Nattokinase historical sketch on experimental and clinical evidence

Nattokinase (NK) is a protease derived from food used mainly in the Japanese diet that has several properties. The main activity is related to improving fibrinolytic activities. Other activities have been demonstrated in the regulation of blood pressure by the action toward angiotensin proteases and in the antiplatelet activities. NK can be given orally and reaches its maximal concentration after 12 hours. In addition, an antithrombotic activity based on various NK activities has been proposed. First, increased fibrinolytic activity increases thrombus dissolution and/or the formation of atherosclerotic plaques; second, its enhanced antiplatelet action adds to clot dissolution. All activities have been studied in animals and humans in vitro and in vivo. Relevant adverse effects of NK therapy have not been described, however clinical experience is restricted to case series and volunteers and is not based on clinical studies, thus clinical trials are required to confirm

Hospital Antibiotic Use during COVID-19 Pandemic in Italy

Antimicrobial resistance (AMR) represents a major issue in healthcare being correlated to global inappropriate use of antibiotics. The aim of this study was to compare the data on hospital antibiotic consumption in 2020–2021 with those related to 2019 in order to evaluate the impact of the COVID-19 pandemic on antibiotic prescriptions and appropriate use at national level and in the different geographical areas. To estimate the consumption of antibiotics, two indicators were calculated: “number of DDD per 1000 inhabitants per day” and “number of DDD per 100 hospitalisation days”. Consumption data on antibiotics dispensed in public health facilities were based on the Italian “traceability of medicines” information flow. Data on hospitalisation days were extracted from the Italian “hospital discharge form” flow. Pearson correlation analysis was performed between the number of patients hospitalised for COVID-19 and the consumption of antibiotics in public healthcare facilities. During 2020, about 1.7 DDD/1000 inhabitants per day (12.3% of the overall consumption of reimbursed antibiotics) were dispensed exclusively in Italian hospitals (+0.8% compared to 2019). Considering the number of DDD per 100 hospitalisation days, consumption increased by 19.3% in 2020 compared to 2019. Comparing the first semester of 2020 and 2019, a decrease of DDD/1000 inhabitants per day was observed (−1.6%) at national level, with opposite trends in the different geographical areas; an increase in the use of azithromycin and carbapenems was also observed, with a stable consumption of third-generation cephalosporins. The use of antibiotics in the second semester of 2020 compared to the same period of 2019 showed a clear reduction at national level (−8.5%), appreciable to a similar extent in all geographic areas. In the first semester of 2021 compared to the same period of 2020, there was a huge reduction (−31.4%) in consumption at national level. However, the variations were heterogeneous between different geographical areas. To our knowledge, this study represents the most comprehensive analysis performed on antibiotic consumption data in hospital settings in Italy during the COVID-19 pandemic to date. Despite international and national guideline recommendations, a substantial overall increase in antibiotic prescriptions was observed during the COVID-19 pandemic, with variability in terms of geographical distribution and prescription strategies. These findings may be related to the dichotomy between perceived and real significance of guidelines, expert panels, or consensus. Therefore, new approaches or strategies to antimicrobial stewardship should be proposed

No substantial gender differences in suspected adverse reactions to ACE inhibitors and ARBs: results from spontaneous reporting system in Campania Region

Background: Today, there is a poor knowledge about gender differences in adverse drug reactions (ADRs) to cardiovascular drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Therefore, the aim of this study was to analyze spontaneous reports of suspected ADRs induced by ACE-inhibitors and ARBs, between January 2001 and June 2015, recorded in a Region of Southern Italy (Campania Region). Methods: We performed a descriptive gender-related analysis of regional safety data, obtained from the spontaneous reporting system. Results: In the considered period, 772 suspected ADRs to ACE inhibitors and ARBs (in monotherapy or in combination) were reported with a slightly higher frequency in men compared with women. In both genders, the most involved category was ARBs in combination, whereas the most prescribed active substance was ramipril. General and administration site conditions, vascular disorders and modification of laboratory parameters were more common in men, while respiratory disorders were most common in women. In 88.2% of cases, not serious ADRs were described more by men than women. Conclusions: This analysis suggested no substantial gender differences. Further studies such as randomized population studies or meta-analysis of ACE inhibitors and ARBs randomized studies are needed to clarify whether gender differences exist in the safety profile of these drugs

Multisystem Inflammatory Syndrome in Children Following COVID-19 Vaccination: A Sex-Stratified Analysis of the VAERS Database Using Brighton Collaboration Criteria

Multisystem inflammatory syndrome in children (MIS-c) is an uncommon, but serious, inflammatory response that occurs after SARS-CoV-2 infection. As time went by, MIS-c was also reported as a potential adverse event following COVID-19 vaccination. A descriptive analysis was performed of Individual Case Safety Reports (ICSRs) associated with anti COVID-19 vaccines and related to the pediatric population from 2020 to 2022. The present pharmacovigilance study aimed to describe cases of MIS-c following COVID-19 vaccination, stratified by sex, reported in the Vaccine Adverse Events Reporting System (VAERS) and meeting the Brighton Collaboration criteria for case definition. We assessed all suspected cases through the case definition and classification of the Brighton Collaboration Group, and only definitive, probable, and possible cases were included in the analysis. The Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI) was computed to assess if males have a lower/higher probability of reporting ICSRs with MIS-c compared with females. Overall, we found 79 cases of potentially reported MIS-c following vaccination. This study demonstrated that MIS-c following vaccination was more commonly reported for male subjects with a median age of 10 years (IQR 10.0–11.4), especially after the first dose of anti COVID-19 vaccines with a median time to onset of 27 days. Even so, the rate of occurrence of MIS-c following anti COVID-19 vaccines is lower (0.12/100,000 vaccinated subjects; 95% CI, 0.12–0.13). Overall, all ICSRs were serious and caused or prolonged hospitalization. Finally, disproportionality analysis showed that males had a higher reporting probability of MIS-c compared with females following immunization with mRNA COVID-19 vaccines. Since only a few years of marketing are available, further data from real-life contexts are needed

