Medicines doi: 10.3390/medicines12040026

Authors: Arif Ul Hasan Sachiko Sato Mami Obara Yukiko Kondo Eiichi Taira

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies.

Medicines doi: 10.3390/medicines12040025

Authors: Benjamin J. Hellinger Thilo Bertsche Yvonne Remane André Gries

Background: Patients presenting at the emergency department (ED) have a wide variety of complaints. In some of those patients a possible reason for their complaints might be an adverse drug reaction (ADR). An appropriate identification of ADR in this setting is required to optimize drug therapy and to prevent serious harm deriving from an overlooked ADR. Methods: This retrospective study assessed medical records of patients for ADR as a reason for the ED presentation in two assessments. In the first assessment, medical records were evaluated for potential ADR leading to ED presentation with a predefined checklist by an examiner not involved in initial patient treatment. In the second assessment the same medical records were assessed for ADR identified by the physician in the initial patient presentation. Discrepancies in identified ADR were compared. For descriptive data analysis and statistical evaluation, the McNemar test was performed. Results: From 35,333 patients admitted to the ED, full data were available from 34,747 patients for evaluation. In those patients, 2071 (6.0%) ADR were identified as being the reason for ED presentation by using the checklist. In 828 (2.4%) patients, emergency department physicians had documented an ADR in the medical records. By using the checklist, ADR identification could be improved significantly as compared to routine care, at 6.0% vs. 2.4%, respectively (p < 0.001). The most common chief complaint in patients with an ADR was worsened general condition. Most common drug class causing ADR were antithrombotics. Conclusions: ADR seem to be overlooked in routine care since a significantly higher number of ADR were found by using a checklist-based method as compared to ADR documented as part of routine examination. Therefore, implementing the checklist in the routine process might improve ADR identification.

Medicines doi: 10.3390/medicines12040024

Authors: Sarah A. Ekkelboom Soraya M. Hobart Laurie J. Barten Staci L. Hemmer

Background/Objectives: Growing evidence supports the use of a single trough concentration, rather than both a peak and trough, to estimate the 24 h area under the curve (AUC24) of vancomycin using Bayesian software (InsightRx® Ver.1.71). However, patients with body mass index (BMI) ≥ 40 kg/m2 are underrepresented in validation studies. Studies in patients with obesity have produced mixed results, potentially because of different population models used. Methods: This single-center, retrospective study evaluated adult inpatients with BMI ≥ 40 kg/m2. Steady-state AUC24 estimates generated by Bayesian software using both two-concentration and one-concentration inputs were compared. Agreement was defined as a percent difference within ±20%. Subgroup analyses were conducted for patients with defined peak and trough concentrations and for comparisons between two Bayesian population models (Carreno vs. Hughes). Linear regression assessed covariates associated with percent difference. Results: Among 82 encounters, 97.5% of one-concentration estimates based on the smaller concentration were within ±20% of the two-concentration AUC24,SS (mean difference: 2.9%, 95% CI: 0.14 to 3.8%). Similar agreement was observed using the larger concentration (97.5%, mean difference: −3.1%, 95% CI: −4.7 to −0.1.5%). Subgroup analysis for encounters with true peak/trough levels (n = 22) also showed 100% agreement within ±20%. The percent difference did not correlate with BMI or other covariates. Comparison of Hughes vs. Carreno models showed larger variability (only 59.1% within ±20%). Conclusions: In patients with BMI ≥ 40 kg/m2, Bayesian AUC24,SS estimation using a single vancomycin concentration is feasible. Greater caution is warranted in the setting of acute kidney injury, poor model fit, or targeting AUC at the extremes of the therapeutic range. The population model used to generate the Bayesian AUC estimate has a much greater influence than the number of concentrations analyzed. Furthermore, measuring two concentrations does not ensure concordance between models.

Medicines doi: 10.3390/medicines12040023

Authors: Esteban Zavaleta-Monestel Jeaustin Mora-Jiménez Kevin Cruz-Mora Ernesto Martinez-Vargas José Pablo Díaz-Madriz Sebastián Arguedas-Chacón Abigail Fallas-Mora Carlos Wu-Chin Jose Miguel Chaverrí-Fernandez

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of hospitalization and functional decline in older adults, accounting for over 80% of all heart failure cases. Given the narrow therapeutic window of currently available inotropes and the vulnerability of this population, levosimendan has been proposed as a potential alternative. This systematic review aimed to evaluate the clinical efficacy and safety of levosimendan in older adults with decompensated HFrEF. Methods: A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted between January and May 2025, following PRISMA 2020 guidelines. The review was registered in PROSPERO (CRD420251032329). Of 379 articles initially identified, 8 studies (randomized, observational, and single-arm designs) enrolling patients aged ≥65 years with decompensated HFrEF met the inclusion criteria. Study quality was assessed using the Cochrane RoB-2 tool and JBI Critical Appraisal Checklists. No meta-analysis was performed due to heterogeneity in study designs, populations, and interventions. Results: A total of 2838 patients were analyzed. Levosimendan was associated with short-term improvements in hemodynamic parameters, including an increase in cardiac index (from 1.65 to 2.37 L/min/m2) and a reduction in pulmonary capillary wedge pressure (from 31 to 16 mmHg) within 24–72 h (p < 0.002). However, no statistically significant differences were observed in 30-, 90-, or 180-day mortality (p > 0.05), and findings on rehospitalization were inconsistent. Reported adverse events included hypotension (36–57%) and atrial arrhythmias (9–50%), with low treatment discontinuation rates (5–8%). Conclusions: Levosimendan may improve short-term hemodynamic parameters in older adults with decompensated HFrEF, but the available evidence is limited and heterogeneous. Its effects on mortality and rehospitalization remain inconclusive. Clinical use should be individualized and closely monitored, particularly in frail patients.

Medicines doi: 10.3390/medicines12030022

Authors: Tanner A. Melton Molly W. Fenske Stacy A. Bernard Kristin C. Cole Kelly M. Pennington Adley I. Lemke

Introduction: Reversible and irreversible nephrotoxicity are known complications of tacrolimus. Approaches to reduce the incidence of nephrotoxicity include the reduction or avoidance of tacrolimus but must be weighed against risk of rejection. Infrequently, basiliximab has been used outside of the induction period to facilitate temporary tacrolimus cessation in the setting of acute kidney injury (AKI). Objective: The primary objective of this study was to describe renal recovery after temporary tacrolimus cessation with non-induction basiliximab (NIB) compared to a matched cohort. Methods: We conducted a single-center study of adult cardiothoracic transplant recipients that received basiliximab beyond post-operative day 7 for temporary tacrolimus cessation in the setting of AKI between January 2019 and November 2023 and matched them to acontrol cohort. Results: Twelve patients underwent temporary tacrolimus cessation with NIB. In total, 7 (58%) patients achieved initial renal recovery at tacrolimus resumption compared to 15 (42%) patients in the matched cohort at an equivalent time point. No difference between treated rejection (17% vs. 19%, p = 0.80) or infection (75% vs. 50%, p = 0.32) was observed between tacrolimus cessation and its matched cohort. Conclusions: The use of NIB for tacrolimus cessation can allow for potential renal recovery after an AKI or in patients at risk of AKI. This approach does not appear to significantly increase the risk of rejection but may increase the risk of infection in the long term.

Medicines doi: 10.3390/medicines12030021

Authors: Yeung-Ae Park Anya Kitt Lee Rahul D. Barmanray Frank Gao Spiros Fourlanos Chris Gilfillan

Background/Objectives: Sodium–glucose co-transporter 2 inhibitors (SGLT2i) are associated with increased rates of diabetic ketoacidosis (DKA). The difference in the management and outcomes of SGLT2i-associated DKA (SGLT2i DKA) from non-SGLT2i-associated DKA (non-SGLT2i DKA) remains unclear due to a lack of specific reporting on dextrose and insulin. This study aims to compare the management and outcome of SGLT2i and non-SGLT2i diabetic ketoacidosis. Methods: In this retrospective cohort study, patients admitted to the Intensive Care Unit (ICU) for diabetic ketosis between 1 January 2020 to 31 December 2021 at a tertiary hospital were identified. For each SGLT2i diabetic ketosis, two non-SGLT2i diabetic ketosis admissions closest to the SGLT2i admission date were evaluated for comparison. Clinical data including biochemistry, ICU length of stay (LOS), time to normalize acidemia and ketonemia, dextrose and insulin requirements, were evaluated. Results: In the SGLT2i group (n = 30), there were 22 DKA and 8 diabetic ketosis cases; in the non-SGLT2i group (n = 60), there were 54 DKA and 6 diabetic ketosis cases. SGLT2i DKA (n = 22) required 62% greater total insulin (154 [117–249] vs. 95 [59–150] units; p = 0.004), which remained statistically significant after weight adjustment (p = 0.02), and longer ICU LOS (52 [42–97] vs. 39 [23–68] hours; p = 0.01) compared to non-SGLT2i DKA (n = 54), despite a comparable time to DKA resolution (22 [15–35] vs. 20 [15–35] hours; p = 0.91). In the intercurrent illness subgroup analysis, neither total insulin dose nor ICU LOS remained statistically significantly different between SGLT2i (n = 16) and non-SGLT2i DKA (n = 21). The majority of cases received 10% dextrose and variable rate intravenous insulin infusion (VRIII). Conclusions: The greater insulin requirement in SGLT2i DKA compared to non-SGLT2i DKA may be explained by the greater proportion of precipitating intercurrent illnesses and demographic differences in SGLT2i DKA, highlighting that SGLT2i DKA (predominantly comprising T2D) and non-SGLT2i DKA (predominantly comprising T1D) represent distinct clinical entities. Our findings in comparison to the literature imply that in SGLT2i DKA, the need for prolonged IV insulin infusion may be reduced through intensive management using intravenous 10% dextrose and VRIII. Prospective studies are warranted to evaluate the efficacy of different management strategies for SGLT2i DKA.

Medicines doi: 10.3390/medicines12030020

Authors: Stefanie Stramel-Stafford Heather Townsend Brian Trimmer James Cohen Jessica Thompson

Objective: The impact of a febrile neutropenia (FN) emergency department (ED) triage screening tool and protocol on time to antibiotic administration (TTA) and patient outcomes was evaluated. Methods: This was a retrospective, quasi-experimental study of adult FN patients admitted through the ED from April 2014 to April 2017. In March 2016 a triage screening tool and protocol were implemented. In patients who screened positive, nursing initiated a protocol that included laboratory diagnostics and a pharmacy consult for empiric antibiotics prior to evaluation by a provider. Patients were evaluated pre- and post-protocol for TTA, 30-day mortality, ED length of stay (LOS), and hospital LOS. Results: A total of 130 patients were included in the study, 77 pre-protocol and 53 post-protocol. Median TTA was longer in the pre-protocol group at 174 min (interquartile range [IQR] 105–224) vs. 109 min (IQR 71–214) post-protocol, p = 0.04. Thirty-day mortality was greater at 18.8% pre-protocol vs. 7.5% post-protocol, p = 0.12. There was no difference in hospital LOS. Pre-protocol patients compared to post-protocol patients who had a pharmacy consult demonstrated a further reduction in TTA (174 min [IQR 105–224] vs. 87.5 min [IQR 61.5–135], p < 0.01) and a reduced mortality (18% vs. 0%, p = 0.04). Conclusions: To our knowledge, this is the first report of a protocol for febrile neutropenia that allows pharmacists to order antibiotics based on a nurse triage assessment. Evaluation of the protocol demonstrated a significant reduction in TTA and trend toward improved mortality.

Medicines doi: 10.3390/medicines12030019

Authors: Mohammad Iftekhar Ullah Sadeka Tamanna

Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5–20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15–25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences.

Medicines doi: 10.3390/medicines12030018

Authors: Ivanka Maduna Dorotea Vidaković Petra Črnac Christian Saleh Hrvoje Budinčević

Background/Objectives: Atrial fibrillation (AF) is the most significant modifying risk factor for the development of cardioembolic stroke, which is associated with worse outcomes and higher intrahospital mortality compared to other types of ischemic stroke. Antithrombotic medications are administered as prophylactic treatment in patients with a risk of stroke. The aim of this study was to determine outcome measures in patients with first-ever ischemic stroke and AF regarding prior antithrombotic therapy. Methods: We collected data on stroke risk factors, CHADS2 score, and international normalized ratio (INR) value in the context of warfarin therapy, as well as data related to localization, stroke severity, and functional outcome at discharge. Results: A total of 754 subjects with first-ever ischemic stroke and AF were included in this cross-sectional study (122 on warfarin, 210 on acetylsalicylic acid, and 422 without prior antithrombotic therapy). The diagnosis of AF was previously unknown in 31% of the subjects. Stroke risk factors (arterial hypertension, hyperlipidemia, diabetes mellitus, and cardiomyopathy) were significantly lower in the group without prior antithrombotic therapy. The anticoagulant group was significantly younger (p = 0.001). Overall, 45.4% of subjects with a previously known AF event and a high risk of developing stroke received anticoagulant therapy. Participants on warfarin had a significantly better functional outcome than those on antiplatelet therapy or without prior antithrombotic therapy (median mRS 4 vs. 5 vs. 5; p = 0.025) and lower NIHSS scores, although the difference was not statistically significant (median 10 vs. 12 vs. 12; p = 0.09). There was no difference between stroke localization among groups (p = 0.116). Conclusions: Our study showed that, in our cohort, first-ever ischemic stroke due to AF was more common in women. Subjects on prior anticoagulant therapy had more favorable outcomes at discharge.

Medicines doi: 10.3390/medicines12030017

Authors: Niki Dermitzaki Foteini Balomenou Anastasios Serbis Natalia Atzemoglou Lida Giaprou Maria Baltogianni Vasileios Giapros

Neonatal sepsis is a major cause of morbidity and mortality in neonates. A particular concern is the increasing prevalence of antibiotic-resistant strains among neonatal intensive care units (NICUs). Two novel beta-lactam/beta-lactamase inhibitors have recently been approved for use in neonates with multidrug-resistant infections: ceftazidime/avibactam and ceftolozane/tazobactam. These agents demonstrate efficacy against a range of multidrug-resistant gram-negative pathogens, including extended-spectrum beta-lactamases (ESBL)-producing and carbapenem-resistant Enterobacterales, as well as multidrug-resistant Pseudomonas aeruginosa. This narrative review aims to summarize the current knowledge concerning the utilization of ceftazidime/avibactam and ceftolozane/tazobactam in the NICU. According to the existing literature, both agents have been shown to be highly effective with a favorable safety profile in the neonatal population.

Medicines doi: 10.3390/medicines12030016

Authors: Antonios Kousaxidis Konstantina-Malamati Kalfagianni Eleni Seretouli Ioannis Nicolaou

Background/Objectives: Diabetes mellitus is a group of chronic metabolic disorders characterized by persistent hyperglycemia. Aldose reductase, the first enzyme in the polyol pathway, plays a key role in the onset of long-term diabetic complications. Aldose reductase inhibition has been widely established as a potential pharmacotherapeutic approach to prevent and treat diabetes mellitus-related comorbidities. Although several promising aldose reductase inhibitors have been developed over the past few decades, they have failed in clinical trials due to unacceptable pharmacokinetic properties and severe side effects. This paper describes the design, synthesis, and pharmacological evaluation of four novel 5-halogenated N-indolylsulfonyl-2-fluorophenol derivatives (3a-d) as aldose reductase inhibitors. Methods: The design of compounds was based on a previously published lead compound (IIc) developed by our research group to enhance its inhibitory capacity. Compounds 3a-d were screened for their ability to inhibit in vitro partially purified aldose reductase from rat lenses, and their binding modes were investigated through molecular docking. Results: The presence of a sulfonyl linker between indole and o-fluorophenol aromatic rings is mandatory for potent aldose reductase inhibition. The 5-substitution of the indole core with halogens resulted in a slight decrease in the inhibitory power of 3a-c compared to IIc. Among halogens, bromine was the most capable of filling the selectivity pocket through hydrophobic interactions with Thr113 and Phe115 residues. Conclusions: Although our strategy to optimize the inhibitory potency of IIc via inserting halogen atoms in the indole scaffold was not fruitful, aromatic ring halogenation can be still utilized as a promising approach for designing more potent aldose reductase inhibitors.

Medicines doi: 10.3390/medicines12030015

Authors: Nuno Sanfins Pedro Andrade Jacinto Azevedo

Background/Objectives: Oppositional defiant disorder (ODD) and conduct disorder (CD) are important behavior disorders in children and adolescents, often linked with long-term psychosocial problems. Antipsychotics are frequently prescribed to manage severe symptoms and improve behavior, but their efficacy in this population is still unclear and a lot of physicians are remittent in prescribing them. This systematic review aims to assess the effectiveness of antipsychotic treatment in reducing symptoms associated with ODD and CD in children and adolescents. Methods: Studies that investigated how effective antipsychotic treatments are for children and teens diagnosed with oppositional defiant disorder (ODD) and conduct disorder (CD) were reviewed. Only studies that met a few main criteria were included: participants were between 5 and 18 years old with an ODD or CD diagnosis; the treatment could be any type of antipsychotic, whether typical or atypical; the accepted study designs were randomized controlled trials (RCTs), cohort studies, systematic reviews with meta-analysis, or observational studies. The outcomes of interest were reductions in aggressive or defiant behaviors, improvements in social functioning, and the occurrence of any adverse effects from the medications. There was no restriction on the language of publication, and studies published from 2000 to 2024 were considered. Studies that focused only on non-antipsychotic drugs or behavioral therapies, as well as case reports, expert opinions, and non-peer-reviewed articles did not meet the inclusion criteria. Results: The review consisted of 13 studies. The results suggest that some antipsychotic drugs—especially atypical antipsychotics—can substantially reduce aggressive and defiant behavior in children and adolescents who have oppositional defiant disorder (ODD) or conduct disorder (CD). Common side effects of these medications include weight gain, sedation, and metabolic problems. Conclusions: Although adverse effects are a concern, the potential of these medications to manage disruptive behaviors should not be overlooked. When used in combination with behavioral therapy and other forms of treatment, antipsychotics can markedly improve the outcomes of these very difficult-to-treat patients. Clinicians who treat these patients need to consider antipsychotics as a serious option. If they do not, they are denying their patients medication that could greatly benefit them.

