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.

Development and Evaluation of a Novel Anti-Ageing Cream Based on Hyaluronic Acid and Other Innovative Cosmetic Actives.

The importance of incorporating hyaluronic acid (HA) as a cosmetic ingredient in skin care formulations emerged lately because the amount of HA naturally found in the epidermis decreases with age, and when applied to the skin through cosmetic products, it confers hydration and reduces the appearance of wrinkles. Currently, the diversity of cosmetic products for mature skin and the use of various and innovative active ingredients supporting their anti-ageing effect represent ample proof that the cosmetic industry is currently relying on these actives. The main objective of this study was the development of an anti-ageing formulation, incorporating HA and different other active ingredients. The developed formulation contains a novel complex of natural waxes, with an essential role in the restoration of the skin's hydro-lipid barrier, in combination with innovative active ingredients-like low-molecular hyaluronic acid (LMW-HA), sodium hyaluronate (NaHA), ectoin, gold, and an anti-ageing botanical complex-contributing to optimal skin hydration specifically designed to reduce the visible signs of ageing. An important objective was represented by the skin compatibility and topography assessment after 28 days (D28) of regular application of the developed cream. Stability testing, physicochemical characteristics, and microbiological control, including efficacy testing of the used preservative (challenge test) were performed for the cosmetic formulation. In silico approaches were applied to demonstrate the safety of cosmetic-related substances and the risk assessment of the cosmetic formulation. Safety and instrumental evaluation were performed to demonstrate the skin tolerance-the compatibility and the efficacy, respectively-of the developed anti-ageing cream. As result, quality control of the developed cosmetic formulation evidenced an appropriate cosmetic preparation with desirable aspect and adequate physicochemical characteristics. The concentrations of restricted ingredients like preservatives and UV filters were in accordance with those recommended by the Regulation (EC) No. 1223/2009 and so were considered to be safe. Additionally, according to the margin of safety (MoS) calculation, cosmetic ingredients incorporated in the developed formulation could be considered safe. The developed formulation was very well tolerated, and wrinkle depth and length in the periorbital area were significantly reduced after 28-day cosmetic treatment. Subjects' assessment questionnaires revealed self-perceived benefits referring to the cosmetic qualities and efficacy of the anti-ageing cream. This study confirmed the skin tolerance and efficacy of the new complex anti-ageing cream incorporating HA, microencapsulated sodium hyaluronate, ectoin, and a botanical extract. The formulated cosmetic product could serve as a daily care for mature skin to alleviate the effects of skin ageing.

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.

Some Brassicaceae Extracts as Potential Antioxidants and Green Corrosion Inhibitors.

Glucosinolates-rich extracts of some Brassicaceae sources, such as broccoli, cabbage, black radish, rapeseed, and cauliflower, were obtained using an eco-friendly extraction method, in a microwave field, with 70% ethanol, and evaluated in order to establish their in vitro antioxidant activities and anticorrosion effects on steel material. The DPPH method and Folin-Ciocâlteu assay proved good antioxidant activity (remaining DPPH, 9.54-22.03%) and the content of total phenolics between 1008-1713 mg GAE/L for all tested extracts. The electrochemical measurements in 0.5 M H2SO4 showed that the extracts act as mixed-type inhibitors proving their ability to inhibit corrosion in a concentration-dependent manner, with a remarkable inhibition efficiency (92.05-98.33%) achieved for concentrated extracts of broccoli, cauliflower, and black radish. The weight loss experiments revealed that the inhibition efficiency decreased with an increase in temperature and time of exposure. The apparent activation energies, enthalpies, and entropies of the dissolution process were determined and discussed, and an inhibition mechanism was proposed. An SEM/EDX surface examination shows that the compounds from extracts may attach to the steel surface and produce a barrier layer. Meanwhile, the FT-IR spectra confirm bond formation between functional groups and the steel substrate.

A Descriptive Analysis of Direct Oral Anticoagulant Drugs Dosing Errors Based on Spontaneous Reports from the EudraVigilance Database.

Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study presents a descriptive analysis of adverse reactions (ADRs) attributed to DOAC dosage errors (overdose, underdose, and improper dose). The analysis was performed based on the Individual Case Safety Reports from the EudraVigilance (EV) database. Results show that data reported for rivaroxaban, apixaban, edoxaban, and dabigatran are mostly regarding underdosing (51.56%) compared to overdosing (18.54%). The most dosage error reports were identified for rivaroxaban (54.02%), followed by apixaban (33.61%). Dabigatran and edoxaban had similar percentages (6.26% and 6.11%, respectively) regarding dosage error reports. Since coagulation issues can become life-threatening events, and factors such as advanced age and renal failure can influence the pharmacokinetics of drugs, the correct usage of DOACs is of utmost importance for the management and prevention of venous thromboembolism. Thus, the collaboration and the complementarity of knowledge of physicians and pharmacists may offer a reliable solution for DOAC dose management and improve patient care.

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.

Microbial Resistance to Antibiotics and Effective Antibiotherapy.

