiving 20 mg nafamostat (OR, 0.49, 95% CI: 0.31-0.77). Overall, nafamostat therapy reduced moderate PEP in high-risk patients (OR: 0.18, 95% CI: 0.0.4-0.84) and mild PEP in low-risk patients (OR: 0.32, 95% CI: 0.17-0.61). Nafamostat is an effective therapy in the prevention of mild post-ERCP pancreatitis. Further research is required to determine the cost-effectiveness of this therapy., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

We conducted a systematic review and meta-analysis to evaluate the effect of nafamostat on the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). PubMed, Web of Science, and Ichushi Web were searched for randomized controlled trials (RCTs) using nafamostat to prevent PEP. In subgroup analyses, we studied the preventive effects of nafamostat according to the severity of PEP, risk category, and dose. A random-effects model was adopted; heterogeneity between studies was examined using the chi-squared test and I 2 statistics. This analysis uses the PRISMA statement as general guidance. 9 RCTs involving 3321 patients were included. The risk of PEP was lower in the nafamostat group than in the control group [4.4% vs. 8.3%, risk ratio (RR): 0.50, 95% confidence interval (CI): 0.36-0.68]. In subgroup analyses, the protective effects were evident in low-risk patients for PEP before ERCP (RR: 0.34, 95% CI: 0.21-0.55). The association between PEP and nafamostat was significant only in patients who developed mild PEP (RR: 0.49; 95% CI: 0.36-0.69). The benefits were independent of the dose. The prophylactic use of nafamostat resulted in a lower risk of PEP. The subgroup analyses suggested uncertain benefits for severe PEP or high-risk patients for PEP. This warrants further investigation through additional RCTs., (© 2023. The Author(s).)

Objectives: To evaluate the efficacy of nafamostat mesilate in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) by conduct a systematic review and meta-analysis., Method: We retrieved for all randomized controlled trials (RCTs) about compare nafamostat mesilate with placebo in preventing PEP published before August 23, 2022, in 5 major electronic databases. The primary outcome was PEP rate, and the secondary outcome was post-ERCP hyperamylasemia (PEHA) rate. Subgroup analyses were performed to reveal the factors that may affect the preventive effect of nafamostat. Assessment of the quality of evidence was conducted based on Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system., Results: According to the search strategy and criteria of inclusion and exclusion, 8 articles with a number of 3210 patients were included. The PEP incidence of the nafamostat group was inferior compared with the placebo group (4.6% vs 8.5%, RR = 0.50, 95% CI: 0.38-0.66). Subgroup analyses revealed that nafamostat had a preventive effect on patients with different risk stratification (High-risk: RR = 0.61, 95% CI: 0.43-0.86, Low-risk: RR = 0.28; 95% CI: 0.17-0.47). Different doses (20 mg: RR = 0.50, 95% CI: 0.36-0.69, 50 mg: RR = 0.45, 95% CI: 0.27-0.74) and duration (<12 hour: RR = 0.55, 95% CI: 0.37-0.81, ≥12 h: RR = 0.44, 95% CI: 0.29-0.66) of administration of nafamostat are adequate for the prevention of PEP, but postoperative administration may not help (preoperative: RR = 0.52, 95% CI: 0.39-0.69, postoperative: RR = 0.54, 95% CI: 0.23-1.23). Nafamostat may not efficacious in preventing severe PEP (Mild: RR = 0.49, 95% CI, 0.35-0.68, Moderate: RR = 0.47, 95% CI: 0.25-0.86, Severe: RR = 0.91, 95% CI, 0.25-3.29) or in low-quality studies (Low-quality: RR = 0.69, 95% CI: 0.13-3.60, High-quality: RR = 0.49, 95% CI: 0.37-0.65)., Conclusion: Preoperative use of nafamostat can effectively prevent PEP in patients with various risk stratification. Nafamostat can prevent mild and moderate PEP, but may not prevent severe PEP and PEHA. There should be more high-quality RCTs in future to strengthen the evidence of nafamostat in preventing PEP., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Neuroblastoma, representing one-tenth of childhood malignancies, is a clinically and prognostically heterogeneous disease. Survival in cases with poor prognosis has recently been significantly improved by rapidly evolving multimodal therapy. Our 4-year-old patient presented with bitemporal swelling and the diagnostic workup confirmed stage IV neuroblastoma (bone marrow and multiple bone metastases). While the tumor responded well to the initial treatment, it relapsed during post-consolidation therapy. As part of the salvage therapy for this high-risk disease with poor prognosis, 131-I-meta-iodo-benzyl-guanidine treatment was performed for the first time in our country, in a case of pediatric neuroblastoma. Neuroendocrine tissue cells express a norepinephrine transporter capable of uptaking the catecholamine analog meta-iodo-benzyl-guanidine. This mechanism makes it an adequate molecule for the imaging (123-I-meta-iodo-benzyl-guanidine) and target therapy (131-I-meta-iodo-benzyl-guanidine) of neuroendocrine tumors, including neuroblastoma. Treatment with 131-I-meta-iodo-benzyl-guanidine requires specific personnel and infrastructural equipment, particularly in pediatric cases. Careful organization and cooperation between nuclear medicine specialists and collaborating clinicians (pediatric oncologists and adult internists if necessary) are essential. Meta-iodo-benzyl-guanidine therapy, already routinely used abroad, has been considered as part of salvage therapy for recurrent neuroblastoma until now, but ongoing clinical trials suggest that it may become part of the first-line treatment soon. As the indications broaden, it is necessary to make it available for more and more children in our country. Orv Hetil. 2023; 164(39): 1550-1555.

