Nanosystems-based antifungal agents have emerged as an effective strategy to address issues related to drug resistance, drug release, and toxicity. Among the different materials used for drug delivery, multifunctional polymers have proven to be ideal due to their versatility. This review provides an overview of the various types of nanoparticles used in antifungal drug delivery systems, with a particular emphasis on the types of polymers used. The review focuses on the application of drug delivery systems and the release behavior of these systems. Furthermore, the review summa-rizes the critical physical properties and relevant information utilized in antifungal polymer nanomedicine delivery systems, and briefly discusses the application prospects of these systems.

Background: Although Tuberculosis (TB) is one of the oldest diseases known to mankind, many practitioners are still unaware of various aspects of management of TB including drug resistant TB. To be able to make an impact on the disease burden we need to understand the knowledge, attitude and practices (KAP) of practitioners, both in government and private sector, towards TB case management. Methodology: A random cross-sectional survey of 99 respondents to assess the KAP towards TB case management using a digital semi-structured questionnaire which was pre-tested and administered to allopathic practitioners from across States in North and Central India. Results: 77% responders were government doctors and 23% were private practitioners. Chest physicians accounted for 61% of the responders. 26% of government and 78% of private doctors relied on sources which are difficult to validate for their knowledge on drug resistant TB management. There were large variations seen in knowledge on modes of transmission, standard precautions, extent of drug resistant TB, diagnostics as well as treatment regimen for drug resistant TB. Conclusion: The knowledge of both sector doctors especially amongst private practitioners with respect to the awareness of extent, diagnosis, and treatment and infection control measures for drug resistant TB is suboptimal which translates to poor diagnostic, therapeutic and infection control choices amongst private practitioners. If India has to achieve the targets for TB Elimination by 2025, serious work needs to be done to upgrade the knowledge of the private sector doctors on drug resistant tuberculosis. The Ministry of Health and Family Welfare, GoI needs to have regular educational programs for the private practitioners coupled with awareness campaigns and frequent surveys to assess the knowledge, attitude and practices being followed in the private sector for TB management including drug resistant TB.

Both Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are main injurious cutaneous medication reactions that mostly affect the epidermis and mucus membranes. TEN and SJS affecting nearly 1 or 2/1,000,000 people per year, and can recognized as medical crises since they may be deadly. Mucocutaneous discomfort, hemorrhagic erosions, erythema, and more or less severe epidermal separation that appear as ulcer and patches of dermic loss are their defining characteristics. The sole difference between TEN and SJS at this time is the degree of skin detachment, making them two extremes of a spectrum of severe cutaneous adverse drug reactions (cADRs). In the majority of cases, drugs are considered as the principal reason of SJS/TEN, but herpes simplex virus and Mycoplasma pneumoniae infections are also recognized causes, along with lesser number of cases in which the cause is still unknown. Among the drugs with a "high" likelihood of producing TEN/SJS are carbamazepine (CBZ), trimethoprim-sulfamethoxazole, phenytoin, aminopenicillins, allopurinol, cephalosporins, other sulfonamide antibiotics, quinolones, phenobarbital, and NSAIDs of the oxicam variety. There is strong genetic evidence for SJS and TEN in Han Chinese due to the substantial association between the human leukocyte antigen (HLA-B*1502) and SJS brought on by CBZ. The diagnosis is made mostly based on clinical symptoms and the histological study of a dermal biopsy. Pemphigus vulgaris, bullous pemphigoid, linear IgA dermatosis, paraneoplastic pemphigus, disseminated fixed bullous drug eruption, acute generalized exanthematous pustulosis (AGEP), and staphylococcal scalded skin syndrome (SSSS) are among the differential diagnoses. The management of patients with SJS/TEN is complicated by the high risk of mortality, necessitating early diagnosis, estimation of the SCORTEN prognosis, identification and discontinuation of the causative drug, specialized supportive care, and high-dose injectable Ig therapeutic interventions. The reported fatality rates for SJS are 1-5% on average and 25-35% for TEN; it can be even higher in patients who are elderly or who have a significant amount of epidermal detachment on their skin. More than 50% of TEN patients who survive the disease experience long-term consequences.

Nanotechnology is making significant transformation to our world, especially in healthcare and the treatment of diseases. It is widely used in different medical applications, such as in treatment and detection. Targeting diseased cell with nanomedicines is one of the numerous applications of nanotechnology. Targeted drug delivery systems for delivering various types of drugs to specific sites are such a dynamic area in pharmaceutical biotechnology and nanotechnology. Compared to conventional drugs, nanomedicines have a higher absorption and bioavailability rate, improving efficacy and minimizing side effects. There are several drug delivery systems including metallic nanoparticles, polymers, liposomes, and microspheres, but one of the most important is the niosomes, which are produced by nonionic surfactants. Because of the amphiphilic nature and structure, hydrophilic or hydrophobic drugs can be loaded into niosome structures. Other compounds, including cholesterol, can also be applied to the niosomes' backbone to rigidize the structure. Several variables such as the type of surfactant in niosome production, the preparation method, and the hydration temperature can affect the structure of the niosomes. Nevertheless, in-silico design of drug delivery formulations requires molecular dynamic simulation tools, molecular docking, and ADME (absorption; distribution; excretion; metabolism) properties, which evaluate physicochemical features of formulation and ADME attitudes before synthesis, investigating the interaction between nano-carriers and specific targets. Hence, experimenting in-vitro and in-vivo is essential. In this review, the basic aspects of niosomes are described including their structure, characterization, preparation methods, optimization with in-silico tools, factors affecting their formation, and limitations.

Drug discovery has been initially attributed to coincidence or trial and error where the traditional approach was complex, lengthy, and expensive. Conventional drug discovery methods require the costly random screening of synthesized compounds or natural products. Another downside for this approach is the wide dependency on the experimental use of animals for in vi-vo testing. Currently, in silico modeling has become a vital tool for drug discovery and repurposing, and molecular docking is being used to find the best matching between a ligand and a molecule. Practical application of in silico docking will predict the biomolecular interactions between the drug and the target host. Beauvericin (BEA) is an emerging mycotoxin produced by the entomopathogenic fungus Beauveria bassiana. Originally investigated for its pesticide capability, BEA is now considered as a molecule of interest for its potentially diverse biotechnological applications in the pharmacological industry and the field of medicine. In this manuscript, we will provide an overview of the repurposing of BEA into a potentially superior therapeutic molecule in a broad range of diseases. Furthermore, considerable attention has been given to the fundamental role of in silico techniques to i) further investigate the spectrum of this secondary metabolite and ii) elucidate the pathways of BEA for its promising therapeutic action

With increasing awareness amongst physicians and improved radiological imaging techniques, the peritoneal cavity is increasingly recognized as an important metastatic site in various malignancies. Prognosis of these patients is usually poor as traditional treatment including surgical resection or systemic treatment is relatively ineffective. Intraperitoneal delivery of chemotherapeutic agents is thought to be an attractive alternative as this results in high tumor tissue concentrations with limited systemic exposure. The addition of hyperthermia aims to potentiate the anti-tumor effects of chemotherapy, resulting in the concept of heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal metastases as it was developed about 3 decades ago. With increasing experience, HIPEC has become a safe and accepted treatment offered in many centers around the world. However, standardization of the technique has been poor and results from clinical trials have been equivocal. As a result, the true value of HIPEC in the treatment of peritoneal metastases remains a matter of debate. The current review aims to provide a critical overview of the theoretical concept and preclinical and clinical study results, to outline areas of persisting uncertainty, and to propose a framework to better define the role of HIPEC in the treatment of peritoneal malignancies.

Introduction Tuberculosis is common in Pakistan. Due to various factors including socioeconomic factors, compliance is poor to anti-tuberculosis drugs, leading to resistance. We aim to determine the prevalence of Multidrug resistance (MDR) tuberculosis in Pakistani population.Methods A prospective observational study was conducted from April 1, 2019, to December 31, 2019, in the Pulmonology department of a tertiary care hospital in Pakistan. Culture and sensitivity were assessed using a sputum sample or, in cases of an absent sputum sample, from Broncho alveolar lavage.ResultsApproximately 71.3% percent patients who had tuberculosis were found to be resistant to Isoniazid and around 48.6% did not respond to Rifampin. Multi-drug resistant was found in 29.4% participants.ConclusionMulti-drug resistance tuberculosis is very prevalent in Pakistan, which may increase burden on health care system and may lead to various complications of tuberculosis.

The influence of lignin modification on drug release and pH-dependent releasing behaviour of oral solid dosage form was investigated using three different formulations. The first formulation contains microcrystalline cellulose (MCC101) as excipient and paracetamol as active pharmaceutical ingredient (API). The second formulation includes Alcell lignin and MCC 101 as excipient and paracetamol, and the third formulation consists of carboxylated Alcell lignin, MCC 101 and paracetamol. Direct compaction was carried out in order to prepare the tablets. Lignin can be readily chemically modified due to the existence of different functional groups in its structure. The focus of this investigation is on lignin carboxylation and its influence on paracetamol control release behaviour at varying pH. Results suggest that carboxylated lignin tablets had the highest drug release, which is linked to their faster disintegration and lower tablet hardness.

Objective: To evaluate the status of receiving education on rational drug use, the criteria in medical drug selection, and level of knowledge of dentists working in a dentistry faculty in Turkey. Material and Methods: This was a descriptive study based on a questionnaire. One hundred seventeen (74%) dentists volunteered to participate in the study. The questionnaire consisted of 20 questions investigating sociodemographic features and rational drug use. Results: The mean age of the dentists was 30.8 ± 7.2 years, and 62.4% were men. The mean period of professional experience was 8.9±7.1 years. The most frequently used resources of references while prescribing medicine were Vademecum (medical drug guide) (61.5%), the internet (59.0%), and colleagues (49.6%). The most frequently reported condition described as ‘good’ was drug indications (43.6%). The dentists had a moderate level of information about posology, and administration route (48.7%), pharmacologic features (48.7%), and contraindications (46.2%). The number of dentists who stated that they considered cost while prescribing was low [always (6%), and frequently (15.4%)]. Rational drug use education had been received by 23.9% of the dentists. Conclusions: The dentists were found to have a lack of adequate and effective education on rational use of drugs. Regular and continuous education before and after graduation is a necessity for dentists and for their patients.

Same-day desensitization (SDD) is a procedure in which desensitization to the drug suspected of causing the hypersensitivity reaction (HR) is performed on the same day as the patient's reaction. In rapid drug desensitization (RDD), desensitization to the suspected drug is performed after an allergological study. The aim of the study was to analyze the diagnostic capacity of the allergist in Oncology Day Hospital (ODH) to establish the phenotype of the HR, in the context of SDD, based exclusively on clinical biomarkers. This is a study of patients treated with desensitization on the same day they had a HR. Later an allergological study (clinical history, skin test, risk assessment, serological biomarkers, drug provocation test if applicable) was performed prior to the following administrations. A total of 35 successful SDDs were performed. A high concordance (91.5% of patients) was found between the phenotype suspected by the allergist after the initial assessment of the patient prior to SDD and the final phenotype after subsequent allergological study performed in the Allergy Department. The presence of the allergist at the ODH allows, in addition to initial treatment according to phenotype, desensitization on the day of the reaction. This will lead to personalized and precision allergology.

In this study, a simple machine learning-based quantitative structure-activity relationship (QSAR) model was developed to predict the inhibitory potency (pIC50 values) of FLT3 tyrosine kinase inhibitors, pivotal in treating Acute Myeloid Leukemia (AML). Distinctively, our model leverages an extensive and diverse dataset, 14 times larger than those employed in prior studies within this field, enabling an unparalleled scope of compound analysis. This vast dataset, combined with further exploration of molecular descriptors, enabled predictions of extraordinary precision, covering a broader spectrum of FLT3 inhibitors than was previously possible. The Random Forest Regressor (RFR) algorithm, selected for its superior predictive performance, was trained with 1080 inputs and validated through comprehensive external and internal methods. It achieved an remarkable coefficient of determination (R^2) of 0.941 and a standard deviation of 0.235 on a test set of 270 compounds, highlighting the efficacy of model in predicting FLT3 inhibitory activity. Key molecular descriptors were identified, enhancing our understanding of structural requirements for inhibitor potency. Additionally, we developed a user-friendly computational tool that enables the rapid prediction of pIC50 values. Utilizing this tool, potential FLT3 inhibitors were identified through ligand-based virtual screening. This study represents a major advancement in FLT3 inhibitor discovery by utilizing a simple QSAR-machine learning model. It enables more efficient and precise identification of potential drug candidates at an early stage, promising a faster development of targeted therapies and streamlining the ligand-based drug design process.

