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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.

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).)

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.)

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.

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.)

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.

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.)

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).)

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.

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.

In order to treat Coronavirus Disease 2019 (COVID-19), we predicted and implemented a drug delivery system (DDS) that can provide stable drug delivery through a computational approach including a clustering algorithm and the Schrödinger software. Six carrier candidates were derived by the proposed method that could find molecules meeting the predefined conditions using the molecular structure and its functional group positional information. Then, just one compound named glycyrrhizin was selected as a candidate for drug delivery through the Schrödinger software. Using glycyrrhizin, nafamostat mesilate (NM), which is known for its efficacy, was converted into micelle nanoparticles (NPs) to improve drug stability and to effectively treat COVID-19. The spherical particle morphology was confirmed by transmission electron microscopy (TEM), and the particle size and stability of 300-400 nm were evaluated by measuring DLSand the zeta potential. The loading of NM was confirmed to be more than 90% efficient using the UV spectrum.

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Peramivir offers a single-dose intravenous (IV) treatment option for influenza (vs 5-day oral dosing for oseltamivir). We sought to compare outcomes of emergency department (ED) patients at high risk for influenza complications treated with IV peramivir vs oral oseltamivir., Methods: During the 2015-16 and 2016-17 influenza seasons, adult patients in two US EDs were randomized to either oral oseltamivir or IV peramivir treatment group. Eligibility included positive molecular influenza test; met CDC criteria for antiviral treatment; able to provide informed consent and agree to follow-up assessment. Outcomes were measured by clinical end-point indicators, including FLU-PRO Score, Ordinal Scale, Patient Global Impression on Severity Score, and Karnofsky Performance Scale for 14 days. Non-inferior t test was performed to assess comparative outcomes between the two groups., Results: Five hundred and seventy-five (68%) of 847 influenza-positive patients were approached. Two hundred and eighty-four met enrollment criteria and 179 were enrolled; of these 95 (53%) were randomized to peramivir, and 84 to oseltamivir. Average FLU-PRO score at baseline was similar (peramivir: 2.67 vs oseltamivir: 2.52); the score decreased over time for both groups (day 5: peramivir: 1.71 vs oseltamivir: 1.62; day 10: peramivir: 1.48 vs oseltamivir: 1.37; day 14: peramivir: 1.40 vs oseltamivir: 1.33; all P < .05 for significantly non-inferior). Influenza-related complications were similar between two groups (All: peramivir: 31% vs oseltamivir: 21%, P > .05; pneumonia: peramivir: 11% vs oseltamivir: 14%, P > .05)., Conclusions: Clinical outcomes of influenza-infected patients treated with single-dose IV peramivir were comparable to those treated with oral oseltamivir, suggesting potential utility of peramivir for influenza-infected patients in the ED., (© 2020 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: The efficacy of neuraminidase inhibitors on improvement of respiratory symptoms triggered by influenza in patients with pre-existing chronic respiratory diseases is unknown., Methods: This 2-week, randomized, open-label study evaluated intravenous peramivir 600 mg on two consecutive days (peramivir-repeat), peramivir 300 mg single dose (peramivir-single), and oral oseltamivir 75 mg twice daily for 5 days in patients with confirmed influenza and chronic respiratory diseases. Patients recorded symptom scores daily. The primary endpoint of cumulative area of time vs symptoms (CATVS) was expressed as an index value of area under the curve vs time of the total score of cough, sore throat, and nasal congestion from baseline to 2 weeks., Results: Of 214 randomized patients, 209 (56% female, 77% aged <65 years, 94% outpatients, 91% bronchial asthma, 62% influenza A) received ≥1 dose of study drug. Mean (standard deviation) CATVS was similar for peramivir-repeat (782.78 [487.17]) vs peramivir-single (717.35 [347.55]; P = .4371), and for peramivir-repeat vs oseltamivir (856.34 [404.99]; P = 1.00). However, CATVS was significantly shorter for peramivir-single vs oseltamivir, with an estimated treatment difference (TD) of -145.07 (95% confidence interval: -284.57, -5.56; P = .0416). In subgroup analyses, CATVS was significantly shorter for peramivir-single vs oseltamivir among patients with influenza A (TD: -206.31 [-383.86, -28.76]; P = .0231), bronchial asthma (TD: -156.57 [-300.22, -12.92]; P = .0328), baseline respiratory severity score <5 (TD: -265.32 [-470.42, -60.21]; P = .0120), and age <65 (TD: -184.30 [-345.08, -23.52]; P = .0249)., Conclusions: In patients with chronic respiratory diseases, peramivir-single was not significantly different from peramivir-repeat and was more effective than oseltamivir at alleviating respiratory symptoms., (© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Control measures in the case of high pathogenicity avian influenza (HPAI) outbreaks in poultry include culling, surveillance, and biosecurity; wild birds in captivity may also be culled, although some rare bird species should be rescued for conservation. In this study, two anti-influenza drugs, baloxavir marboxil (BXM) and peramivir (PR), used in humans, were examined in treating HPAI in birds, using chickens as a model. Chickens were infected with H5N6 HPAI virus and were treated immediately or 24 h from challenge with 20 mg/kg BXM or PR twice a day for five days. As per our findings, BXM significantly reduced virus replication in organs and provided full protection to chickens compared with that induced by PR. In the 24-h-delayed treatment, neither drug completely inhibited virus replication nor ensured the survival of infected chickens. A single administration of 2.5 mg/kg of BXM was determined as the minimum dose required to fully protect chickens from HPAI virus; the concentration of baloxavir acid, the active form of BXM, in chicken blood at this dose was sufficient for a 48 h antiviral effect post-administration. Thus, these data can be a starting point for the use of BXM and PR in treating captive wild birds infected with HPAI virus.