Objective: To optimize the medication administered to children with influenza, we evaluated the effectiveness of peramivir in hospitalized children with influenza A/H3N2 and influenza B/Victoria., Methods: A retrospective study was conducted from October 2019 to March 2020 in children aged 29 days to 18 years with influenza A/H3N2 or B/Victoria. A total of 97 patients were enrolled and treated with intravenous infusion of peramivir., Results: The duration of influenza virus nucleic acid positivity in the influenza A/H3N2 group (3 days) was shorter than that in the influenza B/Victoria group (4 days) (P = 0.008). The remission time of fever symptoms in the influenza A/H3N2 group was 14 h, which was significantly shorter than that in the influenza B/Victoria group (26 h) (P = 0.042). In the 6-18 years age group, the median duration of virus nucleic acid positivity for children with influenza B/Victoria (4 days) was longer than that for children with influenza A/H3N2 (2 days) (P = 0.005). The incidence of adverse drug reactions (ADRs) with peramivir in the influenza A/H3N2 group and the influenza B/Victoria group was 2.04% (n = 1/49) and 4.17% (n = 2/48), respectively (P = 0.617)., Conclusions: A difference in the effectiveness of peramivir against different subtypes of influenza was observed. Compared to those infected with influenza B/Victoria, the children infected with influenza A/H3N2 experienced a significantly shorter duration of influenza virus nucleic acid positivity and remission time of fever symptoms., Competing Interests: Declaration of competing interest All authors declare no potential conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Streptococcus suis , an encapsulated zoonotic pathogen, has been reported to cause a variety of infectious diseases, such as meningitis and streptococcal-toxic-shock-like syndrome. Increasing antimicrobial resistance has triggered the need for new treatments. In the present study, we found that isopropoxy benzene guanidine (IBG) significantly attenuated the effects caused by S. suis infection, in vivo and in vitro, by killing S. suis and reducing S. suis pathogenicity. Further studies showed that IBG disrupted the integrity of S. suis cell membranes and increased the permeability of S. suis cell membranes, leading to an imbalance in proton motive force and the accumulation of intracellular ATP. Meanwhile, IBG antagonized the hemolysis activity of suilysin and decreased the expression of Sly gene. In vivo, IBG improved the viability of S. suis SS3-infected mice by reducing tissue bacterial load. In conclusion, IBG is a promising compound for the treatment of S. suis infections, given its antibacterial and anti-hemolysis activity.