Medicines doi: 10.3390/medicines12020014

Authors: Sourav Chakraborty Piyush Baindara Surojit Das Suresh K. Mondal Pralay Sharma Austin Jose T Kumaravel V Raja Manoharan Santi M. Mandal

Background: Methicillin-resistant Staphylococcus aureus (MRSA) considered under the category of serious threats by the Centers for Disease Control and Prevention (CDC), urges for new antibiotics or alternate strategies to control MRSA. Methods: Ethosome-like liposomes have been developed and characterized using dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Liposomes were confirmed for antibiotics infusion by encapsulation efficiency and release kinetics as well. Further, the antimicrobial potential of liposomes was checked by determination of minimum inhibitory concentrations (MICs), crystal violet assay, and live/dead biofilm eradication assay. Results: The specially designed liposomes consist of amphiphilic molecules, tocopherol, conjugated with ampicillin and, another antibiotic amikacin, loaded in the core. The developed liposomes exhibited good encapsulation efficiency, and sustained release while serving as ideal antibiotic carriers for advanced efficacy along with anti-inflammatory benefits from tocopherol. Conclusively, newly designed liposomes displayed potential antimicrobial activity against MRSA and its complex biofilms. Conclusions: Overall, dual antibiotic-encapsulated liposomes demonstrate the potential to eradicate MRSA and its mature biofilms by dual-targeted action. This could be developed as an efficient anti-infective agent and delivery vehicle for conventional antibiotics to combat MRSA.

Medicines doi: 10.3390/medicines12020013

Authors: Fadel Bahouth Boris Chutko Haitham Sholy Sabreen Hassanain Gassan Zaid Evgeny Radzishevsky Ibrahem Fahmwai Mahmod Hamoud Nemer Samnia Johad Khoury Idit Dobrecky-Mery

Introduction: A direct head-to-head comparison between potent P2Y12 inhibitors: prasugrel versus ticagrelor is still lacking. Purpose: In this single-center study, we sought to address the efficacy and safety of these two third-generation antiplatelet drugs, after about a decade of practical use. Methods: A retrospective observational study included all patients who were admitted with acute coronary syndrome between January 2010 and December 2019 and were discharged with aspirin and either prasugrel or ticagrelor after percutaneous coronary intervention. Patients were divided into two groups based on the dual antiplatelet drugs prescribed. Primary endpoint: A composite endpoint of cardiovascular death, recurrent coronary syndrome, or ischemic stroke at one year. Secondary endpoint: Significant bleeding according to the BARC classification (types 3, 4, or 5). Results: During this period, 746 patients met the inclusion criteria. The primary endpoint was reached in 70 patients (9.4%): 24 patients (8.0%) in the group treated with ticagrelor and 46 patients (10.3%) in the group treated with prasugrel (p-value = 0.303). In terms of safety events, significant bleeding was not statistically different between the ticagrelor and prasugrel groups: 13 (2.9%) vs. 9 (3%), respectively (p-value = 0.9). More patients discontinued their treatment before the end of the year among those treated with ticagrelor compared to those treated with prasugrel (16.7% vs. 9.6%, p-value = 0.003). Conclusions: There was no significant difference in the occurrence of recurrent cardiac events, stroke, or cardiovascular death, nor significant bleeding among ACS patients treated either with prasugrel or ticagrelor.

Medicines doi: 10.3390/medicines12020012

Authors: Christos Ntais Yioula Melanthiou

Background: The introduction of medical cannabis in Greece marks a shift in healthcare policy, yet patient attitudes remain underexplored. Methods: This qualitative study examines the market readiness for medical cannabis through semi-structured interviews with 24 participants—12 users of cannabidiol (CBD)-based formulations and 12 medical cannabis-naive individuals. Results: CBD-experienced patients generally perceive cannabis-based treatments as beneficial for managing musculoskeletal pain, migraines, anxiety, stress and sleep disturbances, despite concerns over product quality, cost and limited medical guidance. Medical cannabis-naive participants express skepticism due to stigma and perceived insufficient evidence but acknowledge potential therapeutic value within a regulated framework. This study highlights the need for better patient education, physician training and clear regulatory guidelines to support responsible market entry. Conclusions: These findings offer important insights for policymakers, healthcare providers and the pharmaceutical industry, emphasizing the need for a structured, evidence-based approach to medical cannabis integration in Greece. Further research is needed to assess long-term patient experiences and the evolving impact of regulatory changes on market dynamics.

Medicines doi: 10.3390/medicines12020011

Authors: Evrydiki Katsikari Alexandra Kyriaki Andreas Vitsos Margarita Vidali Paschalis Harizanis Ioannis Sfiniadakis Maria Kostaki Dimitra Ieronymaki Asimina Terezaki Georgios Ladopoulos Chara Albani Christina Barda Michail Christou Rallis

Background/Objectives: Burn injuries present significant treatment challenges due to the intricate nature of the healing process. Bombyx mori L. (silkworm) derivatives, containing healing-promoting proteins such as sericin and fibroin, as well as the anti-inflammatory enzyme serrapeptase, have shown promise as potential healing agents. This study aimed to identify the optimal dosage of silkworm body and gland extracts for burn healing, compare the selected dose’s effectiveness with that of silkworm cocoons, and assess the combined healing effects of a cocoon dressing and a silkworm body extract gel. Methods: An experimental model was employed using hairless SKH-hr2 female mice subjected to standardized second-degree burns. The mice received treatments with various formulations of silkworm body and gland extracts, silkworm cocoons, and a combined application of a cocoon dressing and silkworm body extract gel. Results: The most effective treatments were the cocoon dressing and the combination of cocoon dressing with 60% body extract gel. By Day 20, complete healing (100%) was observed in the 20% and 60% body and gland extract groups, while the cocoon and 60% gland extract groups exhibited 60% healing, significantly higher than the control group (0% healing). Wound contraction analysis showed the greatest reduction in surface area from Day 3 to Day 17 in the cocoon and 60% body extract groups (p < 0.05). Histopathological assessments revealed that the combination group exhibited the least tissue damage (score: 7), compared to the control (score: 10–13). Conclusions: The study highlights the poorly examined therapeutic potential of silkworm body and gland extracts, demonstrating their efficacy in accelerating burn healing. The effects observed by the silkworm cocoon and body extract suggests a novel and promising approach for burn wound management, warranting further clinical exploration.

Medicines doi: 10.3390/medicines12020010

Authors: George I. Lambrou Athanasia Samartzi Eugenia Vlachou Athanasios N. Tsartsalis

Background/Objectives: Type 2 diabetes mellitus (T2DM) has a growing prevalence, even in developed countries. Because of the increase in life expectancy, the number of older people with T2DM is also increasing. The management and handling of these patients is challenging due to its co-morbidities. Aim: In the present study, we reviewed the literature in order to investigate the impact of sodium–glucose co-transporter 2 inhibitors (SGLT-2 inhibitors) on bone metabolism and fracture incidence. Methods: We searched the literature using the databases of PubMed, CENTRAL and Cochrane Central Register of Controlled Trials up to December 2024. Results: There is a controversial position in the literature concerning the effects of SGLT2 inhibitors when administered in T2DM, with respect to bone metabolism and bone fracture incidence. Multiple studies suggest the SGLT2 inhibitors have a disadvantageous effect on bone metabolism and fracture incidence, while several others suggest a beneficial effect. Conclusions: Patients with type 2 diabetes mellitus are at high risk of alterations in their bone metabolism. SGLT2 inhibitors are a novel class with pleiotropic effects in many organs, such as the kidneys and heart, although their effect on bone metabolism and fracture incidence is still unclear. Until we have more clinical data, all caregivers (medical and nursing staff) should be aware of possible bone fractures in patients receiving this class of agents.

Medicines doi: 10.3390/medicines12020009

Authors: Staci L. Hemmer Sarah K. Scoular

Background/Objectives: Nomograms for adjusting gentamicin therapy in neonates using a single concentration are limited. The Dersch–Mills nomogram is inefficient for short-duration therapies, while the NeoFax nomogram is outdated based on the current American Academy of Pediatrics (AAP) guidelines. Bayesian software has shown accuracy for vancomycin in adults, but its performance for gentamicin in neonates is unclear. This study evaluates the accuracy of Bayesian estimation in predicting peak and trough gentamicin concentrations from a single measured level in neonates. Methods: A single-center, retrospective re-analysis was conducted of gentamicin concentrations in neonates. InsightRx® was used to estimate maximum and minimum concentrations in a dosing interval (Cmax and Cmin) based on a single peak or trough concentration. Bias and accuracy were characterized using the mean difference (MD) between estimated and measured concentrations and the 95% limits of agreement (LOA) for the differences (±1.96 × SD). Results: Fifty-seven neonates (73 peak/trough pairs) were analyzed. Median gestational age was 34 weeks and median postnatal age was 0 days. The MD (LOA) between Cmin estimates and measured troughs was 0.03 mg/L (−0.17 to 0.13) for the trough-only analysis and 0.21 mg/L (−0.38 to 0.8) for the peak-only analysis. The MD (LOA) between Cmax estimates and measured peaks was 0.16 mg/L (−3.2 to 3.3) for the trough-only analysis and 1.2 mg/L (−0.58 to 3.0) for the peak-only analysis. Conclusions: In neonates, a Bayesian analysis of a trough concentration produces reliable Cmin estimates but is not as accurate in estimating Cmax. Analyzing a peak concentration produces Cmax and Cmin values that overestimate true concentrations. If the goal of monitoring is to ensure sufficiently low troughs, a single-level analysis is reasonable if levels are drawn near the end of the dosing interval, but Cmin predictions based on levels drawn early in the dosing interval should be avoided.

Medicines doi: 10.3390/medicines12020008

Authors: Michael P. Lorenzo Kathleen K. Adams Seth T. Housman

Opioid use in the United States has increased dramatically. Bacterial infections are common among persons who inject drugs (PWID), and there is a disparity in the care these individuals receive. As such, outcomes associated with these infections can be poor. Healthcare providers can address these disparities through optimal pharmacotherapy recommendations and assistance with changing approaches to the management of PWID.

Medicines doi: 10.3390/medicines12020007

Authors: Mahmoud Elshehawy Richel Merin Panicker Alaa Amr Abdelgawad Patrick Anthony Ball Hana Morrissey

Background: Hyponatraemia is a rare but potentially life-threatening complication of terlipressin therapy. Case history: In the current case, a 39-year-old female with decompensated liver cirrhosis (Child-Pugh C) and acute variceal bleeding experienced a precipitous decline in serum sodium—from 136 mmol/L to 115 mmol/L—within 48 h of initiating terlipressin therapy. This was accompanied by marked fluid retention, reduced urine output, and symptoms of confusion and agitation. Laboratory tests confirmed dilutional hyponatraemia, characterized by urinary sodium <20 mmol/L and urine osmolality <100 mOsm/kg, indicating excessive free water reabsorption. Outcomes: The prompt discontinuation of terlipressin, fluid restriction and the cautious administration of hypertonic sodium chloride solution (2.7% NaCl) achieved a gradual normalization of sodium levels and resolution of symptoms. Fluid balance monitoring revealed a marked diuretic response following terlipressin cessation. This case aligns with existing reports, emphasizing the dual vasopressin receptor activity of terlipressin and its capacity to induce hyponatraemia, particularly in cirrhotic patients with preserved renal function and higher baseline sodium levels. Conclusions: This case and a literature review underscored the critical need for early fluid balance monitoring to detect retention. This case highlights the importance of individualized risk assessment, multidisciplinary management, and vigilant sodium correction to avoid complications. Practical recommendations are outlined to aid clinicians in the recognition and management of terlipressin-induced hyponatraemia.

Medicines doi: 10.3390/medicines12010006

Authors: Igor Kelečević Ljubica Gugleta Ana-Marija Vejnović Vesna Mijatović Jovin

Introduction: Novel psychoactive substances (NPSs) are substances not controlled by the United Nations’ 1961 Narcotic Drugs and 1971 Psychotropic Substances convention, which pose a threat to public health. The use of NPSs is growing among recreational drug users. NPSs mimic the effects of the existing illegal drugs; they are used as substitutes for the traditional drugs of use. NPSs are commonly marketed as safe substances. NPS abuse is especially risky among vulnerable individuals, such as children and adolescents. The Aim: This study aims to analyze the knowledge and attitudes of primary and high school students regarding NPSs, determining the frequency and patterns of NPS use, and examine motivational factors for their consumption. Methodology: The questionnaire was employed to primary and secondary school students of the city of Novi Sad in November 2024. The data were analyzed using the methods of descriptive and inferential statistics in the statistical software package JASP 0.18.1.0. Results: A total of 1095 participants took part in the survey (53.6% males and 46.4% females). The age range of participants was 11–18 years (mean age 14.637 years). The majority of pupils lived in the city (70.5%). The most numerous students were students with the highest overall grade. The proportion of students who were familiar with NPSs was 38.3%, while 61.7% of them were not aware of their existence. Living in cities correlated positively with the NPS knowledge. The NPS risk awareness was notably low. The proportion of students who tried one or more novel drugs was 1.918%. Conclusions: The abuse of novel psychoactive substances is a growing concern, particularly among young individuals, requiring increased awareness and education on their risks. Educational systems should provide accurate information to prevent false beliefs, while policymakers must legally regulate new drugs. A coordinated approach is crucial for effective prevention, involving education, media, and support from different organizations. Future studies should focus on the impact of education on attitudes towards NPSs.

Medicines doi: 10.3390/medicines12010005

Authors: Nebojsa Nick Knezevic Aleksandar Sic Samantha Worobey Emilija Knezevic

The placebo effect has been widely documented across various medical conditions, demonstrating its ability to influence both subjective and objective outcomes. Placebo responses can significantly improve symptoms in these different conditions, such as pain, Parkinson’s disease, depression, anxiety, and addiction. Psychological mechanisms, particularly the power of patient expectations, appear to play a central role, with neurobiological evidence supporting the activation of dopamine, endogenous opioids, and endocannabinoids in response to placebo interventions. Studies have demonstrated that placebo injections and more complex procedures, including sham surgeries, can produce therapeutic effects comparable to real treatments, particularly in pain management and neurological disorders. Moreover, placebo responses could be amplified when patients are aware of receiving treatment, as shown by research on open-label placebos and open versus hidden medical treatments. The effectiveness of 0.9% sodium chloride solution as a placebo in clinical trials is debated, with some studies indicating its potential to induce clinical improvements, though it may not be an ideal control in inflammatory pain conditions. Advances in neuroimaging have revealed that placebo treatments trigger tangible biological processes in the brain and body and are supported by psychological and physiological mechanisms that interact, suggesting real biological processes are involved in the observed effects. Overall, the growing understanding of placebo mechanisms suggests that incorporating placebo-based strategies, with patient awareness and appropriate ethical considerations, may offer significant potential for improving patient outcomes, particularly in chronic pain, mental health, and neurological conditions.

Medicines doi: 10.3390/medicines12010004

Authors: Hiep X. Nguyen

Vaccination represents a critical preventive strategy in the current global healthcare system, serving as an indispensable intervention against diverse pathogenic threats. Although conventional immunization relies predominantly on hypodermic needle-based administration, this method carries substantial limitations, including needle-associated fear, bloodborne pathogen transmission risks, occupational injuries among healthcare workers, waste management issues, and dependence on trained medical personnel. Microneedle technology has emerged as an innovative vaccine delivery system, offering convenient, effective, and minimally invasive administration. These microscale needle devices facilitate targeted antigen delivery to epidermal and dermal tissues, where abundant populations of antigen-presenting cells, specifically Langerhans and dermal dendritic cells, provide robust immunological responses. Multiple research groups have extensively investigated microneedle-based vaccination strategies. This transdermal delivery technique offers several advantages, notably circumventing cold-chain requirements and enabling self-administration. Numerous preclinical investigations and clinical trials have demonstrated the safety profile, immunogenicity, and patient acceptance of microneedle-mediated vaccine delivery across diverse immunization applications. This comprehensive review examines the fundamental aspects of microneedle-based immunization, including vaccination principles, transcutaneous immunization strategies, and microneedle-based transdermal delivery—including classifications, advantages, and barriers. Furthermore, this review addresses critical technical considerations, such as treatment efficacy, application methodologies, wear duration, dimensional optimization, manufacturing processes, regulatory frameworks, and sustainability considerations, followed by an analysis of the future perspective of this technology.

