Innovative Drugs Research Articles

Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans.

Candidiasis, which presents a substantial risk to human well-being, is frequently treated with azoles. However, drug-drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)-approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle-mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole-mediated liver enzyme inhibition and avoids export-mediated drug resistance in C. albicans.

1549P Accelerating access to innovative oncology drugs: Insights from France's early access reform

1549P Accelerating access to innovative oncology drugs: Insights from France's early access reform

New Evidence of the Impact of the National Drug Price Negotiation Policy on the Availability, Utilization, and Cost of Anticancer Medicines in China: An Interrupted Time Series Study.

The increasing global burden of cancer has become a significant challenge for public health. The Chinese government introduced the National Drug Price Negotiation (NDPN) policy with the goal of lowering the prices of innovative drugs and enhancing their accessibility. This study aims to evaluate the impact of the 2021 NDPN policy on the availability, utilization, and cost of anticancer medicines in China. Data was gathered from 1519hospitals between April 2021 and December 2022, with a focus on eight anticancer drugs affected by the 2021 NDPN policy. The availability, Defined Daily Doses (DDDs), and cost per Defined Daily Dose (DDDc) before and after the intervention were evaluated through interrupted time series analysis. The NDPN policy resulted in a substantial 5.10% increase in the availability of anticancer drugs (p < 0.001). Utilization also experienced a significant surge, with an immediate increase of 11,254.36 DDDs (p < 0.001) and a monthly increase of 1208.28 DDDs (p < 0.001) following policy implementation. The DDDc decreased by US$ 111.00 (p < 0.001) immediately after the policy. Disparities in regional drug utilization were evident, with higher usage in the eastern region. The 2021 NDPN policy has notably enhanced the availability and utilization of anticancer medications in China while reducing their cost, in line with the policy's objectives. However, continuous monitoring is essential to ensure sustained access and to tackle regional disparities in drug utilization.

Unlocking the Potential of Drug Delivery Systems: A Comprehensive Review of Formulation Strategies and Technologies in the Field of Pharmaceutics

: The creation of innovative drug delivery systems to enhance therapeutic effectiveness, safety, and patient compliance has resulted in considerable developments in pharmaceutics in recent years. The most recent formulation techniques and technologies are reviewed in this article to improve medication distribution and accomplish specific therapeutic goals. : This article thoroughly summarizes the most recent formulation techniques and technologies used to enhance medication delivery and provide specific therapeutic effects. It discusses the variety of medication delivery methods, including nanoparticles, liposomes, micelles, and dendrimers, and explores the application of nanotechnology and biotechnology in drug delivery. Additionally, the paper emphasizes the significance of targeted drug delivery systems and their capacity to cross biological barriers including the blood-brain barrier and tumor microenvironment. : The review also addresses the challenges faced in developing and commercializing drug delivery systems and suggests potential solutions to overcome them. Furthermore, the article emphasizes the role of computational modeling and simulation in designing and optimizing drug delivery systems. : Overall, this review paper offers insightful information for pharmaceutics researchers, scientists, and practitioners that will help in the creation of novel drug delivery systems that improve patient outcomes and quality of life.

Strategic Resilience and Financial Analysis of Merck &amp; Co., Inc.: Navigating Challenges and Opportunities in the Pharmaceutical Industry