A 50-year-old woman presented with coma and hemorrhagic shock. A rapid influenza antigen test revealed influenza A infection; other laboratory examinations ruled out any other suspected infections. She was diagnosed with hemorrhagic shock and encephalopathy syndrome (HSES) induced by influenza A. She was administered methylprednisolone pulse therapy and peramivir. Subsequently, she was discharged without any sequelae. Only a few cases of influenza-induced HSES have been reported, and the clinical outcomes were very poor. We herein report a successfully treated adult case of influenza-induced HSES and review this rare syndrome.

Primary small cell carcinoma (SCC) of the pancreas is a rare disease with poor prognosis. Very few cases have been reported in the literature. It is a type of poorly differentiated variety of neuroendocrine tumours of the pancreas with specific immunohistochemical markers. Imaging is not diagnostic for disease, and diagnosis is mainly by biopsy. We report a rare case of SCC of the pancreas who presented with features of obstructive jaundice without any paraneoplastic features. The patient is planned for palliative chemotherapy because of metastasis and is under regular follow-up., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir., Case Presentation: A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/μL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2., Conclusions: In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

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., (© 2020 The British Pharmacological Society.)

Despite advances in cancer treatment modalities, DNA still stands as one of the targets for anticancer agents. DNA minor groove binders (MGBs) represent an important investigational chemotherapeutic class with promising cytotoxic capacity. Herein this study reports the potent cytotoxic effect of a series of repurposed flexible bis-imidamides 1-4, triaryl bis-guanidine 5 and bis-N-substituted guanidines 6,7 having a 1,4-diphenoxybenzene scaffold backbone on MCF-7 and MDA-MB-231 breast cancer cell lines. Of these compounds, imidamide 4 was chosen for further in-vitro, in-vivo and molecular dynamics (MD) studies owing to its promising anti-tumor activity, with IC 50 values on MCF-7 and MDA-MB-231 breast cancer cell lines of 1.9 and 2.08 μM, respectively. Annexin V/propidium iodide apoptosis assay revealed apoptosis induction on imidamide 4 treated MCF-7 cells. RT-PCR assay results demonstrated the proapoptotic effect of compound 4 through increase of mRNA levels of the pro-apoptotic genes; p53, PUMA, and Bax, and inhibiting the anti-apoptotic Bcl-2 gene expression in MCF-7 cells. Moreover, compound 4 induced a G 0 /G 1 cell-cycle arrest in MCF-7 in a dose-dependent manner. Corroborating in-vivo experiments on Ehrlich ascites carcinoma (EAC)-bearing mice, reflected the anticancer strength of derivative 4. For further target validation, molecular dynamics (MD) studies demonstrated an energetically favorable binding of imidamide 4 with the DNA minor groove AT rich site. In effect, imidamide 4 can be viewed as a promising hit dicationic compound with good cytotoxic and apoptotic inducing activity against breast cancer that can be adopted for future optimization., 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 © 2020 Elsevier B.V. All rights reserved.)

Novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has become a public health emergency of international concern. This was first noted in Wuhan, Hubei Province, China, and since then has become widespread globally. We report a 71-year-old woman with documented viral shedding (based on reverse transcription-polymerase chain reaction (RT-PCR) testing) of SARS-CoV-2 for 60 days from the onset of symptoms (55 days from her first positive test and 36 days after complete resolution of symptoms). This is to our knowledge the longest duration of viral shedding reported to date. This case demonstrates that viral shedding after COVID-19 diagnosis can be prolonged.

