Drug Entry Research Articles

Inhibiting Mitochondrial Damage for Efficient Treatment of Cerebral Ischemia-Reperfusion Injury Through Sequential Targeting Nanomedicine of Neuronal Mitochondria in Affected Brain Tissue.

Oxidative stress, predominantly from neuronal mitochondrial damage and the resultant cytokine storm, is central to cerebral ischemia-reperfusion injury (CIRI). However, delivering drugs to neuronal mitochondria remains challenging due to the blood-brain barrier (BBB), which impedes drug entry into affected brain tissues. This study introduces an innovative tannic acid (TA) and melanin-modified heteropolyacid nanomedicine (MHT), which highly specifically eliminates the neuronal mitochondrial reactive oxygen radicals burst to efficiently reduce neuronal mitochondrial damage through a strategically designed sequential targeting strategy from affected brain tissue to neuronal mitochondria. TA endows MHT with sequential targeting ability by binding to matrix proteins exposed to the damaged BBB and mitochondrial outer membrane proteins of neurons, while melanin significantly enhances the antioxidant capacity of MHT. Consequently, MHT effectively inhibits neuronal apoptosis by protecting mitochondria and reversing the inflammatory immune environment through the deactivation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. MHT demonstrated a strong therapeutic effect on CIRI, with an ultralow dose (2 mgkg-1) proving effective in reversing the condition. This work not only introduces a new avenue to significantly reduce CIRI through sequential targeting therapy but also offers a new paradigm for treating other ischemia-reperfusion injury diseases.

How promotion mix helps sustain brand sales during market transitions: insights from the pharmaceutical industry

Purpose Pharmaceutical marketers use detailing, sampling and direct-to-consumer advertising (DTCA) to promote a branded prescription drug (brand drug) to health-care professionals and consumers. These promotion mix elements help raise brand awareness, increase prescription likelihood and guard a product market against competing brand drugs. However, the extent to which these elements remain effective when a brand drug goes off patent and its marketing exclusivity expires, allowing low-price generics to enter the market, remains unclear. This study aims to explore the effectiveness of promotion mix elements before and after the market entry of a generic drug. Design/methodology/approach The authors collected and analyzed a panel data set of 41 brand drugs from 7 therapeutic classes between 2007 and 2014 (3,201 observations) using the two-stage control function approach to address potential endogeneity. Findings The effectiveness of promotion mix elements changes significantly, but not in a universally uniform way, during a market transition. Detailing and DTCA are increasingly effective after a brand drug’s generics enter the market. In contrast, sampling is more effective before the market transition. The positive effects of sampling on brand sales are stronger when the price of a brand drug is higher than the average price of its competing brands. Sampling also helps amplify the positive influences of detailing and DTCA on brand sales. Research limitations/implications This study shows that pharmaceutical promotion is not equally effective in the brand drug market with/without generic competitors. Detailing and DTCA are increasingly effective when generic competition intensifies. In contrast, the distribution of free drug samples is less effective after more generic drugs enter the market. Practical implications Incumbent brands’ promotion expenditures often drop dramatically when the expiration of their patents is near, a practice that likely continues after generics enter the market. Taking into consideration these industry norms and their findings, the authors suggest that promotional decisions during a market transition should not overly focus on cutting promotional expenditures across the board. Since a firm’s promotional expenditure tends to be expensive, factoring in information on the effectiveness of each promotion mix element helps marketers make well-informed strategic decisions on resource allocation during the transition from a market without generics to a market with generics. Originality/value Previous studies do not explicitly account for structural changes in the brand drug market over time. However, the expiration of patent and marketing exclusivity marks a transitional period in which a brand drug eventually competes with its generic counterparts. Given the criticality of such structural change, the authors examine brand drugs’ promotion effectiveness in the presence of their generic counterparts.

