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Clinical and Translational Science Jun 2024Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated... (Review)
Review
Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low-density lipoprotein cholesterol (LDL-C). HoFH primarily results from loss-of-function (LOF) mutations in the LDL receptor (LDLR), reducing LDL-C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL-C; however, many patients with HoFH still fail to reach their target LDL-C levels and many of these lipid-lowering therapies are not indicated for pediatric use. Angiopoietin-like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL-C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low-density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL-C than non-carriers and lower risk of coronary artery disease. Evinacumab is a first-in-class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL-C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH.
Topics: Humans; Translational Research, Biomedical; Hyperlipoproteinemia Type II; Angiopoietin-Like Protein 3; Cholesterol, LDL; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Animals; Anticholesteremic Agents; Receptors, LDL
PubMed: 38845393
DOI: 10.1111/cts.13836 -
Scientific Reports Jun 2024This study introduces a novel approach for synthesizing a Cu(II)-based coordination polymer (CP), {[Cu(L)(4,4´-OBA)]·HO}n (1), using a mixed ligand method. The CP was...
This study introduces a novel approach for synthesizing a Cu(II)-based coordination polymer (CP), {[Cu(L)(4,4´-OBA)]·HO}n (1), using a mixed ligand method. The CP was successfully prepared by reacting Cu(NO)·3HO with the ligand 3,6-bis(benzimidazol-1-yl)pyridazine in the presence of 4,4´-HOBA, demonstrating an innovative synthesis strategy. Furthermore, a novel hydrogel composed of hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) with a porous structure was developed for drug delivery purposes. This hydrogel facilitates the encapsulation of CP1, and enables the loading of paclitaxel onto the composite to form HA/CMCS-CP1@paclitaxel. In vitro cell experiments demonstrated the promising modulation of thyroid cancer biomarker genes S100A6 and ARID1A by HA/CMCS-CP1@paclitaxel. Finally, reinforcement learning simulations were employed to optimize novel metal-organic frameworks, underscoring the innovative contributions of this study.
Topics: Paclitaxel; Copper; Hydrogels; Humans; Thyroid Neoplasms; Chitosan; Cell Line, Tumor; Hyaluronic Acid; Coordination Complexes; Drug Carriers; Metal-Organic Frameworks
PubMed: 38844812
DOI: 10.1038/s41598-024-63940-w -
Scientific Reports Jun 2024Herbal medicine combined with nanoparticles has caught much interest in clinical dental practice, yet the incorporation of chitosan with Salvadora persica (S. persica)...
Herbal medicine combined with nanoparticles has caught much interest in clinical dental practice, yet the incorporation of chitosan with Salvadora persica (S. persica) extract as an oral care product has not been explored. The aim of this study was to evaluate the combined effectiveness of Salvadora persica(S. persica) and Chitosan nanoparticles (ChNPs) against oropharyngeal microorganisms. Agar well diffusion, minimum inhibitory concentration, and minimal lethal concentration assays were used to assess the antimicrobial activity of different concentrations of ethanolic extracts of S. persica and ChNPs against selected fungal strains, Gram-positive, and Gram-negative bacteria. A mixture of 10% S. persica and 0.5% ChNPs was prepared (SChNPs) and its synergistic effect against the tested microbes was evaluated. Furthermore, the strain that was considered most sensitive was subjected to a 24-h treatment with SChNPs mixture; and examined using SEM, FT-IR and GC-MS analysis. S. persica extract and ChNPs exhibited concentration-dependent antimicrobial activities against all tested strains. S. persica extract and ChNPs at 10% were most effective against S. pneumoni, K. pneumoni, and C. albicans. SEM images confirmed the synergistic effect of the SChNPs mixture, revealing S. pneumonia cells with increased irregularity and higher cell lysis compared to the individual solutions. GC-MS and FT-IR analysis of SChNPs showed many active antimicrobial phytocompounds and some additional peaks, respectively. The synergy of the mixture of SChNPs in the form of mouth-rinsing solutions can be a promising approach for the control of oropharyngeal microbes that are implicated in viral secondary bacterial infections.
Topics: Chitosan; Nanoparticles; Plant Extracts; Drug Synergism; Microbial Sensitivity Tests; Salvadoraceae; Oropharynx; Anti-Infective Agents; Candida albicans; Humans; Spectroscopy, Fourier Transform Infrared
PubMed: 38844768
DOI: 10.1038/s41598-024-63636-1 -
Journal of Controlled Release :... Jul 2024The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and...
The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
Topics: Dogs; Animals; Solubility; Molecular Dynamics Simulation; Felodipine; Probucol; Carvedilol; Lipids; Body Fluids; Bile Acids and Salts; Male; Intestinal Secretions
PubMed: 38844179
DOI: 10.1016/j.jconrel.2024.06.008 -
International Journal For Equity in... Jun 2024PCSK9 inhibitors are a novel class of lipid-lowering drugs that have demonstrated favorable efficacy and safety. Evolocumab and alirocumab have been added to China's...
