Lithium is the superior first-line treatment for bipolar disorder (BD). Yet the percentage of patients receiving lithium is abysmally low, especially in the US. Since psychiatrists have failed to place lithium in its appropriate role, we make the case that patients with BD themselves need to be better educated about the unique characteristics and pre-eminence of the drug so that it can be used more often and appropriately. Lithium has a highly unfavorable popular reputation among would-be patients and many psychiatrists. Thus, a direct appeal to patients with BD appears appropriate to try to remediate this situation. The unique assets of lithium are underappreciated or not well known. Conversely, the side effects profile of lithium are overestimated. Here, we make the case that lithium's image needs to be revised not only with better and more accurate information but also with a wholesale renaming and rebranding of the drug. We will not only outline the unique qualities and new information about the side effects of the drug but attempt to change some of the terminology conventionally used to refer to lithium so that its use may be appropriately applied earlier and at an increased frequency for patients with BD.
{"title":"What Patients with Bipolar Disorder Need to Know about Lithium.","authors":"Robert M Post, Janusz K Rybakowski","doi":"10.3390/ph17091223","DOIUrl":"https://doi.org/10.3390/ph17091223","url":null,"abstract":"<p><p>Lithium is the superior first-line treatment for bipolar disorder (BD). Yet the percentage of patients receiving lithium is abysmally low, especially in the US. Since psychiatrists have failed to place lithium in its appropriate role, we make the case that patients with BD themselves need to be better educated about the unique characteristics and pre-eminence of the drug so that it can be used more often and appropriately. Lithium has a highly unfavorable popular reputation among would-be patients and many psychiatrists. Thus, a direct appeal to patients with BD appears appropriate to try to remediate this situation. The unique assets of lithium are underappreciated or not well known. Conversely, the side effects profile of lithium are overestimated. Here, we make the case that lithium's image needs to be revised not only with better and more accurate information but also with a wholesale renaming and rebranding of the drug. We will not only outline the unique qualities and new information about the side effects of the drug but attempt to change some of the terminology conventionally used to refer to lithium so that its use may be appropriately applied earlier and at an increased frequency for patients with BD.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The disease of transthyretin (TTR) amyloidosis (ATTR) has been known since the 1960s, and during the past 60 or so years, there has been a sustained period of steady discoveries that have led to the current model of ATTR pathogenesis. More recent research has achieved major advances in both diagnostics and therapeutics for ATTR, which are having a significant impact on ATTR patients today. Aiding these recent achievements has been the remarkable ability of cryo-electron microscopy (EM) to determine high-resolution structures of amyloid fibrils obtained from individual patients. Here, we will examine the cryo-EM structures of transthyretin amyloid fibrils to explore the structural basis of the two monoclonal antibody therapies for ATTR that are in clinical trials, ALXN-2220 and Coramitug, as well as to point out potential applications of this approach to other systemic amyloid diseases.
{"title":"Structural Basis for Monoclonal Antibody Therapy for Transthyretin Amyloidosis.","authors":"Avi Chakrabartty","doi":"10.3390/ph17091225","DOIUrl":"https://doi.org/10.3390/ph17091225","url":null,"abstract":"<p><p>The disease of transthyretin (TTR) amyloidosis (ATTR) has been known since the 1960s, and during the past 60 or so years, there has been a sustained period of steady discoveries that have led to the current model of ATTR pathogenesis. More recent research has achieved major advances in both diagnostics and therapeutics for ATTR, which are having a significant impact on ATTR patients today. Aiding these recent achievements has been the remarkable ability of cryo-electron microscopy (EM) to determine high-resolution structures of amyloid fibrils obtained from individual patients. Here, we will examine the cryo-EM structures of transthyretin amyloid fibrils to explore the structural basis of the two monoclonal antibody therapies for ATTR that are in clinical trials, ALXN-2220 and Coramitug, as well as to point out potential applications of this approach to other systemic amyloid diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Arterial thrombosis, a condition in which thrombi form in arteries, can lead to various acute cardiovascular diseases and impact the quality of life and survival of patients. Berberine (BBR), a quaternary ammonium alkaloid, has been shown to treat these diseases. However, further exploration is needed to understand underlying mechanisms of BBR.
