Conventional Drug Research Articles

Effects of aerobic and resistance exercises on psychological and cognitive functions in patients with post-stroke migraine

ABSTRACT Objective To investigate the impact of a combination of aerobic and resistance exercises on the psychological and cognitive functions of post-stroke migraine patients. Methods This study recruited 100 patients suffering from post-stroke migraine pain who were admitted to the hospital, categorizing them into a control group (n = 50) and an intervention group (n = 50). The control group received conventional drug treatment, while the intervention group received the exercise-based intervention that combined aerobic exercise with resistance exercise. Results Before treatment, both groups displayed similar Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Mini-mental State Examination (MMSE) and MoCA scores. However, after the intervention, the intervention group exhibited lower scores on these measures compared to the control group (all p < 0.05). Additionally, there were no discernible disparity in Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT-6) scores between the two cohorts of patients before treatment (p > 0.05), whereas the intervention group demonstrated significantly lower MIDAS and HIT-6 scores following the intervention (p < 0.05). Although there were no discernible distinctions in National Institute of Health stroke scale (NIHSS) and Stroke Specialized Quality of Life Scale (SS-QOL) measurements between the two patient groups before treatment (p > 0.05), the intervention group exhibited a significant decrease in NIHSS scores and a notable increase in SS-QOL scores after the intervention (p > 0.05). Moreover, the satisfaction rate and overall satisfaction rate were significantly higher in the intervention group (p < 0.05). Conclusion The combination of aerobic and resistance exercises demonstrated positive effects on the psychological well-being and overall quality of life for post-stroke migraine patients.

B-ultrasound-guided Intrahepatic Infusion of Autologous Bone Marrow Cells for Decompensated Cirrhosis

Objective: To study the therapeutic effect of B-ultrasound-guided intrahepatic infusion of autologous bone marrow nucleated cells on decompensated cirrhosis. Methods: To observe the clinical treatment of 75 cases of decompensated cirrhosis. Among them, 30 cases received routine liver protection and diuretic treatment. 45 cases were treated by percutaneous transhepatic infusion of autologous bone marrow nucleated cells under the guidance of B ultrasound. There were no significant differences in liver function and blood routine indexes between the two groups before treatment (p &gt; 0.05). Results: The indexes of liver function and blood routine at different time periods of 1 month, 3 months, 6 months, and 12 months in the conventional treatment group did not change significantly. 6 cases died of liver failure within 1 year, the fatality rate was 20%. The indexes of liver function and blood routine of percutaneous liver transhepatic infusion of autologous bone marrow nucleated cells at 1 month, 3 months, 6 months, and 12 months under the guidance of B-ultrasound were significantly better than those of the conventional treatment group (p &lt; 0.05). One case died of gastrointestinal bleeding in the group of percutaneous transhepatic infusion of autologous bone marrow nucleated cells guided by B ultrasound, with a fatality rate of 2.5%. Compared with the conventional treatment group, there were significant differences (p &lt; 0.05). Conclusion: Conventional drug therapy has no obvious effect on decompensated cirrhosis. Intrahepatic infusion of bone marrow nucleated cells can significantly promote liver function reconstruction in decompensated cirrhosis.

Patients with High Baseline Neutrophil-to-Lymphocyte Ratio Exhibit Better Response to Filgotinib as Treatment for Rheumatoid Arthritis.

High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200mg + MTX/csDMARD exhibited consistently better responses after 12weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728.

Clinical efficacy and safety analysis of type A botulinum toxin in the treatment of adolescents with refractory overactive bladder.