BACKGROUND
PCSK9 inhibitors are a novel class of lipid-lowering drugs that have demonstrated favorable efficacy and safety. Evolocumab and alirocumab have been added to China's National Reimbursement Drug List through the National Drug Price Negotiation (NDPN) policy. This study aims to evaluate the impact of the NDPN policy on the utilization and accessibility of these two PCSK9 inhibitors.
METHODS
The procurement data of evolocumab and alirocumab were collected from 1,519 hospitals between January 2021 and December 2022. We determined the monthly availability, utilization, cost per daily defined dose (DDDc), and affordability of the two medicines. Single-group interrupted time series (ITS) analysis was performed to assess the impact of the NDPN policy on each drug, and multiple-group ITS analysis was performed to compare the differences between them.
RESULTS
The NDPN policy led to a significant and sudden increase in the availability and utilization of PCSK9 inhibitors, along with a decrease in their DDDc. In the year following the policy implementation, there was an increase in the availability, utilization, and spending, and the DDDc remained stable. The affordability of PCSK9 inhibitors in China have been significantly improved, with a 92.97% reduction in out-of-pocket costs. The availability of both PCSK9 inhibitors was similar, and the DDDc of alirocumab was only $0.23 higher after the intervention. The market share of evolocumab consistently exceeded that of alirocumab. Regional disparities in utilization were observed, with higher utilization in the eastern region and a correlation with per capita disposable income.
CONCLUSIONS
The NDPN policy has successfully improved the accessibility and utilization of PCSK9 inhibitors in China. However, regional disparities in utilization indicate the need for further interventions to ensure equitable medicine access.
Topics: Humans; China; Interrupted Time Series Analysis; PCSK9 Inhibitors; Drug Costs; Antibodies, Monoclonal, Humanized; Health Services Accessibility; Anticholesteremic Agents; Health Policy
PubMed: 38840134
DOI: 10.1186/s12939-024-02208-1 -
Cancer Research Communications Jun 2024Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently...
UNLABELLED
Glioblastoma (GBM) is the deadliest adult brain cancer. Under the current standard of care, almost all patients succumb to the disease and novel treatments are urgently needed. Recognizing that GBMs are addicted to cholesterol, past clinical trials have repurposed statins against GBM but failed. The purpose of this study was to test whether treatments that upregulate the cholesterol biosynthesis pathway in GBM would generate a metabolic vulnerability that can be exploited using statins and to determine the underlying mechanisms.Effects of radiotherapy and temozolomide or dopamine receptor antagonists on the mevalonate pathway in GBM were assessed in vitro and in vivo. The impact of statins on self-renewal of glioma stem cells and median survival was studied. Branches of the mevalonate pathway were probed to identify relevant effector proteins.Cells surviving combination treatments that converge in activating the immediate early response, universally upregulated the mevalonate pathway and increased stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 was inhibited by statins, which led to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.We conclude that a combination of dopamine receptor antagonists and statins could potentially improve radiotherapy outcome and warrants further investigation.
SIGNIFICANCE
Combination therapies that activate the mevalonate pathway in GBM cells after sublethal treatment enhance self-renewal and migratory capacity through Rac-1 activation, which creates a metabolic vulnerability that can be further potentially exploited using statins.
Topics: Glioblastoma; Mevalonic Acid; Humans; Animals; rac1 GTP-Binding Protein; Mice; Brain Neoplasms; Cell Line, Tumor; Temozolomide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasm Recurrence, Local; Xenograft Model Antitumor Assays; Neoplastic Stem Cells; Signal Transduction; Dopamine Antagonists
PubMed: 38837899
DOI: 10.1158/2767-9764.CRC-24-0049 -
Brain and Behavior Jun 2024In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis....
BACKGROUND
In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases.
METHODS
We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD).
RESULTS
PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001).
CONCLUSION
PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.
Topics: Mendelian Randomization Analysis; Humans; PCSK9 Inhibitors; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; Parkinson Disease; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Genome-Wide Association Study; Proprotein Convertase 9
PubMed: 38837845
DOI: 10.1002/brb3.3543 -
Biomaterials Science Jun 2024Current treatment strategies for infection of chronic wounds often result in compromised healing and necrosis due to antibiotic toxicity, and underlying biomarkers...