This study provides a comprehensive analysis of Merck &amp; Co., Inc. (MRK), a prominent player in the global pharmaceutical industry, known for its significant contributions to healthcare through the development of innovative drugs and vaccines. Merck's core focus areas include pharmaceuticals, vaccines, animal health, and healthcare services, with its flagship oncology drug Keytruda being a major revenue contributor. The company faces challenges such as regulatory changes in drug pricing and competition from biosimilars and generics. To mitigate these challenges, Merck has initiated restructuring plans, including the 2024 Restructuring Plan, to optimize operational efficiency and achieve significant cost savings. The paper also presents a comparison of Merck's financial performance with industry peers - Johnson &amp; Johnson, AbbVie and Bristol-Myers Squibb - and evaluates liquidity, solvency and profitability metrics. Despite certain challenges, Merck's robust market positioning, strategic acquisitions, and active involvement in the development of COVID-19 vaccines and therapeutics underscore its potential for sustainable growth. Overall, the study concludes that Merck's strategic investments, coupled with its strong financial position and proactive restructuring efforts, make it an attractive investment prospect, particularly in its core therapeutic areas of oncology and immunology. This paper suggests that future research could delve deeper into the long-term impact of R&amp;D investments, the intricacies of restructuring plans, and evolving market trends to provide a more nuanced understanding of Merck's strategic planning.

Financial Analysis of Enterprises in Pharmaceutical Industry Based on the Harvard Analytical Framework —— Take TongRenTang, Guangzhou Baiyunshan, Yunnan Baiyao as Example

Under the pressure of aging population and impact of COVID-19, the importance of pharmaceutical industry cannot be neglected. This passage will utilize Harvard Analytical Framework to study the financial situation and development opportunities of three old public brands with analyzing information from their annual reports and East Money. Firstly, this passage will use PEST model to analyze the industrial advantages and disadvantages from four aspects, Politics, Economy, Society and Technology. Then this passage will focalize on specific analysis of companies, with accounting analysis and financial analysis. Compared with others, the pharmaceutical industry in China has little external interference. Generally, enterprises listed are promising and competitive. Despite a few adverse events, they all have good solvency and profitability. It will be the foundation of R&amp;D. It is worth noting that with the support of government policies, the R&amp;D of innovative drugs will be a crucial point in this thriving industry. This passage can be a reference for investors and managers of enterprises.

Synthesis and in vitro study of biodegradable and thermoresponsive polymer based on polysuccinimide for drug delivery

Hydrogels, defined as polymer networks with a high water content and insoluble in water, have emerged as pivotal materials in biomedical research due to their resemblance to the natural extracellular matrix. The aim of this study is to develop an injectable, thermoresponsive, and biodegradable hydrogel. The hydrogel (PSI-t) was derived from poly (aspartic acid) (PSI) by grafting hydrophobic dodecylamine (DA) and hydrophilic ethanolamine (EA) groups onto its backbone. PSI-t was found to exhibit a unique sol state at room temperature, which facilitates facile injection, and undergoes rapid gelation at physiological temperatures, highlighting its potential as an injectable thermosensitive hydrogel for targeted drug delivery. In vitro tests confirmed the biocompatibility of the thermosensitive hydrogel, and sustained drug release studies using the model drug, acetaminophen (AP), underscored the efficacy of the hydrogel as a controlled release vehicle. Furthermore, the hydrogel was found to be easily eliminated through bio-hydrolysis, thus enabling prolonged drug effects while mitigating any potential toxicity. These findings suggest that PSI-t is a promising candidate for an innovative and injectable drug delivery system in biomedical applications.

AI-powered omics-based drug pair discovery for pyroptosis therapy targeting triple-negative breast cancer

Due to low success rates and long cycles of traditional drug development, the clinical tendency is to apply omics techniques to reveal patient-level disease characteristics and individualized responses to treatment. However, the heterogeneous form of data and uneven distribution of targets make drug discovery and precision medicine a non-trivial task. This study takes pyroptosis therapy for triple-negative breast cancer (TNBC) as a paradigm and uses data mining of a large TNBC cohort and drug databases to establish a biofactor-regulated neural network for rapidly screening and optimizing compound pyroptosis drug pairs. Subsequently, biomimetic nanococrystals are prepared using the preferred combination of mitoxantrone and gambogic acid for rational drug delivery. The unique mechanism of obtained nanococrystals regulating pyroptosis genes through ribosomal stress and triggering pyroptosis cascade immune effects are revealed in TNBC models. In this work, a target omics-based intelligent compound drug discovery framework explores an innovative drug development paradigm, which repurposes existing drugs and enables precise treatment of refractory diseases.