The objective of this study was to assess the clinical effectiveness and safety of type A botulinum toxin in the treatment of refractory overactive bladder in adolescents. We conducted a retrospective analysis of 37 adolescent patients with refractory overactive bladder who were treated at the Urology Department of Hangzhou Third People's Hospital between January 2018 and August 2023. These patients received intravesical injections of type A botulinum toxin at a concentration of 10 U/mL, with an average of 20 injection points. We recorded changes in urination diaries and urodynamic parameters both before and 1 month after treatment. After 1 month of treatment, significant improvements were observed in several parameters, when compared to the pretreatment values. These included daytime frequency of urination (11.13 ± 6.45), average single void volume (173.24 ± 36.48) mL, nighttime frequency of urination (2.43 ± 0.31), urgency episodes (3.12 ± 0.27), initial bladder capacity (149.82 ± 41.34) mL, and maximum bladder capacity (340.25 ± 57.12) mL (all P < .001). After the first treatment, 5 patients had mild hematuria, 4 patients had urinary tract infection, and 1 patient had urinary retention, which was relieved after catheterization. No serious complications or adverse reactions were observed in other patients. The follow-up period ranged from 6 to 18 months, and the duration of efficacy varied from 2 to 8 months. Eight patients who initially had treatment failure achieved symptom relief after reinjection. In adolescents with refractory overactive bladder who do not respond well to conventional drug therapy, type A botulinum toxin can be administered safely and effectively. It significantly improves lower urinary tract symptoms and enhances the quality of life for these patients.

Development of Anti-HIV Therapeutics: From Conventional Drug Discovery to Cutting-Edge Technology.

The efforts to discover HIV therapeutics have continued since the first human immunodeficiency virus (HIV) infected patient was confirmed in the 1980s. Ten years later, the first HIV drug, zidovudine (AZT), targeting HIV reverse transcriptase, was developed. Meanwhile, scientists were enlightened to discover new drugs that target different HIV genes, like integrase, protease, and host receptors. Combination antiretroviral therapy (cART) is the most feasible medical intervention to suppress the virus in people with HIV (PWH) and control the epidemic. ART treatment has made HIV a chronic infection rather than a fatal disease, but ART does not eliminate latent reservoirs of HIV-1 from the host cells; strict and life-long adherence to ART is required for the therapy to be effective in patients. In this review, we first discussed the scientific history of conventional HIV drug discovery since scientists need to develop more and more drugs to solve drug-resistant issues and release the side effects. Then, we summarized the novel research technologies, like gene editing, applied to HIV treatment and their contributions to eliminating HIV as a complementary therapy.

Fisetin ameliorates polycystic ovary syndrome in rats via a mechanistic modulation of AMP-activated protein kinase and SIRT1 molecular pathway.

Fisetin, a polyphenolic flavonoid, exhibits numerous pharmacological activities against metabolic syndromes. The present research aims to explore the therapeutic efficacy of fisetin in experimental polycystic ovary syndrome (PCOS). Female Sprague-Dawley rats were administered mifepristone (20mg/kg/day) to induce PCOS. PCOS rats were treated with fisetin (20mg/kg and 40mg/kg) and further compared with metformin HCl, the conventional drug for PCOS. The mechanism of fisetin was explored using dorsomorphin (an AMPK inhibitor). Then, rats were sacrificed for further analysis of biochemical and histological parameters. PCOS rats exhibited irregular estrous cycles, increased serum testosterone (4.72 ± 0.139ng/ml), estradiol (750.2 ± 16.56pg/ml), LH (30.33 ± 1.563 mIU/ml), HOMA-IR (1.115 ± 0.049), TNF-α (86.59 ± 3.93pg/ml), IL-6 (55.34 ± 4.432pg/ml), and TBARS (3.867 ± 0.193µmol/mg) along with declined progesterone (11.67 ± 1.54ng/ml), FSH (13.33 ± 1.256 mIU/ml), GSH (33.47 ± 1.348µmol/mg) levels, and SOD (2.163 ± 0.298 U/mg) activity as compared to normal control group. Fisetin high dose significantly lowers testosterone (3.014 ± 0.234ng/ml), estradiol (533.7 ± 15.39pg/ml), LH (16.67 ± 1.62 mIU/ml), HOMA-IR (0.339 ± 0.20), TNF-α (46.02 ± 2.66pg/ml), IL-6 (31.77 ± 3.47pg/ml), and TBARS (1.747 ± 0.185µmol/mg) and enhances progesterone (33.17 ± 1.447ng/ml), FSH (27.17 ± 1.42 mIU/ml), GSH (60.35 ± 1.1.102µmol/mg) levels, and SOD (4.513 ± 0.607 U/mg) activity. The histology of ovarian tissues shows a significant increase in cystic follicles in PCOS rats compared with the normal control group. These alterations were attenuated with fisetin treatment. Administration of dorsomorphin with fisetin can reverse the beneficial effects of fisetin in PCOS rats. Altogether, these present findings highlight the potential of fisetin as a promising therapeutic intervention for the management of PCOS by modulating AMPK/SIRT1 signaling in rats.