BackgroundTimely treatment with neuraminidase inhibitors (NAI) can reduce severe outcomes in influenza patients.AimWe assessed the impact of antiviral treatment on in-hospital deaths of laboratory-confirmed influenza patients in 11 European Union countries from 2010/11 to 2019/20.MethodsCase-based surveillance data from hospitalised patients with known age, sex, outcome, ward, vaccination status, timing of antiviral treatment, and hospitalisation were obtained. A mixed effect logistic regression model using country as random intercept was applied to estimate the adjusted odds ratio (aOR) for in-hospital death in patients treated with NAIs vs not treated.ResultsOf 19,937 patients, 31% received NAIs within 48 hours of hospital admission. Older age (60-79 years aOR 3.0, 95% CI: 2.4-3.8; 80 years 8.3 (6.6-10.5)) and intensive care unit admission (3.8, 95% CI: 3.4-4.2) increased risk of dying, while early hospital admission after symptom onset decreased risk (aOR 0.91, 95% CI: 0.90-0.93). NAI treatment initiation within 48 hours and up to 7 days reduced risk of dying (0-48 hours aOR 0.51, 95% CI: 0.45-0.59; 3-4 days 0.59 (0.51-0.67); 5-7 days 0.64 (0.56-0.74)), in particular in patients 40 years and older (e.g. treatment within 48 hours: 40-59 years aOR 0.43, 95% CI: 0.28-0.66; 60-79 years 0.50 (0.39-0.63); ≥80 years 0.51 (0.42-0.63)).ConclusionNAI treatment given within 48 hours and possibly up to 7 days after symptom onset reduced risk of in-hospital death. NAI treatment should be considered in older patients to prevent severe outcomes.

Apoptosis of cardiomyocytes is a critical outcome of myocardial ischemia-reperfusion injury (MIRI), which leads to the permanent impairment of cardiac function. Upregulated E2F1 is implicated in inducing cardiomyocyte apoptosis, and thus intervention of the E2F1 signaling pathway via RNA interference may hold promising potential for rescuing the myocardium from MIRI. To aid efficient E2F1 siRNA (siE2F1) delivery into cardiomyocytes that are normally hard to transfect, a spherical, α-helical polypeptide (SPP) with potent membrane activity was developed via dendrimer-initiated ring-opening polymerization of N -carboxyanhydride followed by side-chain functionalization with guanidines. Due to its multivalent structure, SPP outperformed its linear counterpart (LPP) to feature potent siRNA binding affinity and membrane activity. Thus, SPP effectively delivered siE2F1 into cardiomyocytes and suppressed E2F1 expression both in vitro and in vivo after intramyocardial injection. The E2F1-miR421-Pink1 signaling pathway was disrupted, thereby leading to the reduction of MIRI-induced mitochondrial damage, apoptosis, and inflammation of cardiomyocytes and ultimately recovering the systolic function of the myocardium. This study provides an example of membrane-penetrating nucleic acid delivery materials, and it also provides a promising approach for the genetic manipulation of cardiomyocyte apoptosis for the treatment of MIRI.

Background: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19)., Methods: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2., Results: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified., Conclusions: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms., Trial Registration: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198., (© 2022. The Author(s).)

Purpose: [131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine ([211At] MABG) is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [211At]MABG in preclinical models of neuroblastoma., Experimental Design: We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [211At]MABG in immunodeficient mice in comparison with [131I]MIBG. We compared the antitumor efficacy of [211At]MABG with [131I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [211At]MABG after tail vein xenografting designed to model disseminated neuroblastoma., Results: The MTD of [211At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid-/- mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Biodistribution of [211At]MABG was similar to [131I]MIBG. Long-term toxicity studies on mice administered with doses up to 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [211At]MABG in the disseminated disease (IMR-05NET/GFP/LUC) model (P = 0.003) suggesting eradication of microscopic disease., Conclusions: [211At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development., (©2022 The Authors; Published by the American Association for Cancer Research.)