Revolutionizing Quinolone Development for DNA Gyrase Targeting; Discovering the Promising Approach to Fighting Microbial Infections

Abstract: DNA gyrase is a type II topoisomerase enzyme that can cause negative supercoiling in DNA by using the energy produced by ATP hydrolysis. There are two main types of topoi-somerases: type I and type II. Type I enzymes cut a single strand of DNA and are further clas-sified as type IA if they connect to a 5′ phosphate of DNA, or type IB if they link to a 3′ phos-phate. Type II topoisomerases break both strands, creating a staggered double-strand break. Antimicrobial resistance is a major concern for the global healthcare system. Resistance is the ability of microorganisms to neutralize and withstand antimicrobial drugs previously used to treat microbial infections. Some known classes of DNA gyrase inhibitors are coumarins, cyclo-thialidines, and quinolones. Antimicrobial medicines such as quinolones have been widely used to treat microbiological diseases. However, the increased use of quinolones has led to the emer-gence of quinolone-resistant bacteria, which poses a serious risk to public health. Microorgan-isms can cause resistance due to changes in the target enzymes, DNA gyrase, and topoisomerase IV, which are responsible for transcription and DNA replication. Additionally, differences in drug entry and efflux may also play a role in resistance. Plasmids that produce the Qnr protein can mediate resistance to quinolones by protecting the quinolone targets from inhibition. This review aims to revolutionize the discovery of quinolone-based antibiotics, specifically targeting DNA gyrase, a critical enzyme in bacterial DNA replication, to enhance the efficacy and spec-ificity of anti-microbail agents against microbial infections.

Emerging Promise of Green Synthesized Metallic Nanoparticles for the Management of Neurological Disorders.

The management of neurological disorders is very challenging due to the presence of the bloodbrain barrier (BBB) that prevents the entry of drugs into the central nervous system (CNS). The advancement of metallic nanoparticles (NPs) provides a novel direction for the treatment of neurological disorders. However, there is a significant concern regarding the toxic effects of metal NPs on biological tissues like the brain. The green synthesis strategy offers a superior alternative to the traditional methods for the development of metallic NPs. Notable metal and metal oxide NPs can be produced using various bio-reductants derived from natural sources such as plant tissues, fungi, bacteria, yeast, and alga. These biological agents play double roles as they expedite the reduction process and act as capping and stabilizing agents. In this paper, we discuss the major neurological disorders and the physical barriers limiting the transport of therapeutics to the CNS. Moreover, a special focus is given to the unique features of green synthesized metallic NPs for therapeutic purposes in various neurological disorders. The insights provided will guide future research toward better outcomes and facilitate the development of innovative treatments for neurological disorders.

Strategic behavior and entry deterrence by branded drug firms: the case of authorized generic drugs.

Pharmaceutical firms that market brand-name drugs lose substantial market share to generic manufacturers after patent expiration. As a response to the threat of generic competition, branded manufacturers pursue defensive strategies. One such strategy is the launch of authorized generic drugs. Authorized generic drugs are produced by branded manufacturers to compete against other generic drug entrants. Such competition may lower the expected profits of generic drug manufacturers and hence deter future generic drug entry. This paper models and empirically examines whether the introduction of authorized generic drugs changes the independent generic firms' decisions on entering the market. We use an instrumental variable approach to evaluate the effect of authorized generic drugs on the responses of generic manufacturers. The results show that the entry of authorized generic drugs deters and delays the entry of generic drugs.

Deciphering Chemical Rules for Drug Penetration into Strongyloides.

Background: Strongyloidiasis, a parasitic infection, presents a significant public health challenge in tropical regions due to the limited repertoire of effective treatments. The screening of chemical libraries against the therapeutically relevant third-stage larvae (L3) of the model parasite Strongyloides venezuelensis yielded meager success rates. This situation is reminiscent of Gram-negative bacteria, where drug entry is a limiting factor. Methods: Here, we set out to determine whether similar barriers are in place and establish whether structural and property requirements exist for anti-strongyloides drug discovery. We focused on dyes as their uptake and effects on viability can be independently assessed in the multicellular parasite, thus providing a means to study the possibility of similar entry rules. We tested different dyes in in vitro assays on L3s. Results: We found that staining was necessary to reduce parasite viability, with some dyes achieving anti-strongyloides effects at concentrations similar to those of the reference drug, ivermectin (IV). Some dyes also showed activity against female adults at concentrations well below that of ivermectin. Unfortunately, the most potent dye, Methylene Blue, was unable to prevent the infection in a preliminary in vivo mouse model assay, presumably due to fast dye clearance. Structural analysis showed that positive charges facilitated the access of the compounds to the L3 tissue, thus providing a structural tool for the introduction of activity. For female adults, low globularity is additionally required. As a proof of concept, we added a positive charge to an inactive compound of one of our chemical libraries and re-determined the activity. Conclusions: These findings allow us to establish structural rules for parasite entry that could be of interest for future drug screening or drug development campaigns. These rules might also be applicable to other related parasites.