Gender Differences in Perceptions of Psoriatic Arthritis Disease Impact, Management, and Physician Interactions: Results from a Global Patient Survey.

We evaluated the impact of gender on disease severity, health-related quality of life (HRQoL), treatment management, and patient-healthcare professional (HCP) interactions from the perspectives of patients with psoriatic arthritis (PsA). Data were collected from a global online patient survey conducted by The Harris Poll (November 2, 2017 to March 12, 2018). Eligible patients were aged ≥ 18years, with a self-reported diagnosis of PsA for > 1year, had visited a rheumatologist/dermatologist in the past 12months, and had reported previously using ≥ 1 conventional synthetic or biologic disease-modifying antirheumatic drug. Data were stratified by gender and analyzed descriptively, inferentially by binomial (chi-square) tests, and by multivariate logistic regression models. Data from 1286 patients who participated were included: 52% were female, 48% were male. Varying perceptions of disease severity between males and females were indicated by differences in symptoms leading to a diagnosis of PsA, and in symptoms reported despite treatment; more females than males reported joint tenderness, skin patches/plaques, and enthesitis. More females than males reported a major/moderate impact of PsA on their physical activity and emotional/mental well-being. Reasons for switching medication differed between genders, with more females switching because they perceived their medication to not be effective enough related to their joint symptoms. More females than males were very satisfied with their communication with their rheumatologist and were more likely to discuss the impact of PsA on their daily lives, their treatment satisfaction, and treatment goals with their rheumatologist. Patients' perceptions of the impact of PsA on HRQoL, treatment management, and interactions with HCPs varied between males and females. More females than males reported major/moderate physical and emotional impacts of PsA. When treating patients, it is important for HCPs to consider the potential impact of gender on patients' experience of PsA and its symptoms. Graphical plain language summary available for this article.

Isolation, characterization, antimicrobial properties, and theoretical investigations of a new isoflavanol from nigerian red propolis for therapeutic applications

The chemical components of Nigerian red propolis were thoroughly examined to identify its phytochemical constituents. The investigation yielded a new isoflavanol, identified as 2′,7-dihydroxy-3′,4-dimethoxyisoflavan-4-ol (DDI), which was isolated from the ethyl acetate extract. Using advanced spectroscopic techniques, such as 1D, 2D NMR as well as HR-LC-MS, the structure and molecular composition of the new compound was determined with extreme precision. The present study offers important information regarding the chemical structure of reddish propolis sourced from the southeast region of Nigeria. The isolated compound suggests that the botanical source of the propolis could be Dalbergia spp. antimicrobial assay of the compound isolated revealed potent antibacterial and antifungal properties with diameter zones of inhibition measuring between 27 and 32 mm. The MIC, MBC, and MFC values were between 6.25 and 25 µg/mL. Further theoretical investigations of DDI were also carried out using DFT/D3(BJ)-B3LYP/6–311 ++ G (d, p) level of theory, of DDI in different environments (DMSO, Ethanol, Gas, and Water), that demonstrated structural stability of DDI in the different solvents with an energy gap of 7.0878 eV, 7.0831 eV, 6.9335 eV, and 7.0899 eV respectively. Molecular docking was employed substantiating the antimicrobial analysis, resulting in a score for receptors Candida tropicalis (1N9G), Escherichia coli (4LFU), Candida albicans (5K04), and Helicobacter pylori (4HI0) with binding affinity of -6.9 Kcal/mol, -8.5 Kcal/mol, -7.9 Kcal/mol, and -7.7 Kcal/mol respectively, compared with a conventional drug (fluconazole and amoxicillin) the docking proteins receptors. The docking for the DDI ligand against the receptor proteins of the studied organisms showed better inhibitory activity than the conventional drug (fluconazole), however, less activity with amoxicillin suggesting a more antifungal activity than antibacterial activity, presenting DDI ligand as a potential drug molecule against candidiasis.

