Antibody-Drug Conjugates-Evolution and Perspectives.

Antineoplastic therapy is one of the main research themes of this century. Modern approaches have been implemented to target and heighten the effect of cytostatic drugs on tumors and diminish their general/unspecific toxicity. In this context, antibody-drug conjugates (ADCs) represent a promising and successful strategy. The aim of this review was to assess different aspects regarding ADCs. They were presented from a chemical and a pharmacological perspective and aspects like structure, conjugation and development particularities alongside effects, clinical trials, safety issues and perspectives and challenges for future use of these drugs were discussed. Representative examples include but are not limited to the following main structural components of ADCs: monoclonal antibodies (trastuzumab, brentuximab), linkers (pH-sensitive, reduction-sensitive, peptide-based, phosphate-based, and others), and payloads (doxorubicin, emtansine, ravtansine, calicheamicin). Regarding pharmacotherapy success, the high effectiveness expectation associated with ADC treatment is supported by the large number of ongoing clinical trials. Major aspects such as development strategies are first discussed, advantages and disadvantages, safety and efficacy, offering a retrospective insight on the subject. The second part of the review is prospective, focusing on various plans to overcome the previously identified difficulties.

Safety Profile of the Trastuzumab-Based ADCs: Analysis of Real-World Data Registered in EudraVigilance.

Trastuzumab (T) and tyrosine kinase inhibitors (TKIs) are among the first-line treatments recommended for HER2-positive breast cancer. More recently, antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) have been authorized, and they represent the second-line therapy in this type of cancer. The present study aimed to evaluate adverse drug reactions (ADRs) associated with T-based ADCs that were spontaneously reported in EudraVigilance-the European pharmacovigilance database. Out of 42,272 ADRs reported for currently approved ADCs on the market, 24% of ADRs were related to T-DM1, while 12% of ADRs were related to T-DXd. T-DM1 had a higher probability of reporting eye, ear and labyrinth, and cardiac and hepatobiliary ADRs, while T-DXd had a higher probability of reporting respiratory, thoracic and mediastinal, blood and lymphatic system, metabolism and nutrition, and gastrointestinal ADRs. The present research found that in terms of hematological disorders, T-DM1 and T-DXd had a higher probability of reporting ADRs than TKIs. Moreover, the data showed that T-DM1 seemed to have a higher risk of cardiotoxicity than T-DXd, while T-DXd had a higher probability of reporting metabolism and nutrition disorders than T-DM1.

An Assessment of Semaglutide Safety Based on Real World Data: From Popularity to Spontaneous Reporting in EudraVigilance Database.

Some glucagon-like peptide-1 receptor agonists (GLP-1 RAs), first used in the treatment of type 2 diabetes mellitus (T2DM), have been approved for the treatment of obesity in patients with or without T2DM (liraglutide-LIR, semaglutide-SEM, and tirzepatide-TIR). Social media had an important influence on the off-label use of GLP-1 RAs for obesity, especially for SEM. We analyzed the Google queries related to SEM to assess people's interest in this drug. We also investigated the occurrence of adverse drug reactions (ADRs) by searching the EudraVigilance database (EV) for Individual Case Safety Reports (ICSRs) that reported SEM as the suspected drug and performed a descriptive and a disproportionality analysis. The data obtained for SEM were compared to other GLP-1 RAs. SEM had the highest proportions of searches on Google associated with the term "weight loss" and presented the lowest number of severe ADRs, but it also had the highest number of ICSRs reported in EV. Even though no unexpected safety issues have been reported for it until now, SEM has a hi3gh tendency for overdose reports. The most frequent off-label use was reported for SEM and TIR. In order to lower the risks of ADRs, the off-label use should be reduced and carefully monitored.

A Real-World Study on the Clinical Characteristics, Outcomes, and Relationship between Antibiotic Exposure and Clostridioides difficile Infection.