Specific mode electroacupuncture stimulation opens the blood-brain barrier of the infarcted border zone in rats during MCAO/R recovery via modulation of tight junction protein expression by VEGFA and NF-κB.

The blood-brain barrier (BBB) strictly limits the entry of most exogenous therapeutic drugs into the brain, which brings great challenges to the drug treatment of refractory central diseases, including the treatment of ischemic stroke. Our previous studies have shown that specific mode electroacupuncture stimulation (SMES) can temporarily open the BBB, but with the mechanisms largely unknown. This study explored whether SMES opens the BBB in the infarcted border zone of rats during middle cerebral artery occlusion/reperfusion recovery, and whether this is related to p65 or vascular endothelial growth factor A (VEGFA) modulation of tight junction protein expression through in vivo and in vitro studies. Evans blue, FITC-dextran, mouse-derived nerve growth factor (NGF), and transendothelial electrical resistance values were used to evaluate the permeability of the BBB. Additionally, microvascular endothelial cells and astrocytes were utilized for in vitro study. Immunofluorescence, immunohistochemistry, western blot, and ELISA were employed to assess related protein expression. SMES significantly increased vascular permeability for Evans blue and NGF in the infarcted border zone, and increased the expression of VEGFA by activating p-p65, thereby reducing the expression of tight junction proteins Occludin and ZO-1. Correspondingly, oxygen glucose deprivation/reoxygenation activated p-p65 in and induced VEGFA secretion from astrocytes in vitro. Their conditioned medium reduced the expression of Occludin in bEnd.3 cells and increased the permeability of FITC-dextran. The mechanism of SMES opening infarcted border zone BBB is partly related to its actions on p65, VEGFA, and tight junction proteins.

Organic cation transporter 1 in the lacrimal gland facilitates the entry of systemic drugs causing ocular surface toxicity

Many of the daily systemic medications (parenteral and oral) used to treat various diseases are known to cause ocular toxicities - leading to vision loss. How these medications gain entry into the eye despite the ocular barriers is an important question to be addressed. Various reports show almost 30–40 % of systemic drugs causing ocular toxicity are organic cation in nature. We hypothesize these systemic drugs (cations) are non-specifically recognized as endogenous substrates by organic cation transporter (OCT1) in the lacrimal gland, thereby facilitating its entry into the anterior eye segment. Therefore, we studied the expression and localization of OCT1 in the lacrimal gland of rabbits. Further, to prove our hypothesis, OCT1 substrates (known as well as predicted from our previous Artificial Intelligence study) were administered intravenously in the presence and absence of topically administered OCT1 blockers. Our findings show, OCT1 gene and protein expression in the lacrimal gland, with its localization in the terminal acinar cells. The tear levels of intravenously administered substrates decreased in the presence of topical OCT1 blockers, indicating – a) the entry of systemic drugs into the eye via lacrimal secretion and b) OCT1 in the lacrimal gland is involved in the drug transport (substrates) from blood to the eye. Though the role of transporters in toxicity is well-known, the current study opens a new avenue for understanding the role of transporters in ocular toxicity.

ATP-binding cassette transporter inhibitor potency and substrate drug affinity are critical determinants of successful drug delivery enhancement to the brain

BackgroundPharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases.MethodsWe employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS.ResultsComplete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans.ConclusionsThis work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded.