Neuroprotective Role of Phytoconstituents-based Nanoemulsion for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disorder (ND), affecting more than 44 million individuals globally as of 2023. It is characterized by cognitive dysfunction and an inability to perform daily activities. The progression of AD is associated with the accumulation of amyloid beta (Aβ), the formation of neurofibrillary tangles (NFT), increased oxidative stress, neuroinflammation, mitochondrial dysfunction, and endoplasmic reticulum stress. Presently, various phytomedicines and their bioactive compounds have been identified for their neuroprotective effects in reducing oxidative stress, alleviating neuroinflammation, and mitigating the accumulation of Aβ and acetylcholinesterase enzymes in the hippocampus and cerebral cortex regions of the brain. However, despite demonstrating promising anti-Alzheimer's effects, the clinical utilization of phytoconstituents remains limited in scope. The key factor contributing to this limitation is the challenges inherent in traditional drug delivery systems, which impede their effectiveness and efficiency. These difficulties encompass insufficient drug targeting, restricted drug solubility and stability, brief duration of action, and a lack of control over drug release. Consequently, these constraints result in diminished bioavailability and insufficient permeability across the blood-brain barrier (BBB). In response to these challenges, novel drug delivery systems (NDDS) founded on nanoformulations have emerged as a hopeful strategy to augment the bioavailability and BBB permeability of bioactive compounds with poor solubility. Among these systems, nanoemulsion (NE) have been extensively investigated for their potential in targeting AD. NE offers several advantages, such as ease of preparation, high drug loading, and high stability. Due to their nanosize droplets, NE also improves gut and BBB permeability leading to enhanced permeability of the drug in systemic circulation and the brain. Various studies have reported the testing of NE-based phytoconstituents and their bioactives in different animal species, including transgenic, Wistar, and Sprague-Dawley (SD) rats, as well as mice. However, transgenic mice are commonly employed in AD research to analyze the effects of Aβ. In this review, various aspects such as the neuroprotective role of various phytoconstituents, the challenges associated with conventional drug delivery, and the need for NDDS, particularly NE, are discussed. Various studies involving phytoconstituent-based NE for the treatment of AD are also discussed.

تحضير وتشخيص بعض المركبات الحلقية غير المتجانسة المشتقة من عقار الميتوكلوبراميد وقياس فعاليتها البايلوجية

This study included the synthesis of some new Schiff bases and heterocyclic compounds [1‐6] from the reaction of metoclopramide with some aromatic aldehydes by the classical Schiff method, then the Schiff bases were treated with chloroacetyl chloride and thioglycolic acid to obtain cyclic derivatives of beta-lactams [5,6] and 4-thiazolidinone [3,4], respectively. These derivatives were characterized by their melting points by FT IR, 1H NMR. Some compounds prepared were evaluated for their antioxidant activity by oxidation with 2,2-diphenyl-1-picrylhydryl (DPPH). Comparison of the antioxidant activity of the bioactive molecules of the compounds [3–6] with that of the conventional drug metoclopramide showed encouraging results.