Medicines doi: 10.3390/medicines12010003

Authors: Nicholas Pavlatos Pawan Daga Aangi Shah Muhammad Khan Jishanth Mattumpuram

Background: Prosthetic valve thrombosis is a rare but serious complication of mechanical valve replacement. Traditionally, prosthetic valve thrombosis has been managed by surgical intervention; however, there is increasing data to support the use of thrombolytics. Methods: We present a case of a 74-year-old female with a history of rheumatic fever and subsequent mechanical aortic valve replacement on warfarin who presented to the emergency department with disequilibrium and chest pain. Results: She was found to have a subtherapeutic international normalized ratio and thrombosed mechanical aortic valve seen on transthoracic echocardiography, transesophageal echocardiography, and fluoroscopy. Conclusions: She was treated with a low-dose ultraslow alteplase infusion of 25 mg of alteplase administered over 25 h. Post-infusion transthoracic echocardiography immediately following infusion and four months later confirmed resolution of thrombosis.

Medicines doi: 10.3390/medicines12010002

Authors: Yuri Ichihara Maho Okawa Minori Minegishi Hiroaki Oizumi Masahiro Yamamoto Katsuya Ohbuchi Yuki Miyamoto Junji Yamauchi

Introduction: In the central nervous system (CNS), proper interaction between neuronal and glial cells is crucial for the development of mature nervous tissue. Hypomyelinating leukodystrophies (HLDs) are a group of genetic CNS disorders characterized by hypomyelination and/or demyelination. In these conditions, genetic mutations disrupt the biological functions of oligodendroglial cells, which are responsible for wrapping neuronal axons with myelin sheaths. Among these, an amino acid mutation of the ubiquitin-fold modifier conjugating enzyme 1 (UFC1) is associated with HLD14-related disease, characterized by hypomyelination and delayed myelination in the brain. UFC1 is a critical component of the UFMylation system, functioning similarly to E2-conjugating enzymes in the ubiquitin-dependent protein degradation system. Methodology: We describe how a missense mutation in UFC1 (p.Arg23Gln) leads to the aggregation of UFC1 primarily in lysosomes in FBD-102b cells, which are undergoing oligodendroglial cell differentiation. Results: Cells with mutated UFC1 exhibit reduced Akt kinase phosphorylation and reduced expression of differentiation and myelination marker proteins. Consistently, these cells exhibit impaired morphological differentiation with a reduced ability to extend widespread membranes. Interestingly, hesperetin, a citrus flavonoid with known neuroprotective properties, was found to restore differentiation abilities in cells with the UFC1 mutation. Conclusions: These findings indicate that the HLD14-related mutation in UFC1 causes its lysosomal aggregation, impairing its morphological differentiation. Furthermore, the study highlights potential therapeutic insights into the pathological molecular and cellular mechanisms underlying HLD14 and suggests hesperetin as a promising candidate for treatment.

Medicines doi: 10.3390/medicines12010001

Authors: Ayda Awaness Rania Elkeeb Sepehr Afshari Eman Atef

Cystic fibrosis (CF) is a rare genetic disorder commonly affecting multiple organs such as the lungs, pancreas, liver, kidney, and intestine. Our search focuses on the pathophysiological changes that affect the drugs’ absorption, distribution, metabolism, and excretion (ADME). This review aims to identify the ADME data that compares the pharmacokinetics (PK) of different drugs in CF and healthy subjects. The published data highlight multiple factors that affect absorption, such as the bile salt precipitation and the gastrointestinal pH. Changes in CF patients’ protein binding and body composition affected the drug distribution. The paper also discusses the factors affecting metabolism and renal elimination, such as drug–protein binding and metabolizing enzyme capacity. The majority of CF patients are on multidrug therapy, which increases the risk of drug–drug interactions (DDI). This is particularly true for those receiving the newly developed transmembrane conductance regulator (CFTR), as they are at a higher risk for CYP-related DDI. Our research highlights the importance of meticulously evaluating PK variations and DDIs in drug development and the therapeutic management of CF patients.

Medicines doi: 10.3390/medicines11080022

Authors: Abrar-Ahmad Zulfiqar Perla Habchi Ibrahima Amadou Dembele

The journal retracts the article titled “Obesity and Frailty Syndrome in the Elderly: Prospective Study in Primary Care” [...]

Medicines doi: 10.3390/medicines11080021

Authors: Aravind Thavamani Sindhoosha Malay Jasmine Khatana Sujithra Velayuthan Senthilkumar Sankararaman

Introduction: Cyclical vomiting syndrome (CVS) is a recurrent debilitating illness characterized by intense episodes of nausea and emesis with widely varied pharmacological management across the country. Aprepitant is now increasingly used in patients with CVS. The impact of aprepitant as an abortive therapy in the readmission of pediatric patients with CVS is currently unknown. Methodology: We analyzed all pediatric patients with a primary diagnosis of CVS using the ICD-10 code in the Pediatric Health Information System database of the Children’s Hospital Association. We evaluated the demographic data, comorbid conditions, and management details during the inpatient stay. CVS patients who received aprepitant during their inpatient hospitalization were compared with patients without aprepitant use. Seven-day readmission rate for CVS was used as the outcome variable to assess the effectiveness of the aprepitant in aborting an episode. Propensity score matching was used to match the two cohorts. Results: We analyzed 1775 patients of which 96 received aprepitant during the inpatient hospitalization. The aprepitant group had a more severe hospitalization course as evidenced by an increased duration of hospital stay (5 vs. 3 days) and total hospitalization costs ($11,790 vs. $6380). There were no significant differences in the 7-day (17% vs. 16%, p = 0.91) readmission rate and results were not altered by propensity score matching. Conclusions: Aprepitant use as an abortive therapy did not affect the 7-day CVS-related readmission rate. Further prospective studies are needed to explore the role of aprepitant as an abortive agent in the management of CVS in the pediatric population.

Medicines doi: 10.3390/medicines11080020

Authors: Vítor Silva Ricardo Madeira João Joaquim Cristiano Matos

In recent years, the off-label use of medications in sports has increased significantly, primarily driven by psychological and social factors. Athletes frequently misuse drugs without adequate medical supervision, relying on unreliable sources of information, which leads to improper usage and serious health risks. This narrative review analyzes literature from PubMed® (Medline), Scopus®, and Web of Science® databases, focusing on studies up to December 2023, to examine the safety concerns related to off-label drug use in sports. The review presents an overview of the off-label use of pharmacological substances by athletes, focusing on both hormonal and non-hormonal drugs. Hormonal substances such as anabolic steroids and growth hormones, and non-hormonal agents like diuretics and β2-agonists, are frequently abused. These practices are associated with severe side effects, including infections, cardiovascular complications, hormonal imbalances, psychological disorders, dependence, and even cases of death. The study emphasizes the need for stronger regulation, public awareness initiatives, and preventive strategies to mitigate the health risks associated with this growing trend.

Medicines doi: 10.3390/medicines11080019

Authors: Subhas S. Karki Umashankar Das Jan Balzarini Erik De Clercq Hiroshi Sakagami Yoshihiro Uesawa Praveen K. Roayapalley Jonathan R. Dimmock

Background: A series of 3,5-benzylidene-4-piperidones, 1a–n, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. Methods: The bioevaluation of 1a–n was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θA and θB and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, 1a–n were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. Results: A positive correlation was noted between the interplanar angle θA of one of the aryl rings and the adjacent olefinic linkage with IC50 values in the Molt4/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (π) value of the aryl substituents and the IC50 values of the compounds towards the Molt4/C8 and CEM cells. The dienones in series 1 demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. Conclusions: The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents.

Medicines doi: 10.3390/medicines11070018

Authors: Jovan Javorac Dejan Živanović Biljana Zvezdin Vesna Mijatović Jovin

The primary objectives of asthma management during pregnancy are to achieve adequate symptom control, reduce the risk of acute exacerbations, and maintain normal pulmonary function, all of which contribute to ensuring the health and well-being of both the mother and the baby. The Global Initiative for Asthma (GINA) recommends that pregnant women with asthma continue using asthma medications throughout pregnancy, as the benefits of well-controlled asthma for both the mother and fetus outweigh the potential risks of medication side effects, poorly controlled asthma, and exacerbations. The classification of asthma medications by the US Food and Drug Administration (FDA) into categories A, B, C, D, and X is no longer applied. Instead, the potential benefits and risks of each medication during pregnancy and lactation are considered individually. The use of medications to achieve good asthma control and prevent exacerbations during pregnancy is justified, encompassing inhaled corticosteroids (ICS), some leukotriene receptor antagonists (LTRA), short-acting beta-2 agonists (SABA), long-acting beta-2 agonists (LABA), short-acting muscarinic antagonists (SAMA), long-acting muscarinic antagonists (LAMA), and, recently, biological therapies, even in the absence of definitive safety data during pregnancy.

Medicines doi: 10.3390/medicines11070017

Authors: Jamie Thygerson Dallin Oyler Jackson Thomas Brandon Muse Benjamin D. Brooks Jessica E. Pullan

Nausea and vomiting during pregnancy (NVP), particularly its severe form, Hyperemesis gravidarum (HG), affects up to 70% of pregnancies and significantly impacts the quality of life for those with the condition as well as generates a great economic burden, with annual costs exceeding $1.7 billion in the United States. Despite the available treatments targeting neurotransmitters like serotonin and dopamine, many patients experience inadequate relief and suffer from severe side effects, including headaches and dizziness. Recent research has underscored the role of GDF15, a protein mainly produced by the placenta and linked to NVP symptoms. This protein, part of the TGF-β superfamily, has been implicated in appetite and weight regulation and is altered in those with HG due to specific genetic mutations. Addressing the challenges of delivering effective treatments, current innovations focus on targeting GDF15 to reduce symptoms while ensuring fetal safety. Promising therapeutic strategies include non-IgG immunotherapies, small peptide and molecule antagonists, and novel administration methods such as transdermal patches. These approaches aim to optimize dosage and reduce adverse effects. The effective development and testing of these treatments necessitate advanced animal models that closely resemble human pregnancy physiology, highlighting the need for further research and funding. This ongoing research holds significant potential to improve the clinical outcomes for HG patients and decrease the economic impact on healthcare systems, urging a dedicated response from the scientific and medical communities to advance these promising treatments.

Medicines doi: 10.3390/medicines11070016

Authors: Justin Bell Adam Bindelglass Jennifer Morrone Sherwin Park Ana Costa Sergio Bergese

Postoperative nausea and vomiting (PONV) is a common complication of ambulatory surgery, leading to numerous deleterious effects such as decreased patient satisfaction, prolonged recovery unit stays, and rarely, more serious complications such as aspiration pneumonia or wound dehiscence. In this paper, we present a narrative review of the literature regarding common risk factors for PONV including patient factors, surgical factors, and anesthetic factors. We then will review anesthetic techniques and antiemetic drugs demonstrated to mitigate the risk of PONV. Finally, we discuss the potential economic benefits of PONV prophylaxis in the perioperative ambulatory setting.

Medicines doi: 10.3390/medicines11070015

Authors: Ola A. Al-Ewaidat Moawiah M. Naffaa

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic condition characterized by an unpredictable course and a wide spectrum of manifestations varying in severity. Individuals with SLE are at an increased risk of cerebrovascular events, particularly strokes. These strokes manifest with a diverse range of symptoms that cannot be solely attributed to conventional risk factors, underscoring their significance among the atypical risk factors in the context of SLE. This complexity complicates the identification of optimal management plans and the selection of medication combinations for individual patients. This susceptibility is further complicated by the nuances of neuropsychiatric SLE, which reveals a diverse array of neurological symptoms, particularly those associated with ischemic and hemorrhagic strokes. Given the broad range of clinical presentations and associated risks linking strokes to SLE, ongoing research and comprehensive care strategies are essential. These efforts are critical for improving patient outcomes by optimizing management strategies and discovering new medications. This review aims to elucidate the pathological connection between SLE and strokes by examining neurological manifestations, risk factors, mechanisms, prediction and prevention strategies, management plans, and available research tools and animal models. It seeks to explore this medical correlation and discover new medication options that can be tailored to individual SLE patients at risk of stroke.

Medicines doi: 10.3390/medicines11070014

Authors: Qingyuan Yu Xian Zhou Rotina Kapini Anthony Arsecularatne Wenting Song Chunguang Li Yang Liu Junguo Ren Gerald Münch Jianxun Liu Dennis Chang

Cytokine storm (CS) is the main driver of SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) in severe coronavirus disease-19 (COVID-19). The pathological mechanisms of CS are quite complex and involve multiple critical molecular targets that turn self-limited and mild COVID-19 into a severe and life-threatening concern. At present, vaccines are strongly recommended as safe and effective treatments for preventing serious illness or death from COVID-19. However, effective treatment options are still lacking for people who are at the most risk or hospitalized with severe disease. Chinese herbal medicines have been shown to improve the clinical outcomes of mild to severe COVID-19 as an adjunct therapy, particular preventing the development of mild to severe ARDS. This review illustrates in detail the pathogenesis of CS-involved ARDS and its associated key molecular targets, cytokines and signalling pathways. The therapeutic targets were identified particularly in relation to the turning points of the development of COVID-19, from mild symptoms to severe ARDS. Preclinical and clinical studies were reviewed for the effects of Chinese herbal medicines together with conventional therapies in reducing ARDS symptoms and addressing critical therapeutic targets associated with CS. Multiple herbal formulations, herbal extracts and single bioactive phytochemicals with or without conventional therapies demonstrated strong anti-CS effects through multiple mechanisms. However, evidence from larger, well-designed clinical trials is lacking and their detailed mechanisms of action are yet to be well elucidated. More research is warranted to further evaluate the therapeutic value of Chinese herbal medicine for CS in COVID-19-induced ARDS.

Medicines doi: 10.3390/medicines11060013

Authors: Michael Cieza-Terrones José C. De La Flor Christian Requejo Daniel Villa Jacqueline Apaza Pablo Rodríguez-Doyágüez Rocío Zamora Carmen Asato-Higa David Rivera-Estrella Antonio Carrasco-Yalán

Background: Idiopathic hypereosinophilic syndrome (IHES) is a disorder characterized by abnormal and persistent peripheral blood hypereosinophilia (eosinophil count ≥ 1.5 × 109/L and ≥10% eosinophils) with duration ≥ 6 months, associated organ damage, and/or dysfunction attributable to tissue eosinophilic infiltrate of unknown cause. IHES affects different organs such as the heart, lungs, nervous system, and skin, with renal involvement being rare in this condition. Case Presentation: We present a case of a young patient with IHES and immune complex-mediated membranoproliferative glomerulonephritis with nephrotic syndrome, as a rare renal manifestation. We discuss the clinical, analytical, and histopathologic renal and hematologic features, comparing them with other reported cases in the literature.

Medicines doi: 10.3390/medicines11060012

Authors: Adi Kurniawan Sukamto Koesnoe Evy Yunihastuti Hamzah Shatri

Background: The COVID-19 pandemic has led to high mortality rates. There have been reports of hypersensitivity reactions with mild to severe symptoms. The COVID-19 vaccine provocation test is a vaccination protocol for individuals with a history of hypersensitivity. This study aims to determine the benefits of COVID-19 vaccine provocation tests in patients with a history of hypersensitivity reactions to COVID-19 vaccines and its influencing factors. Objective: To determine the incidence, severity, outcome of hypersensitivity reactions, and success of the COVID-19 vaccine provocation test. Methods: A retrospective cohort study was conducted, using subjects taken from medical record data at the RSCM who had received COVID-19 vaccination with a history of hypersensitivity. Data was taken from the COVID-19 vaccination records at the RSCM, BPJS Health Primary Care application. Results: From a total of 29,036 doses of the COVID-19 vaccine, 44 patients experienced hypersensitivity reactions. As many as 38.64% did not continue vaccination, 2.27% experienced mild hypersensitivity, and 59.44% were successfully vaccinated. Conclusions: People with a history of hypersensitivity reactions to COVID-19 vaccines can still receive subsequent COVID-19 vaccinations at healthcare facilities equipped with anaphylaxis kits and immunology allergists.

Medicines doi: 10.3390/medicines11050011

Authors: Hiroshi Sakagami

The journal Medicines (ISSN 2305-6320) was launched in 2014 [...]

Medicines doi: 10.3390/medicines11050010

Authors: Marat Syzdykbayev Maksut Kazymov Marat Aubakirov Aigul Kurmangazina Ernar Kairkhanov Rustem Kazangapov Zhanna Bryzhakhina Saule Imangazinova Anton Sheinin

Background: Traumatic brain injury manifests itself in various forms, ranging from mild impairment of consciousness to severe coma and death. Traumatic brain injury remains one of the leading causes of morbidity and mortality. Currently, there is no therapy to reverse the effects associated with traumatic brain injury. New neuroprotective treatments for severe traumatic brain injury have not achieved significant clinical success. Methods: A literature review was performed to summarize the recent interdisciplinary findings on management of traumatic brain injury from both clinical and experimental perspective. Results: In the present review, we discuss the concepts of traditional and new approaches to treatment of traumatic brain injury. The recent development of different drug delivery approaches to the central nervous system is also discussed. Conclusions: The management of traumatic brain injury could be aimed either at the pathological mechanisms initiating the secondary brain injury or alleviating the symptoms accompanying the injury. In many cases, however, the treatment should be complex and include a variety of medical interventions and combination therapy.

Medicines doi: 10.3390/medicines11040009

Authors: Rolf Teschke Gaby Danan

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin–clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim–sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.