Clostridioides difficile is a Gram-positive bacteria that causes nosocomial infections, significantly impacting public health. In the present study, we aimed to describe the clinical characteristics, outcomes, and relationship between antibiotic exposure and Clostridioides difficile infection (CDI) in patients based on reports from two databases. Thus, we conducted a retrospective study of patients diagnosed with CDI from Sibiu County Clinical Emergency Hospital (SCCEH), Romania, followed by a descriptive analysis based on spontaneous reports submitted to the EudraVigilance (EV) database. From 1 January to 31 December 2022, we included 111 hospitalized patients with CDI from SCCEH. Moreover, 249 individual case safety reports (ICSRs) from EVs were analyzed. According to the data collected from SCCEH, CDI was most frequently reported in patients aged 65-85 years (66.7%) and in females (55%). In total, 71.2% of all patients showed positive medical progress. Most cases were reported in the internal medicine (n = 30, 27%), general surgery (n = 26, 23.4%), and infectious disease (n = 22, 19.8%) departments. Patients were most frequently exposed to ceftriaxone (CFT) and meropenem (MER). Also, in the EV database, most CDI-related ADRs were reported for CFT, PIP/TAZ (piperacillin/tazobactam), MER, and CPX (ciprofloxacin). Understanding the association between previous antibiotic exposure and the risk of CDI may help update antibiotic stewardship protocols and reduce the incidence of CDI by lowering exposure to high-risk antibiotics.

A Pharmacovigilance Study Regarding the Risk of Antibiotic-Associated Clostridioides difficile Infection Based on Reports from the EudraVigilance Database: Analysis of Some of the Most Used Antibiotics in Intensive Care Units.

The Gram-positive anaerobic bacterium Clostridioides difficile (CD) can produce intense exotoxins, contributing to nosocomial infections, and it is the most common cause of health-care-associated infectious diarrhea. Based on spontaneous Individual Case Safety Reports from EudraVigilance (EV), we conducted a descriptive analysis of Clostridioides difficile infection (CDI) cases that reported a spontaneous adverse reaction related to using ceftriaxone, colistimethate, ciprofloxacin, gentamicin, linezolid, meropenem, and piperacillin/tazobactam. Most ADR reports registered in EV that were related to CDI were associated with ceftriaxone (33%), ciprofloxacin (28%), and piperacillin/tazobactam (21%). Additionally, the disproportionality analysis performed showed that all studied antibiotics had a lower reporting probability when compared to clindamycin. A causal relationship between a drug and the occurrence of an adverse reaction cannot be established from EV data alone because the phenomena of underreporting, overreporting, and reporting bias may affect the results. Based on the analysis of the collected data, this study underlines the importance of surveillance and monitoring programs for the consumption of antibiotics. Furthermore, it is essential to use standardized laboratory tests to define CDI's nature accurately. To prevent this infection, specialists should collaborate and adhere strictly to antibiotic stewardship programs, hygiene practices, and isolation protocols.

Adverse Drug Reactions Relevant to Drug Resistance and Ineffectiveness Associated with Meropenem, Linezolid, and Colistin: An Analysis Based on Spontaneous Reports from the European Pharmacovigilance Database.

Antimicrobial resistance is considered one of the major threats to public health and is an important factor that influences the patient's outcome in the intensive care unit. Pharmacovigilance can help raise awareness of potential drug resistance (DR) or ineffectiveness (DI) through adverse drug reaction reports that are submitted to different spontaneous reporting systems. Based on spontaneous Individual Case Safety Reports from EudraVigilance, we conducted a descriptive analysis of adverse drug reactions associated with meropenem, colistin, and linezolid, with a focus on DR and DI. Of the total adverse drug reactions (ADRs) reported for each analyzed antibiotic by 31 December 2022, between 2.38-8.42% and 4.15-10.14% of the reports were related to DR and DI, respectively. A disproportionality analysis was conducted to evaluate the frequency of reporting adverse drug reactions relevant to the DR and DI of the analyzed antibiotics compared to other antimicrobials. Based on the analysis of the collected data, this study underlines the importance of post-marketing drug safety monitoring in raising a warning signal regarding antimicrobial resistance, thereby potentially contributing to the reduction in antibiotic treatment failure in an intensive care setting.

Post-Marketing Surveillance of Statins-A Descriptive Analysis of Psychiatric Adverse Reactions in EudraVigilance.