The clinical practice implies a research translation that helps the use of scientific data and thera-peutic evidence for patient benefits. This review critically summarizes the potential impact of cannabinoids in concomitance with other drugs in the following chronic diseases as Epilepsy, Au-tism Spectrum Disorders (ASD), Oncology, Multiple Sclerosis, and Chronic Pain. The potential in-teractions can change the predicted clinical outcomes of therapeutic protocols and need to be evaluated. Some of the effects would be additive, synergistic or antagonistic, but can also enroll changes in absorption, distribution, metabolism, particularly via cytochrome P450 (CYP) isoen-zymes (e.g CYP2C9 and CYP3A4) and excretion. For instance, the combination of canna-bis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases plasma concentration of Δ-9-tetrahydrocannabinol (THC) and CBD (CBD). Opposable, rifampic-in, a CYP3A4 inducer, stands out for the approximately 20-40% reduction in plasma THC levels and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Indeed, pharmacokinetic interactions have been also reported with antiseizure drugs. Moreover, pharmacodynamic interactions between cannabinoids and drugs with sympathomimetic effects (eg tachycardia, hypertension), central nervous system depressants (eg drowsiness, ataxia), and anticholinergics (eg tachycardia and drowsiness) are also expected. Even though pending further studies, there is currently clinical evidence supporting drug interaction with cannabinoids, demanding doctors evaluate the risk of drug combinations with cannabinoids. The tables herein provided were designed to facilitate the identification of bi-orelevant interactions that may compromise therapeutic efficacy and toxicity.

Urothelial cell carcinoma (UCC, bladder cancer) remains a difficult to treat malignancy with rising incidence worldwide. In the U.S., UCC is the sixth most incident neoplasm and ~90% of diagnoses are made in those >55 years of age, ~four times more commonly observed in men than women. The most important risk factor for developing bladder cancer is tobacco smoking, which accounts for ∼50% of cases followed by occupational exposure to aromatic amines and ionizing radiation. The standard of care for advanced UCC includes platinum-based chemotherapy and programmed cell death (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors, administered as frontline, second-line, or maintenance therapy. UCC is highly aggressive and remains generally incurable since these cancers are associated with intrinsic and acquired drug resistance. UCC is highly lethal in the metastatic state and characterized by genomic instability, high PD-L1 expression, DNA damage-response mutations, and high tumor mutational burden. Although immune checkpoint inhibitors (ICIs) achieve long-term durable responses in other cancers, their ability to achieve similar results with metastatic UCC (mUCC) is not as well-defined. Here, we discuss the novel therapies to improve the management of mUCC.

Gastro-retentive floating microspheres were developed as a result of the recent advancements in floating delivery systems for drugs (FDDS), which included the uniform dispersion of multiparticulate dosage forms along the GIT. This could lead to more consistent drug absorption and a lower risk of local irritation. Microballoons (MB), a multi-unit extended release with a sphere-shaped cavity encased in a tough polymer shell, have been developed as a dosage form with exceptional buoyancy in the stomach. This preparation for constrained intestinal absorption is made to float on top of gastric acid, that has a relative density lower than 1.By using enteric acrylic polymers and the emulsion solvent diffusion method, microballoons are prepared and filled to drug in one‘s outer polymer casings. Enteric acrylic plastics are used to generate microballoons that are drug-loaded in one‘s external polymer casings and dissipate in a solution of dichloromethane and ethanol. Cavity development in microparticles seems to be particularly correlated with dichloromethane evaporation. Microballoons with a drug distributed or dispersed all through the particle-matrix have the potential for a controlled drug release and float continuously for more than 12 hours in vitro out over the surface of an acidified dissolution medium with surfactant. The drug is released slowly and at the desired rate as the microballoons glide over the components of the stomach, increasing gastro-retention time and lowering fluctuations in plasma concentration.

Sex differences are essential factors in disease etiology and manifestation in many diseases such as cardiovascular disease, cancer, and neurodegeneration (1). The biological influence of sex differences (including genomic, epigenetic, hormonal, immunological, and metabolic differences between males and females) and the lack of biomedical studies considering sex differences in their study design has led to several policies. For example, the National Institute of Health’s (NIH) sex as a biological variable (SABV) and Sex and Gender Equity in Research (SAGER)) policies to motivate researchers to consider sex differences (2). However, drug repurposing, a promising alternative to traditional drug discovery by identifying novel uses for FDA-approved drugs, lacks sex-aware methods that can improve the identification of drugs that have sex-specific responses (1,3–5). Sex-aware drug repurposing methods either select drug candidates that are more efficacious in one sex or deprioritize drug candidates based on if they are predicted to cause a sex-bias adverse event (SBAE), unintended therapeutic effects that are more likely to occur in one sex. Computational drug repurposing methods are encouraging approaches to develop for sex-aware drug repurposing because they can prioritize sex-specific drug candidates or SBAEs at lower cost and time than traditional drug discovery. Sex-aware methods currently exist for clinical, genomic, and transcriptomic information (3,6,7). They have not expanded to other data types, such as DNA variation, which has been beneficial in other drug repurposing methods that do not consider sex (8). Additionally, some sex-aware methods suffer from poorer performance because a disproportionate number of male and female samples are available to train computational methods (3). However, there is development potential for several different categories (i.e., data mining, ligand binding predictions, molecular associations, and networks). Low-dimensional representations of molecular association and network approaches are also especially promising candidates for future sex-aware drug repurposing methodologies because they reduce the multiple hypothesis testing burden and capture sex-specific variation better than the other methods (9,10). Here we review how sex influences drug response, the current state of drug repurposing including with respect to sex-bias drug response, and how model organism study design choices influence drug repurposing validation.

NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and these efforts continue to be con-troversial. Drug repurposing strategies are a promising alternative to de-novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.

Elevated levels of oxidative stress in the corneal epithelium contribute to the progression of dry eye disease pathology. Previous studies have shown that antioxidant therapeutic intervention is a promising avenue to reduce disease burden and slow disease progression. In this study, we evaluated the pharmacological efficacy of Xanthohumol in preclinical models for dry eye disease. Xanthohumol is a naturally occurring prenylated chalconoid that promotes the transcription of phase II antioxidant enzymes. Xanthohumol exerted a dose-response in preventing tert-butylhydroxide-induced loss of cell viability in human corneal epithelial (HCE-T) cells and resulted in a significant increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of the endogenous antioxidant system. Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles (PLGA NP) were cytoprotective against oxidative stress in vitro, and significantly reduced corneal fluorescein staining in the mouse desiccating stress/ scopolamine model for dry eye disease in vivo by reducing oxidative stress-associated DNA damage in corneal epithelial cells. PLGA NP represent a safe and efficacious drug delivery vehicle for hydrophobic small molecules to the ocular surface. Optimization of NP-based antioxidant formulations with the goal to minimize instillation frequency may represent future therapeutic options for dry eye disease and related ocular surface disease.

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the SARS-CoV-2 virus causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top- ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

Endocannbinoids system (ECS) engrossed a considerable interest as potential therapeutic targets in various carcinomas and cancer related conditions alongside with neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations, so in this short review we tried to shed the light over the potential drug interactions of medicinal cannabis. Hitherto, few data have been provided to the healthcare practitioners about the drug-drug interactions of cannabinoids with other prescription medications. In general, cannabinoids are usually well tolerated, but the bidirectional effects may be expected with concomitant administered agents via affected membrane transporters (glycoprotein p, breast cancer resistance proteins) and metabolizing enzymes (Cytochrome P450 and UDP- glucuronosyltransferases). The caveats should be undertaken to closely monitor the responses of cannabis users with certain drugs to guard their safety, especially for the elderly and people with chronic diseases or kidney and liver conditions.

There are dozens of approved, investigational and experimental antiviral agents. Many of these agents cause serious side effects, which can be revealed only after drug administration. Identification of the side effects prior to drug administration is challenging. Here we describe an ex vivo approach for studying immuno- and neuro-modulatory properties of antiviral agents, which could be associated with potential side effects of these therapeutics. The approach combines drug toxicity/efficacy tests and transcriptomics, which is followed by cytokine and metabolite profiling. We demonstrated the utility of this approach with several examples of antiviral agents. We also showed that the approach can utilize different immune stimuli and cell types. It can also include other omics techniques, such as genomics and epigenomics, to allow identification of individual markers associated with adverse reactions to antivirals with immuno- and neuro-modulatory properties.

Tandem mass spectrometry (TMS) has emerged as a critical analytical tool in pharmaceutical sciences, playing a pivotal role in ensuring the rational use of medications. This article explores the applications of TMS across various stages of drug development, quality assurance, and patient care, highlighting its precision and reliability in advancing therapeutic efficacy. TMS facilitates the accurate identification and quantification of drug compounds, ensuring that pharmaceutical products meet high standards of purity and potency. By detecting even trace levels of impurities or contaminants, TMS strengthens the quality control processes critical to patient safety. In the realm of pharmacokinetics and pharmacodynamics, TMS enables detailed monitoring of drug absorption, distribution, metabolism, and excretion (ADME), allowing for a better understanding of drug behavior in the human body. It is also instrumental in therapeutic drug monitoring (TDM), ensuring that medication levels remain within therapeutic windows, thus optimizing dosing regimens and minimizing adverse effects. Additionally, TMS supports personalized medicine approaches by assessing drug interactions and tailoring treatments to individual patients. Through its application in drug discovery, development, and therapeutic monitoring, TMS serves as an indispensable tool for fostering rational medication use, contributing to more effective, safe, and personalized pharmaceutical care.

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, and AP2-associated protein kinase 1. In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of drug candidates to target receptors, providing insight into their potential efficacy. However, it is crucial to consider both the advantages and limitations of these studies and to complement them with experimental validation to ensure the efficacy and safety of identified drug candidates.

Metered Dose Inhalers (MDIs) play a crucial role in managing respiratory diseases, but their effectiveness depends on whether the intended dose is delivered to the target, which can be influenced by various factors. Accurate assessment of MDI performance is crucial for optimizing MDI delivery and ensuring drug efficacy. This study numerically examined the role of evaporation dynamics and dosimetry methods in assessing MDI delivery efficiency to different regions in a mouth-lung model extending to G11. Experimentally determined spray exit speed, applied dose, and droplet size distribution were implemented as the initial/boundary conditions. Large eddy simulations (LES) were used to resolve the transient inhalation flows, and a chemical species model was applied to simulate vapor and temperature variations in the airflow. A multi-component model was used to consider the heat and mass transfer between the droplets and airflow. The model was validated against literature data and applied to evaluate the impact of evaporation on pulmonary drug delivery using MDI, in comparison to inert particles. Three methods were used to quantify deposition: based on droplet count, droplet mass, and the drug carried by the droplets. Results demonstrate that evaporation notably alters the spray droplet size distribution and subsequent deposition patterns. Compared to inert particles, evaporation led to significantly more droplets ranging from 1–5 µm entering the pulmonary region. For a given region, large discrepancies were observed in deposition fraction (DF) using different dosimetry methods. In the lower lung, the count-based DF (33.9%) and mass-based DF (2.4%) differed by more than one order of magnitude, while the drug-based DF fell between them (20.5%). This large difference highlights the need to include evaporation in predictive dosimetry, as well as to use the appropriate method to quantify the delivery efficiency of evaporating droplets.

Background: Medication errors often stem from incomplete or incorrect transfer of drug information during reviews. To enhance medication review processes, a collaborative healthcare team, including a pharmacist in the surgical ward, is essential. This study aimed to identify the frequency and the kind of intentional and unintentional discrepancies related to the prescriptions within two surgical wards. Methods: A prospective observational study was conducted among adult patients admitted to two surgical settings. The patients were selected between May 30th and November 30th, 2021. The study followed a three-phase structure: patient selection, medication review to identify discrepancies and DRPs, and the detection of any such issues in the discharge letter. Results: The most frequent types of discrepancies collected were substitutions (60.9%) for the Endocrinological Surgery and omissions for General Surgery (53.4%). In Endocrinological Surgery, 45.9% of cases exhibited class C drug interactions. In General Surgery, class D drug interactions were predominantly observed (54.1%), with 93.3% attributed to drugs carrying an elevated risk of prolonging the QT interval. Conclusions: Frequently, the medication review process is superficially carried out, introducing errors that may adversely affect patient health. This study explores the potential positive impact of involving the clinical pharmacist in identifying and managing discrepancies and DRPs.

Drugs-drugs interactions(DDI) are entities composed of different chemical substructures (functional groups). In existing methods that predict drug–drug interactions based on the usage of substructures, each node is considered the center of a substructure, and adjacent nodes eventually become centers of similar substructures, resulting in redundancy. Furthermore, the significant differ- ences in structure and properties among compounds can lead to unrelated pairings, making it difficult to integrate information. This heterogeneity negatively affects the prediction results. To address these issues, we propose a drug–drug interaction prediction method based on substructure signature learning (DDI-SSL). This method extracts useful information from local subgraphs surrounding drugs and effectively utilizes substructures to assist in predicting drug side effects. Additionally, a deep clustering algorithm is used to aggregate similar substructures, allowing any individual subgraph to be reconstructed using this set of global signatures. Furthermore, we developed a layer-independent collaborative attention mechanism to model the mutual influence between drugs, generating signal strength scores for each class of drugs to mitigate noise caused by heterogeneity. Finally, we evaluated DDI-SSL on a comprehensive dataset and demonstrated improved performance in DDI prediction compared to state-of-the-art methods.