Medicines doi: 10.3390/medicines11040008

Authors: Nathan T. Kolasinski Eric A. Pasman Cade M. Nylund Patrick T. Reeves Daniel I. Brooks Katerina G. Lescouflair Steve B. Min

Eosinophilic esophagitis (EoE) disease activity can be caused by treatment non-adherence. Medication possession ratio (MPR) is an established metric of medication adherence. A higher MPR correlates with better outcomes in several chronic diseases, but MPR has not been investigated with respect to EoE. A retrospective cohort study was performed using an established EoE registry for the years 2005 to 2020. Treatment periods were identified, MPRs were calculated, and medical records were assessed for histologic remission (<15 eos/hpf), dysphagia, food impaction, stricture occurrence, and esophageal dilation that corresponded to each treatment period. In total, 275 treatment periods were included for analysis. The MPR in the histologic remission treatment period group was 0.91 (IQR 0.63–1) vs. 0.63 (IQR 0.31–0.95) for the non-remission treatment period group (p < 0.001). The optimal MPR cut-point for histologic remission was 0.7 (Sen 0.66, Spec 0.62, AUC 0.63). With MPRs ≥ 0.7, there were significantly increased odds of histologic remission (odds ratio 3.05, 95% confidence interval 1.79–5.30) and significantly decreased odds of dysphagia (OR 0.27, 95% CI 0.15–0.45), food impaction (OR 0.26, 95% CI 0.11–0.55), stricture occurrence (OR 0.52 95% CI 0.29–0.92), and esophageal dilation (OR 0.29, 95% CI 0.15–0.54). Assessing MPR before repeating an esophagogastroduodenoscopy may decrease unnecessary procedures in the clinical management of eosinophilic esophagitis.

Medicines doi: 10.3390/medicines11030007

Authors: Jeong Man Cho Sojung Sun Eunji Im Hyunwon Yang Tag Keun Yoo

Background: This study investigated how the expression of heat shock protein 27 (HSP27), cellular FLICE-like inhibitory protein (cFLIP), and clusterin (CLU) affects the progression of cancer cells and their susceptibility to doxazosin-induced apoptosis. By silencing each of these genes individually, their effect on prostate cancer cell viability after doxazosin treatment was investigated. Methods: PC-3 prostate cancer cells were cultured and then subjected to gene silencing using siRNA targeting HSP27, cFLIP, and CLU, either individually, in pairs, or all together. Cells were then treated with doxazosin at various concentrations and their viability was assessed by MTT assay. Results: The study found that silencing the CLU gene in PC-3 cells significantly reduced cell viability after treatment with 25 µM doxazosin. In addition, the dual silencing of cFLIP and CLU decreased cell viability at 10 µM doxazosin. Notably, silencing all three genes of HSP27, cFLIP, CLU was most effective and reduced cell viability even at a lower doxazosin concentration of 1 µM. Conclusions: Taken together, these findings suggest that the simultaneous silencing of HSP27, cFLIP, and CLU genes may be a potential strategy to promote apoptosis in prostate cancer cells, which could inform future research on treatments for malignant prostate cancer.

Medicines doi: 10.3390/medicines11030006

Authors: Subrata Deb Robert Hopefl Anthony Allen Reeves Dena Cvetkovic

Pharmacogenomics (PGx) can facilitate the transition to patient-specific drug regimens and thus improve their efficacy and reduce toxicity. The aim of this study was to evaluate the overlap of PGx classification for drug absorption, distribution, metabolism, and elimination (ADME)-related genes in the U.S. Food and Drug Administration (FDA) PGx labeling and in the Clinical Pharmacogenetics Implementation Consortium (CPIC) database. FDA-approved drugs and PGx labeling for ADME genes were identified in the CPIC database. Drugs were filtered by their association with ADME (pharmacokinetics)-related genes, PGx FDA labeling class, and CPIC evidence level. FDA PGx labeling was classified as either actionable, informative, testing recommended, or testing required, and varying CPIC evidence levels as either A, B, C, or D. From a total of 442 ADME and non-ADME gene–drug pairs in the CPIC database, 273, 55, and 48 pairs were excluded for lack of FDA labeling, mixed CPIC evidence level provisional classification, and non-ADME gene–drug pairs, respectively. The 66 ADME gene–drug pairs were classified into the following categories: 10 (15%) informative, 49 (74%) actionable, 6 (9%) testing recommended, and 1 (2%) testing required. CYP2D6 was the most prevalent gene among the FDA PGx labeling. From the ADME gene–drug pairs with both FDA and CPIC PGx classification, the majority of the drugs were for depression, cancer, and pain medications. The ADME gene–drug pairs with FDA PGx labeling considerably overlap with CPIC classification; however, a large number of ADME gene–drug pairs have only CPIC evidence levels but not FDA classification. PGx actionable labeling was the most common classification, with CYP2D6 as the most prevalent ADME gene in the FDA PGx labeling. Health professionals can impact therapeutic outcomes via pharmacogenetic interventions by analyzing and reconciling the FDA labels and CPIC database.

Medicines doi: 10.3390/medicines11020005

Authors: Ronald B. Brown Philip Bigelow

Background: Cancer therapeutics have a low success rate in clinical trials. An interdisciplinary approach is needed to translate basic, clinical, and remote fields of research knowledge into novel cancer treatments. Recent research has identified high dietary phosphate intake as a risk factor associated with cancer incidence. A model of tumor dynamics predicted that reducing phosphate levels sequestered in the tumor microenvironment could substantially reduce tumor size. Coincidently, a low-phosphate diet is already in use to help patients with chronic kidney disease manage high serum phosphate levels. Methods: A grounded-theory literature-review method was used to synthesize interdisciplinary findings from the basic and clinical sciences, including oncology, nephrology, nutritional epidemiology, and dietetic research on cancer. Results: Findings of tumor remission associated with fasting and a ketogenic diet, which lower intake of dietary phosphate, support the hypothesis that a low-phosphate diet will reduce levels of phosphate sequestered in the tumor microenvironment and reduce tumor size. Additionally, long-term effects of a low-phosphate diet may reverse dysregulated phosphate metabolism associated with tumorigenesis and prevent cancer recurrence. Conclusions: Evidence in this article provides the rationale to test a low-phosphate diet as a dietary intervention to reduce tumor size and lower risk of cancer recurrence.

Medicines doi: 10.3390/medicines11020004

Authors: Stephanie Trofymenko Randa Kutob Amit Algotar

Background: Obesity is linked to chronic diseases in adults and children. Its prevalence continues to grow in the United States, necessitating the need for healthcare provider training and presenting an opportunity for the education of future medical providers. Despite this need, effectively implementing obesity education into medical school curricula has been challenging. Anti-obesity bias amongst healthcare providers and trainees represents a significant obstacle to the care of patients with obesity. Obesity bias may affect up to 1/3 of medical students. Methods: This study describes the development and preliminary testing of a brief, 2.5 h multi-modality teaching intervention consisting of online, interactive, and independent learning modules for first-year medical students and a patient panel focused on obesity, obesity bias, and motivational interviewing. The participants took Crandall’s anti-fat attitude (AFA) questionnaire before and after an online independent learning module on motivational interviewing and obesity bias. The AFA consists of three subscales (“dislike”, “fear of fat”, and “willpower”). Individual responses were measured using a nine-point Likert-type response format (0 = very strongly disagree; 9 = very strongly agree). An average composite score was calculated for each subscale. Results: Data were analyzed from 103 first-year medical students enrolled at a college of medicine in the southwestern United States in 2022. The AFA mean composite scores decreased significantly, indicating a decrease in explicit anti-obesity attitude bias after completing the online module. This decrease was present in all three domains of fear (4.63 vs. 3.72, p < 0.001), dislike (1.25 vs. 0.88, p < 0.001) and willpower (3.23 vs. 2.31, p < 0.001). Conclusions: Relatively brief educational interventions can positively impact students’ anti-obesity attitudes.

Medicines doi: 10.3390/medicines11010003

Authors: Swagatika Das Praveen K. Roayapalley Hiroshi Sakagami Naoki Umemura Dennis K. J. Gorecki Mohammad Hossain Masami Kawase Umashankar Das Jonathan R. Dimmock

Background: The objective of this study is to find novel antineoplastic agents that display greater toxicity to malignant cells than to neoplasms. In addition, the mechanisms of action of representative compounds are sought. This report describes the cytotoxicity of a number of dimers of 3,5-bis(benzylidene)-4-piperidones against human malignant cells (promyelocytic leukemia HL-60 and squamous cell carcinoma HSC-2, HSC-3, and HSC-4). Methods: Tumor specificity was evaluated by the selectivity index (SI), that is the ratio of the mean CC50 for human non-malignant oral cells (gingival fibroblasts, pulp cells, periodontal ligament fibroblasts) to that for malignant cells. Results: The compounds were highly toxic to human malignant cells. On the other hand, these molecules were less toxic to human non-malignant cells. In particular, a potent lead molecule, 3b, was identified. A QSAR study revealed that the placement of electron-releasing and hydrophilic substituents into the aryl rings led to increases in cytotoxic potencies. The modes of action of a lead compound discovered in this study designated 3b were the activation of caspases-3 and -7, as well as causing PARP1 cleavage and G2 arrest, followed by sub-G1 accumulation in the cell cycle. This compound also depolarized the mitochondrial membrane and generated reactive oxygen species in human colon carcinoma HCT116 cells. In conclusion, this study has revealed that, in general, the compounds described in this report are tumor-selective cytotoxins.

Medicines doi: 10.3390/medicines11010002

Authors: Hye Lim Bae Kyeonghun Jeong Suna Yang Hyeji Jun Kwangsoo Kim Young Jun Chai

Background: Hypoxia is a well-recognized characteristic of the tumor microenvironment of solid cancers. This study aimed to analyze hypoxia-related genes shared by groups based on tumor location. Methods: A total of 9 hypoxia-related pathways from the Kyoto Encyclopedia of Genes and Genomes database or the Reactome database were selected, and 850 hypoxia-related genes were analyzed. Based on their anatomical locations, 14 tumor types were categorized into 6 groups. The group-specific genetic risk score was classified as high- or low-risk based on mRNA expression, and survival outcomes were evaluated. Results: The risk scores in the Female Reproductive group and the Lung group were internally and externally validated. In the Female Reproductive group, CDKN2A, FN1, and ITGA5 were identified as hub genes associated with poor prognosis, while IL2RB and LEF1 were associated with favorable prognosis. In the Lung group, ITGB1 and LDHA were associated with poor prognosis, and GLS2 was associated with favorable prognosis. Functional enrichment analysis showed that the Female Reproductive group was enriched in relation to cilia and skin, while the Lung group was enriched in relation to cytokines and defense. Conclusions: This analysis may lead to better understanding of the mechanisms of cancer progression and facilitate establishing new biomarkers for prognosis prediction.

Medicines doi: 10.3390/medicines11010001

Authors: Cezara Andreea Soysaler Cătălina Liliana Andrei Octavian Ceban Crina Julieta Sinescu

Heart failure (HF) presents an increasingly significant problem as the population ages. The cause of HF plays a significant role in determining treatment options and outcomes. It is worth noting that several studies have identified gender disparities in both morbidity and mortality, which may suggest differing causes of HF. The purpose of this research is to investigate the influence of various factors, including demographics and comorbidities, on ejection fraction (EF). The objectives of this study involve implementing preventive measures, ensuring timely diagnosis, and implementing interventions that target risk factors and specific comorbidities. These efforts aim to improve the prognosis for individuals affected by heart failure. The main method consists of linear regression. The demographic factors under scrutiny are gender and education, while the comorbidities of interest encompass valvulopathy, ischemia, smoking, obesity, high cholesterol, and diabetes. The main results consist of the fact that high education is associated with a 12.8% better EF on average, while among the factors with a negative role analyzed, ischemia is the most harmful, being 12.8% lower on average. Factors with a smaller impact are smoking, obesity, and high cholesterol. Diabetes does not seem to affect EF.

Medicines doi: 10.3390/medicines10120062

Authors: Hiromitsu Kataoka Sayumi Suzuki Yuichi Suzuki Ryota Sato Makoto Sano Satoshi Mogi Atsushi Sakamoto Kenichiro Suwa Yoshihisa Naruse Hayato Ohtani Masao Saotome Mikihiro Shimizu Keiichi Odagiri Yuichiro Maekawa

Background: Malnutrition in cardiovascular disease is associated with poor prognosis, especially in patients with heart failure and acute coronary syndrome (ACS). High bleeding risk is also linked to coronary artery disease prognosis, including ACS. However, whether the extent of malnutrition and high bleeding risk have a cumulative impact on the long-term prognosis of patients with ACS who undergo percutaneous coronary intervention remains unclear. Methods: We analyzed 275 patients with ACS treated with percutaneous coronary intervention. The Controlling Nutritional Status score and Japanese version of the Academic Research Consortium for High Bleeding Risk criteria (J-HBR) were retrospectively evaluated. The primary and secondary outcomes were adjusted using the inverse probability treatment weighting method. Results: The prevalence of moderate or severe malnutrition in this cohort was 16%. Kaplan–Meier analysis showed a significantly higher incidence of major adverse cardiovascular and cerebrovascular events in patients who were moderately or severely malnourished than in those who were not. Notably, the incidence of these major events was similar between severely malnourished patients with J-HBR and those without. Conclusion: Moderate or severe malnutrition has a significant impact on the long-term prognosis of patients with ACS who undergo percutaneous coronary intervention.

Medicines doi: 10.3390/medicines10110061

Authors: Toshiaki Ara Hiroyuki Kitamura

As an alternative to animal use, computer simulations are useful for predicting pharmacokinetics and cardiovascular activities. For this purpose, we constructed a statistical model to simulate the effects of local anesthetic agents. To train the model, animal experiments were performed on 6-week-old male Hartley guinea pigs. Firstly, the guinea pigs’ backs were shaved, then local anesthetic agents were subcutaneously injected, with subsequent stimulation of the anesthetized site with a needle six times at regular intervals. The number of reactions (score value) was counted. In this statistical model, the probability of reacting to needle stimulation was calculated using the elapsed time, type of local anesthetic agent, and presence or absence of adrenaline. Score values were assumed to follow a binomial distribution at the calculated probability. Parameters were estimated using the Bayesian hierarchical model and Hamiltonian Monte Carlo method. The predicted curves using the estimated parameters fitted well the observed animal values. When score values were predicted using randomly generated parameters, the median of duration was similar between animal experiments and simulations (Procaine: 55 min vs. 50 min, Lidocaine: both 60 min, and Mepivacaine: both 85 min). This approach effectively modeled the effects of local anesthetic agents. It is possible to create the simulator using the parameter values estimated in this study.

Medicines doi: 10.3390/medicines10110060

Authors: Chikage Kato Akira Komatsuzaki Sachie Ono Asami Iguchi Kiyoka Arashi Shiho Motoi Mio Susuga

Background: There is a high prevalence of sleep disorders in Japan, and they are a factor in a decreased quality of life. The main objective of this study was to clarify the background factors of sleep disorders that affect sleep duration, such as subjective symptoms and working hours. Methods: We performed a cross-sectional study on the Japanese national statistics data. Answers from a household questionnaire were used to analyze risk factors for decreases in sleep duration. The subjects were a total of 3972 men and women aged 40–59 years, the age group that forms the core of the working population. For the analysis, a univariate analysis (contingency table) between sleep duration (two groups: sleep duration ≥ 6 h and <6 h) and 42 subjective symptoms was carried out. A multivariate analysis (binomial logistic regression) was conducted using sleep duration and subjective health assessment as objective variables, and odds ratios (ORs) adjusted for sex, working hours, and other factors were obtained. Results: The univariate analysis by subjective symptom showed significant ORs for eight symptoms, including poor sleep quality (OR: 2.24), constipation (OR: 2.24), and dizziness (OR: 1.77). In the multivariate analysis, the model with sleep duration as the objective variable showed significantly adjusted ORs for four variables, including constipation (1.72) and poor sleep quality (1.66). The model with subjective health assessment as the objective variable showed significantly adjusted ORs for eight variables, including dizziness (4.18), while poor sleep quality (1.45) was not significant. Conclusions: The present results suggest the presence of subjective symptoms that may be inferred to be related to decreases in sleep duration.

Medicines doi: 10.3390/medicines10110059

Authors: Mallika Chuansangeam Bunyarat Srithan Pattharawin Pattharanitima Pawit Phadungsaksawasdi

Background: Early detection of elderly patients with COVID-19 who are at high risk of mortality is vital for appropriate clinical decisions. We aimed to evaluate the risk factors associated with all-cause in-hospital mortality among elderly patients with COVID-19. Methods: In this retrospective study, the medical records of elderly patients aged over 60 who were hospitalized with COVID-19 at Thammasat University Hospital from 1 July to 30 September 2021 were reviewed. Multivariate logistic regression was used to identify independent predictors of mortality. The sum of weighted integers was used as a total risk score for each patient. Results: In total, 138 medical records of patients were reviewed. Four identified variables based on the odds ratio (age, respiratory rate, glomerular filtration rate and history of stroke) were assigned a weighted integer and were developed to predict mortality risk in hospitalized elderly patients. The AUROC of the scoring system were 0.9415 (95% confidence interval, 0.9033–0.9716). The optimized scoring system was developed and a risk score over 213 was considered a cut-off point for high mortality risk. Conclusions: A simple predictive risk score provides an initial assessment of mortality risk at the time of admission with a high degree of accuracy among hospitalized elderly patients with COVID-19.