Pharmacokinetic Evaluation of Amlodipine Tablet Compared with Norvask® Tablet in Healthy Indonesian Adults

This study objective to evaluate the pharmacokinetics of Amlodipine 10 mg Produced by PT. Tropica Mas Pharmaceuticals compared to Norvask® 10 mg Tablet Produced by PT. Pfizer Indonesia, in healthy Indonesian Adults through bioequivalence study. This study is utilized by randomized, single-dose, openlabel, two-way cross-over design with a washout period 14 days and fasting. This study involved 18 subjects, with only 17 subjects included in the statistical analysis, because 1 subject withdrew due to diarrhoea in the 2nd period. Plasma samples were collected 17 times for 72-hour per period. Amlodipine concentrations were measured using LCMS/MS. Bioequivalence was determined by value of 90% confidence interval (CI) with α = 5.00% within the range of 80.00–125.00% for AUC and Cmax. The geometric mean ratios (90% CI) of the test drug vs. the innovator drug were 101.67% (97.16 – 106.39) for AUC0-t and 100.46% (95.00 – 106.23) for Cmax. Based on the result, the test drug is bioequivalent to the comparator drug.

Next-generation pediatric care: nanotechnology-based and AI-driven solutions for cardiovascular, respiratory, and gastrointestinal disorders.

Global pediatric healthcare reveals significant morbidity and mortality rates linked to respiratory, cardiac, and gastrointestinal disorders in children and newborns, mostly due to the complexity of therapeutic management in pediatrics and neonatology, owing to the lack of suitable dosage forms for these patients, often rendering them "therapeutic orphans". The development and application of pediatric drug formulations encounter numerous challenges, including physiological heterogeneity within age groups, limited profitability for the pharmaceutical industry, and ethical and clinical constraints. Many drugs are used unlicensed or off-label, posing a high risk of toxicity and reduced efficacy. Despite these circumstances, some regulatory changes are being performed, thus thrusting research innovation in this field. Up-to-date peer-reviewed journal articles, books, government and institutional reports, data repositories and databases were used as main data sources. Among the main strategies proposed to address the current pediatric care situation, nanotechnology is specially promising for pediatric respiratory diseases since they offer a non-invasive, versatile, tunable, site-specific drug release. Tissue engineering is in the spotlight as strategy to address pediatric cardiac diseases, together with theragnostic systems. The integration of nanotechnology and theragnostic stands poised to refine and propel nanomedicine approaches, ushering in an era of innovative and personalized drug delivery for pediatric patients. Finally, the intersection of drug repurposing and artificial intelligence tools in pediatric healthcare holds great potential. This promises not only to enhance efficiency in drug development in general, but also in the pediatric field, hopefully boosting clinical trials for this population. Despite the long road ahead, the deepening of nanotechnology, the evolution of tissue engineering, and the combination of traditional techniques with artificial intelligence are the most recently reported strategies in the specific field of pediatric therapeutics.

Ferrocene-functionalized magnetic core-shell nanoparticles based on hydrosilylation reaction for pH-responsive doxorubicin delivery system