The study aimed to identify clinical pharmacology patterns of prescribed and taken medications in older cardiovascular patients using electronic health records (EHRs) (n = 704) (2019–2022). Medscape Drug Interaction Checker was used to identify pairwise drug-drug interactions (DDIs). Prevalence rates of DDIs were 73.5% and 68.5% among taken and prescribed drugs, respectively. However, total number of DDIs was significantly higher among prescribed medications compared with the list of taken drugs (p < 0.05). Serious DDIs comprised 16% and 7% of all DDIs among prescribed and taken medications, correspondingly (p < 0.05). Median DDI numbers between prescribed versus taken medications were Me = 2, IQR 0-7 and Me = 3, IQR 0-7 per record, respectively. Prevalence of polypharmacy was significantly higher among prescribed medications compared with taken medications (p < 0.05). Women were taking significantly more drugs and had higher rates of polypharmacy and DDIs (p < 0.05). No sex-related differences were observed in the list of prescribed medications. ICD code U07.1 (COVID-19, virus identified) was associated with the highest median DDI number per record. Further research is warranted to improve EHR structure, patient engagement in reporting adverse drug reactions, and genetic profiling of patients to avoid potentially serious DDIs.

Background: This article evaluates the perception of drug use control and strategies in Valencia City (Spain) in a general and clinical population, in two independent studies. Material and Methods: 1071 people participated. In the Study 1 (n= 924) the entire sample came from general population (GP), and in the Study 2 (n=147), 68 were drug users being treated in an Addictive Behaviors Unit (ABU), and 79 people of the GP. The drug use control perception and strategies in both subgroups were compared. The participants filled in the Drug Use Strategies Scale and a Drug Use Survey. Results: A high level of perception of drug control in GP was obtained (72,7% in the Study 1 and 67,5% in the Study 2), and 32.5% in ABU subgroup. People in the PG and drug users in treatment differ in some control strategies. A predictive profile of the perception of control was obtained for the Study 2. Conclusion: The high degree of perception of controlling drug use in the GP, and partially in drug users being treated, and the specific control strategies reported suggests that moderate use and drug control strategies are a great value alternative to bear in mind compared to abstinence.

Flavonoids comprise a large group of structurally diverse polyphenolic compounds of plant origin and are abundantly found in human diet such as fruits, vegetables, grains, tea, dairy products, red wine and so on. Major classes of flavonoids include flavonols, flavones, flavanones, flavanols, anthocyanidins, isoflavones, and chalcones. Owing to their potential health benefits and medicinal significance, flavonoids are now considered as an indispensable component in a variety of medicinal, pharmaceutical, nutraceutical, and cosmetic preparations. However, flavonoids play a significant role in preventing cardiovascular diseases (CVDs), which could be mainly due to their antioxidant, antiatherogenic, and antithrombotic effects. Epidemiological and in vitro/in vivo evidences of antioxidant effects support the cardioprotective function of dietary flavonoids. Further, the inhibition of LDL oxidation and platelet aggregation following regular consumption of food containing flavonoids and moderate consumption of red wine might protect against atherosclerosis and thrombosis. A study suggests that daily intake of 100 mg of flavonoids through diet may reduce the risk of developing morbidity and mortality due to coronary heart disease (CHD) by approximately 10%. This review summarizes dietary flavonoids with their sources and potential health implications in CVDs including various redox-active cardioprotective (molecular) mechanisms with antioxidant effects. Pharmacokinetic (oral bioavailability, drug metabolism), toxicological and therapeutic aspects of dietary flavonoids are also addressed herein with future directions for the discovery and development of useful drug candidates/ therapeutic molecules.

In 2019, Chinese government implemented the first round of National Centralized Drug Procurement (NCDP) pilot (so-called "4+7" policy) in mainland China, achieved a prominent price reduction of 52% on average for 25 bidding winning products. Under cross-price elasticity theory, the price behavior of pharmaceutical enterprises for policy-related drugs might change. This study used drug purchasing data from the Centralized Drug Procurement Survey in Shenzhen 2019, and applied single-group Interruption Time Series (ITS) design to examine the impact of "4+7" policy on the drug price index (DPI) of policy-related drugs. The ITS analysis showed that the DPI of winning (-0.183 per month, p&lt;0.0001) and non-winning (-0.034 per month, p=0.046) products significantly decreased after the implementation of "4+7" policy. No significant difference was found for the immediate change of DPI for alternative drugs (p=0.537), while a significant decrease in change trend was detected in the post-"4+7" policy period (-0.003 per month, p=0.014). The DPI of the overall policy-related drugs significantly decreased (-0.261 per month, p&lt;0.0001) after "4+7" policy. These findings indicate that the price behavior of pharmaceutical enterprises changed under NCDP policy, while the price linkage effect is still limited. It is necessary to further expand the scope of centralized purchased drugs and strengthen the monitoring of related drugs regarding price change and consumption structure.

Nanoprecipitation by liquid anti-solvent precipitation is one of the most versatile methods to produce pure drug nanoparticles (PDNPs) owing to the ability to optimize the properties of the product. Nevertheless, nanoprecipitation shows broad particle size distribution and low physical stability, leading to high batch-to-batch variability and challenging the bench-to-bedside translation. Microfluidics has emerged as a powerful tool to produce PDNPs in a simple, reproducible, and cost-effective manner with excellent control over NP size. In this work, we designed and fabricated T- and Y-shaped Si-made microfluidics device and used it to produce pure NPs of three kinase inhibitors of different lipophilicity and water-solubility, namely imatinib, dasatinib and tofacitinib, without the use of colloidal stabilizers. PDNPs display sizes in the 90-350 nm range (dynamic light scattering) and a rounded shape (high-resolution scanning electron microscopy). Analysis by X-rays diffraction and differential scanning calorimetry confirmed that this method results in highly amorphous NPs. In addition, we show that the flow rate of solvent, the anti-solvent, and the channel geometry of the device play a key role in the size of the generated NPs.

The development of targeted therapeutics for cancer continues to receive intense research attention as laboratories and pharmaceutical companies seek to develop drugs and technologies that improve treatment efficacy and mitigate harmful side effects. In the aftermath of World War I, it was discovered that mustard gas destroys rapidly dividing cells and could be used to treat cancer. Since then, chemotherapy has remained a predominant treatment for cancer; however, the destruction of dividing cells throughout the body yields devastating side effects including off-target damage of the digestive tract, bone marrow, skin, and reproductive tract. Furthermore, the high mutation rate of cancerous cells often renders chemotherapy ineffective long-term. Therapies with improved specificity, localization, and efficacy are redefining cancer treatment. Herein, we define and summarize the principal advancements in targeted cancer treatment and briefly comment on the march towards personalized medicine in the treatment of human cancer.

There are guidelines on lactation following maternal analgo-sedative exposure, but these do not consider the effect of maternal fasting, nor fluid abstention on human milk macronutrient composition. We therefore performed a structured search (PubMed) on ‘human milk composition’ and screened title, abstract and full paper on ‘fasting’ or ‘abstention’ and ‘macronutrient composition’ (lactose, protein, fat, solids, triglycerides, cholesterol). This resulted in 6 papers and one abstract related to religious fasting (n=129 women) and observational studies in lactating women (n=23, healthy volunteers, fasting). These data reflect two different ‘fasting’ patterns: an acute (18-25h) model in 71 (healthy volunteers, Yom Kippur/Ninth of Av) women and a chronic fasting (Ramadan) model in 81 women. Changes were most related to electrolytes and were moderate, with almost no changes in macronutrients during acute fasting. We therefor conclude that neither short term fasting nor fluid abstention (18-25h) affect human milk macronutrient composition, so that women can be reassured when this topic were raised during consulting. Besides the nutritional relevance, this also matters as clinical research samples – especially to estimate analgo-sedative exposure by lactation - are commonly collected after maternal procedural sedation, associated with maternal fasting and physiology-based pharmacokinetic (PBPK) models assume stable human milk composition.

SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using molecular docking based virtual screening of all approved drugs. The results of this study confirm preliminary reports that some of the drugs approved for treatment of other viral infections have the potential for treatment of COVID-19. Selected antiviral drugs, approved for human therapeutic applications, were ranked for potential effectiveness against COVID-19, based on predicted binding energy to the target Mpro of SARS-CoV-2, and novel candidates for drug repurposing were identified in this study. In addition, potential mechanisms for beneficial off target effects of some drugs in clinical trials were identified by using molecular docking.

Polycystic ovary syndrome (PCOS) is the predominant endocrine disorder among women of re-productive age and represents the leading cause of anovulatory infertility, which imposes a con-siderable health and economic burden. Currently, medications used to treat PCOS can lead to certain adverse reactions, such as affecting fertility and increasing the risk of venous thrombosis. Drug delivery systems utilizing nanomaterials, characterized by prolonged half-life, preci-sion-targeted delivery, enhanced bioavailability, and reduced toxicity, are currently being em-ployed in the management of PCOS. This innovative approach is gaining traction as a favored strategy for augmenting the therapeutic efficacy of medications. Consequently, this paper dis-cusses the roles of nanoparticles, nanocarriers, and targeted ligands within nanomaterial-based drug delivery systems, aiming to identify optimal methodologies for treating PCOS using nano-materials. Additionally, prospective research avenues concerning nanomaterial-based delivery systems in the context of PCOS, as well as the implications of existing insights on the advancement of novel therapies for PCOS, are highlighted.

Objective: Evaluation of individuals with intravenous drug addiction who developed infective endocarditis (IE) is required for a better understanding of the management that can be applied in these cases. This study aimed to shed light on the complex interplay between intravenous drug use and IE with the ultimate goal of improving patient care and outcomes Method: The study examined the clinical outcomes of 43 patients admitted with infective endocarditis (IE) associated with injection drug use. Data was collected over an average follow-up period of 12 months, providing a substantial timeframe to assess the long-term effects of different treatment approaches. The research focused on comparing the outcomes between two distinct groups: patients who received medical treatment alone and those who underwent surgical intervention in addition to medical management. Results This study included 43 intravenous drug users who were diagnosed with infective endocarditis (IE). The mean age of the patient cohort was 31 ± 9 years with a predominance of males (74.4%). All cases involved native valve IE, with the aortic valve being the most commonly affected (62.9%), followed by the tricuspid (30.2%) and mitral valves (6.9 %). Multiple valve involvement was observed in 13.9% of the cases. The study population had a high prevalence of comorbidities, particularly HIV infection (65.1%) and hepatitis C infection (25.5%). The study also revealed that 19.3% of the patients had previously experienced IE. Mortality rates were slightly higher in patients with recurrent IE (23.2%) than in those who experienced their first episode. Transthoracic echocardiography proved to be a highly effective diagnostic tool for detecting vegetation in 95% of the cases. Microbiological analysis identified Staphylococcus aureus as the predominant causative organism, isolated from blood cultures in 55.8% of the cases. These findings highlight the complex nature of IE in intravenous drug users, emphasizing the importance of comprehensive management strategies that address both cardiac manifestations and underlying comorbidities in this high-risk population. Conclusions: Injection drug use–associated infective endocarditis presents a significant challenge in modern healthcare, with patients facing a high risk of complications and poor clinical outcomes despite current therapeutic approaches. This persistent issue underscores the complexity of treating individuals with both infectious diseases and substance use disorders. The multifaceted nature of these cases often involves immediate cardiac infection, as well as concurrent medical, psychological, and social challenges that can complicate treatment and recovery.

DNA - the repository of genetic information harbours sequences rich in Guanine that adopt non-B form four-stranded DNA secondary structures termed as G-quadruplexes (G4s). Such non-canonical structures tend to impede the progression of routine replisome and are implicated to have crucial roles in replication, transcription and epigenetic regulation while also ensuring genomic stability. It is now fully established that G4s are enzymatically unfolded by helicases, thus, preventing transient yet apparent impediments to the vital replisome progression. This unfolding of G-quadruplex ensures genetic and epigenetic stability. Given the importance of G4 biology for multiple human parasites such as, Mycobacterium tuberculosis, research efforts probing parasitic G4 biology is gaining momentum with the hope to enable therapeutic intervention. We herein shed light on G4s, conditions that lead to their formation and the mechanisms employed by cells to cause their unfolding. Towards the end, potential drug discovery avenues that arise from targeting parasitic helicases and G4 biology are summarized.

Extracellular vesicles (EVs) are natural carriers of biomolecules that play a crucial role in cell-to-cell communication and tissue homeostasis under normal and pathological conditions, including inflammatory diseases and cancer. Since the discovery of the pro-regenerative and immune-modulating properties of EVs, EV-based therapeutics have entered clinical trials for conditions such as myocardial infarction and autoimmune diseases, among others. Due to their unique advantages—such as superior bioavailability, substantial packaging capacity, and the ability to traverse biological barriers—EVs are regarded as a promising platform for targeted drug delivery. However, achieving sufficient accumulation of therapeutic agents at the target site necessitates a larger quantity of EVs per dose compared to using EVs as standalone drugs. This challenge can be addressed by administering larger doses of EVs, increasing the drug dosage per administration, or enhancing the selective accumulation of EVs at target cells. In this review, we will discuss methods to improve the isolation and purification of EVs, approaches to enhance cargo packaging—including proteins, RNAs, and small-molecule drugs—and technologies for displaying targeting ligands on the surface of EVs to facilitate improved targeting. Ultimately, this guide can be applied to the development of novel classes of EV-based therapeutics and to overcoming existing technological challenges.