Medicines doi: 10.3390/medicines10100058

Authors: Supawadee Suppadungsuk Charat Thongprayoon Jing Miao Pajaree Krisanapan Fawad Qureshi Kianoush Kashani Wisit Cheungpasitporn

The exponential growth of artificial intelligence (AI) has allowed for its integration into multiple sectors, including, notably, healthcare. Chatbots have emerged as a pivotal resource for improving patient outcomes and assisting healthcare practitioners through various AI-based technologies. In critical care, kidney-related conditions play a significant role in determining patient outcomes. This article examines the potential for integrating chatbots into the workflows of critical care nephrology to optimize patient care. We detail their specific applications in critical care nephrology, such as managing acute kidney injury, alert systems, and continuous renal replacement therapy (CRRT); facilitating discussions around palliative care; and bolstering collaboration within a multidisciplinary team. Chatbots have the potential to augment real-time data availability, evaluate renal health, identify potential risk factors, build predictive models, and monitor patient progress. Moreover, they provide a platform for enhancing communication and education for both patients and healthcare providers, paving the way for enriched knowledge and honed professional skills. However, it is vital to recognize the inherent challenges and limitations when using chatbots in this domain. Here, we provide an in-depth exploration of the concerns tied to chatbots’ accuracy, dependability, data protection and security, transparency, potential algorithmic biases, and ethical implications in critical care nephrology. While human discernment and intervention are indispensable, especially in complex medical scenarios or intricate situations, the sustained advancements in AI signal that the integration of precision-engineered chatbot algorithms within critical care nephrology has considerable potential to elevate patient care and pivotal outcome metrics in the future.

Medicines doi: 10.3390/medicines10100057

Authors: Jonathan Lai Erik Almazan Thomas Le Matthew T. Taylor Jihad Alhariri Shawn G. Kwatra

Background: Sarcoidosis is a multisystem granulomatous disease with a wide variety of presentations and clinical courses. Cutaneous manifestations and comorbidities associated with sarcoid prognosis remain understudied. Methods: An EPIC query was run for patients age 18+ at the Johns Hopkins Hospital with a diagnosis of sarcoidosis of the skin according to the ICD-10-CM code D86.3. Data were obtained from a population-based sample of 240 patients from 2015 to 2020. Results: A total of 240 patients were included in the cohort study. The mean (SD) age was 43.76 (11.72) years, and 30% of participants were male; 76.25% of patients identified as black, 19.58% as white, and 4.17% as other. The average age of onset in remissive patients was significantly higher than progressive (47 ± 12 vs. 40 ± 10, p = 0.0005); 49% of black patients experienced progressive sarcoid compared to 32.6% of white patients (p = 0.028). Progressive disease was associated with the presence of lupus pernio (aOR = 3.29, 95% CI, 1.60–6.77) and at least one autoimmune comorbidity (aOR 6.831, 95% CI 1.819–11.843). Conclusions: When controlling for patient demographics, lupus pernio and the presence of at least one autoimmune condition were associated with progressive cutaneous sarcoidosis.

Medicines doi: 10.3390/medicines10100056

Authors: Jobar Bouzan Peter Willschrei Marcus Horstmann

Background: Cognitive impairment is poorly addressed in G8 screening. The aim of the present study was to evaluate the additional value of Mini-Cog© in urogeriatric patients concurrently screened by G8 scores. Methods: Seventy-four consecutive urogeriatric patients aged 75 and above were evaluated. All patients underwent G8 and Mini-Cog© screening. Patients with a G8 score above 14 were considered geriatric “healthy or fit”. A Mini-Cog© from four to five points was considered inconspicuous in screening for cognitive impairment. The additional information of a Mini-Cog© screening during G8 screening was evaluated by looking at G8 “fit and healthy” patients who had conspicuous Mini-Cog© tests and vice versa. Additionally, the results of the neuropsychological subitem “E” of the G8 score were compared with the results of the Mini-Cog© screening. Results: The mean age of the patients was 83 y (min. 75–max. 102). Sixty-one of the patients were males, and 13 were females. Twenty-nine of the patients had a normal G8 score and were considered “healthy or fit”, and 45 were not. Forty-three of the patients had an inconspicuous Mini-Cog©, and 31 had a conspicuous Mini-Cog© of less than four points. The majority of G8 “healthy or fit” patients (n = 24/29) had an inconspicuous Mini-Cog© test. However, of them, five patients had a Mini-Cog© of less than four points, which is suspicious for cognitive disorders. Furthermore, of the 43 patients with a normal G8 subscore in item “E” of two points, 6 patients had a conspicuous Mini-Cog© of less than four points. Conclusions: As shown by the present study, the Mini-Cog© might extend the G8 screening with regard to the detection of cognitive functional impairments that are not detected by the G8 screening alone. It can be easily added to G8 screening.

Medicines doi: 10.3390/medicines10100055

Authors: José C. De La Flor Maribel Monroy-Condori Jacqueline Apaza-Chavez Iván Arenas-Moncaleano Francisco Díaz Xavier E. Guerra-Torres Jorge L. Morales-Montoya Ana Lerma-Verdejo Edna Sandoval Daniel Villa Coca-Mihaela Vieru

Background: Monoclonal immunoglobulin deposition disease (MIDD) includes three entities: light chain deposition disease (LCDD), heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD). The renal presentation can manifest with varying degrees of proteinuria and/or nephrotic syndrome, microhematuria, and often leads to end-stage renal disease. Given the rarity of LHCDD, therapeutic approaches for this condition remain inconclusive, as clinical trials are limited. Case presentation: We report two male patients with underlying monoclonal gammopathy of renal significance (MGRS) associated with LHCDD lesions. Both cases had non-nephrotic proteinuria, moderately impaired renal function, and normal levels of C3 and C4. Light microscopy of the renal biopsies in both patients did not show lesions of nodular glomerulosclerosis. Immunofluorescence showed a staining pattern with interrupted linear IgA-κ in patient #1 and IgA-λ in patient #2 only along the glomerular basement membrane (GBM). Electron microscopy of patient #1 revealed electrodense deposits in the subendothelial and mesangial areas only along the GBM. Discussion: In this case series, we discuss the clinical, analytical, and histopathological findings of two rare cases of LHCDD. Both patients exhibited IgA monoclonality and were diagnosed with monoclonal gammopathy of undetermined significance (MGUS) by the hematology department at the time of renal biopsy. Treatment with steroids and cytotoxic agents targeting the clone cells responsible for the deposition disease resulted in a favorable renal and hematologic response.

Medicines doi: 10.3390/medicines10090054

Authors: Swagatika Das Praveen K. Roayapalley Sarvesh C. Vashishtha Umashankar Das Jonathan R. Dimmock

There is a need for novel antiepileptic agents whose modes of action differ from those of current antiepileptic drugs. The objective of this study was to determine whether 1-diethylamino-3-phenylprop-2-en-1-one (2) could prevent or at least diminish convulsions caused by different mechanisms. This amide afforded protection in the maximal electroshock and subcutaneous pentylenetetrazole screens when given intraperitoneally to both mice and rats. A number of specialized tests in mice were conducted and are explained in the text. They revealed (2) to have efficacy in the 6 Hz psychomotor seizure test, the corneal kindling model, the mouse temporal epilepsy screen and a peripheral neuronal transmission test using formalin. Three screens in rats were undertaken, which revealed that (2) blocked chloride channels, inhibited peripheral neuronal transmission (tested using sciatic ligation and von Frey fibres) and afforded protection in the lamotrigine-resistant kindled rat model. The biodata generated reveal that (2) is an important lead molecule in the quest for novel structures to combat epilepsy.

Medicines doi: 10.3390/medicines10090053

Authors: Hidetaka Hamasaki

Background: Previous research has demonstrated the effectiveness of mindfulness interventions in improving glycemic control. By enhancing attention control, emotion regulation, and self-awareness, mindfulness shows promise in managing the lifestyle factors associated with cardiovascular disease risk. However, the impact of mindfulness on glycemic control in people with diabetes remains unclear. This overview aims to summarize the current evidence of the impact of mindfulness interventions on glycemic control in people with diabetes and propose suggestions for future research. Methods: The author searched electronic databases (PubMed/MEDLINE, Embase, and Cochrane Library) to identify relevant systematic reviews and meta-analyses. The current evidence regarding the effects of mindfulness on glycemic control in people with diabetes was summarized. Results: This review evaluated a total of five systematic reviews and meta-analyses of randomized controlled trials (RCTs). Mindfulness interventions show potential for improving glycemic control as measured by hemoglobin A1c (HbA1c) levels, as well as reducing stress, depression, and anxiety in people with diabetes. Four out of five systematic reviews and meta-analyses reported a significant reduction in HbA1c levels by approximately 0.3%. However, the available studies lacked adequate description of key characteristics of study subjects, such as body mass index, medication, and disease conditions, which are essential for assessing the impact of mindfulness on glycemic control. Moreover, there was significant heterogeneity in the intervention methods employed across the included RCTs. Conclusions: Mindfulness interventions are effective in improving glycemic control in people with type 2 diabetes. However, the overall quality of the reviewed studies raises uncertainty regarding the effectiveness of mindfulness as a treatment for people with diabetes. Further research is necessary to elucidate the biological effects of mindfulness on physiological, neurological, and endocrinological functions in humans.

Medicines doi: 10.3390/medicines10090052

Authors: Jamir Pitton Rissardo Ursula Medeiros Araujo de Matos Ana Letícia Fornari Caprara

Background: Gabapentin (GBP)-induced movement disorders (MDs) are under-recognized adverse drug reactions. They are commonly not discussed with patients, and their sudden occurrence can lead to misdiagnosis. This literature review aims to evaluate the clinical–epidemiological profile, pathological mechanisms, and management of GBP-associated MD. Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction between 1990 and 2023. Results: A total of 99 reports of 204 individuals who developed a MD associated with GBP were identified. The MDs encountered were 135 myoclonus, 22 dyskinesias, 7 dystonia, 3 akathisia, 3 stutterings, 1 myokymia, and 1 parkinsonism. The mean and median ages were 54.54 (SD: 17.79) and 57 years (age range: 10–89), respectively. Subjects were predominantly male (53.57%). The mean and median doses of GBP when the MD occurred were 1324.66 (SD: 1117.66) and 1033 mg/daily (GBP dose range: 100–9600), respectively. The mean time from GBP-onset to GBP-associated MD was 4.58 weeks (SD: 8.08). The mean recovery time after MD treatment was 4.17 days (SD: 4.87). The MD management involved GBP discontinuation. A total of 82.5% of the individuals had a full recovery in the follow-up period. Conclusions: Myoclonus (GRADE A) and dyskinesia (GRADE C) were the most common movement disorders associated with GBP.

Medicines doi: 10.3390/medicines10090051

Authors: Eleni Avramidou Antonios Gkantaras Iasonas Dermitzakis Konstantinos Sapalidis Maria Eleni Manthou Paschalis Theotokis

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease exhibiting stromal fibrosis and follicular cell destruction due to lymphoplasmacytic infiltration. Besides deprecated analyses, histopathological approaches have not employed the use of electron microscopy adequately toward delineating subcellular-level interactions. Methods: Biopsies for ultrastructural investigations were obtained from the thyroids of five patients with HT after a thyroidectomy. Transmission electron microscopy (TEM) was utilized to study representative tissue specimens. Results: Examination indicated interstitial extravasated blood cells and a plethora of plasma cells, based on their subcellular identity landmarks. These antibody-secreting cells were profoundly spotted near follicular cells, fibroblasts, and cell debris entrenched in collagenous areas. Pathological changes persistently affected subcellular components of the thyrocytes, including the nucleus, endoplasmic reticulum (ER), Golgi apparatus, mitochondria, lysosomes, and other intracellular vesicles. Interestingly, significant endothelial destruction was observed, specifically in the larger blood vessels, while the smaller vessels appeared comparatively unaffected. Conclusions: Our TEM findings highlight the immune-related alterations occurring within the thyroid stroma. The impaired vasculature component and remodeling have not been described ultrastructurally before; thus, further exploration is needed with regards to angiogenesis in HT in order to achieve successful prognostic, diagnostic, and treatment-monitoring strategies.

Medicines doi: 10.3390/medicines10090050

Authors: Christina E. Larder Michèle M. Iskandar Stan Kubow

Osteoarthritis (OA) is the most common joint disorder, with a social and financial burden that is expected to increase in the coming years. Currently, there are no effective medications to treat it. Due to limited treatment options, patients often resort to supplements, such as collagen hydrolysates (CHs). CHs are products with low molecular weight (MW) peptides, often between 3 and 6 kDa, and are a result of industrialized processed collagen. Collagen extraction is often a by-product of the meat industry, with the main source for collagen-based products being bovine, although it can also be obtained from porcine and piscine sources. CHs have demonstrated positive results in clinical trials related to joint health, such as decreased joint pain, increased mobility, and structural joint improvements. The bioactivity of CHs is primarily attributed to their bioactive peptide (BAP) content. However, there are significant knowledge gaps regarding the digestion, bioavailability, and bioactivity of CH-derived BAPs, and how different CH products compare in that regard. The present review discusses CHs and their BAP content as potential treatments for OA.

Medicines doi: 10.3390/medicines10080049

Authors: Ana Leticia Fornari Caprara Hossam Tharwat Ali Ahmed Elrefaey Sewar A. Elejla Jamir Pitton Rissardo

An aura is a subjective experience felt in the initial phase of a seizure. Studying auras is relevant as they can be warning signs for people with epilepsy. The incidence of aura tends to be underestimated due to misdiagnosis or underrecognition by patients unless it progresses to motor features. Also, auras are associated with seizure remission after epilepsy surgery and are an important prognostic factor, guiding the resection site and improving surgical outcomes. Somatosensory auras (SSAs) are characterized by abnormal sensations on one or more body parts that may spread to other parts following a somatotopic pattern. The occurrence of SSAs among individuals with epilepsy can range from 1.42% to 80%. The upper extremities are more commonly affected in SSAs, followed by the lower extremities and the face. The most common type of somatosensory aura is paresthetic, followed by painful and thermal auras. In the primary somatosensory auras, sensations occur more commonly contralaterally, while the secondary somatosensory auras can be ipsilateral or bilateral. Despite the high localizing features of somatosensory areas, cortical stimulation studies have shown overlapping sensations originating in the insula and the supplementary sensorimotor area.

Medicines doi: 10.3390/medicines10080048

Authors: Kosuke Karatsu Ryota Tamura Tsubasa Miyauchi Junki Sogano Utaro Hino Takashi Iwama Masahiro Toda

Background: Postoperative trigeminal neuropathy may be seen after surgery for middle and posterior cranial fossa lesions. Although neuropathic pain is a cause of reduced quality of life, global consensus on postoperative pain management is lacking. Mirogabalin besylate is a selective ligand for the α2δ subunit of voltage-gated calcium channels. Although mirogabalin has been used for patients with postherpetic neuralgia and painful diabetic peripheral neuropathy, few reports have assessed the effect on postsurgical neuropathy. In this report, we describe a clinical effectiveness of mirogabalin for trigeminal neuropathy after skull base surgery. Case description: Case 1: A 51-year-old female with right trigeminal schwannoma was operated on via the anterior transpetrosal approach. She had tingling and numb feelings in the right face postoperatively. Mirogabalin was orally administered after the operation. Her continuous facial numbness immediately improved. Case 2: A 55-year-old female with left middle fossa base meningioma extending into the infratemporal fossa was operated on via the infratemporal fossa approach. She had a tingling feeling in the left face postoperatively. Mirogabalin was orally administered for this symptom after the operation, which gradually improved. Conclusions: Mirogabalin may show significant pain relief for patients with trigeminal neuropathy after skull base surgery. Further studies using a larger number of patients are warranted to confirm these findings.

Medicines doi: 10.3390/medicines10080047

Authors: John O. Obasuyi Mathias A. Emokpae

There is an indication of abrupt rise in chronic kidney disease (CKD) in Nigeria and thyroid function involvement has not been sufficiently evaluated. This study determined thyroid gland function among subjects with CKD in Benin City, Nigeria. A total of 184 randomized CKD patients attending specialist clinic and 80 healthy control subjects were recruited for this study. A well-structured questionnaire was used to obtain data on socio-demography. Blood specimens were collected and used for the determination of thyroid function parameters; thyroid stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (fT3), thyroxine (T4), free thyroxine (fT4), thyroid peroxidase antibody (TPO-Abs), thyroid globulin antibody (Tg-Abs) and Deiodinase enzyme Type 1 (D1). SPINA GD and SPINA GT were calculated using Michaelis-Menten model. The CKD was classified into stages using Modification of Drug in Renal Disease (MDRD) formula. Thyroid dysfunctions observed were clinical hyperthyroidism 1 (0.54%), non-thyroidal illness 78 (42.4%), clinical hypothyroidism 11 (6.0%), sub-clinical hyperthyroidism 3 (1.60%), and sub-clinical hypothyroidism 11 (6.0%), while euthyroid were 80 (43.5%). SPINA GD of CKD patients (33.85 ± 10.94) was not significantly different when compared with controls (24.85 ± 1.57), whereas, SPINA GT was significantly higher (p < 0.01) among CKD patients (3.74 ± 0.31) than controls (2.68 ± 0.11). Autoimmune thyroid disease demonstrated by positive Tg-Abs and TPO-Abs were observed among approximately 7.9% of CKD patients. Serum TPO-Abs concentration increased with CKD progression. Thyroid dysfunction is involved in the pathogenesis of CKD patients. The etiologies are multifactorial and immunological mechanisms of autoimmune thyroid disease may be a contributing factor.