Wastewater-based epidemiology to monitor 68 NPS/conventional drug use in Taipei metropolitan area in Taiwan during and after COVID-19 pandemic

Amidst far-reaching COVID-19 effects and social constraints, this study leveraged wastewater-based epidemiology to track 38 conventional drugs and 30 new psychoactive substances (NPS) in northern Taiwan. Analyzing daily samples from four Taipei wastewater plants between September 2021 and January 2024—encompassing club reopenings, holidays, Lunar New Year, an outbreak, and regular periods—thirty-one drugs were detected, including 5 NPS. Tramadol, zolpidem tartrate, CMA, and MDPV were newly detected in Taiwanese sewage with frequency of 1.4 %− 89.0 %. Conventional drug use typically increased post-pandemic, aside from benzodiazepines and methadone. Methamphetamine showed 100 % frequency, indicating ongoing daily consumption despite COVID-19 measures. Methamphetamine and morphine's consumption dipped then rose around club reopening, hinting at limited access. The consumption trend of methadone appeared to compensate for the use of morphine. Ketamine and NPS demonstrated similar patterns throughout the entire period. NPS as party drugs seemed influenced by an unstable supply chain and complexities in implementation. Benzodiazepines, commonly abused alongside synthetic cathinones in Taiwan exhibited an opposing trend to NPS while aligned with acetaminophen, suggesting elevated stress and anxiety levels during the pandemic. No significant differences were observed in drug consumption between weekdays and weekends, potentially indicating that COVID-19 measures blurred the traditional distinctions between these timeframes. Environmental ImplicationNew psychoactive substances refer to chemically modified variants of controlled drugs designed to mimic the effects of the original drugs while evading modern detection methods, categorizing them as hazardous materials. The study presents a sewage monitoring project conducted from 2021 to 2024, collecting samples from four WWTPs to analyze NPS and conventional drug trends during and after the COVID-19 pandemic. The findings uncovered connections between drug consumption patterns and pandemic-related policies. In light of the persistent drug abuse and their environmental presence, the results bear critical importance for both environmental and public health. We provide a thorough assessment of these relationships and prioritize areas for future research.

Plant Molecular Farming: An Emerging Opportunity For Biopharmaceuticals

Conventional drug production methods are costly. Now, it has been proved that plants are potentially a new source of pharmaceutical proteins, including vaccines, antibodies, blood substitutes, and other therapeutic entities. Unlike mammalian-derived rDNA drugs, plant-derived antibodies, vaccines, and other proteins are particularly advantageous since they are free of mammalian viral vectors and human pathogens. Plants made therapeutics are cheaper, safer, and can be abundantly produced and easily stored. Recombinant proteins and other metabolites are produced in transgenic plants for industrial or pharmaceutical purposes, which are known as molecular farming. Transgenic plants carry one or more foreign genes transferred through the techniques of transformation. Although initially these were produced only in a limited number of plant species (e.g., tobacco, petunia, tomato, etc.), later these could be produced in any plant species, including both dicots and monocots. Transgenic plants resistant to herbicides, insects, viruses, and a host of abiotic stresses have already been produced. These plants have also been produced for improved nutritional quality and are suitable for food processing. The aim of this review paper is to understand plant molecular farming, the advantages and limitations of the process, and biosafety concerns.

Trends and Prospects of Nano-delivered Phytopharmaceuticals for disease of Public health importance: A Review

A significant amount of effective medicine can be found in phytochemicals thatare found in natural products or herb extracts. These natural drugs can be used in the treatment of public health diseases such as diabetes, cardiovascular disease, malaria, HIV, COVID-19, gastrointestinal disorders, neurodegenerative diseases, and cancer. There are significant therapeutic limitations when phytomedicines are administered in conventional pharmaceutical dosage forms like powders,tablets, solutions, brews, and balms. These include low aqueous solubility, poor permeability, degradation, and instability. As a result, there is low production yield, poor absorption and bioavailability, poor potency and efficacy, and toxicity in the body. As a result, phytomedicines are not as effective as they could be. Polymeric nanoparticles, lipid nanoparticles, liposomes, sterosomes, and metallic nanoparticles are novel drug delivery systems that circumvent the problems of conventional drug delivery systems. These nanocarriers can enhance phytomedicine's solubility, stability, and control, prolong the release of herbal medicine, and target specific sites within the body. As a result, herbal medicine can achieve maximum potency and efficacy with significantly fewer adverse effects. The use of phytopharmaceuticals as treatments for diseases that affect public health is extensively covered in this paper, as is the topic of nano-derived phytopharmaceuticals.