Toxoplasma gondii is a protozoan and the etiologic agent of toxoplasmosis causes high mortality in immunocompromised individuals and newborns. Despite the medical importance of toxoplasmosis, few drugs are available for its treatment, which are associated with side events and parasite resistance. Here, we show a screening of molecules present in Covid-Box as a way of discovering new hits with anti-T. gondii activity. Covid-Box contains 160 molecules with known or predicted activity against SARS-CoV-2. Our analysis selected 23 Covid-Box molecules that can inhibit the tachyzoite forms of the RH strain of T. gondii in vitro by more than 70% at 1 µM after seven days of treatment. The inhibitory curves showed that most of these molecules inhibited the proliferation of tachyzoites with IC50 values below 0.80 µM; Cycloheximide and (-)-Anisomycin were the most active drugs, with IC50 values of 0.02 μM. Cell viability assays showed that the compounds are not toxic at active concentrations, and most are highly selective for parasites. Overall, all 23 compounds were selective, and for three of them (Apilimod, Midostaurin, and Salinomycin), this is the first report of activity against T. gondii. To better understand the effect of the drugs, we analyzed the effect of six of them on the ultrastructure of T. gondii using transmission electron microscopy. The main changes observed in parasite morphology after treatment with the selected drugs were changes in cell division and parasite organelles.

Multiple Myeloma (MM), is a hematological malignancy and poses significant therapeutic challenges. This review synthesizes evidence from pivotal clinical trials to guide induction treatment for transplant-eligible (TE), newly diagnosed MM (NDMM) patients. Emphasizing the evolution from three-drug to four-drug induction therapies, we highlight the integration of monoclonal antibodies, particularly CD38 recombinant monoclonal antibody agents, into treatment regimens. Our analysis includes a comprehensive literature review of research from major databases and conferences conducted between 2010 and 2024, culminating in the detailed evaluation of 47 studies. The findings underscore the superiority of quadruple regimens in TE NDMM, notably those incorporating daratumumab, in achieving superior responses including progression-free survival (PFS), minimal residual disease (MRD) negativity, overall response rate (ORR), and overall survival (OS) when compared to triple-drug regimens. As treatment regimens evolve with additional agents, the improved outcomes with treatment-related adverse events should be carefully balanced. This review advocates for a paradigm shift towards quadruple induction therapies for TE NDMM, offers a detailed insight into the current landscape of MM treatment, and reinforces a new standard of care.

As the world population grows, fulfilling the need for biomaterials in the healthcare system becomes increasingly important. Biomaterials, which include metals, polymers, ceramics, and composites, play an important role in the creation of medical devices that improve people's lives. The European Society for Biomaterials described biomaterials as non-biological materials used in medical devices to interact with biological systems. This definition has developed to encompass materials that treat, assess, or replace tissues or bodily functions. Biocompatibility, as defined by the FDA, is a key feature of biomaterials, as is the requirement to fulfil design requirements such as mechanical performance, geometry, and electrical control. Over the last decade, advances in regenerative medicine and tissue engineering have boosted biomaterials' usage in medical applications dramatically. Despite its promise, scientists, engineers, and physicians continue to face significant challenges due to the complexity of biomaterials. Biomaterials have various benefits, including biodegradability, non-toxicity, and biocompatibility, making them extremely useful for replacing, sustaining, or improving biological activities in damaged tissues. They are used in a wide range of applications, including tissue engineering implants, human tissue healing and regeneration, medication delivery systems, and biosensors. This study gives insights into the fundamental characteristics, case studies, and ethical issues associated with the usage and use of biomaterials, further examining their potential and significance in healthcare and medicine.

Lithium is the superior first-line treatment for bipolar disorder (BD). Yet the percentage of patients receiving lithium is abysmally low, especially in the USA. Since psychiatrists have failed to place lithium in its appropriate role, we make the case that patients with BD themselves need to be better educated about the unique characteristics and preeminence of the drug so that it can be used more often and appropriately. Lithium has a highly unfavorable popular reputation among would-be patients and many psychiatrists. Thus, a direct appeal to patients with BD appears appropriate to try to remediate this situation. The unique assets of lithium are underappreciated or not well known. Conversely, the side effects profile of lithium are overestimated. Here, we make the case that lithium’s image needs to be revised not only with better and more accurate information but with a wholesale re-naming and rebranding of the drug. We will not only outline the unique qualities and new information about the side effects of the drug but attempt to change some of the terminology conventionally used to refer to lithium so that its use may be appropriately applied earlier and at an increased frequency for patients with BD.

Feline infectious peritonitis (FIP) is a severe and invariably fatal disease affecting both domestic and wild felines with limited effective therapeutic options available. By considering the significant immunomodulatory effects of vitamin E observed in both animal and human models under physiological and pathological conditions, we have provided a full in-silico investigation of vitamin E and related compounds and their effect on the crystal structure of feline infectious peritonitis virus 3C-like protease (FIPV-3CLpro). This work revealed the β-tocotrienol and δ-tocotrienol analogues as inhibitor candidates for this protein, suggesting their potential as possible drug compounds against FIP or their supplementary use with current medicines against this disease.

Our world is rife with challenges, many of which arise from both natural phenomena and human-made issues. While natural problems like diseases and environmental changes often elude our immediate control, a troubling number of today's issues are unintended consequences of human innovations. A striking example is the evolution of drug resistance. The discovery of antibiotics in the early days of modern medicine marked a monumental breakthrough, drastically reducing mortality rates and improving quality of life. Pioneers like Alexander Fleming, who discovered penicillin in 1928, ushered in a new era of medical treatment, transforming healthcare by effectively combating bacterial infections.However, the widespread and often indiscriminate use of these drugs has led to the emergence of drug-resistant pathogens. This natural phenomenon, accelerated by human practices such as overprescription and the misuse of antibiotics in agriculture, exemplifies a double-edged sword—initially celebrated solutions have now become significant challenges. The same drugs that once cured deadly infections are losing efficacy, making us vulnerable to diseases previously thought under control.The inventors of these drugs acted with the intent to save lives and alleviate suffering, unaware of the long-term consequences. Today, the responsibility to address drug resistance lies with us, armed with hindsight and a deeper understanding of microbial resistance complexities. This review explores the origins and evolution of drug resistance, the role of scientific knowledge, and the implications for future actions.

Cancer is a highly heterogeneous disease and remains a global health challenge affecting millions of human lives worldwide. Despite advancements in conventional treatments like surgery, chemotherapy, and immunotherapy, the rise of multidrug resistance, tumor recurrence, and severe side effects necessitates innovative therapeutic approaches. The complex nature of the tumor microenvironment (TME) further compromises the efficacy of traditional chemotherapy drugs. Recently, stimulus-responsive nanomedicines designed to target TME characteristics (e.g., pH, redox, enzymes) have gained attention for their potential to enhance anticancer efficacy while minimizing adverse effects. Among various nanocarriers, hydrogels are an interesting class of nanocarriers used in cancer therapy due to their high water content, adjustable mechanical characteristics, and ability to respond to external/internal stimuli. These properties make hydrogels an ideal nanocarrier for controlled drug release within the TME. This review comprehensively surveys the latest advancements in stimulus-responsive hydrogels for cancer therapy, exploring various stimuli-responsive mechanisms, including biological (e.g., pH, redox), chemical (e.g., enzymes, glucose), and physical (e.g., temperature, light), as well as dual- or multi-stimuli responsiveness. This review will offer novel perspectives on the development of stimulus-responsive hydrogels for cancer therapy.

Skin inflammation associated with chronic diseases has the direct action of keratinocytes in its immunopathogenesis, leading to a series of immune responses. However, there are still no highly targeted treatments, and the development of more specific therapies is highly desirable. In the present work, nanocapsules containing quinizarin (QZ/NC) were developed, evaluating their act in a model of the keratinocytes inflammatory process in vitro with the action of Photodynamic Therapy, analyzing the permeation in a 3D skin model. Physicochemical, stability, cytotoxicity and permeation analyses of the nanomaterials were carried out. The nanocapsules showed desirable physicochemical characteristics and were stable during the analysis period, without spectroscopic modifications. The cell viability test carried out showed no cytotoxicity at the lowest QZ/NC concentrations. The permeation and cellular uptake studies showed the permeation of QZ/NC in 3D skin models and the intracellular incorporation and internalization of the drug, enhancing its action in the drug delivery technique. Promising results were presented using the model developed to induce the inflammatory process in vitro and applying the synthesized nanomaterial in conjunction with PDT, where a decrease in the levels of cytokines analyzed was observed, representing a possible new therapeutic approach for inflammatory skin diseases.

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p&gt;5 × 10-8). Our results are consistent with prior finding regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, and allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.

Paracetamol, also known as acetaminophen, is one of the most widely used over-the-counter analgesics and antipyretics globally. While generally considered safe when used as directed, excessive or prolonged use of paracetamol can lead to adverse effects on various organ systems within the human body. This comprehensive review explores the physiological mechanisms underlying paracetamol toxicity, its effects on different organs, risk factors for overdose, diagnostic methods, and potential management strategies.

Antibody-drug conjugates (ADCs), a groundbreaking advancement in cancer therapy, synergistically combine the precision of monoclonal antibodies with the potent destruction capabilities of cytotoxic drugs, signifying a new era in the targeted oncological treatments. This comprehensive paper delves into the evolving field of antibody-drug conjugates (ADCs) and their pivotal role in cancer therapy. We have conducted an in-depth exploration of the structural components of ADCs, including target antigens, monoclonal antibodies, chemical linkers, and cytotoxic payloads, each playing a crucial role in determining the efficacy and safety profile of these novel therapies. A detailed market analysis reveals the leading pharmaceutical companies shaping the ADC landscape, reflecting the growing interest and potential in this therapeutic approach. We further dissect the engineering intricacies of ADCs, focusing on their ability to target specific cancer cell antigens while minimizing off-target effects, thus offering a more focused treatment with reduced systemic side effects compared to traditional chemotherapy. This approach holds promise in a heightened therapeutic index and decreased toxicity. The mechanisms and effector functions of ADCs are explored, highlight- ing their multifaceted strategy in combating cancer. We include a comprehensive look at how ADCs operate from initial blood circulation to the induction of apoptosis in cancer cells. We also review several key ADCs currently in use or under investigation, offering insights into their unique mechanisms of action, pharmacokinetics, and clinical implications. The discussion extends to drug creation modalities, focusing on innovative conjugation techniques that enhance ADC homogeneity and therapeutic efficacy. In conclusion, the paper underscores the transformative potential of ADCs in the realm of cancer treatment, marking a shift towards more precise and targeted therapeutic approaches. By offering a thorough analysis of ADC technology, this paper sheds light on the prospects of these groundbreaking therapies in the ongoing fight against cancer.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Despite the latest advances, a major clinical issue in EOC is the disappointing prognosis related to chemoresistance in almost one-third of cases. Drug resistance relies on heterogeneous cancer stem cells (CSCs), endowed with tumor-initiating potential, leading to relapse. No biomarkers of chemoresistance have been validated yet. Recently, major signaling pathways, micro ribonucleic acids (miRNAs), and circulating tumor cells (CTCs) have been advocated as putative biomarkers and potential therapeutic targets for drug resistance. However, further investigation is mandatory before their routine implementation. In accordance with the increasing rate of therapeutic efforts in EOC, the need for biomarker-driven personalized therapies is growing. This review aims to discuss the emerging hallmarks of drug resistance with an in-depth insight into the underlying molecular mechanisms lacking so far. Finally, a glimpse of novel therapeutic avenues and future challenges will be provided.

Cancer is among the leading causes of death worldwide. Therefore, timely diagnosis and appropriate treatment are very important. There are many disadvantages that come with traditional cancer treatments, such as chemotherapy and radiotherapy. In these treatments, the specific drug concentration affects not only the tumor site but also healthy tissues or organs. One of the foremost promising uses of nanotechnology is in the field of medical technology and specific site targeting can be achieved due to manipulation of materials at a nanometric scale. Nanotechnology offers specific benefits in terms of cancer therapy by enhancing it and reducing its adverse effects by guiding drugs to selectively target cancer cells. In addition, the use of minute amounts of medicine can lead to cost savings. Furthermore, nanoparticles can also be used as imaging agents to improve cancer diagnostics, therapeutics, and treatment management. Thus, this review has focused on the different types of nanoparticles used in cancer therapy, their action mechanisms, and their benefits and applications in diagnosis, imaging, and treatment. This review sums up the parameters that need to be considered when designing systems for cancer therapy while considering the desired characteristics of the nanoparticles from the biological point of view.