Adverse drug reactions during hepatitis C treatment with direct-acting antivirals: The role of medication errors, their impact on treatment discontinuation and their preventability. New insights from the Campania Region (Italy) spontaneous reporting system

What is known and Objective: Medication errors, such as unnecessary treatment discontinuation during treatment with direct-acting antivirals (DAAs), can lead to imbalances in the benefit-to-risk ratio. This risk is especially high when the medication error leads to adverse drug reactions (ADRs). However, to date, evidence on the frequency of this phenomenon is scarce. This study aims to provide better insight into ADRs possibly due to medication errors leading to DAA discontinuation and their preventability. Methods: The Italian Pharmacovigilance Network database was used to extract individual case safety reports (ICSRs) generated from July 2012 to March 2017 via the Campania Region (Italy) spontaneous reporting system. ICSRs that included ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, dasabuvir, daclatasvir, sofosbuvir, simeprevir or elbasvir/grazoprevir as suspected drugs were included in this study. A preventability assessment was then performed utilizing the "P-Method," an algorithm that evaluates known risk factors due to medication errors that can be detected in ICSRs. Results and discussion: Of the 355 cases included in this study, 6 (1.69%) were classified as preventable and 52 (14.6%) were classified as potentially preventable. The most frequently identified critical criteria (risk factor) for preventable or potentially preventable cases were drug-drug interactions and incorrect drug dosing as part of the antiviral treatment scheme. In total, 89 of the 355 cases (25.1%) discontinued use of the DAAs due to ADRs, of which 20 of the 89 cases (22.5%) were due to an unimportant medical event as classified by the European Medicine Agency important medical event list. What is new and Conclusion: This study found a proportion of preventable/potentially preventable ADRs involving DAA, which could be improved in the Campania Region (Italy). Additionally, the study identified a high proportion of seemingly unnecessary DAA discontinuations among patients who experienced ADRs

Exploring Contemporary Data on Lipid-Lowering Therapy Prescribing in Patients Following Discharge for Atherosclerotic Cardiovascular Disease in the South of Italy

Current international guidelines strongly recommend the use of high-intensity lipid-lowering therapy (LLT) after hospitalization for atherosclerotic cardiovascular disease (ASCVD) events. With this study, our aim was to evaluate LLT prescribing in a large Italian cohort of patients after discharge for an ASCVD event, exploring factors associated with a lower likelihood of receiving any LLT and high-intensity LLT. Individuals aged 18 years and older discharged for an ASCVD event in 2019–2020 were identified using hospital discharge abstracts from two local health units of the Campania region. LLT treatment patterns were analyzed in the 6 months after the index event. Logistic regression models were developed for estimating patient predictors of any LLT prescription and to compare high-intensity and low-to-moderate-intensity LLT. Results: A total of 8705 subjects were identified. In the 6 months post-discharge, 56.7% of patients were prescribed LLT and, of those, 48.7% were high-intensity LLT. Female sex, older age, and stroke/TIA or PAD conditions were associated with a higher likelihood of not receiving high-intensity LLT. Similar predictors were found for LLT prescriptions. LLT utilization and the specific use of high-intensity LLT remain low in patients with ASCVD, suggesting a substantial unmet need among these patients in the contemporary real-world setting

Hypernatremia During Intravenous Treatment With Fosfomycin: A Retrospective Medical Record Review Study and an Analysis of Spontaneous Reports in the EudraVigilance Database

Background: Hypernatremia is a serious event that can occur during intravenous (IV) treatment with fosfomycin, and it can also be caused by a wrong drug preparation. Considering the clinical significance of hypernatremia, we decided to carry out two studies by using two different data sources with the aim to evaluate cases of IV fosfomycin-induced hypernatremia.Methods: A retrospective medical record review was performed from June 2017 to June 2019 using data from two hospitals in Southern Italy. The information collected was related to the patients, the antibiotic treatment regimen, type of adverse drug reaction (ADR), hypernatremia severity classification, and drug withdrawal due to ADRs. Moreover, a pharmacovigilance study was performed from the date of the European marketing authorization of fosfomycin to October 11, 2021, using data reported on the European website of suspected ADRs. Information related to the patient characteristics, treatment, hypernatremia, and type of reporter was retrieved.Results: From the retrospective medical record review, a total of 62 patients (48 men and 14 women) in treatment with fosfomycin were identified, of which 17 experienced ADRs. Specifically, 11 patients experienced hypernatremia. During the period from June 2017 to June 2018, a total of 63.7% of hypernatremia events were related to the wrong reconstitution of the drug. According to these results, a surveillance and training campaign about the correct drug reconstitution was managed. However, from June 2018 to June 2019, we still had four new hypernatremia cases. Drug withdrawal occurred in only one patient with hypernatremia. From the pharmacovigilance study, a total of 25 cases of IV fosfomycin-induced hypernatremia were retrieved. No substantial difference was found for patients' distribution by sex. Most cases were classified as serious (68%) and reported "Recovered/resolved" as the outcome (44%). In the majority of cases, fosfomycin was the only suspected drug reported (72%).Conclusion: Our results show that training campaigns on the correct drug preparation need to be strengthened to allow a reduction of hypernatremia cases. Moreover, when close monitoring and management is performed by the infectious disease (ID) specialist and hospital pharmacist, there also is a reduction in antibiotic withdrawal due to hypernatremia