The influenza A virus (IAV) is of a major public health concern as it causes annual epidemics and has the potential to cause pandemics. At present, the neuraminidase inhibitors (NAIs) are the most widely used anti-influenza drugs, but, more recently, the drug baloxavir marboxil (BXM), a polymerase inhibitor, has also been licensed in some countries. Mutations in the viral genes that encode the antiviral targets can lead to treatment resistance. Worldwide, a low prevalence of antiviral resistant strains has been reported. Despite that, this situation can change rapidly, and resistant strain surveillance is a priority. Thus, the aim of this was to evaluate Brazilian IAVs antiviral resistance from 2017 to 2019 through the identification of viral mutations associated with reduced inhibition of the drugs and by testing the susceptibility of IAV isolates to oseltamivir (OST), the most widely used NAI drug in the country. Initially, we analyzed 282 influenza A(H1N1)pdm09 and 455 A(H3N2) genetic sequences available on GISAID. The amino acid substitution (AAS) NA:S247N was detected in one A(H1N1)pdm09 strain. We also identified NA:I222V ( n = 6) and NA:N329K ( n = 1) in A(H3N2) strains. In addition, we performed a molecular screening for NA:H275Y in 437 A(H1N1)pdm09 samples, by pyrosequencing, which revealed a single virus harboring this mutation. Furthermore, the determination of OST IC 50 values for 222 A(H1N1)pdm09 and 83 A(H3N2) isolates revealed that all isolates presented a normal susceptibility profile to the drug. Interestingly, we detected one A(H3N2) virus presenting with PA:E119D AAS. Moreover, the majority of the IAV sequences had the M2:S31N adamantanes resistant marker. In conclusion, we show a low prevalence of Brazilian IAV strains with NAI resistance markers, in accordance with what is reported worldwide, indicating that NAIs still remain an option for the treatment of influenza infections in Brazil. However, surveillance of influenza resistance should be strengthened in the country for improving the representativeness of investigated viruses and the robustness of the analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sousa, Martins, Miranda, Garcia, Resende, Santos, Debur, Rodrigues, Cavalcanti, Gregianini, Iani, Pereira, Fernandes, Ferreira, Santos, Motta, Brown, Almeida, Siqueira and Matos.)

An epidemic of avian type H7N9 influenza virus, which took place in China in 2013, was enhanced by a naturally occurring R294K mutation resistant against Oseltamivir at the catalytic site of the neuraminidase. To cope with such drug-resistant neuraminidase mutations, we applied the molecular docking technique to evaluate the fitness of the available drugs such as Oseltamivir, Zanamivir, Peramivir, Laninamivir, L-Arginine and Benserazide hydrochloride concerning the N9 enzyme with single (R294K, R119K, R372K), double (R119&#95;294K, R119&#95;372K, R294&#95;372K) and triple (R119&#95;294&#95;372K) mutations in the pocket. We found that the drugs Peramivir and Zanamivir score best amongst the studied compounds, demonstrating their high binding potential towards the pockets with the considered mutations. Despite the fact that mutations changed the shape of the pocket and reduced the binding strength for all drugs, Peramivir was the only drug that formed interactions with the key residues at positions 119, 294 and 372 in the pocket of the triple N9 mutant, while Zanamivir demonstrated the lowest RMSD value (0.7 Å) with respect to the reference structure.

Activated effector T cells (Teff) and/or compromised regulatory T cells (Treg) underlie many chronic inflammatory diseases. We discovered a novel pathway to regulate survival and expansion of Teff without compromising Treg survival and a potential therapeutic to treat these diseases. We found dimethylguanidino valeric acid (DMGV) as a rheostat for Teff survival: while cell-intrinsic DMGV generated by Alanine-Glyoxylate Aminotransferase 2 (AGXT2) is essential for survival and expansion by inducing mitochondrial ROS and regulation of glycolysis, an excessive (or exogenous) DMGV level inhibits activated Teff survival, thereby the AGXT2-DMGV-ROS axis functioning as a switch to turn on and off Teff expansion. DMGV-induced ROS is essential for glycolysis in Teff, and paradoxically DMGV induces ROS only when glycolysis is active. Mechanistically, DMGV rapidly activates mitochondrial calcium uniporter (MCU), causing a surge in mitochondrial Ca 2+ without provoking calcium influx to the cytosol. The mitochondrial Ca 2+ surge in turn triggers the mitochondrial Na + /Ca 2+ exchanger (NCLX) and the subsequent mitochondrial Na + import induces ROS by uncoupling the Coenzyme Q cycle in Complex III of the electron transport chain. In preclinical studies, DMGV administration significantly diminished the number of inflammatory T cells, effectively suppressing chronic inflammation in mouse models of colitis and rheumatoid arthritis. DMGV also suppressed expansion of cancer cells in vitro and in a mouse T cell leukemic model by the same mechanism. Our data provide a new pathway regulating T cell survival and a novel mode to treat autoimmune diseases and cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Shen, Fan, Chen and Lee.)