Medicines doi: 10.3390/medicines10080046

Authors: Paul W. Davis Pajaree Krisanapan Supawit Tangpanithandee Charat Thongprayoon Jing Miao Mohamed Hassanein Prakrati Acharya Michael A. Mao Iasmina M. Craici Wisit Cheungpasitporn

Background: Contrast-induced encephalopathy (CIE) is an infrequent but serious neurological condition that occurs shortly after the administration of contrast during endovascular and angiography procedures. Patients suffering from chronic kidney disease (CKD) or end-stage kidney disease (ESKD) are considered to be at a higher risk of contrast medium neurotoxicity, due to the delayed elimination of the contrast medium. However, the occurrence and characteristics of CIE in CKD/ESKD patients have not been extensively investigated. Methods: We conducted a comprehensive literature search, utilizing databases such as MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, up to September 2022. The purpose was to identify documented cases of CIE among patients with CKD or ESKD. Employing a random-effects model, we calculated the pooled incidence and odds ratio (OR) of CIE in CKD/ESKD patients. Results: Our search yielded a total of eleven articles, comprising nine case reports and two observational studies. Among these studies, 2 CKD patients and 12 ESKD patients with CIE were identified. The majority of the CKD/ESKD patients with CIE (93%) had undergone intra-arterial contrast media and/or endovascular procedures to diagnose acute cerebrovascular disease, coronary artery disease, and peripheral artery disease. The male-to-female ratio was 64%, and the median age was 63 years (with an interquartile range of 55 to 68 years). In the two observational studies, the incidence of CIE was found to be 6.8% in CKD patients and 37.5% in ESKD patients, resulting in a pooled incidence of 16.4% (95% CI, 2.4%–60.7%) among the CKD/ESKD patients. Notably, CKD and ESKD were significantly associated with an increased risk of CIE, with ORs of 5.77 (95% CI, 1.37–24.3) and 223.5 (95% CI, 30.44–1641.01), respectively. The overall pooled OR for CIE in CKD/ESKD patients was 32.9 (95% CI, 0.89–1226.44). Although dialysis prior to contrast exposure did not prevent CIE, approximately 92% of CIE cases experienced recovery after undergoing dialysis following contrast exposure. However, the effectiveness of dialysis on CIE recovery remained uncertain, as there was no control group for comparison. Conclusions: In summary, our study indicates an association between CIE and CKD/ESKD. While patients with CIE showed signs of recovery after dialysis, further investigations are necessary, especially considering the lack of a control group, which made the effects of dialysis on CIE recovery uncertain.

Medicines doi: 10.3390/medicines10080045

Authors: Mirjam Bonanno Rocco Salvatore Calabrò

Translational neuroscience is intended as a holistic approach in the field of brain disorders, starting from the basic research of cerebral morphology and with the function of implementing it into clinical practice. This concept can be applied to the rehabilitation field to promote promising results that positively influence the patient’s quality of life. The last decades have seen great scientific and technological improvements in the field of neurorehabilitation. In this paper, we discuss the main issues related to translational neurorehabilitation, from basic research to current clinical practice, and we also suggest possible future scenarios.

Medicines doi: 10.3390/medicines10070044

Authors: Yang Lei Jennifer Halasz Kerri L. Novak Stephen E. Congly

Background: High-dose proton pump inhibitor (PPI) therapy, given either intermittently or continuously for non-variceal upper gastrointestinal bleeding (NV-UGIB), is efficacious. Using intermittent PPI for low-risk patients may be cost-saving. Our objective was to estimate the annual cost savings if all low-risk NV-UGIB patients received intermittent PPI therapy. Methods: Patients who presented to hospital in Calgary, Alberta, who received a PPI for NV-UGIB from July 2015 to March 2017 were identified using ICD-10 codes. Patients were stratified into no endoscopy, high-risk, and low-risk lesion groups and further subdivided into no PPI, oral PPI, intermittent intravenous (IV), and continuous IV subgroups. Average length of stay (LOS) in each subgroup and costs were calculated. Results: We identified 4141 patients with NV-UGIBs, (median age 61, 57.4% male). One-thousand two-hundred and thirty-one low-risk patients received continuous IV PPI, with an average LOS of 6.8 days (95% CI 6.2–7.3) versus 4.9 days (95% CI 3.9–5.9) for intermittent IV patients. If continuous IV PPI patients instead received intermittent IV PPI, 3852 patient days and CAD 11,714,390 (2017 CAD)/year could be saved. Conclusions: Using real-world administrative data, we demonstrate that a sizable portion of low-risk patients with NV-UGIB who were given continuous IV PPI if switched to intermittent IV therapy could generate significant potential cost savings.

Medicines doi: 10.3390/medicines10070043

Authors: Tomoyuki Abe Hiroshi Sakagami Shigeru Amano Shin Uota Kenjiro Bandow Yoshihiro Uesawa Shiori U Hiroki Shibata Yuri Takemura Yu Kimura Koichi Takao Yoshiaki Sugita Akira Sato Sei-ichi Tanuma Hiroshi Takeshima

Background. Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound B), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one order of magnitude higher TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

Medicines doi: 10.3390/medicines10070042

Authors: Katsuya Sakai Tsubasa Kawasaki Hiroya Kiminarita Yumi Ikeda

Background and Objectives: This report described two cases with clear longitudinal changes in motor estimation error (difference between the motor imagery and motor execution) and their progression and motor and activities of daily living (ADL) function changes in patients with PD. Materials and Methods: Patient 1 was a 68-year-old man (Hoehn and Yahr [H and Y] stage: IV, diagnosed with PD for 11.8 years) and patient 2 was a 68-year-old woman (H and Y stage: II, diagnosed with PD for 9.6 years). Imagined two-step test (iTST), two-step test (TST), and PD-related assessments (Unified Parkinson’s Disease Rating Scale [UPDRS], and Freezing of Gait Questionnaire [FOGQ]) were assessed at baseline and after 6 months. Motor estimation error was calculated as the iTST distance minus TST distance. Results: In patient 1, motor estimation error was greater after 6 months (baseline: 5.7 [4.8%]/after 6 months: 25.7 cm [26.1%]). Moreover, UPDRS and FOGQ total scores deteriorated after 6 months (UPDRS total: 29/34 point, and FOGQ: 9/16 point). Conversely, in patient 2, motor estimation error did not change notably (−3.6 [7.6%]/−2.5 cm [7.0%]), while UPDRS and FOGQ total scores improved after 6 months (UPDRS total: 17/12 point, and FOGQ: 6/1 point). Conclusions: This report indicated that greater motor estimation error may be associated with declining motor and ADL function and disease progression in patients with PD.

Medicines doi: 10.3390/medicines10070041

Authors: Natapon Rattanamusik Suriyon Uitrakul Atchara Charoenpiriya

Background: The association between Graves’ disease (GD) and serum vitamin D levels has been studied for decades although the results were controversial. Moreover, the difference in vitamin D levels between the different stages of GD is not well studied. Therefore, this study aimed to compare the vitamin D levels between active and remission GD and to investigate the factors affecting vitamin D levels in GD patients. Methods: This cross-sectional study was performed between 1 January to 31 December 2021. The eligible patients were in either the active or remission stage of GD. The demographic and clinical data of the patients willing to participate in the study were collected, as well as their vitamin D levels. Comparisons of continuous parameters between the active and remission groups were performed using the Mann–Whitney U test, while categorical parameters were performed using the Chi-square test. Results: 75 patients were diagnosed with GD, with 54.7% in the active stage. The mean vitamin D level was lower in the active GD group than in the remission GD group (28.23 vs. 31.58 ng/mL, respectively, p-value 0.079). The prevalence of vitamin D deficiency (i.e., serum vitamin D level < 20 ng/mL) in the active GD group was 14.6%, and in the remission GD group was 0% (p-value 0.02). Moreover, there was a significant negative correlation between the serum vitamin D level and serum free T4 level (p-value 0.03). Conclusions: In spite of non-significance, patients with active GD had lower mean vitamin D levels compared to those with remission GD. The prevalence of vitamin D deficiency was significantly higher in the active GD patients. Additionally, a negative correlation between serum vitamin D levels and serum free T4 levels was observed in this study.

Medicines doi: 10.3390/medicines10070040

Authors: E. Scott Sills Samuel H. Wood

Platelet-rich plasma (PRP) is an ‘orthobiologic’ with recognized roles in plastic surgery, musculoskeletal disorders, dentistry, dermatology, and more recently, ‘ovarian rejuvenation’. Intraovarian PRP involves a complex secretome discharged after platelet activation, comprising multiple cytokine mediators delivered surgically to older or inactive ovarian tissue. Loss of oocyte meiotic fidelity and impaired fertilization accompanying advanced maternal age are already managed by IVF, but only with eggs provided by younger donors. However, if the observed effect of rectifying embryo ploidy error can be proven beyond case reports and small series, activated PRP (or its condensed plasma cytokines) would deliver a welcome therapeutic disruption that is difficult to overstate. Because shortcomings in ovarian function are presently addressed mainly by pharmacological approaches (i.e., via recombinant gonadotropins, GnRH analogs, or luteal support), autologous PRP would represent an unusual departure from these interventions. Given the diversity of platelet cargo proteins, the target response of intraovarian PRP is probably not confined to oocytes or follicles. For example, PRP manipulates signal networks driving improved perfusion, HOX regulation, N-glycan post-translational modification, adjustment of voltage-gated ion channels, telomere stabilization, optimization of SIRT3, and ribosome and mitochondria recovery in older oocytes. While multichannel signals operating on various pathways are not unique to reproductive biology, in intraovarian PRP this feature has received little study and may help explain why its standardization has been difficult. Against this background, our report examines the research themes considered most likely to shape clinical practice.

Medicines doi: 10.3390/medicines10070039

Authors: Dora Palčevski Andrej Belančić Ivan Mikuličić Eduard Oštarijaš Robert Likić Oliver Dyar Vera Vlahović-Palčevski

Background: Antimicrobials are some of the most prescribed drugs by junior doctors, but studies suggest most medical graduates feel unprepared for their future prescribing tasks. The aim of the present study was to compare the self-reported preparedness to prudently prescribe antimicrobials of final-year medical students in Croatia in 2015 and 2019. Methods: The same self-reported web-based survey on the preparedness to prescribe antibiotics was used in both 2015 and 2019. All final-year students at all four medical schools in Croatia (Osijek, Rijeka, Split, and Zagreb) were invited to participate in both 2015 and 2019. Preparedness scores were divided into “topic preparedness scores” and “global preparedness scores”. Topic preparedness scores represented the percentage of students at a medical school who felt sufficiently prepared for each topic. They were first established at a medical school level and then at the national level. Global preparedness scores were determined for each student separately and then calculated at the medical school and national levels. Results: The country’s global preparedness score, representing the average proportion of topics in which students felt sufficiently prepared, was slightly higher in 2015 compared with the 2019 results (62.7% vs. 56.5%; p = 0.191). Croatian students reported higher preparedness in 2015 than in 2019 for 25 out of 27 topics included in the survey. The majority of students reported a need for more education on antibiotic use both in 2015 and 2019 (78.0% vs. 83.0%; p = 0.199). Conclusions: Despite increasing antimicrobial stewardship activities in various healthcare settings, medical students who are about to start prescribing antibiotics on their own do not feel sufficiently prepared to do so. Antimicrobial stewardship programs should be designed to incorporate undergraduate medical student education, for instance, as a specific, mandatory course or integrated into other courses, such as clinical pharmacology.

Medicines doi: 10.3390/medicines10070038

Authors: Victor Abiola Adepoju Olanrewaju Oladimeji Olusola Daniel Sokoya

Background: TB is a major cause of morbidity and mortality, with slum residents being disproportionately affected. This study aimed to assess health-seeking behavior among adult residents of slum communities presenting with coughs in Lagos, Nigeria. Methods: A community-based, cross-sectional study was conducted across six urban slums in Nigeria as part of community outreaches to mark World TB Day. A structured, pretested questionnaire was used to capture relevant sociodemographic details and questions regarding symptoms of coughs and related symptoms as well as care-seeking behavior. Data were explored, analyzed, and presented using descriptive statistics. Results: A total of 632 respondents participated in this study. The majority were 25–34 years old (24.7%), male (65.8%), Christian (55.7%), married (73.7%), with secondary education (37.8%), with 3–4 persons per household (41%) and with 1–2 persons per room (44.5%). In total, 26.6% had had a cough for two weeks or more and were considered as presumptive TB patients. Overall, 37.2% of respondents with a cough visited patent proprietary medicine vendors (PPMVs) as the first port of call. Good health-seeking behavior was exhibited by only 36.2% of respondents. In total, 38.9% delayed seeking care from a health facility (government or private) more than one month after the onset of symptoms. None of the factors included in the multivariate analysis showed a significant association with good health-seeking behavior (i.e., visiting government or private hospitals/clinics). Conclusions: The poor health-seeking behavior, delay in seeking TB care and preference for PPMVs emphasizes the need for National tuberculosis programs (NTPs) to further engage these informal providers in TB prevention, diagnosis and treatment services in urban slum communities.

Medicines doi: 10.3390/medicines10060037

Authors: Nina Werkhäuser Ursula Pieper-Fürst Hacer Sahin Antonia Claas Ralph Mösges

Background: Rhinosinusitis is commonly treated with decongestants, analgesics, and local corticosteroids. Phytotherapeutics are also utilised for symptomatic relief, including cineole, the main component of eucalyptus oil. Methods: The current non-interventional, anonymised survey investigated quality of life in participants with rhinosinusitis (with or without additional symptoms of bronchitis) via the German version of a validated quality of life questionnaire (RhinoQol). Overall, 310 subjects administered a cineole preparation (Sinolpan) and 40 subjects applying nasal decongestant were recruited in German pharmacies. Results: Significant improvements in frequency (64.0%), bothersomeness (52.1%), and impact (53.9%) of rhinosinusitis symptoms were reported upon treatment with cineole over a mean treatment period of seven days (p < 0.001 each). The overall treatment efficacy of cineole was evaluated as good or very good by 90.0% of the participants, and the quality of life during work or leisure time improved upon treatment. Six (non-serious) possibly related side effects were reported in four participants who were administered cineole. The tolerability of the treatment was assessed as good or very good by 93.9% of the participants. Conclusions: Cineole can be considered as a safe and well-tolerated rhinosinusitis treatment conferring a clear improvement in quality of life outcomes.

Medicines doi: 10.3390/medicines10060036

Authors: Leonardo Marques da Fonseca Israel Diniz-Lima Marcos André Rodrigues da Costa Santos Tatiany Nunes Franklim Kelli Monteiro da Costa Ariely Costa dos Santos Alexandre Morrot Debora Decote-Ricardo Raphael do Carmo Valente Celio Geraldo Freire-de-Lima Jhenifer Santos dos Reis Leonardo Freire-de-Lima

Cancer cells are characterized by metabolic reprogramming, which enables their survival in of-ten inhospitable conditions. A very well-documented example that has gained attraction in re-cent years and is already considered a hallmark of transformed cells is the reprogramming of carbohydrate metabolism. Such a feature, in association with the differential expression of en-zymes involved in the biosynthesis of glycoconjugates, generically known as glycosyltransfer-ases, contributes to the expression of structurally atypical glycans when compared to those ex-pressed in healthy tissues. The latest studies have demonstrated that glycophenotypic alterations are capable of modulating multifactorial events essential for the development and/or progres-sion of the disease. Herein, we will address the importance of glycobiology in modern medi-cine, focusing on the ability of unusual/truncated O-linked glycans to modulate two complex and essential phenomena for cancer progression: the acquisition of the multidrug resistance (MDR) phenotype and the activation of molecular pathways associated with the epithelial–mesenchymal transition (EMT) process, an event deeply linked with cancer metastasis.

Medicines doi: 10.3390/medicines10060035

Authors: Jamir Pitton Rissardo Ana Leticia Fornari Caprara Maritsa Casares Holly J. Skinner Umair Hamid

Background: Adverse effects of antiseizure medications (ASMs) remain one of the major causes of non-adherence. Cosmetic side effects (CSEs) are among the most commonly reported side effects of ASMs. In this context, alopecia is one of the CSEs that has a high intolerance rate leading to poor therapeutical compliance. Methods: We performed a literature review concerning alopecia as a secondary effect of ASMs. Results: There are 1656 individuals reported with ASM-induced alopecia. Valproate (983), lamotrigine (355), and carbamazepine (225) have been extensively reported. Other ASMs associated with alopecia were cenobamate (18), levetiracetam (14), topiramate (13), lacosamide (7), vigabatrin (6), phenobarbital (5), gabapentin (5), phenytoin (4), pregabalin (4), eslicarbazepine (3), brivaracetam (2), clobazam (2), perampanel (2), trimethadione (2), rufinamide (2), zonisamide (2), primidone (1), and tiagabine (1). There were no reports of oxcarbazepine and felbamate with drug-induced alopecia. Hair loss seen with ASMs was diffuse and non-scarring. Telogen effluvium was the most common cause of alopecia. A characteristic feature was the reversibility of alopecia after ASM dose adjustment. Conclusions: Alopecia should be considered one important adverse effect of ASMs. Patients reporting hair loss with ASM therapy should be further investigated, and specialist consultation is recommended.