DeepB3P: A transformer-based model for identifying blood-brain barrier penetrating peptides with data augmentation using feedback GAN

IntroductionThe blood–brain barrier (BBB) serves as a critical structural barrier and impedes the entry of most neurotherapeutic drugs into the brain. This poses substantial challenges for central nervous system (CNS) drug development, as there is a lack of efficient drug delivery technologies to overcome this obstacle. BBB penetrating peptides (BBBPs) hold promise in overcoming the BBB and facilitating the delivery of drug molecules to the brain. Therefore, precise identification of BBBPs has become a crucial step in CNS drug development. However, most computational methods are designed based on conventional models that inadequately capture the intricate interaction between BBBPs and the BBB. Moreover, the performance of these methods was further hampered by unbalanced datasets. ObjectivesThis study addresses the problem of unbalanced datasets in BBBP prediction and proposes a powerful predictor for efficiently and accurately identifying BBBPs, as well as generating analogous BBBPs. MethodsA transformer-based deep learning model, DeepB3P, was proposed for predicting BBBP. The feedback generative adversarial network (FBGAN) model was employed to effectively generate analogous BBBPs, addressing data imbalance. ResultsThe FBGAN model possesses the ability to generate novel BBBP-like peptides, effectively mitigating the data imbalance in BBBP prediction. Extensive experiments on benchmarking datasets demonstrated that DeepB3P outperforms other BBBP prediction models by approximately 9.09%, 4.55% and 9.41% in terms of specificity, accuracy, and Matthew’s correlation coefficient, respectively. For accelerating the progress in BBBP identification and CNS drug design, the proposed DeepB3P was implemented as a webserver, which is accessible at http://cbcb.cdutcm.edu.cn/deepb3p/. ConclusionThe interpretable analyses provided by DeepB3P offer valuable insights and enhance downstream analyses for BBBP identification. Moreover, the BBBP-like peptides generated by FBGAN hold potential as candidates for CNS drug development.

Cutting-edge Approach of Carbon Nanostructures: Targeted Drug Delivery to Central Nervous System.

Drug delivery through the blood-brain barrier (BBB) is one of the key challenges in the modern era of medicine due to the highly semipermeable characteristics of BBB that restrict the entry of various drugs into the central nervous system (CNS) for the management of brain disorders. Drugs can be easily incorporated into carbon nanocarriers that can cross the bloodbrain barrier. Numerous nanocarriers have been developed, including polymeric nanoparticles, carbon nanoparticles, lipid-based nanoparticles, etc. Among these, carbon nanostructures could be superior due to their easier BBB penetration and strong biocompatibility. Several CDs (Carbon dots) and CD-ligand conjugates have explored effectively penetrating the BBB, which enables significant progress in using CD-based drug delivery systems (DDS) to manage CNS diseases. Despite the drug delivery applications, they might also be used as a central nervous system (CNS) drug; few of the carbon nanostructures show profound neurodegenerative activity. Further, their impact on neuronal growth and anti- amyloid action is quite interesting. The present study covers diverse carbon nanostructures for brain-targeted drug delivery, exploring a variety of CNS activities. Moreover, it emphasizes recent patents on carbon nanostructures for CNS disorders.

A review on camelid nanobodies with potential application in veterinary medicine.

The single variable domains of camelid heavy-chain only antibodies, known as nanobodies, have taken a long journey since their discovery in 1989 until the first nanobody-based drug's entrance to the market in 2022. On account of their unique properties, nanobodies have been successfully used for diagnosis and therapy against various diseases or conditions. Although research on the application of recombinant antibodies has focused on human medicine, the development of nanobodies has paved the way for incorporating recombinant antibody production in favour of veterinary medicine. Currently, despite many efforts in developing these biomolecules with diversified applications, significant opportunities exist for exploiting these highly versatile and cost-effective antibodies in veterinary medicine. The present study attempts to identify existing gaps and shed light on paths for future research by presenting an updated review on camelid nanobodies with potential applications in veterinary medicine.