The aim of this study was to determine, in the diet-induced obesity model in rats, the potential of Guanabenz to reduce body weight and ameliorate some metabolic disturbances. Obesity was induced in rats by a high-fat diet. After 10 weeks, rats were treated intraperitoneally with Guanabenz at the two doses: 2 or 5 mg/kg b.w./day, once daily for 25 days. The spontaneous activity of rats was measured for 24 h on the 1st and 24th day of the Guanabenz treatment with a special radio-frequency identification system. Gastric emptying was measured in intragastric phenol red-treated mice by measuring the color of the stomach homogenate 30 min after phenol red administration. Intraperitoneal administration of Guanabenz for 25 days to obese rats resulted in a significant decrease in body weight compared to the baseline values (about 11% at a dose of 5 mg/kg). Both body weight and the amount of adipose tissue in the groups receiving Guanabenz decreased to the levels observed in the control rats fed only standard feed. The anorectic effect occurred in parallel with a reduction in plasma triglyceride levels. We also confirmed the beneficial effect of Guanabenz on plasma glucose level. The present study demonstrates that the administration of Guanabenz strongly inhibits gastric emptying (about 80% at a dose of 5 mg/kg). Guanabenz can successfully and simultaneously attenuate all the disorders and risk factors of metabolic syndrome: hypertension, hyperglycemia, obesity, and dyslipidemia. However, the exact cellular mechanisms of its action require further research., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In this manuscript, we present the guideline for use of meta-[ 211 At] astatobenzylguanidine ([ 211 At] MABG), a newly introduced alpha emitting radiopharmaceutical to the up-coming World's first clinical trial for targeted alpha therapy (TAT) at Fukushima Medical University in Japan, focusing on radiation safety issues in Japan. This guideline was prepared based on a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on Oct. 5th, 2021. The study showed that patients receiving [ 211 At] MABG do not need to be admitted to a radiotherapy room and that TAT using [ 211 At] MABG is possible on an outpatient basis. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers or patient's family members. In this guideline, the following contents are also included: precautions for patients and their families, safety management associated with the use of [ 211 At] MABG, education and training, and disposal of medical radioactive contaminants. TAT using [ 211 At] MABG in Japan should be carried out according to this guideline. Although this guideline is based on the medical environment and laws and regulations in Japan, the issues for radiation protection and evaluation methodology presented in this guideline are useful and internationally acceptable as well., (© 2022. The Author(s).)

To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional carboxylic acid moiety to obtain an extra interaction with enteropeptidase, yielding 2a . The oral administration of 2a significantly elevated the fecal protein output, a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas subcutaneous administration did not change this parameter. Thus, systemic exposure of 2a was not required for its pharmacological effects. Further optimization focusing on the in vitro IC 50 value and T 1/2 , an indicator of dissociation time, followed by enhanced in vivo pharmacological activity based on the ester stability of the compounds, revealed two series of potent enteropeptidase inhibitors, a dihydrobenzofuran analogue ( ( S )-5b , SCO-792) and phenylisoxazoline ( 6b ), which exhibited potent anti-obesity effects despite their low systemic exposure following their oral administration to DIO rats.

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 IC 50 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of this study was to use a network meta-analysis (NWA) to evaluate the relative efficacy and safety of various neuraminidase inhibitors (NAIs) in reducing the duration of influenza symptoms, and thereby, informing the selection of suitable therapeutic regimens for patients with influenza. We conducted a systematic review of randomized controlled trials comparing the clinical effects of four NAIs administered to patients with influenza and placebo. Relevant studies were found in the PubMed and Cochrane databases. Unpublished studies were collected from the ClinicalTrials.gov registry and through hand searching. We carried out NWA to compare the different regimens with each other and across subgroups of age and medical status (high-risk patients). A total of 58 two-arm studies were identified. Five regimens were efficacious in reducing the time to alleviation of influenza symptoms in all populations; this efficacy was comparable. No significant improvements were seen in combination therapy groups. The mean difference in the time to alleviation of symptoms ranged from 12.78 to 19.51 h. According to the summarized mean difference and surface under the cumulative ranking curve (SUCRA), peramivir (SUCRA = 82.6%), zanamivir (SUCRA = 64%), and oseltamivir (SUCRA = 55.1%) were the three top-ranking drugs for treating influenza. Zanamivir and peramivir were the preferred pharmacologic intervention among all investigated interventions based on the calculated "value preference of SUCRA." This study is a network meta-analysis to explore the therapeutic effects of NAIs in patients with influenza. Peramivir might be the best choice for reducing the time to alleviation of symptoms., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate., Methods: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis., Findings: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry., Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events., Funding: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230)., Competing Interests: Declaration of interests The authors report no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model., Methods: CD-1 mice received an intraperitoneal injection of R848 (200 μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 μL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR., Results: R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment., Conclusions: Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19., (© 2022. The Author(s).)