Innovative Nanotechnology in Drug Delivery Systems for Advanced Treatment of Posterior Segment Ocular Diseases.

Funduscopic diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), significantly impact global visual health, leading to impaired vision and irreversible blindness. Delivering drugs to the posterior segment of the eye remains a challenge due to the presence of multiple physiological and anatomical barriers. Conventional drug delivery methods often prove ineffective and may cause side effects. Nanomaterials, characterized by their small size, large surface area, tunable properties, and biocompatibility, enhance the permeability, stability, and targeting of drugs. Ocular nanomaterials encompass a wide range, including lipid nanomaterials, polymer nanomaterials, metal nanomaterials, carbon nanomaterials, quantum dot nanomaterials, and so on. These innovative materials, often combined with hydrogels and exosomes, are engineered to address multiple mechanisms, including macrophage polarization, reactive oxygen species (ROS) scavenging, and anti-vascular endothelial growth factor (VEGF). Compared to conventional modalities, nanomedicines achieve regulated and sustained delivery, reduced administration frequency, prolonged drug action, and minimized side effects. This study delves into the obstacles encountered in drug delivery to the posterior segment and highlights the progress facilitated by nanomedicine. Prospectively, these findings pave the way for next-generation ocular drug delivery systems and deeper clinical research, aiming to refine treatments, alleviate the burden on patients, and ultimately improve visual health globally.

Metformin instigates cellular autophagy to ameliorate high-fat diet-induced pancreatic inflammation and fibrosis/EMT in mice

BackgroundChronic pancreatic dysfunction is frequently observed as a consequence of prolonged high-fat diet consumption and is a serious public health concern. This pro-diabetic insult aggravates inflammation-influenced fibrotic lesions and is associated with deregulated autophagy. Metformin, a conventional anti-hyperglycemic drug, might be beneficial for pancreatic health, but the complex molecular regulations are not clarified. Considering the worldwide prevalence of chronic pancreatic dysfunction in obese individuals, we aimed to unwind the molecular intricacies explaining the involvement of oxidative stress, inflammation and fibrosis and to approbate metformin as a plausible intervention in this crossroad. Main methodsAge-matched Swiss Albino mice were exposed to high-fat diet (60 kcal%) against control diet (10 kcal%) to establish diet-induced stress model. Metformin treatment was introduced after 4 weeks to metformin-control and HFD-exposed metformin groups. After 8 weeks, metabolic and molecular outcomes were assessed to establish the impact of metformin on chronic consequences of HFD-mediated injury. Key findingsHigh-fat diet administration to healthy mice primes oxidative stress-mediated chronic inflammation through Nrf2/Keap1/NF-κB interplay. Besides, pro-inflammatory cytokine bias leading to fibrotic (increased TGF-β, α-SMA, and MMP9) and pro-EMT (Twist1, Slug, Vimentin, E-cadherin) repercussions in pancreatic lobules were evident. Metformin distinctly rescues high-fat diet-induced remodeling of pancreatic pro-diabetic alterations and cellular survival/death switch. Further, metformin abrogates the p62-Twist1 crosstalk in an autophagy-dependent manner (elevated beclin1, LC3-II/I, Lamp2) to restore pancreatic homeostasis. ConclusionOur research validates the therapeutic potential of metformin in the inflammation-fibrosis nexus to ameliorate high-fat diet-induced pancreatic dysfunction and related metabolic alterations.