A closed-loop smart dressing based on microneedle and electrochemical micropump for early diagnosis and in-time therapy of chronic wound

Early diagnosis combined with in-time treatment is a promising strategy for chronic wound care, preventing wound deterioration and promoting healing. Different smart dressings have recently emerged to enable real-time wound status monitoring and offer active intervention. However, the drawbacks of existing smart dressings, including limited drug loading capacity and poor drug penetration into the deeper wound dermal and subcutaneous tissues, are yet to be addressed, resulting in unsatisfactory therapeutic effectiveness. In this study, a Microneedle-embedded closed-loop smart Dressing (MelD) is developed to simultaneously achieve chronic wound early diagnosis and in-time therapy. The simple impedance sensing electrodes are utilized to monitor wound impedance for chronic wound early diagnosis. Based on the sensing data, the drug delivery micropump in MelD is automatically activated for in-time therapy. By integrating micropump electrodes with a drug reservoir coupled-microneedle array, a practice solution for delivering enough drug fluid into deeper wound dermal/ subcutaneous tissues is developed. Compared to untreated diabetic mice, MelD, delivering sufficient growth factor to the wound and promoting drug entry into deep tissue layers, induces faster wound healing in treated mice. Meanwhile, MelD facilitates tissue formation and nascent collagen deposition. The enhanced drug storage dosage, improved drug penetration and closed-loop operation of Meld enable the first successful attempt of ensuring sufficient and efficient drug delivery by miniaturized all-in-one smart dressing, expanding the usage of closed-loop chronic wound care from laboratorial demonstration on limited kinds of superficial wounds to a wider range of wound types.

Applications of Nanotechnology-mediated Herbal Nanosystems for Ophthalmic Drug.

In recent years, herbal nanomedicines have gained tremendous popularity for novel drug discovery. Nanotechnology has provided several advances in the healthcare sector, emerging several novel nanocarriers that potentiate the bioavailability and therapeutic efficacy of the herbal drug. The recent advances in nanotechnology with accelerated strategies of ophthalmic nanosystems have paved a new path for overcoming the limitations associated with ocular drug delivery systems, such as low bioavailability, poor absorption, stability, and precorneal drug loss. Ophthalmic drug delivery is challenging due to anatomical and physiological barriers. Due to the presence of these barriers, the herbal drug entry into the eyes can be affected when administered by following multiple routes, i.e., topical, injectables, or systemic. However, the advancement of nanotechnology with intelligent systems enables the herbal active constituent to successfully entrap within the system, which is usually difficult to reach employing conventional herbal formulations. Herbal-loaded nanocarrier drug delivery systems demonstrated enhanced herbal drug permeation and prolonged herbal drug delivery. In this current manuscript, an extensive search is conducted for original research papers using databases Viz., PubMed, Google Scholar, Science Direct, Web of Science, etc. Further painstaking efforts are made to compile and update the novel herbal nanocarriers such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, nanostructure lipid carriers, micelles, niosomes, nanoemulsions, dendrimers, etc., which are mostly used for ophthalmic drug delivery system. This article presents a comprehensive survey of diverse applications used for the preventative measures and treatment therapy of varied eye disorders. Further, this article highlights the recent findings that the innovators are exclusively working on ophthalmic nanosystems for herbal drug delivery systems. The nanocarriers are promising drug delivery systems that enable an effective and supreme therapeutic potential circumventing the limitations associated with conventional ocular drug delivery systems. The nanotechnology-based approach is useful to encapsulate the herbal bioactive and prevent them from degradation and therefore providing them for controlled and sustained release with enhanced herbal drug permeation. Extensive research is still being carried out in the field of herbal nanotechnology to design an ophthalmic nanosystem with improved biopharmaceutical properties.