Background: Severe coronavirus disease 2019 (COVID-19) may require continuous administration of analgesics, sedatives, and muscle relaxants. Nafamostat has recently been reported as a therapeutic agent for COVID-19. However, there is a lack of information on the compatibility of nafamostat with the aforementioned drug classes. This study evaluated the physical compatibility of nafamostat with these drug classes., Methods: Nafamostat was combined with 1-3 target drugs (fentanyl, morphine, midazolam, dexmedetomidine, and rocuronium). Fifteen physical compatibility tests were conducted. Nafamostat was dissolved in 5% glucose solution; the final concentration was 10 mg/mL. All other medications were diluted in 0.9% sodium chloride to obtain clinically relevant concentrations. The power of hydrogen (pH) of all medications was measured during each test. Compatibility tests were conducted with 4 test solutions in which nafamostat and the target drugs were compounded at equal volume ratios (1:1, 1:1:1, or 1:1:1:1). Visual appearance, turbidity, and pH were evaluated immediately after mixing and at 1 and 3 hours. Physical incompatibilities were defined as gross precipitation, cloudiness, appearance of the Tyndall effect, or a turbidity change of ≥0.5 nephelometric turbidity units (NTU) based on nafamostat., Results: The mean pH of nafamostat was 3.13 ± 0.03. The combination of nafamostat, fentanyl, and dexmedetomidine had the highest pH (3.39 ± 0.01; 3 hours after mixing). All drugs were compatible with nafamostat until 3 hours after admixture, with a mean turbidity value of ≤0.03 NTU., Conclusions: Infusions combining nafamostat with the tested sedatives, analgesics, and muscle relaxants could be safely administered.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with complications such as post-ERCP pancreatitis (PEP). Protease inhibitors, including nafamostat mesylate (NM), have been evaluated for prophylaxis against PEP., Aim: We describe the first multicenter randomized controlled trial assessing the prophylactic efficacy of NM against PEP., Methods: In this multicenter prospective study, we aimed to enroll 800 patients aged ≥ 20 years with a planned ERCP between December 2012 and March 2019. The primary outcome was the incidence and severity of PEP in patients who did not receive NM (non-NM) versus those who did (NM; 20 mg). Secondary outcomes included the incidence of PEP by NM initiation (pre- and post-ERCP), risk factors for PEP, and NM-related adverse events., Results: Only 441 of the planned 800 patients were enrolled (non-NM: n = 149; NM: n = 292 [pre-ERCP NM: n = 144; post-ERCP NM: n = 148]). Patient characteristics were balanced at baseline with no significant differences between groups. PEP occurred in 40/441 (9%) patients (non-NM: n = 15 [10%]; NM: n = 25 [9%]), including 17 (12%) and eight (8%) in the pre-ERCP and post-ERCP NM groups, respectively. In the NM group, the incidence of PEP was lower in the low-risk group than in the high-risk group. Pancreatic injection and double-guidewire technique were independent risk factors for PEP. NM-related adverse events of hyperkalemia occurred in two (0.7%) patients., Conclusions: We found no evidence for the prophylactic effect of NM against PEP, regardless of the timing of administration; however, further studies are needed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Introduction: We conducted a post-marketing surveillance of laninamivir octanoate hydrate for Inhalation Suspension Set in patients under the age of 5 infected with the influenza virus to evaluate safety and efficacy of the drug., Methods: Subjects enrolled by the centralized enrollment system were administered laninamivir once using a nebulizer based on the package insert., Results: Safety was evaluated in 1104 patients. The incidence of ADRs was 1.00% (11/1104). Compared to the incidence of ADRs of 2.04% (9/441) in the clinical trials for development, no increase in the frequency of ADRs was noted. Serious ADRs were noted in 3 patients (5 cases): 2 cases of convulsive attack, each 1 case of muscular weakness, a depressed level of consciousness, and pain in extremities. Excluding 2 patients with unknown outcomes, all of the patients recovered or their symptoms were alleviated. To detect risk factors for the occurrence of ADRs, 16 attributes were examined, and none of them were found to be significant. Efficacy was evaluated in 881 patients. The median time (95% CI) to fever resolution was 37.0 (33.0-39.0) h in type A virus (785 patients), 45.0 (34.0-56.0) h in type B virus (95 patients), and 22.0 h (1 patient) in the mixed type. This was similar to the time to fever resolution in the clinical trials., Conclusion: The results of this surveillance verified that there are no noticeable problems with the safety or efficacy of laninamivir for children under the age of 5 infected with the influenza A and B viruses., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.