Statins are included in the category of high-frequency prescription drugs, and their use is on an upward trend worldwide. In 2012, the FDA issued a warning about possible cognitive adverse drug reactions (ADRs) related to statins, some of which are listed in the Summary of Product Characteristics, but there are still concerns about their potential risk of psychiatric events. The aim of this research was to investigate spontaneous reports containing psychiatric ADRs associated with statins by analyzing the EudraVigilance (EV) database. From January 2004 to July 2021, a total of 8965 ADRs were reported for the Systems Organ Class (SOC) "psychiatric disorders", of which 88.64% were registered for atorvastatin (3659), simvastatin (2326) and rosuvastatin (1962). Out of a total of 7947 individual case safety reports (ICSRs) of the 3 statins mentioned above, in 36.3% (2885) of them, statins were considered the only suspected drug, and in 42% (3338), no other co-administered drugs were mentioned. Moreover, insomnia has been reported in 19.3% (1536) of cases, being the most frequent adverse reaction. A disproportionality analysis of psychiatric ADRs was performed. The Reporting Odds Ratio (ROR) and 95% confidence interval (95% CI) were calculated for simvastatin, atorvastatin and rosuvastatin compared with antiplatelets and antihypertensive drugs. The reporting probability for most ADRs of these statins compared to antiplatelets was higher. The reporting probability for insomnia, nightmares and depression produced by statins compared to antihypertensive drugs was also higher. The results of this analysis augment the existing data about a possible correlation between the administration of statins and the occurrence of psychiatric side effects.

Biopolymeric Prodrug Systems as Potential Antineoplastic Therapy.

Nowadays, cancer represents a major public health issue, a substantial economic issue, and a burden for society. Limited by numerous disadvantages, conventional chemotherapy is being replaced by new strategies targeting tumor cells. In this context, therapies based on biopolymer prodrug systems represent a promising alternative for improving the pharmacokinetic and pharmacologic properties of drugs and reducing their toxicity. The polymer-directed enzyme prodrug therapy is based on tumor cell targeting and release of the drug using polymer-drug and polymer-enzyme conjugates. In addition, current trends are oriented towards natural sources. They are biocompatible, biodegradable, and represent a valuable and renewable source. Therefore, numerous antitumor molecules have been conjugated with natural polymers. The present manuscript highlights the latest research focused on polymer-drug conjugates containing natural polymers such as chitosan, hyaluronic acid, dextran, pullulan, silk fibroin, heparin, and polysaccharides from Auricularia auricula.

Valorization of Grape Pomace and Berries as a New and Sustainable Dietary Supplement: Development, Characterization, and Antioxidant Activity Testing.

Grape pomace and berries represent natural sources of phytochemicals that can increase the quality of life of consumers by contributing to the prevention of chronic diseases; thus, the development of a dietary supplement was necessary. The raw material (r.m.) used for the development of the dietary supplement consisted of dried and powdered bilberries (Vaccinium myrtillus L.), red currants (Ribes rubrum L.), and red fermented pomaces (Vitis vinifera L.) from Feteasca Neagra and Cabernet Sauvignon cultivars. The particle size distribution, powder flow, total phenolic content (TPC), HPLC-DAD phenolic profile assessment, and radical scavenging assay (RSA) were employed for the analysis of the raw material. After encapsulation, the average mass and uniformity of mass, the disintegration, and the uniformity of content for the obtained capsules were performed to obtain a high-quality dietary supplement. All the assays performed complied to the compendial requirements and the TPC was determined at 9.07 ± 0.25 mg gallic acid equivalents/g r.m. and RSA at 48.32 ± 0.74%. The highest quantities of phenolic compounds determined were 333.7 ± 0.50 µg/g r.m. for chlorogenic acid, followed by rutin, ferulic acid, and (+)-catechin with 198.9 ± 1.60 µg/g r.m., 179.8 ± 0.90 µg/g r.m. and 118.7 ± 0.75 µg/g r.m., respectively. The results of this study can be used for the manufacturing and assessing of pilot scale-up capsule batches and thinking of quality assurance, we recommend that the industrial batch extracts should be standardized in polyphenols, and the manufacturing process should be validated.

Dendrimers as Non-Viral Vectors in Gene-Directed Enzyme Prodrug Therapy.