This study describes the development of an innovative pH-sensitive drug delivery system (DDS) utilizing ferrocene (Fc) and magnetic nanoparticles (MNPs) for cancer therapy. One potential method for generating a diverse range of functional NPs involves attaching functional substances to MNPs. In this investigation, we display the successful modification of Fe3O4 NPs by an Fc derivative (4-Ferrocenylbutyl)dimethylsilane through a hydrosilylation reaction toward the synthesis of the Fe3O4@SiO2@VTES@Fc nanocarrier (NC). The doxorubicin (DOX) drug was loaded onto Fe3O4@SiO2@VTES@Fc NC with a drug loading capacity of about 80 % via π-π stacking interactions. Also, the prepared materials were thoroughly characterized using FT-IR, XRD, FE-SEM, EDX-MAP, VSM, DAPI, MTT, antioxidants, and CV techniques. In vitro studies on the release of DOX from Fe3O4@SiO2@VTES@Fc NC indicated a pH-responsive behavior with a lower release rate (< 10 %) at pH 7.4 compared to pH 5 (approximately 70 %) over a period of 96 h. Moreover, cytotoxicity assessments demonstrated notable cytotoxic effects of DOX-loaded Fe3O4@SiO2@VTES@Fc on MCF-7 cells (IC50 value: ∼8 µg/mL). The study findings suggest that the fabricated magnetic core-shell NC (Fe3O4@SiO2@VTES@Fc/DOX) exhibits stimulus-responsive behavior and holds promise as a sophisticated approach to specifically transport therapeutic agents into tumor sites while minimizing exposure to healthy tissues.

A Point Cloud Graph Neural Network for Protein-Ligand Binding Site Prediction.

Predicting protein-ligand binding sites is an integral part of structural biology and drug design. A comprehensive understanding of these binding sites is essential for advancing drug innovation, elucidating mechanisms of biological function, and exploring the nature of disease. However, accurately identifying protein-ligand binding sites remains a challenging task. To address this, we propose PGpocket, a geometric deep learning-based framework to improve protein-ligand binding site prediction. Initially, the protein surface is converted into a point cloud, and then the geometric and chemical properties of each point are calculated. Subsequently, the point cloud graph is constructed based on the inter-point distances, and the point cloud graph neural network (GNN) is applied to extract and analyze the protein surface information to predict potential binding sites. PGpocket is trained on the scPDB dataset, and its performance is verified on two independent test sets, Coach420 and HOLO4K. The results show that PGpocket achieves a 58% success rate on the Coach420 dataset and a 56% success rate on the HOLO4K dataset. These results surpass competing algorithms, demonstrating PGpocket's advancement and practicality for protein-ligand binding site prediction.

Evaluating the role of amino acids and isothermal dry particle coating in modulating buccal permeation of large molecule drug vancomycin

The formulation and delivery of macromolecules through the oral route pose considerable challenges due to factors such as large molecular weight, pH sensitivity, and limited formulation approaches. This challenge is compounded if the drug is poorly permeable, necessitating innovative drug delivery strategies. Vancomycin, a widely prescribed glycopeptide antibiotic, has an oral bioavailability of less than 10%, leading to predominantly intravenous administration and potential patient discomfort. This study explores the potential of the buccal route as a non-invasive, highly vascularised alternative route of administration, offering a rapid onset of action while bypassing the first-pass metabolism. In this study, vancomycin was coated with L-glutamic acid using an isothermal dry particle coater to modulate permeation through the buccal cell line, TR146. Results confirm significant impact of both amino acid concentration and dry particle coating on the rate and extent of drug permeability. With the introduction of L-glutamic acid and utilisation of the isothermal dry particle coater, vancomycin’s permeation profile increased six-fold compared to the control due to the formation of drug ion-pair complex. Imaging studies showed the presence of layered micronized glutamic acid particles on the surface of dry coated vancomycin particles which confirms the role of dry coating and amino acid concentration in modulating drug permeation. Microbiology experiments in Staphylococcus aureus, minimum inhibitory concentration and biofilm disruption studies, provided confirmatory evidence of antimicrobial activity of dry coated glutamic acid-vancomycin ion pair particulate structure. This study demonstrates, for the first-time, buccal delivery of dry coated large molecule drug, vancomycin, through controlled deposition of amino acid using innovative particle coating strategy.