Objective: The risk factors and the impact of NAI treatments in patients with severe influenza A-associated pneumonia remain unclear., Methods: A multicenter, retrospective, observational study was conducted in Zhejiang, China during a severe influenza epidemic in August 2017-May 2018. Clinical records of patients (>14 y) hospitalized with laboratory-confirmed influenza A virus infection and who developed severe pneumonia were compared to those with mild-to-moderate pneumonia. Risk factors related to pneumonia severity and effects of NAI treatments (monotherapy and combination of peramivir and oseltamivir) were analyzed., Results: 202 patients with influenza A-associated severe pneumonia were enrolled, of whom 84 (41.6%) had died. Male gender (OR = 1.782; 95% CI: 1.089-2.917; P = 0.022), chronic pulmonary disease (OR = 2.581; 95% CI: 1.447-4.603; P = 0.001) and diabetes mellitus (OR = 2.042; 95% CI: 1.135-3.673; P = 0.017) were risk factors related to influenza A pneumonia severity. In cox proportional hazards model, severe pneumonia patients treated with double dose oseltamivir (300mg/d) had a better survival rate compared to those receiving a single dose (150 mg/d) (HR = 0.475; 95%CI: 0.254-0.887; P = 0.019). However, different doses of peramivir (300 mg/d vs. 600 mg/d) and combination therapy (oseltamivir-peramivir vs. monotherapy) showed no differences in 60-day mortality (P = 0.392 and P = 0.658, respectively)., Conclusions: Patients with male gender, chronic pulmonary disease, or diabetes mellitus were at high risk of developing severe pneumonia after influenza A infection. Double dose oseltamivir might be considered in treating influenza A-associated severe pneumonia., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: This meta-analysis compared the efficacy and safety of peramivir compared to other neuraminidase inhibitors (NAIs). Materials and Methods: Data from PubMed, Embase, and Cochrane databases and ClinicalTrials.gov were searched until January 2019. Randomized controlled trials (RCTs) and observational studies (OSs) comparing peramivir with other NAIs for treating influenza were included. The Grading of Recommendations, Assessments, Development, and Evaluations (GRADE) system was used to judge the overall certainty of evidence; the result was moderate. The primary outcome was time to alleviation of symptoms. Twelve articles involving 2681 patients were included in this meta-analysis. We used a random-effect model to pool the effect size, which is expressed as the difference in means (MD), risk ratio (RR), and 95% confidence interval (CI). Results: Overall, peramivir was superior to other NAIs (MD = -11.214 hours, 95% CI: -19.119 to -3.310). The incidence of adverse events (RR = 1.023, 95% CI: 0.717 to 1.460) and serious adverse events (RR = 1.068, 95% CI: 0.702 to 1.625) in the peramivir group was similar to those in the oseltamivir group. In addition, peramivir had higher efficacy than each NAI alone. Conclusion: In conclusion, the efficacy of peramivir might be higher than that of other NAIs, and this agent is tolerated as well as other NAIs., Competing Interests: The authors declare no conflicts of interest.

The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U- 13 C-glucose, U- 13 C-glutamine, and U- 13 C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. SIGNIFICANCE: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies., (©2019 American Association for Cancer Research.)

In addition to its role in the treatment of pancreatitis, the serine protease inhibitor nafamostat exhibits a retinal protective effect. However, the exact mechanisms underlying this effect are unknown. In this study, the neuroprotective effects of nafamostat and its orally active derivative sepimostat against excitotoxicity were further characterised in vitro and in vivo. In primary rat cortical neurons, nafamostat completely suppressed N-methyl-D-aspartate (NMDA)-induced cell death. Intravitreal injection of nafamostat and sepimostat protected the rat retina against NMDA-induced degeneration, whereas the structurally related compounds, gabexate and camostat, did not. The neuroprotective effects of nafamostat and the NR2B antagonist ifenprodil were remarkably suppressed by spermidine, a naturally occurring polyamine that modulates the NR2B subunit. Both nafamostat and sepimostat inhibited [ 3 H]ifenprodil binding to fractionated rat brain membranes. Thus, nafamostat and sepimostat may exert neuroprotective effects against excitotoxic retinal degeneration through NMDA receptor antagonism at the ifenprodil-binding site of the NR2B subunit.

Cardiovascular diseases (CVDs) are among the leading threats to human health. The advanced glycation end product (AGE) and receptor for AGE (RAGE) signaling pathway regulates the pathogenesis of CVDs, through its effects on arterial stiffness, atherosclerosis, mitochondrial dysfunction, oxidative stress, calcium homeostasis, and cytoskeletal function. Targeting the AGE/RAGE pathway is a potential therapeutic strategy for ameliorating CVDs. Vitamin D has several beneficial effects on the cardiovascular system. Experimental findings have shown that vitamin D regulates AGE/RAGE signaling and its downstream effects. This article provides a comprehensive review of the mechanistic insights into AGE/RAGE involvement in CVDs and the modulation of the AGE/RAGE signaling pathways by vitamin D.