Background: To compare peramivir 300 mg single-dose, peramivir 600 mg repeat-dose, and oseltamivir effects on health-related quality of life, including respiratory symptoms and general conditions, time to symptom alleviation, time to fever resolution, incidence of exacerbations, and virus titer, in influenza patients with chronic respiratory disease., Methods: We report additional outcomes from a 2-week, multicenter, randomized, open-label study in Japan (UMIN000030118). Influenza patients with chronic respiratory disease received intravenous peramivir (300 mg single-dose [n = 66], 600 mg repeat-dose [600 mg/d of 2 consecutive days; n = 70]) or oral oseltamivir (75 mg twice daily, 5 days; n = 72). The principal endpoint of this analysis was change from baseline to Day 14 at each time point in Chronic Obstructive Pulmonary Disease Assessment Test (CAT) scores., Results: Both peramivir regimens reduced total CAT score at Day 3 more than oseltamivir (peramivir 600 mg vs oseltamivir, P = .0032; peramivir 300 mg vs oseltamivir, P = .0203). Cough/phlegm CAT scores were most improved with peramivir 600 mg. Median time to alleviation of three respiratory symptoms was longer with peramivir 600 mg (68.9 hours) than with peramivir 300 mg (50.6 hours, hazard ratio [HR] 1.57; P = .0191) and shorter with peramivir 300 mg than oseltamivir (78.8 hours, HR 0.62; P = .0141). Alleviation of seven influenza symptoms and fever resolution was shortest with peramivir 300 mg., Conclusions: Rapid improvement in CAT score, including cough, and shorter time to alleviation of respiratory symptoms associated with peramivir is of potential benefit to patients with chronic respiratory disease., (© 2021 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na + /H + exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS)., Methods: Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR., Results: Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP + astrocytes and Iba1 + microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation., Conclusion: Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment., (© 2021. The Author(s).)

The aerial part of Biebersteinia heterostemon Maxim. (Geraniaceae Biebersteiniaceae) known as ming jian na bao in Chinese, has been traditionally used in Tibetan folk medicine for treatment of diabetes and hypertension. The aim of the present study was to evaluate the effects of galegine obtained from an ethanol extract of the entire Biebersteinia heterostemon plant on the rat's cardiovascular system in order to characterize its contributions as an antihypertensive agent. The antihypertensive effect of galegine was investigated in pentobarbital-anesthetized hypertensive rats at three dose levels based on the LD 50 of galegine. Meanwhile a positive control group received dimaprit with the same procedure. Dimaprit infusion induced a significant hypotension which declined by an average margin of 20%. Simultaneously, single administration of galegine at the doses of 2.5, 5, and 10 mg/kg by intraperitoneal injection induced an immediate and dose-dependent decrease in mean arterial blood pressure (MABP) by an average margin of 40% with a rapid increase in heart rate (HR). We demonstrated that galegine is effective in reducing blood pressure in anesthetized hypertensive rats with rapid onset and a dose-related duration of the effects. The results indicate that galegine was the bioactive compound which can be used as a pharmacophore to design new hypertensive agents.