DIPG-65. NOVEL PATIENT-BASED PHARMACOKINETIC DRUG SCREENING REVEALS GEMCITABINE POTENTIAL IN PEDIATRIC H3K27-ALTERED DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND Pediatric H3K27-altered diffuse midline glioma (DMG) remains incurable, with median overall survival of less than one year. Ineffectiveness of chemotherapy is largely attributed to the blood–brain barrier, hindering drug exposure to the tumor. Current drug sensitivity testing use concentrations vastly different from those attainable in the human brain, with optimal combination, timing, and sequence of drugs remaining underexplored. This study aims to systematically select and validate EMA/FDA approved drugs for effective treatment of DMG, based on human pharmacokinetics. METHODS In silico anticancer drug pharmacokinetic (PK) properties were correlated with published DMG cell sensitivities and ranked based on therapeutic index potential. Predictions of brain extracellular fluid time-concentration profiles (AUChumanECF) using plasma PK values of drug candidates, corresponding to human values, were made via physiologically based pharmacokinetic (PBPK) modeling with LeiCNS-PK3.0. In vitro cellular treatment protocols were established that mimic clinically achievable AUChumanECF, to be validated in vivo. RESULTS This PBPK drug screening approach revealed gemcitabine as a highly potent drug for DMG therapy for most cell lines tested (AUCplasma/AUCin_vitro = 337.6±233.0). Replicating a phase I clinical study in pediatric leukemia patients (3 weekly courses of 3600 mg/m2), 3 weekly 6-hour exposures to 12.5 µM.h gemcitabine demonstrated up to 99% cell kill as compared to viability at start of treatment. Notably, the cytotoxic effects of gemcitabine became apparent 3-5 days following drug exposure for most cell lines, and would have been missed using conventional drug screening with direct readouts. CONCLUSIONS This human PBPK-based drug screening approach underscores the significance of precise timing and dosing in elucidating clinically relevant therapeutic effects, highlighting high-dose gemcitabine as a potential therapy for DMG. Cytotoxic effects of gemcitabine on DMG cell viability are cumulative, and undetected when using conventional drug screening. This underlines the importance of investigating real-life human exposure patterns in the context of DMG.

Synthesis of novel pyrido[3,4‐d]pyrimidine‐thiazolidione‐1,2,4‐oxadiazoles as potent EGFR targeting anticancer agents

AbstractIn this study, we designed and synthesized a number of novel pyrido[3,4‐d]pyrimidine‐thiazolidine‐1,2,4‐oxadiazole derivatives and investigated them in vitro for their inhibitory action toward epidermal growth factor receptor (EGFR) kinases and antiproliferative activity against two different cell lines, MCF‐7 and A‐549. When compared to the lead chemicals, 5‐fluorouracil and erlotinib, some of the compounds demonstrated acceptable activity. Among them, the most promising compounds 4d and 4e displayed potent anticancer activity against both MCF‐7 and A‐549 cell lines (IC50 values remaining: 1.97 ± 0.28 μM to 8.14 ± 0.52 μM, respectively); the comparative IC50 values for 5‐fluorouracil and erlotinib in these cell lines were 5.56 ± 0.34 μM, 12.66 ± 0.76 μM, and 3.64 ± 0.49 μM, 9.54 ± 0.75 μM, respectively; as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.34 ± 0.07 μM and 0.42 ± 0.06 μM) were more effective than the conventional drug Erlotinib (IC50 = 0.42 ± 0.02 μM).