Experimental studies have demonstrated protective effects of NHE-1 inhibition on cardiac function; however, clinical trials utilizing NHE-1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase-derived reactive oxygen species (ROS) from microglial cells have been shown to contribute to injury following stroke. We have recently demonstrated that NHE-1 inhibition enhances ROS in macrophages in a Hv1-dependent manner. As Hv1 protein is highly expressed in microglia, we hypothesized that "NHE-1 inhibition may augment neurovascular injury by activating Hv1," providing a potential mechanism for the deleterious effects of NHE-1. The goal of this study was to determine whether neurovascular injury and functional outcomes after experimental stroke differed in wild-type and Hv1 mutant Dahl salt-sensitive rats treated with an NHE-1 inhibitor. Stroke was induced using both transient and permanent of middle cerebral artery occlusion (MCAO). Animals received vehicle or NHE-1 inhibitor KR32568 (2 mg/kg, iv) either 30 min after the start of MCAO or were pretreated (2 mg/kg, iv, day) for 3 days and then subjected to MCAO. Our data indicate that Hv1 deletion confers both neuronal and vascular protection after ischemia. In contrast to our hypothesis, inhibition of NHE-1 provided further protection from ischemic stroke, and the beneficial effects of both pre- and post-treatment with KR32568 were similar in wild-type and Hv1 -/- rats. These data indicate that Hv1 activation is unlikely to be responsible for the increased incidence of cerebrovascular events observed in the heart disease patients after NHE-1 inhibition treatment., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrial OXPHOS pathways could offer an actionable therapeutic target in the clinic., (© 2019 Agarwal et al.)

Background: Nitric oxide is a mediator of potential importance in numerous physiological and inflammatory processes in the lung. Aminoguanidine (AG) has been shown to have anti-inflammation and radical scavenging properties. This study aimed to investigate the effects of AG, an iNOS inhibitor, on lipopolysaccharide (LPS)-induced systemic and lung inflammation in rats., Methods: Male Wistar rats were divided into control, LPS (1 mg/kg/day i.p.), and LPS groups treated with AG 50, 100 or 150 mg/kg/day i.p. for five weeks. Total nitrite concentration, total and differential white blood cells (WBC) count, oxidative stress markers, and the levels of IL-4, IFN-γ, TGF-β1, and PGE2 were assessed in the serum or bronchoalveolar lavage fluid (BALF)., Results: Administration of LPS decreased IL-4 level (p < 0.01) in BALF, total thiol content, superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.001) in BALF and serum, and increased total nitrite, malondialdehyde (MDA), IFN-γ, TGF-β1 and PGE2 (p < 0.001) concentrations in BALF. Pre-treatment with AG increased BALF level of IL-4 and total thiol as well as SOD and CAT activities (p < 0.05 to p < 0.001), but decreased BALF levels of total nitrite, MDA, IFN-γ, TGF-β1, and PGE2 (p < 0.01 to p < 0.001). AG treatment decreased total WBC count, lymphocytes and macrophages in BALF (p < 0.01 to p < 0.001) and improved lung pathological changes including interstitial inflammation and lymphoid infiltration (p < 0.05 to p < 0.001)., Conclusions: AG treatment reduced oxidant markers, inflammatory cytokines and lung pathological changes but increased antioxidants and anti-inflammatory cytokines. Therefore, AG may play a significant protective role against inflammation and oxidative stress that cause lung injury.

Objective: To evaluate the difference of clinical efficacy of peramivir alone and peramivir combined with immunomodulators (either ribonucleic acid or thymopetidum) in the treatment of severe influenza A with primary viral pneumonia., Methods: A retrospective analysis was applied to 45 patients who were diagnosed with severe influenza A with primary viral pneumonia in our hospital from December 2017 to March 2018. The cases were divided into three groups: the peramivir group, the peramivir combined with ribonucleic acid group, and the peramivir combined with thymopetidum group., Results: The duration of viral nucleic acid positivity in the peramivir group, the peramivir combined with ribonucleic acid group, and the peramivir combined with thymopetidum group was 6.13 ± 2.06, 6.53 ± 2.72, and 6.10 ± 1.37 days, respectively. The remission time of the clinical symptoms of the peramivir group, the peramivir combined with ribonucleic acid group, and the peramivir combined with thymopetidum group was 8.06 ± 2.73, 7.94 ± 2.89, and 7.67 ± 1.58 days, respectively. Comparisons between the peramivir group and the peramivir combined with ribonucleic acid group or the peramivir combined with thymopetidum group revealed no significant differences in the duration of virus nucleic acid positivity, remission time of clinical symptoms, time to fever alleviation, and time to cough alleviation., Conclusions: There is no observed benefit in the addition of ribonucleic acid or thymopetidum when peramivir sodium chloride injection is used in the treatment of severe influenza A with primary viral pneumonia. This trial is registered with ChiCTR1800019417.