The value of the reflective discussion in decision-making using multi-criteria decision analysis (MCDA): an example of determining the value contribution of tabelecleucel for the treatment of the Epstein Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD)

BackgroundThe aim of this study was to assess the contribution of the reflective multidisciplinary discussion in determining the value contribution of innovative drugs through the multi-criteria decision analysis (MCDA). This methodology considers all relevant criteria for healthcare decision-making in a global, transparent, and systematic manner and from the perspective of relevant stakeholders. The determination of value contribution of tabelecleucel for the treatment of Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV+ PTLD) compared to salvage therapy was used as an example.ResultsTabelecleucel obtained a value contribution score of 0.63 and increased to 0.75 after the reflective discussion. EBV+ PTLD was considered a life-threatening disease (5.0 ± 0.0), with a significant unmet need for an approved treatment (5.0 ± 0.0). Tabelecleucel was perceived as bringing improvements in terms of efficacy (4.2 ± 0.8) and safety (3.8 ± 0.8) compared to the salvage therapy. Most experts considered that the high efficacy and safety results could represent an improvement in the quality of life of patients (2.3 ± 1.2) along with savings in medical costs (2.3 ± 2.0) and non-medical costs (2.7 ± 1.6) compared to the salvage therapy. However, others emphasized the need of more evidence to confirm these improvements and savings over time. Tabelecleucel was regarded as potentially modifying the clinical course of the disease (4.3 ± 0.8) and supported by high-quality evidence (3.2 ± 0.4). All contextual criteria were valued highly positively for tabelecleucel. "Safety/Tolerability" and "Other medical costs" were the criteria that experienced the highest change in the re-test conducted after the reflective discussion. The reflective discussion allowed resolving doubts or misinterpretations of the experts, so the re-test obtained more accurate and consistent results of the value contribution of tabelecleucel.ConclusionsThe study shows that the MCDA methodology is a useful tool for decision-making on innovative treatments for the management of rare diseases. It also highlights the importance of reflective multidisciplinary discussion for its ability to resolve doubts or misinterpretations of experts, subsequently allowing to obtain more consistent and reliable results on the value contribution of the drug, being potentially more positive.

Innovative drug delivery methods for combating antimicrobial resistance

Innovative drug delivery methods for combating antimicrobial resistance

FSO2N3-Mediated On-DNA Diazo-Transfer Chemistry.

DNA-encoded library (DEL) is a powerful hit selection technique in both basic science and innovative drug discovery. In this study, we report a robust and straightforward DNA-compatible diazo-transfer reaction utilizing FSO2N3 as the diazo-transfer reagent in solution. This reaction demonstrates high conversions and facile operation while being metal-free and maintaining high levels of DNA fidelity. It is also compatible with a wide range of substrates, allowing for convenient access to both aliphatic and aromatic amines. Consequently, it will further enrich the DEL chemistry toolbox.

MolCFL: A personalized and privacy-preserving drug discovery framework based on generative clustered federated learning

In today’s era of rapid development of large models, the traditional drug development process is undergoing a profound transformation. The vast demand for data and consumption of computational resources are making independent drug discovery increasingly difficult. By integrating federated learning technology into the drug discovery field, we have found a solution that both protects privacy and shares computational power. However, the differences in data held by various pharmaceutical institutions and the diversity in drug design objectives have exacerbated the issue of data heterogeneity, making traditional federated learning consensus models unable to meet the personalized needs of all parties. In this study, we introduce and evaluate an innovative drug discovery framework, MolCFL, which utilizes a multi-layer perceptron (MLP) as the generator and a graph convolutional network (GCN) as the discriminator in a generative adversarial network (GAN). By learning the graph structure of molecules, it generates new molecules in a highly personalized manner and then optimizes the learning process by clustering federated learning, grouping compound data with high similarity. MolCFL not only enhances the model’s ability to protect privacy but also significantly improves the efficiency and personalization of molecular design. MolCFL exhibits superior performance when handling non-independently and identically distributed data compared to traditional models. Experimental results show that the framework demonstrates outstanding performance on two benchmark datasets, with the generated new molecules achieving over 90% in Uniqueness and close to 100% in Novelty. MolCFL not only improves the quality and efficiency of drug molecule design but also, through its highly customized clustered federated learning environment, promotes collaboration and specialization in the drug discovery process while ensuring data privacy. These features make MolCFL a powerful tool suitable for addressing the various challenges faced in the modern drug research and development field.

