How do filter types of renal replacement therapy affect survival in critically ill patients? Concerns about adsorption of nafamostat mesylate on AN69 membranes.

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.

Preventing bisphosphonate induced osteonecrosis of the jaw with a polyguanidine conjugate (GuaDex): A promising new approach.

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.

Safety and Efficacy of Camostat Mesylate for Covid-19: a systematic review and Meta-analysis of Randomized controlled trials.

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, I2 = 85%). CONCLUSION: Camostat mesylate did not improve clinical outcomes in patients with COVID-19, compared to placebo.

Preclinical studies of RA475, a guanidine-substituted spirocyclic candidate RPN13/ADRM1 inhibitor for treatment of ovarian cancer.

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.

Duration of fever in children infected with influenza A(H1N1)pdm09, A(H3N2) or B virus and treated with baloxavir marboxil, oseltamivir, laninamivir, or zanamivir in Japan during the 2012-2013 and 2019-2020 influenza seasons.

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.

COVID-19 Drug Treatments Are Prone to Sequestration in Extracorporeal Membrane Oxygenation Circuits: An Ex Vivo Extracorporeal Membrane Oxygenation Study.

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.

Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.

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.

New strategy to treat spinal cord injury: Nafamostat mesilate suppressed NLRP3-mediated pyroptosis during acute phase.

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.

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

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

The Effectiveness and Safety of Nafamostat Mesylate in the Treatment of COVID-19: a Meta-Analysis.

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.

Core-shell structured carbon dots with up-conversion fluorescence and photo-triggered nitric oxide-releasing properties.

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.

Nafamostat Reduces the Incidence of post-ERCP Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

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.

Filter Lifespan, Treatment Effect, and Influencing Factors of Continuous Renal Replacement Therapy for Severe Burn Patients.

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.

Efficacy of nafamostat mesylate in the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: a systematic review and meta-analysis of randomized controlled trials.

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 I2 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.

[131-I-meta-iodo-benzyl-guanidine therapy in childhood neuroblastoma.] / Gyermekkori neuroblastoma kezelésében alkalmazott 131-I-meta-jodo-benzil-guanidin terápia.

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.

Nafamostat mesilate for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review and meta-analysis based on prospective, randomized, and controlled trials.

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.

Effectiveness of intravenous peramivir for the treatment of influenza A/H3N2 and influenza B/Victoria in hospitalized children.

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.

Isopropoxy Benzene Guanidine Ameliorates Streptococcus suis Infection In Vivo and In Vitro.

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.

Effect of neuraminidase inhibitor (oseltamivir) treatment on outcome of hospitalised influenza patients, surveillance data from 11 EU countries, 2010 to 2020.

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.