Medicines doi: 10.3390/medicines10060034

Authors: Lakshmi Reka Chamari Maheshika Godage Jayantha Wijayabandara Aravinda Siriwardhene

Background: The rhizome of Languas galangal is traditionally used in Sri Lanka for the treatment of skin infections caused by fungi. The aim of the present study was to evaluate the antifungal activity of L. galangal rhizome and to develop a topical antifungal formulation from it. Methods: The dried, powdered rhizome of L. galangal was successively extracted with hexane, dichloromethane, ethyl acetate and methanol using Soxhlet extraction. The agar well diffusion method was used to assess the antifungal activity against Candida albicans and Aspergillus nger. The antifungal activities of the extracts were compared with clotrimazole as the positive control and dimethyl sulfoxide (DMSO) as the negative control. The most active hexane extract was used to prepare the cream. The antifungal activity of the formulated cream was tested. Results: The hexane extract of L. galangal rhizome powder was more effective on C. albicans and A. niger. The hexane extract of L. galangal showed the maximum zone of inhibition against C. albicans and A. niger (20.20 mm ± 0.46, 18.20 mm ± 0.46) compared to the other three extracts, while clotrimazole, which was used as a positive control, produced a larger zone of inhibition (36.10 mm ± 0.65) and dimethyl sulfoxide (DMSO), the negative control, did not produce inhibitory zones. Stability testing of the formulated cream showed a stable and good appearance. Conclusions: The cream developed using the hexane extract showed in vitro antifungal activity against C. albicans and A. niger. Further evaluations on shelf life, stability and safety are required.

Medicines doi: 10.3390/medicines10060033

Authors: Jamir Pitton Rissardo Ana Letícia Fornari Caprara

Background: Fluoroquinolones (FQNs) are related to several central nervous system side effects. This review aims to evaluate the clinical-epidemiological profile, pathophysiological mechanisms, and management of FQNs-associated movement disorders (MDs). Methods: Two reviewers identified and assessed relevant reports in six databases without language restriction between 1988 and 2022. Results: A total of 45 reports containing 51 cases who developed MDs secondary to FQNs were reported. The MDs included 25 myoclonus, 13 dyskinesias, 7 dystonias, 2 cerebellar syndromes, 1 ataxia, 1 tic, and 2 undefined cases. The FQNs reported were ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin, levofloxacin, gemifloxacin, and pefloxacin. The mean and median age were 64.54 (SD: 15.45) and 67 years (range: 25–87 years). The predominant sex was male (54.16%). The mean and median time of MD onset were 6.02 (SD: 10.87) and 3 days (range: 1–68 days). The mean and median recovery time after MD treatment was 5.71 (SD: 9.01) and 3 days (range: 1–56 days). A complete recovery was achieved within one week of drug withdrawal in 80.95% of the patients. Overall, 95.83% of the individuals fully recovered after management. Conclusions: Future cases need to describe the long-term follow-up of the individuals. Additionally, FQN-induced myoclonus should include electrodiagnostic studies.

Medicines doi: 10.3390/medicines10050032

Authors: Abdelaziz Ghanemi Mayumi Yoshioka Jonny St-Amand

Coronavirus disease-2019 (COVID-19) has had and will have impacts on public health and health system expenses. Indeed, not only it has led to high numbers of confirmed COVID-19 cases and hospitalizations, but its consequences will remain even after the end of the COVID-19 crisis. Therefore, therapeutic options are required to both tackle the COVID-19 crisis and manage its consequences during the post COVID-19 era. Secreted protein acidic and rich in cysteine (SPARC) is a biomolecule that is associated with various properties and functions that situate it as a candidate which may be used to prevent, treat and manage COVID-19 as well as the post-COVID-19-era health problems. This paper highlights how SPARC could be of such therapeutic use.

Medicines doi: 10.3390/medicines10050031

Authors: Dimitrios Symeonidis Ismini Paraskeua Athina A. Samara Effrosyni Bompou Alexandros Valaroutsos Maria P. Ntalouka Dimitrios Zacharoulis

Introduction: Primary sclerosing cholangitis sets the scene for several pathologies of both the intrahepatic and the extrahepatic biliary tree. Surgical treatment, when needed, is almost unanimously summarized in the creation of a Roux-en-Y hepaticojejunostomy, a procedure with a relatively high associated failure rate. Presentation of case: A 70-year-old male, diagnosed with primary sclerosing cholangitis, was submitted to a Roux-en-Y hepaticojejunostomy due to a dominant stricture of the extrahepatic biliary tree. Recurrent episodes of acute cholangitis dictated a workup in the direction of a possible stenosis at the level of the anastomosis. The imaging studies were inconclusive while both the endoscopic and the transhepatic approach failed to assess the status of the anastomosis. A laparotomy, with the intent to revise a high suspicion for stenosis hepaticojejunostomy, was decided. Intraoperatively, a decision to assess the hepaticojejunostomy prior to the scheduled surgical revision, via endoscopy, was made. In this direction, an enterotomy was made on the short jejunal blind loop in order to gain luminal access and an endoscope was propelled through the enterotomy towards the biliary enteric anastomosis. Results: The inspection of the anastomosis under direct endoscopic vision showed no evidences of stenosis and averted an unnecessary, under these circumstances, revision of the anastomosis. Conclusions: The surgical revision of a Roux-en-Y hepaticojejunostomy is a highly demanding operation with an increased associated morbidity, and it should be reserved as the final resort in the treatment algorithm. An approach of utilizing surgery to facilitate the endoscopic assessment prior to proceeding to the surgical revision of the anastomosis appears justified.

Medicines doi: 10.3390/medicines10050030

Authors: Esmael Besufikad Belachew Adey Feleke Desta Dinksira Bekele Deneke Bizunesh Dires Fenta Alemwosen Teklehaymanot Alem Abdo Kedir Abafogi Fekade Yerakly Lukas Mesele Bezabih Dareskedar Tsehay Sewasew Eva J. Kantelhardt Tesfaye Sisay Tessema Rawleigh Howe

Background: Breast cancer (BC) is the most common type of cancer in Ethiopia. The incidence of BC is also rising, but the exact figure is still poorly known. Therefore, this study was conducted to address the gap in epidemiological data on BC in southern and southwestern Ethiopia. Materials and Methods: This is a five-year (2015–2019) retrospective study. The demographic and clinicopathological data were collected from biopsy reports of different kinds of breast carcinomas in the pathology department of Jimma University Specialized Hospital and Hawassa University Specialized Referral Hospital. Histopathological grades and stages were conducted using Nottingham grading and TNM staging system, respectively. Collected data were entered and analyzed using SPSS Version-20 software. Results: The mean age of patients at diagnosis was 42.27 (SD = 13.57) years. The pathological stage of most BC patients was stage III, and most of them had tumor sizes greater than 5 cm. Most patients had moderately differentiated tumor grade, and mastectomy was the most common type of surgery at the time of diagnosis. Invasive ductal carcinoma was the most common histological type of BC, followed by invasive lobular carcinoma. Lymph node involvement was seen in 60.5% of cases. Lymph node involvement was associated with tumor size (χ2 = 8.55, p = 0.033) and type of surgery (χ2 = 39.69, p < 0.001). Conclusions: This study showed that BC patients in southern and southwestern Ethiopia displayed advanced pathological stages, relatively young age at diagnosis, and predominant invasive ductal carcinoma histological patterns.

Medicines doi: 10.3390/medicines10050029

Authors: Pierre-Louis Naillon Valentin Flaudias Georges Brousse Catherine Laporte Julien S. Baker Valentin Brusseau Aurélie Comptour Marek Zak Jean-Baptiste Bouillon-Minois Frédéric Dutheil

Background: Cannabis use by physicians can be detrimental for them and their patients. We conducted a systematic review and meta-analysis on the prevalence of cannabis use by medical doctors (MDs)/students. Method: PubMed, Cochrane, Embase, PsycInfo and ScienceDirect were searched for studies reporting cannabis use in MDs/students. For each frequency of use (lifetime/past year/past month/daily), we stratified a random effect meta-analysis depending on specialties, education level, continents, and periods of time, which were further compared using meta-regressions. Results: We included 54 studies with a total of 42,936 MDs/students: 20,267 MDs, 20,063 medical students, and 1976 residents. Overall, 37% had used cannabis at least once over their lifetime, 14% over the past year, 8% over the past month and 1.1 per thousand (‰) had a daily use. Medical students had a greater cannabis use than MDs over their lifetime (38% vs. 35%, p < 0.001), the past year (24% vs. 5%, p < 0.001), and the past month (10% vs. 2%, p < 0.05), without significance for daily use (0.5% vs. 0.05%, NS). Insufficient data precluded comparisons among medical specialties. MDs/students from Asian countries seemed to have the lowest cannabis use: 16% over their lifetime, 10% in the past year, 1% in the past month, and 0.4% daily. Regarding periods of time, cannabis use seems to follow a U-shape, with a high use before 1990, followed by a decrease between 1990 and 2005, and a rebound after 2005. Younger and male MDs/students had the highest cannabis use. Conclusions: If more than a third of MDs tried cannabis at least once in their lifetime, this means its daily use is low but not uncommon (1.1‰). Medical students are the biggest cannabis users. Despite being common worldwide, cannabis use is predominant in the West, with a rebound since 2005 making salient those public health interventions during the early stage of medical studies.

Medicines doi: 10.3390/medicines10040028

Authors: Amane Otaki Atsuko Furuta Kazuhito Asano

Background: Quercetin, a polyphenolic flavonoid found in various plants and foods, is known to have antioxidant, antiviral and anticancer effects. Although quercetin is well known to exert anti-inflammatory and anti-allergic effects, the precise mechanisms by which quercetin favorably modifies the clinical status of allergic diseases, such as allergic rhinitis (AR), remain unclear. The present study examined whether quercetin could modulate the production of the endogenous anti-inflammatory molecule, Clara cell 10-kD protein (CC10), in vitro and in vivo. Methods: Human nasal epithelial cells (1 × 105 cells/mL) were stimulated with 20 ng/mL of tumor necrosis factor-alpha (TNF) in the presence of quercetin for 24 h. CC10 levels in culture supernatants were examined by ELISA. Sprague Dawley rats were sensitised with toluene 2,4-diisocyanate (TDI) by intranasal instillation of 10% TDI in ethyl acetate at a volume of 5.0 μL once daily for five days. This sensitisation procedure was repeated after an interval of two days. The rats were treated with different dosages of quercetin once daily for five days starting on the 5th day following the second sensitization. Nasal allergy-like symptoms induced by the bilateral application of 5.0 μL of 10% TDI were assessed by counting sneezing and nasal-rubbing behaviours for 10 min immediately after the TDI nasal challenge. The levels of CC10 in nasal lavage fluids obtained 6 h after TDI nasal challenge were examined using ELISA. Results: The treatment of cells with low doses of quercetin (<2.5 μM) scarcely affected TNF-induced CC10 production from nasal epithelial cells. However, the ability of nasal epithelial cells to produce CC10 after TNF stimulation significantly increased on treatment with quercetin doses (>5.0 μM). The oral administration of quercetin (>25 mg/kg) for five days significantly increased the CC10 content in nasal lavage fluids and attenuated the nasal symptoms induced by the TDI nasal challenge. Conclusions: Quercetin inhibits AR development by increasing the ability of nasal epithelial cells to produce CC10.

Medicines doi: 10.3390/medicines10040027

Authors: Hiroshi Kusunoki Kazumi Ekawa Masakazu Ekawa Nozomi Kato Keita Yamasaki Masaharu Motone Hideo Shimizu

Background: The rise in antibody titers against the novel coronavirus (SARS-CoV-2) and its duration are considered an important indicator for confirming the effect of a COVID-19 vaccine, and self-paid tests of antibody titer are conducted in many facilities nationwide. Methods: The relationship between the number of days after the second and third dose of vaccines, age, and antibody titer was determined from the medical records of general internal medicine clinics that conducted self-paid testing of the SARS-CoV-2 antibody titer using Elecsys Anti-SARS-CoV-2 S (Roche Diagnostics); the relationship between the number of days after two or more doses of vaccines and antibody titer was also determined. We also examined the antibody titers in cases of spontaneous infection with SARS-CoV-2 after two or more doses of the vaccine. Results: Log-transformed SARS-CoV-2 antibody titers measured within 1 month from the second or third dose of vaccine showed a negative correlation with age (p < 0.05). In addition, the log-transformed antibody titers also showed a negative correlation trend with the number of days after the second dose of vaccine (p = 0.055); however, there were no significant correlations between the log-transformed antibody titers and the number of days after the third dose of vaccine. The median antibody titer after the third vaccination was 18,300 U/mL, more than 10 times the median antibody titer after the second dose of vaccine, of 1185 U/mL. There were also some cases of infection after the third or fourth dose of vaccine, with antibody titers in the tens of thousands of U/ml after infection, but the patients still received further booster vaccinations after the infection. Conclusions: The antibody titers after the third vaccination did not attenuate after a short follow-up period of one month, while they tended to attenuate after the second vaccination. It is considered that many people in Japan received further booster vaccinations after spontaneous infection, even though they already had antibody titers in the tens of thousands of U/mL due to “hybrid immunity” after spontaneous infection following two or more doses of vaccine. The clinical significance of the booster vaccination in this population still needs to be thoroughly investigated and should be prioritized for those with low SARS-CoV-2 antibody titers.

Medicines doi: 10.3390/medicines10040026

Authors: Cezara-Andreea Soysaler Cătălina Liliana Andrei Octavian Ceban Crina-Julieta Sinescu

Hypertension frequently coexists with obesity, diabetes, hyperlipidemia, or metabolic syndrome, anditsassociation with cardiovascular disease is well established. The identification and management of these risk factors is an important part of overall patient management. In this paper, we find the most relevant patterns of hospitalized patients with cardiovascular diseases, consideringaspects of their comorbidities, such as triglycerides, cholesterol, diabetes, hypertension, and obesity. To find the most relevant patterns, several clusterizations were made, playing with the dimensions of comorbidity and the number of clusters. There are three main patient types who require hospitalization: 20% whose comorbidities are not so severe, 44% with quite severe comorbidities, and 36% with fairly good triglycerides, cholesterol, and diabetes but quite severe hypertension and obesity. The comorbidities, such as triglycerides, cholesterol, diabetes, hypertension, and obesity, were observed in different combinations in patients upon hospital admission.

Medicines doi: 10.3390/medicines10040025

Authors: Charat Thongprayoon Pradeep Vaitla Caroline C. Jadlowiec Napat Leeaphorn Shennen A. Mao Michael A. Mao Fahad Qureshi Wisit Kaewput Fawad Qureshi Supawit Tangpanithandee Pajaree Krisanapan Pattharawin Pattharanitima Prakrati C. Acharya Pitchaphon Nissaisorakarn Matthew Cooper Wisit Cheungpasitporn

Background: Better understanding of the different phenotypes/subgroups of non-U.S. citizen kidney transplant recipients may help the transplant community to identify strategies that improve outcomes among non-U.S. citizen kidney transplant recipients. This study aimed to cluster non-U.S. citizen kidney transplant recipients using an unsupervised machine learning approach; Methods: We conducted a consensus cluster analysis based on recipient-, donor-, and transplant- related characteristics in non-U.S. citizen kidney transplant recipients in the United States from 2010 to 2019 in the OPTN/UNOS database using recipient, donor, and transplant-related characteristics. Each cluster’s key characteristics were identified using the standardized mean difference. Post-transplant outcomes were compared among the clusters; Results: Consensus cluster analysis was performed in 11,300 non-U.S. citizen kidney transplant recipients and identified two distinct clusters best representing clinical characteristics. Cluster 1 patients were notable for young age, preemptive kidney transplant or dialysis duration of less than 1 year, working income, private insurance, non-hypertensive donors, and Hispanic living donors with a low number of HLA mismatch. In contrast, cluster 2 patients were characterized by non-ECD deceased donors with KDPI <85%. Consequently, cluster 1 patients had reduced cold ischemia time, lower proportion of machine-perfused kidneys, and lower incidence of delayed graft function after kidney transplant. Cluster 2 had higher 5-year death-censored graft failure (5.2% vs. 9.8%; p < 0.001), patient death (3.4% vs. 11.4%; p < 0.001), but similar one-year acute rejection (4.7% vs. 4.9%; p = 0.63), compared to cluster 1; Conclusions: Machine learning clustering approach successfully identified two clusters among non-U.S. citizen kidney transplant recipients with distinct phenotypes that were associated with different outcomes, including allograft loss and patient survival. These findings underscore the need for individualized care for non-U.S. citizen kidney transplant recipients.