Low drug load, high retention mometasone furoate cream with polyglyceryl − 3 oleate as a chemical enhancer: Formulation development, in vivo and in vitro evaluation and molecular mechanisms

The study aimed to create a low loading, high retention, easier to apply O/W mometasone furoate (MF) cream using a chemical enhancer (CE) approach to provide more options for patients with atopic dermatitis (AD) and to investigate molecular mechanisms of its increased release and retention. A Box-Behnken design determined the optimal formulation based on stability and in vitro skin retention. Evaluations included appearance, rheological properties, irritation, in vivo tissue distribution and pharmacodynamics. Molecular mechanisms of enhanced release were studied using high-speed centrifugation, molecular dynamics and rheology. The interaction between the CE, MF and skin was studied by tape stripping, CLSM, ATR-FTIR and SAXS. The formulation was optimized to contain 0.05% MF and used 10% polyglyceryl-3 oleate (POCC) as the CE. There was no significant difference from Elocon® cream in in vivo retention and pharmacodynamics but increased in vivo retention by 3.14-fold and in vitro release by 1.77-fold compared to the basic formulation. POCC reduced oil phase cohesive energy density, enhancing drug mobility and release. It disrupted skin lipid phases, aiding drug entry and formed hydrogen bonds, prolonging retention. This study highlights POCC as a CE in the cream, offering insights for semi-solid formulation development.

MSGD: a manually curated database of genomic, transcriptomic, proteomic and drug information for multiple sclerosis.

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. 'Omics' technologies (genomics, transcriptomics, proteomics) and associated drug information have begun reshaping our understanding of multiple sclerosis. However, these data are scattered across numerous references, making them challenging to fully utilize. We manually mined and compiled these data within the Multiple Sclerosis Gene Database (MSGD) database, intending to continue updating it in the future. We screened 5485 publications and constructed the current version of MSGD. MSGD comprises 6255 entries, including 3274 variant entries, 1175 RNA entries, 418 protein entries, 313 knockout entries, 612 drug entries and 463 high-throughput entries. Each entry contains detailed information, such as species, disease type, detailed gene descriptions (such as official gene symbols), and original references. MSGD is freely accessible and provides a user-friendly web interface. Users can easily search for genes of interest, view their expression patterns and detailed information, manage gene sets and submit new MS-gene associations through the platform. The primary principle behind MSGD's design is to provide an exploratory platform, aiming to minimize filtration and interpretation barriers while ensuring highly accessible presentation of data. This initiative is expected to significantly assist researchers in deciphering gene mechanisms and improving the prevention, diagnosis and treatment of MS. Database URL: http://bio-bigdata.hrbmu.edu.cn/MSGD.

Accelerated infected wound healing by probiotic-based living microneedles with long-acting antibacterial effect

Delays in infected wound healing are usually a result of bacterial infection and local inflammation, which imposes a significant and often underappreciated burden on patients and society. Current therapies for chronic wound infection generally suffer from limited drug permeability and frequent drug administration, owing to the existence of a wound biofilm that acts as a barrier restricting the entry of various antibacterial drugs. Here, we report the design of a biocompatible probiotic-based microneedle (MN) patch that can rapidly deliver beneficial bacteria to wound tissues with improved delivery efficiency. The probiotic is capable of continuously producing antimicrobial substances by metabolizing introduced glycerol, thereby facilitating infected wound healing through long-acting antibacterial and anti-inflammatory effects. Additionally, the beneficial bacteria can remain highly viable (>80 %) inside MNs for as long as 60 days at 4 °C. In a mouse model of Staphylococcus aureus-infected wounds, a single administration of the MN patch exhibited superior antimicrobial efficiency and wound healing performance in comparison with the control groups, indicating great potential for accelerating infected wound closure. Further development of live probiotic-based MN patches may enable patients to better manage chronically infected wounds.

Impact of Incorporating Future Mandatory Price Reductions with Generic Drug Entry on the Cost-Effectiveness of New Drugs: A Policy Simulation Study of Dupilumab in Atopic Dermatitis Treatment.