Objective: The RHO family of GTPases, particularly RAC1, has been linked with hepatocarcinogenesis, suggesting that their inhibition might be a rational therapeutic approach. We aimed to identify and target deregulated RHO family members in human hepatocellular carcinoma (HCC)., Design: We studied expression deregulation, clinical prognosis and transcription programmes relevant to HCC using public datasets. The therapeutic potential of RAC1 inhibitors in HCC was study in vitro and in vivo. RNA-Seq analysis and their correlation with the three different HCC datasets were used to characterise the underlying mechanism on RAC1 inhibition. The therapeutic effect of RAC1 inhibition on liver fibrosis was evaluated., Results: Among the RHO family of GTPases we observed that RAC1 is upregulated, correlates with poor patient survival, and is strongly linked with a prooncogenic transcriptional programme. From a panel of novel RAC1 inhibitors studied, 1D-142 was able to induce apoptosis and cell cycle arrest in HCC cells, displaying a stronger effect in highly proliferative cells. Partial rescue of the RAC1-related oncogenic transcriptional programme was obtained on RAC1 inhibition by 1D-142 in HCC. Most importantly, the RAC1 inhibitor 1D-142 strongly reduce tumour growth and intrahepatic metastasis in HCC mice models. Additionally, 1D-142 decreases hepatic stellate cell activation and exerts an anti-fibrotic effect in vivo., Conclusions: The bioinformatics analysis of the HCC datasets, allows identifying RAC1 as a new therapeutic target for HCC. The targeted inhibition of RAC1 by 1D-142 resulted in a potent antitumoural effect in highly proliferative HCC established in fibrotic livers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca 2+ ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury. We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones. A correlation between their predicted docking affinities for the acidic pocket (AcP site) in chicken ASIC1 and their inhibition of homo- and heteromeric hASIC1 channels in HEK-293 cells was found. Their activity on murine ASIC1a currents and their selectivity vs mASIC2a were assessed in engineered CHO-K1 cells, highlighting a limited isoform selectivity. Neuroprotective effects were confirmed in vitro , on primary rat cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation, and in vivo , in ischemic mice. Early lead 3b , showing a good selectivity for hASIC1 in human neurons, was neuroprotective against focal ischemia induced in mice.

BIT225 is a first-in-class inhibitor of human immunodeficiency virus (HIV) type 1 Vpu. A phase II trial enrolled 36 HIV-1-infected, treatment-naive participants in Thailand to receive standard-of-care antiretroviral therapy (ART), tenofovir disoproxil fumarate/emtricitabine/efavirenz (Atripla), with 100 or 200 mg of BIT225 or placebo (daily) for 12 weeks. Combined treatment with BIT225 and ART was found to be generally safe and well tolerated, with antiviral efficacy comparable to that of ART alone. The secondary end point-soluble CD163, a marker of monocyte/macrophage inflammation-was noted to be significantly decreased in the BIT225 arm. Plasma-derived activated CD4+ and CD8+ T cells, natural killer cells, and interleukin 21 were increased in those treated with BIT225. These findings are consistent with inhibition of the known effects of HIV Vpu and may reflect clinically important modulation of inflammatory and immune function. Further clinical study is planned to both confirm and extend these important findings in treatment-naive, and treatment-experienced individuals. Clinical Trials Registration. Australian New Zealand Clinical Trials Registry (Universal Trial Number U1111-1191-2194)., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The effects of the clinically used protease inhibitor nafamostat on influenza virus replication have not been well studied. Primary human tracheal (HTE) and nasal (HNE) epithelial cells were pretreated with nafamostat and infected with the 2009 pandemic [A/Sendai-H/108/2009/(H1N1) pdm09] or seasonal [A/New York/55/2004(H3N2)] influenza virus. Pretreatment with nafamostat reduced the titers of the pandemic and seasonal influenza viruses and the secretion of inflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, in the supernatants of the cells infected with the pandemic influenza virus. HTE and HNE cells exhibited mRNA and/or protein expression of transmembrane protease serine 2 (TMPRSS2), TMPRSS4, and TMPRSS11D. Pretreatment with nafamostat reduced cleavage of the precursor protein HA0 of the pandemic influenza virus into subunit HA1 in HTE cells and reduced the number of acidic endosomes in HTE and HNE cells where influenza virus RNA enters the cytoplasm. Additionally, nafamostat (30 mg/kg/day, intraperitoneal administration) reduced the levels of the pandemic influenza virus [A/Hyogo/YS/2011 (H1N1) pdm09] in mouse lung washes. These findings suggest that nafamostat may inhibit influenza virus replication in human airway epithelial cells and mouse lungs and reduce infection-induced airway inflammation by modulating cytokine production., (© 2020 Wiley Periodicals LLC.)

The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.

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.