Current treatment strategies for infection of chronic wounds often result in compromised healing and necrosis due to antibiotic toxicity, and underlying biomarkers affected by treatments are not fully known. Here, a multifunctional dressing was developed leveraging the unique wound-healing properties of chitosan, a natural polysaccharide known for its numerous benefits in wound care. The dressing consists of an oxygenating perfluorocarbon functionalized methacrylic chitosan (MACF) hydrogel incorporated with antibacterial polyhexamethylene biguanide (PHMB). A non-healing diabetic infected wound model with emerging metabolomics tools was used to explore the anti-infective and wound healing properties of the resultant multifunctional dressing. Direct bacterial bioburden assessment demonstrated superior antibacterial properties of hydrogels over a commercial dressing. However, wound tissue quality analyses confirmed that sustained PHMB for 21 days resulted in tissue necrosis and disturbed healing. Therefore, a follow-up comparative study investigated the best treatment course for antiseptic application ranging from 7 to 21 days, followed by the oxygenating chitosan-based MACF treatment for the remainder of the 21 days. Bacterial counts, tissue assessments, and lipidomics studies showed that 14 days of application of MACF-PHMB dressings followed by 7 days of MACF dressings provides a promising treatment for managing infected non-healing diabetic skin ulcers.
Topics: Chitosan; Anti-Bacterial Agents; Hydrogels; Wound Healing; Animals; Bandages; Biguanides; Wound Infection; Male; Oxygen; Chronic Disease; Fluorocarbons
PubMed: 38836321
DOI: 10.1039/d4bm00355a -
Scientific Reports Jun 2024Natural polymer-based hydrogels have demonstrated great potential as wound-healing dressings. They help to maintain a moist wound environment as well as promote faster...
Natural polymer-based hydrogels have demonstrated great potential as wound-healing dressings. They help to maintain a moist wound environment as well as promote faster healing. In this work, a multifunctional hydrogel was prepared using keratin, sodium alginate, and carboxymethyl chitosan with tannic acid modification. Micro-morphology of hydrogels has been performed by scanning electron microscopy. Fourier Transform Infrared Spectroscopy reveals the presence of hydrogen bonding. The mechanical properties of the hydrogels were examined using a universal testing machine. Furthermore, we investigated several properties of the modified hydrogel. These properties include swelling rate, water retention, anti-freezing properties, antimicrobial and antioxidant properties, hemocompatibility evaluation and cell viability test in vitro. The modified hydrogel has a three-dimensional microporous structure, the swelling rate was 1541.7%, the elastic modulus was 589.74 kPa, the toughness was 211.74 kJ/m, and the elongation at break was 75.39%, which was similar to the human skin modulus. The modified hydrogel also showed inhibition of S. aureus and E. coli, as well as a DPPH scavenging rate of 95%. In addition, the modified hydrogels have good biological characteristics. Based on these findings, the K/SA/CCS hydrogel holds promise for applications in biomedical engineering.
Topics: Chitosan; Tannins; Alginates; Hydrogels; Humans; Keratins; Biocompatible Materials; Staphylococcus aureus; Antioxidants; Escherichia coli; Wound Healing; Cell Survival; Spectroscopy, Fourier Transform Infrared; Elastic Modulus; Anti-Bacterial Agents
PubMed: 38834664
DOI: 10.1038/s41598-024-63186-6 -
International Journal of Nanomedicine 2024Nanoparticle systems integrating alginate and chitosan emerge as a promising avenue to tackle challenges in leveraging the potency of pharmacological active agents.... (Review)
Review
Nanoparticle systems integrating alginate and chitosan emerge as a promising avenue to tackle challenges in leveraging the potency of pharmacological active agents. Owing to their intrinsic properties as polysaccharides, alginate and chitosan, exhibit remarkable biocompatibility, rendering them conducive to bodily integration. By downsizing drug particles to the nano-scale, the system enhances drug solubility in aqueous environments by augmenting surface area. Additionally, the system orchestrates extended drug release kinetics, aligning well with the exigencies of chronic drug release requisite for antibacterial therapeutics. A thorough scrutiny of existing literature underscores a wealth of evidence supporting the utilization of the alginate-chitosan nanoparticle system for antibacterial agent delivery. Literature reviews present abundant evidence of the utilization of nanoparticle systems based on a combination of alginate and chitosan for antibacterial agent delivery. Various experiments demonstrate enhanced antibacterial efficacy, including an increase in the inhibitory zone diameter, improvement in the minimum inhibitory concentration, and an enhancement in the bacterial reduction rate. This enhancement in efficacy occurs due to mechanisms involving increased solubility resulting from particle size reduction, prolonged release effects, and enhanced selectivity towards bacterial cell walls, stemming from ionic interactions between positively charged particles and teichoic acid on bacterial cell walls. However, clinical studies remain limited, and there are currently no marketed antibacterial drugs utilizing this system. Hence, expediting clinical efficacy validation is crucial to maximize its benefits promptly.
Topics: Chitosan; Alginates; Anti-Bacterial Agents; Humans; Nanoparticles; Particle Size; Drug Liberation; Drug Carriers; Microbial Sensitivity Tests; Animals; Drug Delivery Systems; Solubility; Bacteria
PubMed: 38832335
DOI: 10.2147/IJN.S469572