The introduction of high-cost medications often poses challenges in achieving cost-effectiveness for drug insurance coverage. Incorporating future price reductions for these medications may enhance their cost-effectiveness. We examined the influence of future cost reductions mandated by the national insurer's equal pricing for equivalent drugs (EPED) policy on the cost-effectiveness of dupilumab, a biologic drug for moderate to severe atopic dermatitis in the Korean healthcare system. We conducted a policy simulation study using semi-Markovian cost utility analysis of dupilumab in combination with supportive care (SC) versus SC alone, with and without the EPED policy adjustment. The EPED would lower dupilumab's price to 70% following the entry of a biosimilar drug in 10.3 years. Scenario analyses quantified the impact of changing time to the EPED, chemical versus biological designation, response criteria, discount rates, and time horizons on the Incremental Cost-Effectiveness Ratio (ICER) and acceptability with and without EPED adjustment. The EPED adjustment of dupilumab's future price significantly improved its cost-effectiveness, with a 9.7% decrease in ICER and a substantial 14.6% increase in acceptability. Assuming EPED in 5 years, the ICER fell below the predefined willingness-to-pay threshold. If dupilumab were a chemical drug, EPED adjustment demonstrated a 19.1% increase in acceptability. Incorporating future cost reductions via the EPED system in economic evaluations is crucial, especially for drugs facing imminent generic entry. This study underscores the importance of EPED adjustment in the cost-effectiveness analysis of innovative medications, especially for those nearing willingness-to-pay thresholds.

Dynamic Simulations of Interaction of the PEG-DPPE Micelle-Encapsulated Short-Chain Ceramides with the Raft-Included Membrane.

The lipid raft subdomains in cancer cell membranes play a key role in signal transduction, biomolecule recruitment, and drug transmembrane transport. Augmented membrane rigidity due to the formation of a lipid raft is unfavorable for the entry of drugs, a limiting factor in clinical oncology. The short-chain ceramide (CER) has been reported to promote drug entry into membranes and disrupt lipid raft formation, but the underlying mechanism is not well understood. We recently explored the carrier-membrane fusion dynamics of PEG-DPPE micelles in delivering doxorubicin (DOX). Based on the phase-segregated membrane model composed of DPPC/DIPC/CHOL/GM1/PIP2, we aim to explore the dynamic mechanism of the PEG-DPPE micelle-encapsulating DOXs in association with the raft-included cell membrane modulated by C8 acyl tail CERs. The results show that the lipid raft remains integrated and DOX-resistant subjected to free DOXs and the micelle-encapsulating ones. Addition of CERs disorganizes the lipid raft by pushing CHOL aside from DPPC. It subsequently allows for a good permeability for PEG-DPPE micelle-encapsulated DOXs, which penetrate deeper as CER concentration increases. GM1 is significant in guiding drugs' redistributing between bilayer phases, and the anionic PIP2 further helps DOXs attain the inner bilayer surface. These results elaborate on the perturbing effect of CERs on lipid raft stability, which provides a new comprehensive approach for further design of drug delivery systems.

Glucose-modified BSA/procyanidin C1 NPs penetrate the blood-brain barrier and alleviate neuroinflammation in Alzheimer's disease models

Alzheimer's disease (AD) is a chronic neurodegenerative disease with high prevalence, long duration and poor prognosis. The blood-brain barrier (BBB) is a physiologic barrier in the central nervous system, which hinders the entry of most drugs into the brain from the blood, thus affecting the efficacy of drugs for AD. Natural products are recognized as one of the promising and unique therapeutic approaches to treat AD. To improve the efficiency and therapeutic effect of the drug across the BBB, a natural polyphenolic compound, procyanidin C-1 (C1) was encapsulated in glucose-functionalized bovine serum albumin (BSA) nanoparticles to construct Glu-BSA/C1 NPs in our study. Glu-BSA/C1 NPs exhibited good stability, slow release, biocompatibility and antioxidant properties. In addition, Glu-BSA/C1 NPs penetrated the BBB, accumulated in the brain by targeting Glut1, and maintained the BBB integrity both in vitro and in vivo. Moreover, Glu-BSA/C1 NPs alleviated memory impairment of 5 × FAD mice by reducing Aβ deposition and Tau phosphorylation and promoting neurogenesis. Mechanistically, Glu-BSA/C1 NPs significantly activated the PI3K/AKT pathway and inhibited the NLRP3/Caspase-1/IL-1β pathway thereby suppressing neuroinflammation. Taken together, Glu-BSA/C1 NPs could penetrate the BBB and mitigate neuroinflammation in AD, which provides a new therapeutic approach targeting AD.