Gene-directed enzyme prodrug therapy (GDEPT) has been intensively studied as a promising new strategy of prodrug delivery, with its main advantages being represented by an enhanced efficacy and a reduced off-target toxicity of the active drug. In recent years, numerous therapeutic systems based on GDEPT strategy have entered clinical trials. In order to deliver the desired gene at a specific site of action, this therapeutic approach uses vectors divided in two major categories, viral vectors and non-viral vectors, with the latter being represented by chemical delivery agents. There is considerable interest in the development of non-viral vectors due to their decreased immunogenicity, higher specificity, ease of synthesis and greater flexibility for subsequent modulations. Dendrimers used as delivery vehicles offer many advantages, such as: nanoscale size, precise molecular weight, increased solubility, high load capacity, high bioavailability and low immunogenicity. The aim of the present work was to provide a comprehensive overview of the recent advances regarding the use of dendrimers as non-viral carriers in the GDEPT therapy.

Applications and Limitations of Dendrimers in Biomedicine.

Biomedicine represents one of the main study areas for dendrimers, which have proven to be valuable both in diagnostics and therapy, due to their capacity for improving solubility, absorption, bioavailability and targeted distribution. Molecular cytotoxicity constitutes a limiting characteristic, especially for cationic and higher-generation dendrimers. Antineoplastic research of dendrimers has been widely developed, and several types of poly(amidoamine) and poly(propylene imine) dendrimer complexes with doxorubicin, paclitaxel, imatinib, sunitinib, cisplatin, melphalan and methotrexate have shown an improvement in comparison with the drug molecule alone. The anti-inflammatory therapy focused on dendrimer complexes of ibuprofen, indomethacin, piroxicam, ketoprofen and diflunisal. In the context of the development of antibiotic-resistant bacterial strains, dendrimer complexes of fluoroquinolones, macrolides, beta-lactamines and aminoglycosides have shown promising effects. Regarding antiviral therapy, studies have been performed to develop dendrimer conjugates with tenofovir, maraviroc, zidovudine, oseltamivir and acyclovir, among others. Furthermore, cardiovascular therapy has strongly addressed dendrimers. Employed in imaging diagnostics, dendrimers reduce the dosage required to obtain images, thus improving the efficiency of radioisotopes. Dendrimers are macromolecular structures with multiple advantages that can suffer modifications depending on the chemical nature of the drug that has to be transported. The results obtained so far encourage the pursuit of new studies.

An Exploratory Research of 18 Years on the Economic Burden of Diabetes for the Romanian National Health Insurance System.

The prevalence of diabetes mellitus (DM) rises constantly each year worldwide. Because of that, the funds allocated for the DM treatment have increased over time. Regarding the number of DM cases, Romania is among the top ten countries in Europe. Based on the National Diabetes Programme (NDP), antidiabetic drugs and other expenditures (Self-monitoring blood glucose (SMBG) test, HbA1c, insulin pumps/insulin pumps supplies) are free of charge. This programme has undergone many changes in drugs supply, in the last two decades: re-organizing the NDP, authorization of new molecules with high prices (e.g., SGLT-2 inhibitors, etc.) or new devices (e.g., insulin pumps, etc.) The main purpose of this study is to identify and analyse the impact of the DM costs on the Romanian health budget and to highlight the evolution of these costs. A retrospective longitudinal research on the official data regarding the DM costs from 2000 to 2017 was performed. The DM funds (DMF) were adjusted with the inflation rate. In this period, the average share of DMF in the total funds allocated for health programmes was 21.3 ± 3.4%, and DMF average growth rate was 25.4% (r = 0.488, p = 0.047). On the other hand, the DMF increased more than 14 times, in spite of the patients' number having increased only about 2.5 times. Referring to the structure of DMF, the mean value of the antidiabetic drugs cost was of 96,045 ± 67,889 thousand EUR while for other expenditures it was of 11,530 ± 7922 thousand EUR (r = 0.945, p < 0.001). Between 2008 and 2017, the total DMF was 181,252 ± 74,278 thousand EUR/year. Moreover, the average patients' number was 667,384 ± 94,938 (r = 0.73, p = 0.016), and the cost of treatment was 215 ± 36 EUR/patient/year. Even if the cost is rising, the correct and optimal treatment is a main condition for the diabetic patient's health and for the prevention of its complications, which have multiple socio-economic repercussions.