Innovative Drugs Research Articles

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

Implications of China’s Innovative Drug Investment Bubble

Implications of China’s Innovative Drug Investment Bubble

Comprehensive study of medications solubility in supercritical CO2 with and without co-solvent; Laboratory, theoretical, and intelligent approaches

Determining the dissolution characteristics of medicines in supercritical CO2 is vital for formulating innovative drug delivery systems through an efficient supercritical process. This study investigates the solubility of three poorly bioavailable drugs −Topiramate, Meclizine, and Dimenhydrinate- in supercritical CO2, both with and without ethanol co-solvent, over a temperature range of 308 K to 348 K and pressures from 17 MPa to 41 MPa. The solubility of these medicines in supercritical CO2 (binary system) is notably low, ranging from 2.5 × 10-6 − 4.54 × 10-6, 0.26 × 10-5 − 2.3 × 10-5, and 0.20 × 10-5 − 1.91 × 10-5 in mole fraction, respectively. However, in the presence of ethanol (ternary system), their supercritical solubility significantly increases by factors of 2.75–5.84, 1.40–3.20, and 2.04–4.85, respectively.The supercritical solubility of the mentioned compounds are theoretically evaluated using several approaches, including empirical models, a machine learning methodology employing a multilayer perceptron neural network, thermodynamic models based on two cubic equations of state (Peng-Robinson (PR) and Soave–Redlich–Kwong (SRK)), and a non-cubic equation of state (perturbed chain-statistical associating fluid theory (PC-SAFT)), as well as two expanded liquid models (UNIQUAC and Wilson).The findings revealed that all the specified models demonstrate acceptable accuracy in correlating the experimental data of the specified drugs in both binary and ternary systems. Among these, the PR and SRK thermodynamic models, along with some empirical models, show the best results. Furthermore, the machine learning model exhibited outstanding accuracy in forecasting the supercritical solubility of the desired drugs, with over 99.9% alignment between their predicted and experimental data.

Pegylated chitosan nanoparticles of fluoxetine enhance cognitive performance and hippocampal brain derived neurotrophic factor levels in a rat model of local demyelination

Cognitive impairment is a common feature in neurodegenerative diseases such as multiple sclerosis (MS). This study aims to explore the potential of enhancing the beneficial effects of fluoxetine (FLX), a neuroprotective agent known for its ability to increase neural plasticity by utilizing nanoparticles. The study specifically focuses on the synthesis and evaluation of PEGylated chitosan nanoparticles of FLX and its effect on demyelination and the subsequent cognitive impairment (CI) in the hippocampus of rats induced by local injection of lysophosphatidylcholine (LPC). Chitosan/polyethylene glycol nanoparticles were synthesized, and their properties were analyzed. Demyelination was induced in rats via hippocampal injections of lysolecithin. Behavioral assessments included open field maze, elevated plus maze, and novel object recognition memory (NORM) tests. Hippocampal levels of insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) were measured using enzyme-linked immunoassay (ELISA). The extent of remyelination was quantified using Luxol fast blue staining. Nanoparticle size measured 240.2 nm with 53 % encapsulation efficacy. Drug release exhibited a slow pattern, with 76 % released within 4 h. Nanoparticle-treated rats displayed reduced anxiety-like behavior, improved memory, increased BDNF levels, and a reduced extent of demyelination, with no change in IGF- levels. In addition, FLX -loaded chitosan nanoparticles had better effect on cognitive improvement, BDNF levels in the hippocampus that FLX. Altering pharmacokinetics and possibly pharmacodynamics. These findings highlight the potential of innovative drug delivery systems, encouraging further research in this direction.

A comprehensive study of pharmaceutics solubility in supercritical solvent through diverse thermodynamic and hybrid Machine learning approaches

The pharmaceutical industry is increasingly drawn to the research of innovative drug delivery systems through the use of supercritical CO2 (scCO2)-based techniques. Measuring the solubility of drugs in scCO2 at varying conditions is a crucial parameter in this context. In this research, the supercritical solubility of two pharmaceutical ingredients, namely Febuxostat and Chlorpromazine, has been assessed theoretically using various thermodynamic approaches, including PR, SRK, UNIQUAC, and Wilson models. Additionally, hybrid machine learning models of PO-GPR, and PO-KNN were applied to anticipate the supercritical solubility of these medicines. Verification of the accuracy of each model for each pharmaceutical substance is conducted against previously reported experimental solubility data. In the comparison between the SRK and PR models, it is observed that the SRK model displays greater precision in correlating the solubility of both drugs. It consistently achieves a mean Radj value of 0.995 across all cases and mean AARD% values of 14.47 and 9.30 for Febuxostat and Chlorpromazine, respectively. Furthermore, the findings indicate that the UNIQUAC model surpasses the Wilson model in precisely representing the solubility of both medicines. It consistently achieves a mean Radj value higher than 0.985 across both cases and mean AARD% values of 11.39 and 7.08 for Febuxostat and Chlorpromazine, respectively. Additionally, the performance of both hybrid machine learning models proved to be excellent in anticipating the supercritical solubility of both compounds.

Redesigning amino/carboxyl ends of DARPin G3 for high thermostability and production in tobacco transplastomic plants.