Anti-BCMA–engineered exosomes for bortezomib-targeted delivery in multiple myeloma

AbstractExosomes have emerged as promising vehicles for delivering therapeutic cargoes to specific cells or tissues, owing to their superior biocompatibility, reduced immunogenicity, and enhanced targeting capabilities compared with conventional drug delivery systems. In this study, we developed a delivery platform using exosomes derived from monocytes, specifically designed for targeted delivery of bortezomib (Btz) to multiple myeloma (MM) cells. Our approach involved the genetic modification of monocytes to express antibodies targeting B-cell maturation antigen (anti-BCMA), because BCMA selectively expresses on myeloma cells. This modified anti-BCMA was then efficiently incorporated into the monocyte-derived exosomes. These adapted exosomes effectively encapsulated Btz, leading to enhanced drug accessibility within MM cells and sustained intracellular accumulation over an extended period. Remarkably, our results demonstrated that anti-BCMA–modified exosome-loaded Btz (anti-BCMA-Exo-Btz) outperformed free Btz in vitro, exhibiting a more potent myeloma-suppressive effect. In orthotopic MM xenograft models, anti-BCMA-Exo-Btz exhibited a significant antitumor effect compared with free Btz. Furthermore, it demonstrated remarkable specificity in targeting Btz to myeloma cells in vivo. Importantly, we observed no significant histological damage in mice treated with anti-BCMA-Exo-Btz and a slight effect on peripheral blood mononuclear cells. In addition, our study highlighted the multifunctional potential of monocyte exosomes, which induced cell apoptosis, mediated immune responses, and enhanced the osteogenic potential of mesenchymal stromal cells. In conclusion, our study suggests that exosomes modified with targeting ligands hold therapeutic promise for delivering Btz to myelomas, offering substantial potential for clinical applications.

Analysis of the Clinical Effect of Multi-Drug Combination Therapy on Patients with Gynecological Inflammation

Objective: To investigate the effect of multi-drug combination therapy for patients diagnosed with gynecological inflammation. Methods: A total of 100 patients diagnosed with gynecological inflammation between August 2023 and January 2024 were selected as the study subjects. The patients were separated into a control group and an observation group, with 50 patients in each group. The control group underwent conventional drug therapy while the observation group combined lactobacillus vaginal capsule treatment. The clinical effects of the treatments were compared. Results: The total efficacy of the treatment received in the observation was higher. The time taken for gynecological symptom relief was shorter, and the values of vaginal pH, interleukin-6 (IL-6), and C-reactive protein (CRP) were lower after treatment (P &lt; 0.05) compared to the control group. Conclusion: The multi-drug combination therapy can achieve rapid symptomatic relief and improve the vaginal microenvironment in patients with gynecological inflammation, which can reduce their inflammatory response and improve their prognosis.

Phyto-fabrication and characterization of gold nanoparticles by using Timur (Zanthoxylum armatum DC) and their effect on wound healing

Abstract Nanotechnology has revolutionized the drug delivery approaches to improve the existing issues of conventional drug delivery systems, especially, the green synthesis of nanoparticles is becoming more suitable for different activities. In this study, phyto-fabricated gold nanoparticles (GNPs) were synthesized using Zanthoxylum armatum aqueous extract. GNPs were characterized by different techniques using UV-Vis absorption spectroscopy, X-Ray diffraction (XRD), Fourier transformation infrared spectroscopy (FTIR), Dynamic light scattering (DLS), and scanning electron microscopy (SEM). UV-Vis spectroscopy showed peak at 550 nm. XRD confirmed the crystalline nature of nanoparticles. FTIR showed presence of different functional groups such as C–O, N–H, C═O, C–H, and O–H. SEM and DLS have shown particle size of 30 nm. The antibacterial activity of plant extract and green synthesized GNP were tested against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Klebsiella pneumonia which revealed remarkable inhibition of these microorganisms. Burn wound was created on 16 rats and randomized into four groups. Group I was untreated. Group II rats were treated by applying topical ointment cream. Group III rats were treated by applying Zanthoxylum armatum cream, and group IV rats were treated by applying GNPs-based cream. Treatment was carried out for 14 days. Wounds treated with GNPs-based cream decreased consistently and almost completely. It can be concluded that GNPs-based cream can be used as an ointment to treat wounds especially burn wounds.