(1) Background: Hemispherotomy is the generally accepted treatment for hemispheric drug resistant epilepsy (DRE). Lateral or vertical approaches are performed according to the surgeon's preference. Multiples technical variations have been proposed since Delalande first described his vertical technique. We propose a sub-insular variation of the vertical parasagittal hemispherotomy (VPH) and describe our case series of patients operated on with this procedure. (2) Methods: a continuous series of patients operated on by the senior author (CR) with the modified sub-insular VPH was retrospectively analyzed. We report the demographic pre-operative characteristics, epilepsy and functional outcome as well as the surgical complications.(3) Results: Twenty-five patients were operated on between August 2008 and August 2023, twenty-three of them have at least a 3-month follow-up. On this last group 86,3% of patients were seizure-free. Only two patients developed post-operative hydrocephalus (8.7%), all patients with autonomous preoperative walk and 86,3% of the total series were able to walk without assistance (86.3%) and perform adapted social activities at last follow-up.(4) Conclusion: The modified vertical parasagittal sub-insular hemispherotomy is a successful surgical technique for hemispheric DRE with seizure freedom rates similar to the biggest series reported in the literature. Compared to other series, patients operated with our modified technique had a lower rate of postoperative hydrocephalus and excellent long-term motor and cognitive outcome.

Skin cancer is a disease that reflects most malignant neoplasms worldwide, whose rate of involvement has increased significantly in recent decades. Treatments that offer efficient results with attenuation of adverse reactions and greater patient compliance have been the subject of many systematic investigations. This review aims to qualitatively present published works that showed new strategies to increase the penetration power of natural substances through the skin in the topical treatment against skin cancer. In this sense, nanoengineering mechanisms, the iontophoresis technique, and photodynamic therapy using natural products (NP) contribute to new knowledge about substance carrier strategies in topical treatments against skin cancer.

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1-14 years enrolled March 2019 to December 2020 from five facilities in Kisumu County, Kenya were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for VF (&gt; 1000 copies/ml)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; median age was 9 years (interquartile range (IQR) 7,12), 344 (49%) were female and median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associate with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual class resistance. A history of VF in prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT.

The prevalence of antiviral drugs (AVTs) has seen a substantial increase in response to the COVID-19 pandemic, leading to heightened concentrations of these pharmaceuticals in wastewater systems. The hydrophilic nature of AVTs has been identified as a significant factor contributing to the low degradation efficiency observed in wastewater treatment plants. This characteristic often necessitates the implementation of additional treatment steps to achieve complete degradation of AVTs. Semiconductor-based photocatalysis has garnered considerable attention due to its promising potential in achieving efficient degradation rates and subsequent mineralization of pollutants, leveraging the inexhaustible energy of sunlight. However, in recent years, there have been few comprehensive reports that have thoroughly summarized and analyzed the application of photocatalysis for the removal of AVTs. This review commences by summarizing the types and occurrence of AVTs. Furthermore, it places a significant emphasis on delivering a comprehensive summary and analysis of the characteristics pertaining to the photocatalytic elimination of AVTs. Ultimately, the review sheds light on the identified research gaps and key concerns, offering invaluable insights to steer future investigations in this field.

Background: The clinical outcomes of antiretroviral drugs may be modified by drug interactions; thus, it is important to update the drug interactions in people living with HIV. Aim: To update clinically relevant drug interactions in people living with HIV on antiretroviral therapy. Methods: A systematic review in Medline/PubMed database from July 2017 to December 2022, using the Mesh terms: Anti-retroviral agents and drug interactions or herb-drug interactions or food-drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full text were retrieved. The clinical relevance of drug interaction was grouped into 5 levels according to gravity and probability of occurrence. Results: 361 articles were identified and 148 were included, which allowed the identification of 894 drug interaction pairs. Among these 894 drug pairs, 355 have not been identified previously; and 89 (25.1%) and 72 (20.2%) were of levels 1 and 2, respectively. In addition, for 197 (55.5%) pairs the mechanism was pharmacokinetic. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs) with 91 (25.6%) and 76 (21.4%) pairs, respectively were more frequent. Conclusions: In people living with HIV on antiretroviral therapy, we identify 355 new drug interaction pairs, of them 161 (45.3%) are assessed as levels 1 and 2 and thus, clinically relevant; a figure that is lower compared to 2014-2107 update. The pharmacokinetic mechanism is the most frequently identified. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs) are the antiretroviral groups with the highest number of clinically relevant drug interactions.

Drug-resistant tuberculosis (DR-TB) is still a major public health concern in South Africa. Mutations in M. tuberculosis can cause varying levels of phenotypic resistance to anti-TB medications. There have been no prior studies on gene mutations and the genotyping of DR-TB in the rural Eastern Cape Province; hence we aimed to identify DR-TB mutations, genetic diversity and allocated lineages among patients in this area. Using Xpert® MTB/RIF, we assessed the rifampin-resistance of sputum samples collected from 1157 patients suspected of having tuberculosis. GenoType MTBDR plus VER 2.0 was used for the detection of mutations causing resistance to anti-TB medications. The next step was to spotlight type 441 isolates. The most prevalent rifampin resistance-conferring mutations were in rpoB codon S531L, in INH-resistant strains, katG gene at codon S315TB and the inhA gene at codon C-15TB had highest mutations; 54.5% and 24.7%, respectively. In addition, 24.6% of strains showed mutations in both the rpoB and inhA genes, while 69.9% of strains showed mutations in both the katG and rpoB genes. Heteroresistance was seen in 17.9% of all cases in the study. According to spoligotyping analysis, Beijing families predominated. Investigating the evolutionary lineages of M. tuberculosis isolates can be done using the information provided by the study's diversity of mutations. In locations where these mutations have been discovered, decision-making regarding standardization of treatment regimens or individualized treatment may be aided by the detection frequency of rpoB, katG, and inhA mutations in various study areas.

Antibody-drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancers, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development [1]. Therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options [1-4]. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection [5-7]. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy and targeted agents are occurring.

Drug induced liver injury (DILI) is the most common cause of acute liver failure and 5-10% of patients hospitalized for jaundice are diagnosed with DILI. For a diagnosis of DILI to be made, there should be exclusion of other etiologies of liver injury and the use of a precipitator drug, latency of symptoms, and resolution of liver injury once the offending drug is identified and discontinued. In our case report, we present a patient with idiosyncratic hepatocellular pattern DILI after two doses of ocrelizumab for treatment of multiple sclerosis. Ocrelizumab was given 16 and 27 days prior to the onset of icterus, jaundice, and fatigue, in a patient without the evidence of prior exposure to hepatitis B virus. At presentation labs revealed severe acute hepatocellular liver injury with R factor of 30.42, marked hyperbilirubinemia, and transient hypoalbuminemia. No evidence of latent or active hepatitis B infection was detected. Drug dechallenge led to return of liver chemistries to near-normal levels 31 days after the onset of her symptoms. This case indicates DILI diagnosis associated with the use of ocrelizumab, and warrants careful monitoring of liver functions in patients even in the absence of hepatitis B.

Autoimmune disorders and some types of blood cancer originate when B lymphocytes malfunction. In particular, when B cells produce antibodies recognizing the body’s proteins, it leads to various autoimmune disorders. And when B cells of various developmental stages transform into cancer cells, it results in blood cancers, including multiple myeloma, lymphoma, and leukemia. Thus, new methods of targeting B cells are required for various patient groups. Here, we used protein kinase inhibitors alectinib, brigatinib, ceritinib, crizotinib, entrectinib, and lorlatinib previously approved as drugs treating anaplastic lymphoma kinase (ALK)-positive lung cancer cells. We hypothesized that the same inhibitors will efficiently target leukocyte tyrosine kinase (LTK)-positive, actively protein-secreting mature B lymphocytes, including plasma cells. We isolated CD19-positive human B cells from the blood of healthy donors and used two alternative methods to stimulate cell maturation toward plasma cells. Using cell proliferation and flow cytometry assays, we found that ceritinib and entrectinib eliminate plasma cells from B cell populations. Alectinib, brigatinib, and crizotinib also inhibited B cell proliferation, while lorlatinib had no or limited effect on B cells. More generally, we concluded that several drugs previously developed to treat ALK-positive malignant cells can be also used to treat LTK-positive B cells.

Increasing environmental distress is associated with a growing asthma incidence and, with no treatments available, montelukast (MTK) – an antagonist of the cysteinyl leukotrienes receptor 1 – is widely used in the management of symptoms among adults and children. Recently, new molecular targets have been identified and MTK has been proposed for repurposing in other therapeutic applications, with several ongoing clinical trials. The proposed applications include neuroinflammation control, which could be explored in some neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (AD and PD). However, this drug has been associated with an increasing number of reported neuropsychiatric adverse drug reactions. Besides, and despite being on the market since 1998, MTK metabolism is still poorly understood and the mechanisms underlying neuropsychiatric ADRs remain unknown. We review the role of MTK as modulator of leukotriene pathways and systematize the knowledge about MTK metabolism. Known toxic effects of MTK are discussed, and repurposing applications are presented comprehensively, with a focus on AD and PD.

Therapeutic Drug Monitoring (TDM) is potentially a useful tool that can be employed to increase the efficacy and decrease the toxicity of antifungal drugs. The aim of this narrative review is to provide an overview of the current use of TDM in clinical practice, and to present the evidence available regarding its use in proactive clinical settings for preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations in everyday practice. Articles concerning the use of TDM of triazoles in the treatment of fungal infections were retrieved through an electronic search using PubMed. In clinical practice, TDM has an increasingly important role in the management of antifungal drugs as a consequence of the improvement in the knowledge of the pharmacokinetics and pharmacodynamics of these drugs. The currently available evidence shows a direct exposure-response relationship for triazoles, though the PK/PD profile is unpredictable. Current guidelines and treatment consensus statements recommend the proactive TDM of voriconazole, posaconazole, and itraconazole to optimize dosage regimens and improve outcomes for adult and pediatric patients.

The treatment of peptides has played an important role in clinical practice since the discovery of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States (US and other regional mar-kets, and peptides continue to undergo drug discovery steadily. Peptide research and development has lev-eraged a wider range of structures known from other plant sources, via pharmacology and medicinal molecular biology, beyond its conventional focus on individual endogenous peptides. We build a comprehensive database of peptides that have met scientific studies with more than 150 constantly evolving peptides. Here we provide a simple overview of the peptide-based drug therapy environment, comprising evolutionary points of view, structural properties, operational thresholds, and explanation of the therapeutic area.

Randomized clinical trials represent the gold standard in therapeutic research. Nevertheless, observational cohorts of patients treated for multidrug-resistant (MDR) or rifampin-resistant (RR) tuberculosis (TB) also play an important role in generating evidence to guide MDR/RR TB Generally, summary exposure classifications (e.g., ‘ever versus never’, ‘exposed at baseline’) have been used to characterize drug exposure, in the absence of detailed longitudinal data on MDR-TB regimen These summary classifications, along with an absence of data on covariates that change throughout the course of treatment, constrain researchers’ ability to answer the most relevant questions while accounting for known This paper highlights the importance of regimen changes in improving inference from observational studies of longer MDR-TB treatment regimens and offers an overview of the data and analytic strategies required to do

BACKGROUND: From March to April 2020, Spain was the center of the SARS-CoV-2 pandemic, particularly Madrid with approximately 30% of the cases in Spain. The aim of this study is to report the suspected serious adverse drug reactions (SADRs) in COVID-19 patients versus non-COVID-19 patients detected by the prospective pharmacovigilance program based on automatic laboratory signals (ALSs) in the hospital (PPLSH) during that period. We also compared the results with the suspected SADRs detected during the same period for 2019. METHODS: All ALSs that reflected potential SADRs (including neutropenia, pancytopenia, thrombocytopenia, anemia, eosinophilia, leukocytes in cerebrospinal fluid, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis and hyponatremia were prospectively monitored in hospitalized patients during the study periods. We analyzed the incidence and the distribution of causative drugs for the COVID-19 patients. RESULTS: The incidence rate of SADRs detected in the COVID-19 patients was 760.63 (95% CI 707.89–816.01) per 10,000 patients, 4.75-fold higher than the SADR rate for non-COVID-19 patients (160.15 per 10,000 patients,95% CI 137.09–186.80), and 5.84-fold higher than the SADR rate detected for the same period in 2019 (130.19 per 10,000 patients, 95% CI 109.53–154.36). The most frequently related drugs were tocilizumab (59.84%), dexketoprofen (13.93%), azithromycin (8.43%), lopinavir-ritonavir (7.35%), dexamethasone (7.62%), and chloroquine/hydroxychloroquine (6.91%). CONCLUSIONS: The incidence rate of SADRs detected by the PPSLH in patients with COVID-19 was 4.75-fold higher than that of the non-COVID-19 patients. Caution is recommended when using medications for COVID-19 patients, especially drugs that are hepatotoxic, myotoxic, and those that induce thromboembolic events.

Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Many important aspects about 2019-nCoV remain largely unknown, among which, the limitation of antiviral therapies represents one of the most critical problems. More recently, it was confirmed that human ACE2 is the receptor for the entry of 2019-nCoV into lower respiratory tract epithelial cells. Give this observation, it is thus expected that the virus could be inhibited if we decrease the expression of ACE2. Here by screening two databases, Connectivity Map (CMap) and our JeaMoon Map (JMap), we identified a number of candidate agents that decrease ACE2 expression. CMap analysis identified 5 compounds, among which, Azathioprine is a possible therapeutic strategy for anti-2019-nCoV. Moreover, JMap analysis revealed a number of comounds, biologics, and traditional Chinese medicine, among which, Andrographis, Urtica, Sambucus, Astragalus, valproic acid, butyrate, and epoxomicin represent the most significant and possible strategies for anti-2019-nCoV therapies. This study provides a number of clues and possible therapeutic strategies for 2019-nCoV prevention and treatment.

Many approaches have been developed over time to counter the bioavailability limitations of poorly soluble drugs. With advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of pure drugs and a minimum of surface active agents required for stabilization. They are carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10 and 800 nm. By reducing particle size to nanoscale, the particle surface area available for the molecule dissolution in the direction of dissolution medium is increased, and thus bioavailability is enhanced. This approach has proven successful, as demonstrated by the number of such drug products on the market. R&D and industry have offered many technological solutions to reduce the particle size to nanoscale, and also devised solutions for the handling of particle of nanodimensions, such as methods to accurately measure nanoparticle size and techniques to prevent physicochemical and stability related problems, such as aggregation. The present work provides an overview of the more recent achievements in improving the bioavailability of poorly soluble drugs according to their administration route, and describes the methods developed to overcome physicochemical and stability related problems.

Currently, drug screening is primarily based on human cell culture for initial high-throughput screening, and subsequently, rodent model to confirm the biological effects. However, the mammalian system is known for time-consuming and highly-cost to be difficult to perform high-throughput drug screening, which exists a critical gap between in vitro cell-based models and the in vivo mammalian models. Therefore, the zebrafish could bridge this gap in preclinical toxicity screening along the drug development pipeline because of its efficiency. We aimed to develop an in vivo zebrafish platform for rapid drug screening. Zebrafish, due to its high genomic conservation with mammals and rapid development and differentiation, it has many advantages, such as short life span, large number of offspring and low cost, easy manipulation for generating transgenic species, to serve as animal model for disease-based research. In 96-well microplates, zebrafish embryos were incubated with small molecular compounds that affected bone mineralization. The level of osteogenic mineralization was evaluated by fluorescent dye staining and quantified by image analysis software. Quantitative real time-PCR (qRT-PCR) was performed to evaluate the biological pathways involved in bone metabolism at the molecular level. The system was validated by demonstrating that response to alendronate and Dorsomorphin in zebrafish. In our study, we screened for 24 compounds within the CYCU-1120~1152 chemical library and identified 3 compounds, pentamidine (CYCU-1140), BML-267 (CYCU-1147), and alendronate (CYCU-1152), increased embryonic mineralization; while 6 compounds, RWJ-60475 (CYCU-1126), levamisole HCL (CYCU-1128), tetramisole HCL (CYCU-1129), fenvalerate (CYCU-1132), NSC-663284 (CYCU-1138), and BML-267ester (CYCU-1148), were inhibitory to bone mineralization. We also found that alendronate enhanced the level of bone mineralization by inhibiting osteoclast-related genes. To sum up, our research showed that zebrafish may have potential to be a drug-screening and mechanism-analysis platform for bone mineralization.

In vitro studies show that diclofenac inhibits enzymatic steroid glucuronidation. This study was designed to investigate the influence of diclofenac on the excretion of stanozolol and 3'-hydroxystanozolol via analyses in hair, blood and urine in vivo in a rat study. Brown Norway rats were administered with stanozolol (weeks 1-3) and diclofenac (weeks 1-6). Weekly assessment of steroid levels in hair was complemented with spot urine and serum tests. Levels of both stanozolol and 3'-hydroxystanozolol steadily increased in hair during stanozolol treatment and decreased post-treatment, but remained readily detectable for 6 weeks. In contrast, compared to control rats, diclofenac significantly reduced urinary excretion of 3’-hydroxystanozolol which was undetectable in most samples. This is the first report of diclofenac altering steroid metabolism in vivo, detrimentally affecting detection in urine, but not in hair which holds considerable advantages over urinalysis for anti-doping tests.

Europium (Eu)-doped fluorapatite (FA) nanorods has a similar biocompatibility with hydroxyapatite (HA) in terms, attracted much attention as cell imaging biomaterials due to their luminescent property. Here, we will discuss the new feature of europium doped fluorapatite (Eu-FA) nanorods as anticancer drug carrier. Eu-FA nanorods was prepared using a hydrothermal method. The morphology, crystal structure, fluorescence and composition are investigated. The specific crystal structure, enabling an effective loading of drug molecules. Doxorubicin (DOX), used as an anticancer model drug, was shown to be effectively loaded onto the surface of the nanorods. The DOX release was fairly pH-dependent, occurring more rapidly at pH 5.5 than pH 7.4 was observed. The intracellular penetration of the DOX-loaded Eu-FA nanorods (Eu-FA/DOX) can be imaged in situ due to the self-fluorescence property. Treatment of melanoma A375 cells with Eu-FA/DOX elicited a more effective apoptosis rate than direct DOX treatment. Overall, Eu-FA show great promise for tracking and treating tumor, may potentially useful as a multifunctional carrier system to effectively load and sustainably deliver drugs.

Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.

Lead optimization in drug discovery is a crucial phase where initial hits are refined into compounds with improved pharmacological properties. While traditional methods rely on manual experimentation and modifications, AI-driven techniques have revolutionized this process by leveraging big data and predictive modeling. This review explores how AI-driven approaches accelerate lead optimization, showcasing examples like deep neural networks and reinforcement learning. Integration of multi-omic data and experimental validation further enhances AI-driven strategies. The future lies in refining these AI methods, democratizing tools, and interdisciplinary collaboration to streamline drug discovery and address medical needs efficiently.

Antimicrobial peptides (AMPs) have emerged as a promising solution to tackle bacterial infections and combat antibiotic resistance. However, their clinical application has been hindered by their vulnerability to protease degradation and toxicity towards mammalian cells. To overcome these challenges, our study aims to develop a method to enhance the stability and safety of AMPs, applicable to effective drug-device combination products. KR12 antimicrobial peptide was chosen and in order to further enhance its delivery and efficacy, HIV TAT protein-derived cell-penetrating peptide (CPP) was fused to form CPP-KR12. A new product, CPP-KR12@Si, was developed by forming silica nanoparticles with self-entrapped CPP-KR12 peptide using the biomimetic silica precipitability due to its cationic nature. Peptide delivery from CPP-KR12@Si to bacteria and cells was delivered at a slightly delayed rate with improved stability against trypsin treatment and a reduction in cytotoxicity over CPP-KR12. Finally, the antimicrobial potential of CPP-KR12@Si/bone graft substitute (BGS) combination product was demonstrated, which is coated with CPP-KR12 in the form of nanoparticles on the surface of BGS. Self-entrapped AMP in silica nanoparticles is a safe and effective AMP delivery method that will be useful for developing a drug/device combination product for tissue regeneration.

As cancer remains resistant to several modes of treatment, novel therapeutics are still under active investigation to overcome treatment inefficacy in cancer. Given the high attrition rate of de novo drug discovery, drug screening, and drug repurposing have offered time- and cost-effective alternative strategies for the identification of potentially effective therapeutics. In contrast to large-scale drug screens, computational approaches for drug repurposing leverage the increasing amounts of biomedical data to predict candidate therapeutic agents prior to testing in biological models. Current studies in drug repurposing for cancer therapy prediction have increasingly focused on the prediction of combination therapies, as combination therapies have numerous advantages over monotherapies. These include increased effect from synergistic interactions, reduced toxicity from lowered drug doses, and a reduced risk of resistance due to multiple non-overlapping mechanisms of action. This review provides a summary of several classes of computational methods used for drug combination therapy prediction in cancer research, including networks, regression-based machine learning, classifier machine learning models, and deep learning approaches, with the goal of presenting current progress in the field, particularly to non-computational cancer biologists. We conclude by discussing the need for further advancements in technologies that incorporate disease mechanisms, drug characteristics, multi-omics data, and clinical considerations to generate effective patient-specific drug combinations, as holistic data integration will inevitably result in optimal targeted therapeutics for cancer.

This paper presents a computational approach designed to construct and query a literature-based knowledge graph for predicting novel drug therapeutics. The main objective is to offer a platform that discovers drug combinations from FDA-approved drugs and accelerates their investigations by domain scientists. Specifically, the paper introduced the following algorithms: (1) an algorithm for constructing the knowledge graph from drug, gene, and disease mentions in the biomedical literature; (2) an algorithm for vetting the knowledge graph from drug combinations that may pose a risk of drug interaction; (3) and two querying algorithms for searching the knowledge graph by a single drug or a combination of drugs. The resulting knowledge graph had 844 drugs, 306 gene/protein features, and 19 disease mentions. The original number of drug combinations generated was 2,001. We queried the knowledge graph to eliminate noise generated from chemicals that are not drugs. This step resulted in 614 drug combinations. When vetting the knowledge graph to eliminate the potentially risky drug combinations, it resulted in predicting 200 combinations. Our domain expert manually eliminated extra 54 combinations which left only 146 combination candidates. Our three-layered knowledge graph, empowered by our algorithms, offered a tool that predicted drug combination therapeutics for scientists who can further investigate from the viewpoint of drug targets and side effects.

Abstract: This paper outlines the methodology and results for a two species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA) ) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two species (free-drug and bound-drug) mass transport setup including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of drug between the free and bound-drug states. The model is solved by a 2-D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over our previously developed model using the finite-difference method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 hours (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug.

The central nervous system (CNS) is the final frontier in drug delivery because of the blood-brain barrier (BBB), which poses significant barriers to the access of most drugs to their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role in behavioral functions and abnormal KYNA levels have been observed in neuropsychiatric conditions. The current challenge lies in delivering KYNA to the CNS owing to its polar side chain. Recently, C-3 side chain modified KYNA analogs have been shown to cross the BBB; however, it is unclear whether they retain the biological functions of the parent molecule. This study examined the impact of KYNA analogs, specifically SZR-72, SZR-104, and the newly developed SZRG-21, on behavior. The analogs were administered intracerebroventricularly (i.c.v.), and their effects on the motor domain were compared with those of KYNA. Specifically, open field (OF) and rotarod (RR) tests were employed to assess motor activity and skills. SZR-104 increased horizontal exploratory activity in the OF test at a dose of 0.04 μmol/4 μL, while SZR-72 decreased vertical activity at doses of 0.04 and 0.1 μmol/4 μL. In the RR test, however, neither KYNA nor its analogs showed any significant differences in motor skills at either dose. Side chain modification affects affective motor performance and exploratory behavior, as the results show for the first time. In this study, we showed that KYNA analogs alter emotional components such as motor-associated curiosity and emotions. Consequently, drug design necessitates the development of precise strategies to traverse the BBB while paying close attention to modifications in their effects on behavior.

Wound infection is a common complication of chronic wounds. It can impair healing, which may not occur without external help. Antimicrobial dressings (AMDs) are a type of external help to infected chronic wounds. In this study, highly porous membranes made of only chitosan and containing the antiseptic polyhexanide (poly(hexamethylene biguanide); PHMB) were prepared by cryogelation, aiming to be used in AMDs. These membranes exhibited high water swelling capacity, fast water absorption and high water vapor transmission. The best drug loading method involved simultaneous loading by soaking in a PHMB solution and sterilization by autoclaving, resulting in sterilized, drug-loaded membranes. The drug release kinetics was comparable to that of a commercial PHMB-releasing AMD assayed under the same conditions. These membranes exhibited high antibacterial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, which are bacterial species commonly found in infected wounds, and blood clotting activity. The obtained results suggest that these membranes may be suitable for use in the development of AMDs.

The COVID-19 was described as a respiratory illness, however further studies recognize it as a complex heterogeneous multisystemic disorder. Global efforts have been proposed to combat COVID-19, emerging diverse therapeutic options, in which discovering new drug therapies, development of vaccines and drug repurposing have been considered the most promising approaches to fight the virus. This study aimed to repurpose known drugs for use against the COVID-19, finding better therapeutic options. Seventeen biological databases were used in this study. The genetic algorithm (GA) was performed for a set of drug target classes and COVID-19 proteins as input, whose drug candidates are obtained according to the target similarities found in the target-target similarity predictive network, resulting in a drug-target interaction network. Thus, recommended drugs correspond to the union of the drug subsets found during each GA execution. Twenty-eight drugs were indicated to be the best therapeutic targets for the virus, in special, the Cyclosporine drug was administered as adjuvant to steroid treatment for COVID-19 patients which showed positive outcomes, reducing mortality in moderate and severe cases. The drugs found have used to treat other diseases, evidencing that the COVID-19 is a multisystemic disorder and suggests that the viruses’ mechanism of action presents some comorbidity with other human diseases. Evidence shows that the drugs found in this research might act together to fight the virus in a broader fashion, however further studies including in vitro and in vivo experiments are needed to find the best combination of these drugs.