Redesigning the N- and C-capping repeats of the native DARPin G3 significantly improved its stability, and may facilitate its purification from the total soluble proteins of high-temperature dried leaf materials of transplastomic plants. Designed ankyrin repeat proteins (DARPins) constitute a promising class of binding molecules that can overcome the limitations of monoclonal antibodies and enable the development of novel therapeutic approaches. Despite their inherent stability, detailed studies have revealed that the original capping repeats derived from natural ankyrin repeat proteins impair the stability of the initial DARPin design. Consequently, the development of thermodynamically stabilized antibody mimetics may facilitate the development of innovative drugs in the future. In this study, we replaced the original N- and C-capping repeats with improved caps to enhance the thermostability of native DARPin G3. Computational analyses suggested that the redesigned thermostable DARPin G3 structure possessed optimal quality and stability. Molecular dynamics simulations verified the stability of the redesigned thermostable DARPin G3 at high temperatures. The redesigned thermostable DARPin G3 was expressed at high levels in tobacco transplastomic plants and subsequently purified from high-temperature dried leaf materials. Thermal denaturation results revealed that the redesigned thermostable DARPin G3 had a higher Tm value than the native DARPin G3, with a Tm of 35.51°C greater than that of native DARPin G3. The results of the in vitro bioassays confirmed that the purified thermostable DARPin G3 from high-temperature dried leaf materials maintained its binding activity without any loss of affinity and specifically bound to the HER2 receptor on the cell surface. These findings demonstrate the successful improvement in the thermostability of DARPin G3 without compromising its biological activity.

Comprehensive Screening and Characterization of α-glucosidase Inhibitory Components in the Edible Medicinal Plant Pholidota cantonensis Rolfe Using UPLC-Q-TOF-MS/MS Analysis and Molecular Docking.

Pholidota cantonensis Rolfe is an edible medicinal plant in the genus Pholidota of the family Orchidaceae. This plant is used to prepare medicated food in China and has been reported to possess anti-α-glucosidase activity. To date, little is known about the active substances responsible for the observed anti-α-glucosidase activity. In the present study, we aimed to screen and characterize the α-glucosidase inhibitory fraction of P. cantonensis using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) analysis and molecular docking. As a result, the 50% ethanol fraction obtained from D101 macroporous adsorption resin column chromatography (D50 fraction) had the highest total phenol content (353.83 ± 6.06mg GAE/g) and the most prominent α-glucosidase inhibitory activity (IC50 = 30.01 ± 7.30µg/mL). Forty-five compounds were identified from the D50 fraction by using UPLC-Q-TOF-MS/MS analysis. Molecular docking results showed that six main constituents, namely, crepidatin, 2,7-dihydroxy-4-methoxyl-9,10-dihydrophenylene, 4,4',5,6-tetrahydroxystilbene, 4,7-dihydroxy-2-methoxyl-9,10-dihydrophenylene, (-)-lariciresinol, and thunalbene, in the D50 fraction occupied the catalytic sites of α-glucosidase through strong hydrophobic interactions, hydrogen bonding, and other patterns. The binding energies were between - 29.95 and - 11.41kJ/mol, indicating good binding between the tested compounds and α-glucosidase. The active ingredients responsible for the α-glucosidase inhibitory activity may include phenanthrenes, stilbenes, dibenzyls, and lignans. The D50 fraction has potential value for developing innovative drugs for the prevention and treatment of diabetes mellitus (DM) and is worthy of in-depth research.

Novel Approaches for the Enhancement of Bioavailability of Drugs: An Updated Review.

In medicine, bioavailability is the percentage of a drug that enters the bloodstream and can be used to treat a patient. It has proven challenging throughout time to develop techniques that allow oral administration of most drugs, regardless of their properties, to achieve therapeutic systemic availability. This will be an impressive feat, considering that over 90% of pharmaceuticals are known to have limitations on their oral bioavailability. Improving bioavailability is crucial for optimizing the efficacy and safety of drugs. This review covers a wide range of techniques, including physical, chemical, and formulation approaches, highlighting their mechanisms, advantages, and limitations. Inhibitions of efflux pumps, inhibition of presystemic metabolism, and innovative drug delivery systems that capitalize on the gastrointestinal regionality of medicines are some of the new techniques that have drawn increased interest. Nanotechnology in pharmaceuticals is also being used in this field. We have collected the literature data from 2009 to 2024 using Science Direct, PubMed/Medline, Scopus, and Google Scholar.

Modified by the Innovative Drugs and Strategies-Pattern of Selected Indications for Pediatric Liver Transplantation.

Liver transplantation (LTx) constitutes a major life-saving routine treatment for children with end-stage liver disease. However, the analysis of LTx registries in children provides much information about changes in the indication profiles in the recent years. The article provides a comprehensive review about the successes, hopes, and challenges related to changing indications for LTx in children based on the literature review and our own experience. Retrospective review of the indications for LTx at a tertiary referral pediatric hospital was also presented. In the context of the new therapies that have emerged, the need for LTx has decreased in patients with chronic hepatitis B and C infection and tyrosinemia type 1. In primary hyperoxaluria type 1, new RNAi-based therapy has eliminated the requirement for LTx (both isolated or combined). There is a hope that introduction of ileal bile acid transporter (IBAT) blockers reduces the need for LTx in patients with Alagille syndrome or progressive familial intrahepatic cholestasis. The number of children qualified for LTx with urea cycle disorders (UCDs) as a prophylaxis of neurodevelopmental impairment is increasing.

Comparative analysis of FDA approvals by top 20 pharma companies (2014–2023)

This article addresses the research and development (R&D) productivity challenge of the pharmaceutical industry, focusing on United States Food and Drug Administration (FDA)-related new drug approvals of the top 20 pharmaceutical companies (2014-2023). We evaluated the degree of innovation in new drugs to determine the innovativeness of these leading companies. A key finding of our analysis is the decline in the number of new drugs approved by the FDA for these leading companies over the investigated time period. This trend suggests that some of the leading companies are losing ground in R&D innovation, raising concerns about their ability to sustain competitive advantage, ensure long-term market success, and maintain viable business models.