Medicines doi: 10.3390/medicines10030024

Authors: Chan Hum Park Takashi Tanaka Yoshie Akimoto Jin Pyeong Jeon Takako Yokozawa

Background: Hachimijiogan (HJG) and Bakumijiogan (BJG), two derivative prescriptions of Rokumijiogan (RJG), were selected to investigate their renoprotective potential in the 5/6 nephrectomized (5/6Nx) rat model. Methods: Rats were treated with HJG and BJG orally at 150 mg/kg body weight/day once daily for 10 weeks after resection of 5/6 of the renal volume, and their renoprotective effects were compared with 5/6Nx vehicle-treated and sham-operated control rats. Results: Improvements in renal lesions, glomerulosclerosis, tubulointerstitial injury, and arteriosclerotic lesions estimated by histologic scoring indices in the HJG-treated group were compared with those in the BJG-treated group. HJG- and BJG-treated groups ameliorated the renal function parameters. Elevated levels of renal oxidative stress-related biomarkers were reduced, while decreased antioxidant defence systems (superoxide dismutase and the glutathione/oxidized glutathione ratio) were increased in the HJG-treated group rather than the BJG-treated group. In contrast, BJG administration significantly reduced expression of the inflammatory response through oxidative stress. The HJG-treated group showed a decrease in inflammatory mediators through the JNK pathway. To gain a deeper understanding of their therapeutic action, the effects of the main components detected in HJG and BJG were evaluated using the LLC-PK1 renal tubular epithelial cell line, which is the renal tissue most vulnerable to oxidative stress. Corni Fructus and Moutan Cortex-originated compositions afforded important protection against oxidative stress induced by peroxynitrite. Conclusions: From our described and discussed analyses, it can be concluded that RJG-containing prescriptions, HJG and BJG are an excellent medicine for chronic kidney disease. In the future, appropriately designed clinical studies in people with chronic kidney disease are necessary to evaluate the renoprotective activities of HJG and BJG.

Medicines doi: 10.3390/medicines10030023

Authors: Olivier Bruyère Johann Detilleux Jean-Yves Reginster

Objective: The aim of this study was to evaluate the cost-effectiveness of different glucosamine formulations and preparations used for the management of osteoarthritis in Thailand compared with placebo. Methods: We used a validated model to simulate the individual patient Utility score from aggregated data available from 10 different clinical trials. We then used the Utility score to calculate the quality-adjusted life year (QALY) over 3 and 6 months treatment period. We used the public costs of glucosamine products available in Thailand in 2019 to calculate the incremental cost-effectiveness ratio. We separated the analyses for prescription-grade crystalline glucosamine sulfate (pCGS) and other formulations of glucosamine. A cost-effectiveness cut-off of 3.260 USD/QALY was considered. Results: Irrespective of the glucosamine preparation (tablet or powder/capsule), the data show that pCGS is cost-effective compared with placebo over a 3 and 6 months. However, the other glucosamine formulations (e.g., glucosamine hydrochloride) never reached the breakeven point at any time. Conclusions: Our data show that pCGS is cost-effective for the management of osteoarthritis in the Thai context while other glucosamine formulations are not.

Medicines doi: 10.3390/medicines10030022

Authors: Abrar-Ahmad Zulfiqar Ibrahima Amadou Dembele Emmanuel Andres

Introduction: The aim of our study is to evaluate the nutritional status of patients in an acute geriatric unit. Methods: Patients included in the study were hospitalized in an acute geriatric unit over a period of 6 months. The nutritional status of each patient was evaluated with anthropometric measurements (the BMI and MNA scales), and biological measurements (albumin). Frailty was evaluated using three scales: the Fried scale, the CFS and the modified SEGA scale. Results: A total of 359 patients were included, comprising 251 women (70%) with an average age of 85.28 years. The study showed that 102 elderly subjects were considered undernourished according to the BMI scale, 52 subjects were undernourished according to the MNA scale, and 50 subjects were undernourished according to their albumin levels. The relationships between undernutrition and frailty syndrome studied in our work show that elderly subjects who are undernourished according to the BMI and MNA scales are significantly frail according to Fried and Rockwood, whereas those who are undernourished according to their albumin levels are significantly frail according to Fried and the modified SEGA scale. Conclusion: The relationship between undernutrition and the frailty syndrome is close, and their joint screening is necessary, whether on an outpatient or in-hospital basis, in order to prevent negative events related to comorbidities and geriatric syndromes.

Medicines doi: 10.3390/medicines10030021

Authors: Subrata Deb Mohamed Ben-Eltriki Hans Adomat Mei Y. Chin Emma S. Tomlinson Guns

Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administered with abiraterone. The goal of the present study was to understand the effect of dexamethasone on the disposition of abiraterone. Methods: Adult male CD-1 mice were treated with either dexamethasone (80 mg/kg/day) or vehicle for three consecutive days, followed by the administration of a single dose of abiraterone acetate (180 mg/kg) as an oral gavage. Blood samples were collected by tail bleeding at timepoints between 0 to 24 h. Subsequently, abiraterone was extracted from the mouse serum using a neutral pH condition and serum abiraterone levels were determined using a liquid chromatography–mass spectrometry assay. Results: Our results demonstrated that dexamethasone lowered the maximum plasma concentration and area under the curve parameters by approximately five- and ten-fold, respectively. Similar effects were also observed on the plasma half-life and oral clearance parameters. This is the first report of dexamethasone effect on abiraterone disposition in vivo. Conclusions: We conclude that dexamethasone has the potential to reduce the plasma abiraterone level and thus compromise its CYP17A1 inhibitory ability in the procancerous androgen biosynthesis pathway. Thus, use of a higher abiraterone dose may be warranted when used alongside dexamethasone.

Medicines doi: 10.3390/medicines10030020

Authors: Joao Victor Souza-Peres Kimberly Flores Bethany Umloff Michelle Heinan Paul Herscu Mary Beth Babos

A lack of reliable information hinders the clinician evaluation of suspected herb–drug interactions. This pilot study was a survey-based study conceived as a descriptive analysis of real-life experiences with herb–drug interaction from the perspective of herbalists, licensed health-care providers, and lay persons. Reported dietary supplement–drug interactions were evaluated against the resources most commonly cited for the evaluation of potential supplement–drug interactions. Disproportionality analyses were performed using tools available to most clinicians using data from the U.S. Federal Adverse Event Reporting System (FAERS) and the US Center for Food Safety and Applied Nutrition (CFSAN) Adverse Event Reporting System (CAERS). Secondary aims of the study included exploration of the reasons for respondent use of dietary supplements and qualitative analysis of respondent’s perceptions of dietary supplement–drug interaction. While agreement among reported supplement–drug interactions with commonly cited resources for supplement–drug interaction evaluation and via disproportionality analyses through FAERS was low, agreement using data from CAERS was high.

Medicines doi: 10.3390/medicines10030019

Authors: Athanasios Garavelas Panagiotis Mallis Efstathios Michalopoulos Eros Nikitos

Background: The intraovarian administration of autologous platelet-rich plasma (PRP) acts beneficially for the stimulation of follicle production in women presenting different forms of ovarian dysfunction. This pilot study aimed to evaluate and provide significant data regarding the efficacy of PRP to rejuvenate the ovaries. Methods: A total of 253 women aged 22–56 years, were divided into five groups, based on their status. All participants signed for informed consent for the current study. Blood sampling, preparation of PRP and intraovarian infusion of the latter were performed on all participants. The evaluation of PRP efficacy, a two-month follow-up detecting the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-mullerian hormone (AMH), was performed for all participants. For women with advanced ages (>48 years), the restoration and regularity of the menstrual cycle were additionally evaluated. Results: After the two-month follow-up, the majority of the participants presented improvement in their hormonal profiles. Additionally, 17% of the women in this pilot study successfully conceived. The restoration of the menstrual cycle was detected in 15% of the women with advanced ages. Conclusions: Intraovarian infusion of autologous PRP exhibited remarkable evidence and promising results to restore ovarian insufficiency.

Medicines doi: 10.3390/medicines10020018

Authors: Raed Y. Ageeli Sunita Sharma Melissa Puppa Richard J. Bloomer Randal K. Buddington Marie van der Merwe

Background: The intestinal ecosystem, including epithelium, immune cells, and microbiota, are influenced by diet and timing of food consumption. The purpose of this study was to evaluate various dietary protocols after ad libitum high fat diet (HFD) consumption on intestinal morphology and mucosal immunity. Methods: C57BL/6 male mice were fed a 45% high fat diet (HFD) for 6 weeks and then randomized to the following protocols; (1) chow, (2) a purified high fiber diet known as the Daniel Fast (DF), HFD consumed (3) ad libitum or in a restricted manner; (4) caloric-restricted, (5) time-restricted (six hours of fasting in each 24 h), or (6) alternate-day fasting (24 h fasting every other day). Intestinal morphology and gut-associated immune parameters were investigated after 2 months on respective protocols. Results: Consuming a HFD resulted in shortening of the intestine and reduction in villi and crypt size. Fasting, while consuming the HFD, did not restore these parameters to the extent seen with the chow and DF diet. Goblet cell number and regulatory T cells had improved recovery with high fiber diets, not seen with the HFD irrespective of fasting. Conclusion: Nutritional content is a critical determinant of intestinal parameters associated with gut health.

Medicines doi: 10.3390/medicines10020017

Authors: Veronica Gagliardi Giuseppe Gagliardi Francesco Ceccherelli Antonello Lovato

Background: The regulation of microcirculation depends on the dynamic interaction of different factors: the autonomic nervous system plays a pivotal role in the blood flow and acupuncture can modulate it, obtaining different results depending on the site, the frequency, and the intensity of the stimulation. Methods: 18 healthy subjects have been enrolled and have undergone two sessions of electroacupuncture stimulations: one session using high frequency and one with low frequency. Microcirculation has been monitored continuously during stimulation using the laser Doppler method. Results: The microcirculatory parameters have shown a significant difference between high and low-frequency stimulation, suggesting that low-frequency stimulation is more effective for obtaining a vasodilator effect. Discussion: Our results show that low-frequency stimulation can increase the cutaneous microcirculatory flux, without significantly modifying blood pressure and heart rate. The auricular stimulation causes an increase in the activity of the vagus nerve, increasing the cholinergic activity without acting on post-junctional muscarinic receptors. Conclusion: Auricular acupuncture has a significant impact on the regulation of microcirculation.

Medicines doi: 10.3390/medicines10020016

Authors: Adriana Piccolo Francesco Corallo Davide Cardile Michele Torrisi Chiara Smorto Simona Cammaroto Viviana Lo Buono

Patients affected by global aphasia are no longer able to understand, produce, name objects, write and read. It occurs as a result of functional damage of ischemic or hemorrhagic origin affecting the entire peri-silvan region and frontal operculum. Rehabilitation training aims to promote an early intervention in the acute phase. We described a case of a 57-year-old female patient with left intraparenchymal fronto-temporo-parietal cerebral hemorrhage and right hemiplegia. After admission to clinical rehabilitative center, the patient was not able to perform simple orders and she presented a severe impairment of auditory and written comprehension. Eloquence was characterized by stereotypical emission of monosyllabic sounds and showed compromised praxis-constructive abilities. Rehabilitation included a program of Neurologic Music Therapy (NMT), specifically Symbolic Communication Training Through Music (SYCOM) and Musical Speech Stimulation (MUSTIM). Rehabilitative treatment was measured by improved cognitive and language performance of the patient from T0 to T1. Music rehabilitative interventions and continuous speech therapy improve visual attention and communicative intentionality. In order to confirm the effectiveness of data presented, further extensive studies of the sample would be necessary, to assess the real role of music therapy in post-stroke global aphasia.

Medicines doi: 10.3390/medicines10020015

Authors: Jhenifer Santos dos Reis Israel Diniz-Lima Marcos André Rodrigues da Costa Santos Pedro Marçal Barcelos Kelli Monteiro da Costa Raphael do Carmo Valente Lorrane de Souza Chaves Luma Petel de Campos Ariely Costa dos Santos Rafaela Gomes Correia de Lima Debora Decote-Ricardo Alexandre Morrot Jose Osvaldo Previato Lucia Mendonça-Previato Celio Geraldo Freire-de-Lima Leonardo Marques da Fonseca Leonardo Freire-de-Lima

In this article, we discuss the main aspects regarding the recognition of cell surface glycoconjugates and the immunomodulation of responses against the progression of certain pathologies, such as cancer and infectious diseases. In the first part, we talk about different aspects of glycoconjugates and delve deeper into the importance of N-glycans in cancer immunotherapy. Then, we describe two important lectin families that have been very well studied in the last 20 years. Examples include the sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), and galectins. Finally, we discuss a topic that needs to be better addressed in the field of glycoimmunology: the impact of oncofetal antigens on the cells of the immune system. New findings in this area are of great importance for advancement, especially in the field of oncology, since it is already known that cellular interactions mediated by carbohydrate–carbohydrate and/or carbohydrate proteins are able to modulate the progression of different types of cancer in events that compromise the functionality of the immune responses.

Medicines doi: 10.3390/medicines10020014

Authors: Medicines Editorial Office Medicines Editorial Office

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Medicines doi: 10.3390/medicines10010013

Authors: Yapeng Wang Li Li Zhanlan Wei Shan Lu Wenxue Liu Janghui Zhang Junbo Feng Dongjin Wang

Background: Edoxaban is a novel oral anticoagulant which may decrease the risk of stroke and systemic embolism in patients suffering from atrial fibrillation (AF). However, the decreased efficacy of edoxaban versus warfarin for the avoidance of stroke and systemic embolism in AF with creatinine clearance (CrCl) > 95 mL/min has been reported. The purpose of this meta-analysis is to further clarify the safety (major bleeding) and efficacy (stroke or systemic embolism) of edoxaban for AF patients with various CrCl. Methods: A systematic search of studies on edoxaban and warfarin in AF patients related to renal function was conducted in PubMed, Medline, Web of Science databases, EBSCO, Embase, and the Cochrane Central Register of Controlled Trials. In this meta-analysis (protocol number: PROSPERO CRD 42021245512), we included studies that provide specific data on three outcomes: ischemic stroke or systemic embolism (S/SE), bleeding, and all-cause mortality. Results: This meta-analysis enrolled two randomized controlled trials (RCTs) studies and two retrospective studies that enrolled 28,065 patients. According to CrCl, subjects are divided into three groups (CrCl 30–50 mL/min, CrCl 50–95 mL/min, CrCl > 95 mL/min). In AF patients with CrCl 30–50 mL/min, edoxaban 30 mg daily is similar to warfarin in the prevention of ischemic S/SE and all-cause mortality, resulting in lower bleeding rate and better net clinical outcome (ischemic S/SE: hazard ratio (HR), 0.85, 95% confidence interval (CI), 0.19–1.87; all-cause mortality: HR, 0.65, 95% CI, 0.35–1.19; bleeding: HR, 0.75, 95% CI, 0.60–0.93; net clinical outcome: HR, 0.75, 95% CI, 0.63–0.90). In the group of CrCl 50–95 mL/min, the net clinical outcome was more favorable with edoxaban 60 mg daily than warfarin (HR, 0.81, 95% CI: 0.68–0.96), and there was no significant difference between edoxaban 60 mg daily and warfarin in terms of prevention of bleeding, ischemic S/SE, and all-cause mortality. For AF patients with CrCl > 95 mL/min, there was a statistically significant difference in lower bleeding rate between edoxaban 60 mg daily and warfarin (bleeding: HR: 0.70, 95% CI: 0.58–0.84). There was no differential safety in ischemic S/SE, all-cause mortality, and net clinical outcome. Conclusion: Overall, edoxaban was superior to warfarin in terms of net clinical outcome in various groups of CrCl with AF patients. Although there was no significant difference in net clinical outcome between edoxaban and warfarin for AF patients with CrCl > 95 mL/min, edoxaban is not inferior to warfarin in safety and effectiveness in the various levels of CrCl. Edoxaban may be a more effective and safe treatment than warfarin for patients with chronic kidney disease (CKD) who require anticoagulation. More high-quality and long-term clinical research are needed to further estimate the effects of edoxaban.

Medicines doi: 10.3390/medicines10010012

Authors: Nor Fariza Ngah Nor Asiah Muhamad Roslin Azni Abdul Aziz Elias Hussein Mohammad Aziz Salowi Zabri Kamarudin Noor Hisham Abdullah Tahir Aris

Introduction. Cataract is the leading cause of blindness. About 90% of cataract blindness occurs in low- and middle-income countries. The prevalence of blindness and low vision in any country depends on the socioeconomic status, the availability of medical and healthcare facilities, and the literacy of the population. Aim: This paper aims to estimate the cataract surgery rate (CSR) at Pusat Pembedahan Katarak, MAIWP-Hospital Selayang (Cataract Operation Centre), and provide descriptive assessments of the patients who received eye treatments in the center. Methods: The data were retrieved from the clinical database from 2013 to 2016. Information on the patient’s sociodemographic and clinical and treatment history was collected. Results: The cataract surgery rate for 2013 was about 27 and increased to 37.3 in 2014. However, it declined to 25 in 2015 before it resumed to 36 in 2016. For female patients who received eye treatments at Pusat Pembedahan Katarak, MAIWP-Hospital Selayang, the rate was higher (53.7%) compared to male patients (46.3%). The mean duration of cataract surgery from 2013 to 2016 was 21.25 ± 11.071 min. Conclusion: The increased cataract surgery rate for MAIWP-HS through smart partnerships for day care cataract surgery proved that better accessibility makes the short- and long-term strategies for the reduction and prevention of blindness in Malaysia possible to achieve.

Medicines doi: 10.3390/medicines10010011

Authors: Noha Soliman Diaa Mamdouh Aisha Elkordi

Choroidal melanoma is a rare malignant tumour, yet it is the most common primary intra-ocular neoplasm and second on the list of top ten most malignant melanoma sites in the body. Clinical presentation can be non-specific and includes photopsia, floaters, progressive visual field loss, and blurry vision. The tumour is quite often diagnosed clinically during fundus examination; however, the most valued diagnostic tests are A- and B-scan ultrasonography (US). Several factors affect prognosis, including the patient’s age, tumour size, histological features, and presence of metastases. Still, with primary treatment and tight surveillance, around 50% of choroidal melanoma patients metastasise.