Drug repurposing, the practice of utilizing existing drugs for novel clinical indications, has tremendous potential for improving human health outcomes and increasing therapeutic development efficiency. The goal of multidisease multitarget drug repurposing, also known as shotgun drug repurposing, is to develop platforms that assess the therapeutic potential of each existing drug for every clinical indication. Our Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun multitarget repurposing implements several pipelines via large scale modelling and simulation of interactions between comprehensive libraries of drugs/compounds and protein structures. In these pipelines, each drug is described by an interaction signature that is then compared to all other signatures that are then sorted and ranked based on similarity. Pipelines within the platform are benchmarked based on their ability to recover known drugs for all indications in our library, and predictions are generated based on the hypothesis that (novel) drugs with similar signatures may be repurposed for the same indication(s). The drug-protein interactions in the platform used to create the drug-proteome signatures may be determined by any screening or docking method but the primary approach used thus far has been an in house similarity docking protocol. In this study, we calculated drug-proteome interaction signatures using the publicly available molecular docking method Autodock Vina and created hybrid decision tree pipelines that combined our original bio- and cheminformatic approach with the goal of assessing and benchmarking their drug repurposing capabilities and performance. The hybrid decision tree pipeline outperformed the corresponding two docking-based pipelines it was synthesized from, yielding an average indication accuracy of 13.3% at the top10 cutoff (the most stringent), relative to 10.9% and 7.1% for its constituent pipelines, and a random control accuracy of 2.2%. We demonstrate that docking based virtual screening pipelines have unique performance characteristics and that the CANDO shotgun repurposing paradigm is not dependent on a specific docking method. Our results also provide further evidence that multiple CANDO pipelines can be synthesized to enhance drug repurposing predictive capability relative to their constituent pipelines. Overall, this study indicates that pipelines consisting of varied docking based signature generation methods can capture unique and useful signal for accurate comparison of drug-proteome interaction signatures, leading to improvements in the benchmarking and predictive performance of the CANDO shotgun drug repurposing platform.

Nanotechnology has enabled the development of novel therapeutic strategies such as targeted nanodrug delivery systems, control and stimulus-responsive release mechanisms, and the production of theranostic agents. As a prerequisite for the use of nanoparticles as drug delivery systems, the amount of loaded drug must be precisely quantified, a task for which two approaches are currently used. However, both approaches suffer from the inefficiencies of drug extraction and of the solid-liquid separation process, as well as from dilution errors. This work describes a new, reliable, and simple method for direct drug quantification in polymeric nanoparticles using attenuated total reflection Fourier transform infrared spectroscopy, which can be adapted for a wide variety of drug delivery systems. Silk fibroin nanoparticles and naringenin were used as model polymeric nanoparticle carrier and drug, respectively. The specificity, linearity, detection limit, precision and accuracy of the spectroscopic approach were determined in order to validate the method. A good linear relation was observed within 0.00 to 7.89 % of naringenin relative mass with an R2 of 0.973. The accuracy was determined by the spike and recovery method. Results showed an average 104% recovery. The limit of detection and limit of quantification of the drug loading content were determined to be 0.3 and 1.0 %, respectively. The method's robustness is demonstrated by the notable similarities between the calibrations carried out in two different equipment and institutions.

Bioavailability, release and stability of pharmaceuticals under physicochemical conditions is the major cause of drug candidates failing during their clinical trials. Therefore, extensive efforts have been invested in the development of novel drug delivery systems able to transport drugs to a desired site and to improve the bioavailability. Hydrogels, and peptide hydrogels in particular, have been extensively investigated due to their excellent biocompatibility and biodegradability properties. However, peptide hydrogels often have weak mechanical strength, which limits their therapeutic efficacy. Therefore, a number of methods in improving their rheological properties have been established. This review will cover the broad area of drug delivery focusing on the recent developments in this research field. We will discuss the variety of different types of nanocarrier drug delivery systems, and then, more specifically, the significance and perspectives of peptide-based hydrogels. In particular, the interplay of intermolecular forces that govern the self-assembly of peptide hydrogels, progress made in understanding the distinct morphologies of hydrogels, and applications of non-canonical amino acids in hydrogel design will be discussed in more detail.

Aging affects structure and functions of all organs and systems in the organism. Significant changes in the hormonal levels are registered in elderly individuals. They often become a predisposition for chronic diseases, including cardiovascular, neurodegenerative, and metabolic disorders. Therefore, immense scientific efforts are concentrated in the investigation of molecular mechanisms and drugs with potential to diminish the senescent hormonal changes. Sirtuin 1 (SIRT1), a member of the sirtuin deacetylases family, has been extensively studied as regulator of multiple pathways related to antioxidant properties, optimal immune response and metabolism. SIRT1 plays a crucial role in regulating various hormonal pathways and maintaining homeostasis. In the present work we review the interplay between SIRT1 and hormonal regulations, including endocrine role of the hypothalamic-pituitary-thyroid, -adrenal, -gonadal, and -liver axes, of other endocrine glands and of non-endocrine tissues in aging body. The application of natural SIRT1 activators, such as resveratrol, curcumin, paeonol, and Buyang Huanwu Decoction, for treatment of senescence and aging is discussed. SIRT1 activators improve mitochondrial function, reduce oxidative stress, and promote longevity but their clinical application is limited by low bioavailability and poor permeability across biological barriers. For this reason, advanced delivery strategies, including nose-to-brain drug delivery and nanotechnology-based formulations, are reviewed.

Canine parvovirus (CPV) infection is a widespread ailment among young dogs globally, characterized by high morbidity, mortality, and significant infectivity. Due to its grim prognosis, it is often likened to canine "cancer" with a medium-term mortality rate of 46.43% and late-stage mortality reaching up to 100%.Current treatment modalities primarily encompass fluid therapy, antiemetics, antimicrobial medications, pain relievers, and enteral nutrition. However, the absence of specific internationally recognized medications necessitates substantial care expenses. This review aims to elucidate recent advancements in pharmacological interventions for mitigating CPV infection symptoms, underscoring the potential of novel pharmaceutical technologies in veterinary medicine to enhance clinical outcomes for afflicted animals and their caregivers，lay a theoretical foundation for the development of specific drugs.

Diabetes is a major health concern that the next-generation of on-demand insulin releasing implants may overcome for personalized therapy. Therein, 3D-printed phenylboronic acid-containing subcutaneous implants with on-demand glucose-triggered drug release abilities are produced using high resolution stereolithography technology. To that end, the methacrylation of phenylboronic acid is targeted following a two-step reaction. The resulting photocurable phenylboronic acid derivative is accordingly incorporated within bioinert polyhydroxyethyl methacrylate-based hydrogels at varying loadings. The end result are sub-centimeter scaled 3D-printed bionert implants that can be remotely activated with 1,2-diols and 1,3-diols such as glucose for on-demand drug administration such as insulin. As a proof of concept, varying glucose concentration from hypoglycemia to hyperglycemia levels readily allow the release of pinacol, i.e. a model molecule with similar release properties than insulin, at respectively low and high rates. In addition, the results demonstrated that adjusting the geometry and size of the 3D-printed part is a simple and suitable method for tailoring the release behavior and dosage.

Herein, we investigated hydrogels composed of boronic Acid functionalized alginate and blended with polyvinyl alcohol of different molecular weights to control the release of metoclopramide hydrochloride (MTC) as a function of pH and shear stress. The functionalization of alginate introduced dynamic covalent bonding and pH-responsive properties that can modulate network connectivity. The study investigated the viscoelastic properties of the hydrogels, their drug release profiles, and their responsiveness to changes in pH and shear forces. The results showed higher PVA molecular weight and alkaline pH conditions increased hydrogel viscosity and stiffness due to a more stable and interconnected network structure than acidic pH. Metoclopramide release revealed that the hydrogels exhibited pH-responsive drug release behavior. The drug was more readily released under acidic conditions due to the instability of sp2-hybridized boronate ester bonds. The influence of shear forces on the release of metoclopramide was also investigated at shear rates of 1, 10, and 100 s-1, revealing their effect on matrix stiffening. The research shows that AlgBA/PVA hydrogels have unique properties, such as dynamic covalent bonding, that make them sensitive to external mechanical forces. This sensitivity makes them ideal for applications where physiological conditions trigger drug release

Today, polymeric Drug Delivery Systems (DDS) appear as an interesting solution against bacterial resistance, having great advantages such as low toxicity, biocompatibility, and biodegradability. In this work, two polyketones (PK) have been post-functionalized with taurinate (PKT) or sulfanilate (PKSK) and employed as biocompatible carriers for Vancomycin against bacterial infections. Mod-ified PKs were easily prepared by Paal-Knorr reaction and loaded with Vancomycin at variable pH. All polymers were characterized by FT-IR, DSC, TGA, SEM and elemental analysis. Antimicrobial activity was tested against Gram positive Staphylococcus aureus ATCC 25923 and correlated to the different pH used for its loading (between 2.3 and 8.8). Distinctively, minimum inhibitory con-centrations achieved with PKT and PKSK loaded with Vancomycin are similar, 0.23μg/mL and 0.24μg/mL respectively, i.e. six times lower that Vancomycin alone. The use of post-functionalized aliphatic polyketones has thus been demonstrated to be a promising way to obtain very efficient polymeric DDS.

Salmonella sp. is a globally prevalent organism responsible for causing salmonellosis, a foodborne illness. Salmonella Typhimurium represents a type of Salmonella sp. not associated with typhoid fever but capable of causing stomach and intestinal inflammation or severe infection. In the present study, 150 uncharacterized proteins of S. Typhimurium were randomly selected from UniProtKB and analyzed using TMHMM, PROSITE, STRING, DEG, and BLASTp. Results indicated that 32 uncharacterized proteins (21%) were predicted to be transmembrane proteins involved in various biological pathways. Among them, 30 transmembrane proteins were predicted to be essential and non-host homologous. This study's findings suggest their potential as drug targets against salmonellosis.

Cancer, characterized by abnormal cell proliferation driven by genetic mutations, remains a significant health challenge. Tailoring effective therapies depends on factors like tumor location, grade, and stage, alongside patient condition. Leveraging Nano-carrier encapsulated drugs offers a promising avenue, as they accumulate preferentially at tumor sites, enhancing therapeutic efficacy while mitigating side effects. Polymeric Nano-carriers, with their customizable properties, further optimize drug delivery efficiency and specificity. Incorporating active targeting ligands such as antibodies, carbohydrates, peptides, folates, and aptamers-onto polymeric nanoparticle surfaces through techniques like functionalization, adsorption, and conjugation plays a pivotal role in directing therapeutic agents to tumor cells. Consequently, polymeric nanoparticles emerge as the carrier of choice for delivering drugs to various tumor types, including breast, colon, lung, prostate, liver, and spleen tumors.

Chemical combinations are believed to reduce drug toxicity, delay cancer cell growth, and achieve enhanced efficacy compared with single active drugs. This research investigated the synergistic effect of DOX and Zm-093, a new sulfonamide derivative, on improving the potential for inducing apoptosis in breast cancer (BC) cell lines. First, the Zm-093 compound was synthesized and its structure was confirmed by FT-IR and NMR. Then, the IC50 values for DOX and Zm-093 were calculated to be 1.21 and 51.24 μM, respectively. To investigate the synergistic effect, Compusyn software was utilized to calculate the combination index (CI). Different methods, including western blotting, flow cytometry, and TUNEL, were used to evaluate the potential synergistic effects of these compounds on inducing apoptosis in MCF-7 cells. Combining the indexes obtained at all concentrations revealed synergistic results. The proapoptotic proteins Bax, tBid, and caspase-3, however, increased 2.4, 3.3, and 5.7 times more than those in the control group. Flow cytometry analysis and the TUNEL method in cells treated with DOX and Zm-093 showed that apoptosis was significantly higher than in other groups. The results confirmed the synergistic effect of DOX and ZM-093 on apoptotic factors expression in MCF-7 cells.