Currently, the efficacy of antibiotics is severely affected by the emergence of the antimicrobial resistance phenomenon, leading to increased morbidity and mortality worldwide. Multidrug-resistant pathogens are found not only in hospital settings, but also in the community, and are considered one of the biggest public health concerns. The main mechanisms by which bacteria develop resistance to antibiotics include changes in the drug target, prevention of entering the cell, elimination through efflux pumps or inactivation of drugs. A better understanding and prediction of resistance patterns of a pathogen will lead to a better selection of active antibiotics for the treatment of multidrug-resistant infections.

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.

The Particularities of Pharmaceutical Care in Improving Public Health Service during the COVID-19 Pandemic.

Nowadays, humanity is confronted with one of the most difficult challenges. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified for the first time in Hubei, China in December 2019 and produced the COVID-19 pandemic, a devastating disease that led to many complications and deaths. The authorities and the global healthcare system have been alerted regarding the prevention and treatment of this pathology. Even though worldwide quarantine was declared, health care professionals, including pharmacists, have been at the frontline in this war. Since the beginning of the pandemic, the authorities relied on the involvement of the community, hospital, or clinical pharmacists in offering support to the entire population. Also, the authorities implemented measures for emergency authorization of the vaccines, or the drugs used in COVID-19 treatment. In order to facilitate the population's access to healthcare services, the authorities have established regulations regarding, the extension of prescriptions by pharmacists, working hours, prevention of shortages and price-increase, drive-thru services, etc. However, several countries have taken financial measures to support the pharmacies' activity. At the same time, pharmaceutical associations elaborated guidelines for the protection of pharmacists and patients alike. Additionally, the pharmacies have come to support the health system and patients by adapting pharmaceutical care to the new needs like preparation and supply of disinfectants, patient care, information, and counseling, especially to COVID-19 patients, as well as the implementation of home drugs-delivery systems. The important roles played by pharmacists were to perform COVID-19 tests and further vaccines, as well as to combat the abundance of misinformation and fake news. The clinical and hospital pharmacy services have also been adapted. Strengthening the role of the pharmacist in the medical team was important for the purpose of providing correct and complete information regarding drugs used in the COVID-19 pathology. In all these activities, pharmacists needed creativity and professionalism, but also the support of pharmacy owners and managers. With this crisis, pharmaceutical care has entered a new phase, demonstrating the ability of pharmacists to be competent and accessible providers of public health. Based on this information, we conducted a narrative review whose purpose was to identify the impact of the authorities' decisions on pharmaceutical practice, the involvement of professional associations, and the responsibilities of the pharmacy owners and management. On the other hand, we performed a global assessment on the pharmaceutical care services provided by community pharmacists as well as by clinical or hospital pharmacists during the COVID-19 pandemic.

Advantages of Hyaluronic Acid and Its Combination with Other Bioactive Ingredients in Cosmeceuticals.

This study proposes a review on hyaluronic acid (HA) known as hyaluronan or hyaluronate and its derivates and their application in cosmetic formulations. HA is a glycosaminoglycan constituted from two disaccharides (N-acetylglucosamine and D-glucuronic acid), isolated initially from the vitreous humour of the eye, and subsequently discovered in different tissues or fluids (especially in the articular cartilage and the synovial fluid). It is ubiquitous in vertebrates, including humans, and it is involved in diverse biological processes, such as cell differentiation, embryological development, inflammation, wound healing, etc. HA has many qualities that recommend it over other substances used in skin regeneration, with moisturizing and anti-ageing effects. HA molecular weight influences its penetration into the skin and its biological activity. Considering that, nowadays, hyaluronic acid has a wide use and a multitude of applications (in ophthalmology, arthrology, pneumology, rhinology, aesthetic medicine, oncology, nutrition, and cosmetics), the present study describes the main aspects related to its use in cosmetology. The biological effect of HA on the skin level and its potential adverse effects are discussed. Some available cosmetic products containing HA have been identified from the brand portfolio of most known manufacturers and their composition was evaluated. Further, additional biological effects due to the other active ingredients (plant extracts, vitamins, amino acids, peptides, proteins, saccharides, probiotics, etc.) are presented, as well as a description of their possible toxic effects.

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.

High-throughput NIR-chemometric methods for determination of drug content and pharmaceutical properties of indapamide tablets.

This paper describes the development, validation and application of NIR-chemometric methods for API content and pharmaceutical characterization (disintegration time and crushing strength) of indapamide intact tablets. Development of the method for chemical characterization was performed on samples corresponding to 80, 90, 100, 110 and 120% of indapamide content and for pharmaceutical characterization on samples prepared at nine different compression forces (covering the interval 7-45 kN). NIR spectra of prepared tablets were recorded in transmission mode, and partial least-squares followed by leave-one-out cross-validation were used to develop models for the prediction of the drug content and the pharmaceutical properties of tablets. All developed models were validated in terms of trueness, precision and accuracy. No statistical differences were found between results predicted by NIR-chemometric methods and the ones determined by reference methods. Therefore, the developed NIR-chemometric methods meet the requirements of a high-throughput method for the determination of drug content, pharmaceutical properties of indapamide tablets.