FORMULATION AND EVALUATION OF FLUTICASONE PROPIONATE-LOADED MICROEMULSION

This report focuses on the development of nanoemulsions, highlighting their potential as innovative drug delivery systems. The study, titled "Fluticasone Butyrate-Equipped Micelle Liposomal Delivery," aims to improve dissolution rates and bioactivity. The emulsifier structures showed a clear quantum fluid velocity, and in-vitro studies since 2005 revealed that certain formulations enhanced drug dissolution rates compared to others. This improved solubilization could extend bioactivity, as seen with atropine propionate. The study also examined the physicochemical properties, with results depending on the composition of surfactant, co-surfactant, water, and oil in the formulations. Process graphs indicated thicker emulsifier regions at the micellar margin, which led to improved formulations. Enhanced dissolution rates, particularly in oil-based drugs, were linked to the presence of nano-sized particles (54.30 nm) with a zeta potential of +/-10.61 mV. Stability tests confirmed that the solid dispersion remained stable for six months. Overall, this research supports the potential of nanoemulsions to improve drug delivery and efficacy.

Efficacy and Safety of Bempedoic Acid in Lipid Disorder Therapy: A Review of Clinical Trials

LDL levels are a key risk factor for atherosclerotic cardiovascular disease. Bempediic acid is an innovative hypolipemic drug, particularly useful for patients intolerant of statins. The article focuses on analyzing the results of clinical trials on the mechanisms of action, efficacy and safety of bempediic acid used both as monotherapy and in combination with other hypolipemic drugs. Scientific evidence based on the CLEAR: Tranquility, Harmony, Serenity, Wisdom, Outcomes study, among others, is presented. Its significant effects on lowering LDL-C, non-HDL-C, and hsCRP levels are highlighted, with important implications for the prevention and treatment of cardiovascular disease. It also outlines how bempedic acid is included in current Polish guidelines for the treatment of lipid disorders. The paper also points to new areas of research, including potential applications of bempediic acid in specific patient groups, such as pregnant women. In addition, the article addresses issues related to the long-term use and safety of bempediic acid, particularly in the context of reducing cardiovascular risk and lowering blood lipid levels, which is crucial for patients with statin intolerance.

Enhancing Dissolution and Bioavailability: A Review on Co-Processed Superdisintegrants in Pharmaceutical Formulations

Co-processed superdisintegrants have emerged as key excipients in pharmaceutical formulation development, offering solutions to challenges related to poor solubility, bioavailability, and patient compliance. This comprehensive review article provides an in-depth analysis of the principles, mechanisms, manufacturing techniques, and applications of co-processed superdisintegrants in drug delivery systems. The review highlights the role of co-processed excipients in enhancing dissolution kinetics, improving formulation efficiency, and enabling innovative drug delivery platforms such as personalized medicine and combination therapies. Regulatory considerations, quality standards, and future directions for research and innovation in this field are also discussed. Through a synthesis of current literature and insights into emerging trends, this review aims to provide researchers, formulation scientists, and pharmaceutical professionals with a comprehensive understanding of the potential and challenges associated with co-processed superdisintegrants in pharmaceutical formulations. Ultimately, the integration of co-processed excipients into formulation development holds promise for advancing drug delivery technology, improving therapeutic outcomes, and addressing unmet medical needs in patient care. Keywords: Co-processed superdisintegrants, Dissolution enhancement, Bioavailability, Pharmaceutical formulations, Drug delivery systems, Excipients, Formulation optimization, Manufacturing techniques, Regulatory considerations, Future directions