Abstract: A. baumannii exhibits resilience in harsh environments and progressively develops resistance to diverse antibacterial agents over time. This adaptability poses a significant challenge in treating an infection caused by this bacterium within healthcare settings. The presence of peptidoglycan, a crucial precursor for cell wall synthesis, contributes to this challenge. Peptidoglycan serves not only as a structural support in bacterial cells but also provides protection against adverse environmental conditions. The synthesis of the peptidoglycan layer involves a group of substrates such as N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), within a three-partitioned process occurring in the membrane, periplasmic space, and cytoplasm of each bacterium. Initiated in the cytoplasm and extending to the inner cell membrane, this synthesis starts with the production of nucleotide precursors. The first step involves the synthesis of UDP-GlcNAc, orchestrated by Glm (GlmS, GlmM, and GlmU) enzymes using fructose-6-phosphate. Subsequently, enzymes from the Mur family, namely MurB, MurA, MurD, MurC, MurI, MurF, and MurE, synthesize UDP-N-acetylmuramyl-pentapeptide (UDP-Mpp) from UDP-GlcNAc. Concurrently, on the cytosolic side, the production of membrane-surrounded undecaprenyl phosphate occurs, involving membrane-side proteins MraY and MurG in the biosynthesis of peptidoglycan. This review emphasizes updated information on Mur family proteins, encompassing physicochemical properties, nature of binding site, number and type of binding site residues, functional domain details, three-dimensional structural aspects, and their functions within bacterial cells. Special attention is directed towards their enzymatic role in peptidoglycan biosynthesis due to the limited availability of precursors in the market. Additionally, the review provides a comprehensive summary of existing inhibitors and ongoing efforts in identifying new targeted inhibitors, recognizing these enzymes as potential candidates for antibacterial drug design and discovery.

Glioblastoma (GB), even though not frequent, is an extremely aggressive brain tumor, with a strong impact on patient outcomes, in terms of both length and quality of life. The protocol estab-lished by Stupp and coworkers in 2005, based on radiotherapy and temozolomide chemotherapy, after maximum safe surgical resection, remains the gold standard for GB treatment. However, it is evident nowadays that the extreme GB intratumoral and intertumoral heterogeneity, invasive-ness and recurrence are not compatible with a routinary and unfortunately uneffective treatment. In this review article, we summarize the principal challenging issues in finding new valuable therapies for GB and focus on the impact that extracellular vesicle (EV) research and exploitation can have in the field. EVs are natural particles delimited by a lipidic bilayer and full of functional cellular content, released and uptaken by cells as key means of cell communications. Moreover, being stable in body fluids, well-immunotolerated, able to cross physiological, inter-species, and inter-kingdom barriers, and to target specific cells, releasing inherent or externally loaded functionally active molecules, EVs can be potentially ideal allies in fighting GB and assuring to GB patients a better prognosis. Here we report the main results obtained until now, focusing on both EV sources and molecular cargo used in the different functional studies, mainly in vivo. Finally, we perform a SWOT analysis reporting both the main advantages and the pitfalls of developing EV-based GB therapeutic strategies to highlight the main directions to explore for realizing the promise of EV exploitation for GB treatment.

The field of biobanking human biospecimens has evolved significantly, transitioning from the basic, often poorly documented collection of clinical leftovers kept privately to well-organized and extensively documented collections overseen by both commercial and non-profit platforms. The increasing demand for high-quality and clinically annotated biospecimens is propelled by unprecedented levels of health research activities. Meeting this growing demand presents both new opportunities and challenges, particularly in developing strategies to establish international biospecimen sourcing (IBS) platforms. These platforms aim to facilitate collaboration among biobanks to address future biospecimen needs. In this manuscript, we delve into the advantages and challenges of establishing IBS platforms to provide high-quality and cost-effective biospecimens to drive drug discovery research, ultimately leading to improved health and quality of life for everyone.

Cardiovascular disease (CVD) accounts for nearly one-third of all global fatalities, establishing itself as a leading cause of death. To address this pressing issue, there is a growing demand for improved diagnostic methods and secure, non-invasive imaging techniques that can deliver precise insights into the progression of CVD. The success of personalized therapy for CVD depends on a couple of critical factors: accurate diagnosis and early detection. Therapeutic options for conditions like CVD, which develop over several decades, are highly specific to the individual's condition and the stage of the disease. In the field of biomedicine, nanotechnology has become increasingly prominent as a tool with diverse applications, including diagnostics, biosensing, and drug delivery. This review article offers an in-depth look at the most recent developments in the utilization of nanotechnology for detecting and managing prevalent cardiovascular diseases, providing valuable insights into this crucial area of healthcare research.

The contamination of aquatic environments by pharmaceutical products consistently takes the attention of researchers due to the compounds' toxicity even at low concentrations. In response, we have developed an ecologically sustainable biosurfactant derived from a microorganism and incorporated into the bacterial cellulose. This bioproduct, along with the bacterial cellulose itself, was employed as a sorbent for pharmaceuticals (hormones and paracetamol) present in water. Bacterial cellulose membranes were generated through the cultivation of Gluconacetobacter xylinus ATCC 53582. The biosurfactant was produced by pre-inoculating Bacillus subtilis in a synthetic medium, followed by immersing the bacterial cellulose membranes in the biosurfactant solution, for incorporation. Tests were conducted using water experimentally contaminated with parace-tamol and 17α-ethinylestradiol (EE2), evaluating the biosurfactant's effect on bacterial cellulose sorption. Paracetamol levels were analyzed using spectrophotometry, and EE2 levels were as-sessed using high-performance liquid chromatography. In summary, bacterial cellulose exhibited superior adsorption for EE2 compared to paracetamol. The incorporation of biosurfactant onto bacterial cellulose reduced hormone adsorption but enhanced paracetamol sorption. Our findings indicated that adsorption is more effective with bacterial cellulose in its original and freeze-dried forms, without the incorporation of biosurfactant. Notably, we achieved more promising results in remediating the hormone EE2 compared to the paracetamol.

Chitosan nanoparticle delivery systems have potential for enhancing bone healing and addressing osteomyelitis. The objective was to deliver antimicrobial agents capable of preventing or treating osteomyelitis. Each formulation was optimized to achieve desired characteristics in terms of size (ranging from 100 to 400 nm), PDI (less than 0.5), zeta potential (typically negative), and in vitro release profiles for gentamicin. Entrapment percentages varied with gentamicin ranging from 10% to 65%. The chitosan nanoparticles exhibited substantial antimicrobial efficacy, particularly against both P. aeruginosa and MRSA, with zones of inhibition ranging from 13 to 24 mm and complete reduction in colony forming units observed between 3 to 24 hours. These chitosan nanoparticle formulations loaded with antimicrobials hold promise for addressing orthopedic complications.

Xpert MTB/RIF is rapid molecular diagnostic tool capable of simultaneously detecting Mycobacterium tuberculosis and rifampicin resistance. This study aimed to access the diagnostic precision of Xpert MTB/RIF assay to detect pulmonary and extra-pulmonary tuberculosis and to evaluate the performance for the detection of rifampicin resistance. Of 37695 samples, 7156(18.98%) were tuberculosis positive, 509(7.11%) were rifampicin-resistant. The sensitivity, specificity, PPV, NPV, Diseases prevalence and accuracy of Xpert MTB/RIF assay for PTB were 99.87% (95%CI:99.75-99.94), 99.92%(95%CI:99.88-99.95), 99.71%(95%CI:99.54-99.82),99.97%(95%CI:99.93-99.98),21.38% (95%CI:20.92-21.86),and 99.91%(95%CI:99.87-99.94), respectively. For EPTB, the sensitivity, specificity, PPV, NPV, Diseases prevalence and accuracy of Xpert MTB/RIF assay accounted for 99.45% (95%CI:98.73-99.82),99.84%(95%CI:99.73-99.92),98.70%(95%CI:97.73-99.25),99.93% (95%CI:99.84-99.97),10.64%(95%CI:9.99-11.31),and 99.80%(95%CI:99.68-99.88), respectively. Despite its high sensitivity for detecting tuberculosis and rifampicin resistance, Xpert MTB/RIF had contradictory results for 20.5% of cases among patients with negative smear results and 54.9% of cases among patients with a high risk of Multidrug-resistant tuberculosis. Of 47 fluoroquinolone-resistant, 16.56% (26/157) of Multidrug-resistant tuberculosis isolates and 4.02% (20/498) isoniazid-resistant are fluoroquinolone-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Further, our study indicated that increased fluoroquinolone resistance among Rifampicin-resistant and isoniazid-resistant tuberculosis endangers the success of newly endorsed MDR-TB regimens.

Drug delivery through Liposomes has shown tremendous potential in terms of the therapeutic application of nanoparticles. There are several drug-loaded liposomal formulations approved for clinical use that help mitigate harmful effects of life-threatening diseases. Developments in the field of liposomal formulations and drug delivery have made it possible for clinicians and researchers to find therapeutic solutions for complicated medical conditions. A key aspect in the development of drug-loaded liposomes is a careful review of optimization techniques to improve the overall formulation stability and efficacy. Optimization studies help in improving/modulating the various properties of drug-loaded liposomes and are vital for the development of this class of delivery systems. A comprehensive overview of the various process variables and factors involved in the optimization of drug-loaded liposomes is presented in this review. The influence of different independent variables on drug release and loading properties with the application of a statistical experimental design is also explained in this article.

The COVID-19 pandemic has unveiled the critical role that supercomputers play in addressing global health crises. This perspective article explores the transformative impact of supercomputing in pandemic response, highlighting how these powerful machines have transitioned from crisis management tools to essential components of preparedness strategies. In this article, we examine the key contributions of supercomputers in combating the pandemic, including their ability to accelerate scientific research, facilitate data analysis, model complex scenarios, and optimize resource allocation. Furthermore, we delve into the role of supercomputing in strengthening public health infrastructure and preparedness. We analyze the lessons learned from the pandemic and emphasize the need for proactive investment in supercomputing capabilities, data infrastructure, and computational expertise as a crucial element of pandemic preparedness efforts. By harnessing the potential of supercomputers, countries can establish robust computational frameworks that enable real-time monitoring, early detection, and effective response to future outbreaks. Moreover, we address the challenges faced by supercomputing initiatives, including the need for enhanced international collaboration, equitable access to computing resources, and the ethical considerations associated with data privacy and security. We discuss potential strategies to overcome these challenges and foster a global network of interconnected supercomputing centers dedicated to pandemic preparedness and response. Finally, we highlight ongoing research and development efforts aimed at advancing supercomputing technologies, such as exascale computing and quantum computing, and their potential to revolutionize pandemic response. We emphasize the importance of sustained investment in research and development to ensure that supercomputing remains at the forefront of future pandemic preparedness strategies.

Encapsulated nanofibers have emerged as a promising approach for the treatment of acne, owing to their ability to provide controlled release, targeted delivery, increased efficacy, and improved stability. Electrospinning is a well-established method for producing encapsulated nanofibers and has been shown to be effective for encapsulating various active ingredients. However, there are still several challenges that need to be addressed in the development of encapsulated nanofibers for acne treatment. One major challenge is the need for comprehensive in vitro and in vivo studies to evaluate the safety and efficacy of these treatments. The cost and scalability of production also need to be considered to make these treatments accessible and affordable for patients. In addition, the long-term stability of encapsulated active ingredients is another challenge in the development of encapsulated nanofibers for acne treatment. Regulatory frameworks need to be developed to ensure the safety and efficacy of these treatments. Future research may focus on developing multifunctional nanofibers that combine active ingredients with other properties, such as antimicrobial, anti-inflammatory, and wound-healing properties, to provide a comprehensive approach to acne treatment. Moreover, the development of nanofiber-based skincare products may have a significant impact on the cosmetic industry. Overall, while there are still challenges to overcome, the potential benefits of encapsulated nanofibers for acne treatment make them an exciting and promising area of research for the future. In particular, the integration of smart drug delivery systems and responsive materials may enable the development of more personalized and effective treatments for acne. The development of new materials and encapsulation techniques, as well as the exploration of combination therapies that target multiple aspects of acne pathogenesis, are also future perspectives for encapsulated nanofibers in acne treatment.

Background – Mali was one of the first countries in sub-Saharan Africa to initiate a National Schistosomiasis Control Programme (NSCP) in 1982. The WHO's 2021-30 roadmap sets out criteria for eliminating and controlling schistosomiasis as a public health problem. Our study aimed to assess the impact of annual Mass Drug Distribution (MDD) with praziquantel (PZQ) among school-age children in the sentinel sites (SS) of the NSCP. Methods –The study took place at twelve SS in Kayes and Koulikoro regions. Two-round observational cross-sectional studies were carried out in December 2014-2015 and in April 2018 after four to five years of annually MDD. Overall, 2442 schoolchildren aged 7 to 14 were successfully examined. The urine filtration and Kato-Katz method were used for determining Schistosoma haematobium and S. mansoni eggs, respectively. Results –Of the twelve SS treated from 2014-2015, one has achieved the criterion of elimination of S. haematobium as a public health problem (prevalence of heavy intensity infection PHI < 1%) (ie, ≥50 S. haematobium eggs per 10 mL of urine or ≥400 S. mansoni eggs per g of stool), four met the morbidity control criterion (PHI< 5%) while two sites remained confined below the morbidity control criterion (PHI>5%). Five SS had no heavy intensity infection. The prevalence of S. mansoni was less than 1%. Conclusion –The impact evaluation of MDD with praziquantel in the SS of NSCP highlights that MDD has significantly reduced the PHI of schistosomiasis. However, the high prevalence of schistosomiasis or its increase in some sites requires in-depth studies.