Methods and results: Rats were administered BBR via intramuscular injection. Then, an FeCl3-coated filter paper was applied to a carotid artery to induce thrombosis. The size of the thrombus and the blood flow velocity were evaluated by carotid ultrasound. The shape of the thrombus was observed using staining and microscopy. The expression levels of mRNA and proteins were verified. Additionally, mass spectrometry and single-cell RNA sequencing analysis were conducted. The administration of BBR resulted in a significant reduction in the thrombus area and an extension of the thrombus-clogging time. Furthermore, BBR administration effectively reversed the decreasing tissue-plasminogen activator (t-PA) expression and alterations in fibrinolysis system of model group. Additionally, the expression of PKM2 was suppressed following BBR administration, and the overexpression of PKM2 inhibited t-PA expression.
Conclusions: BBR ameliorates thrombosis by modulating expression of PKM2, subsequently impacting the expression of t-PA within fibrinolytic system. These preliminary findings suggest that BBR could be a potential preventive and therapeutic strategy for arterial thromboembolic diseases.
{"title":"Berberine Targets PKM2 to Activate the t-PA-Induced Fibrinolytic System and Improves Thrombosis.","authors":"Zeqi Sun, Tong Zhao, Xue Bai, Huimin Li, Jin Gao, Yutong Hao, Yiyang Li, Yanli Xie, Ange Hu, Qiang Huang, Xin Liu, Yong Zhang","doi":"10.3390/ph17091219","DOIUrl":"https://doi.org/10.3390/ph17091219","url":null,"abstract":"<p><strong>Background: </strong>Arterial thrombosis, a condition in which thrombi form in arteries, can lead to various acute cardiovascular diseases and impact the quality of life and survival of patients. Berberine (BBR), a quaternary ammonium alkaloid, has been shown to treat these diseases. However, further exploration is needed to understand underlying mechanisms of BBR.</p><p><strong>Methods and results: </strong>Rats were administered BBR via intramuscular injection. Then, an FeCl<sub>3</sub>-coated filter paper was applied to a carotid artery to induce thrombosis. The size of the thrombus and the blood flow velocity were evaluated by carotid ultrasound. The shape of the thrombus was observed using staining and microscopy. The expression levels of mRNA and proteins were verified. Additionally, mass spectrometry and single-cell RNA sequencing analysis were conducted. The administration of BBR resulted in a significant reduction in the thrombus area and an extension of the thrombus-clogging time. Furthermore, BBR administration effectively reversed the decreasing tissue-plasminogen activator (t-PA) expression and alterations in fibrinolysis system of model group. Additionally, the expression of PKM2 was suppressed following BBR administration, and the overexpression of PKM2 inhibited t-PA expression.</p><p><strong>Conclusions: </strong>BBR ameliorates thrombosis by modulating expression of PKM2, subsequently impacting the expression of t-PA within fibrinolytic system. These preliminary findings suggest that BBR could be a potential preventive and therapeutic strategy for arterial thromboembolic diseases.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11434879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Laura Négrier, Bertrand Décaudin, Anthony Treizebré, Marie Guilbert, Pascal Odou, Anthony Martin Mena
Introduction: Drug incompatibilities are among the most common medication errors in intensive care units. A precipitate can form and block the catheter or cause an adverse event in the patient. Intensive care units have implemented various strategies for limiting the occurrence of these incompatibilities, which have already been studied in vitro under standardized conditions. The objective of the present in vitro study was to continue these assessments by determining the impact of the infusion line geometry and the drugs' position in the infusion set-up on the prevention of vancomycin-piperacillin/tazobactam incompatibility.
Methods: Infusion lines with a different common volume, a multilumen medical infusion device, a dilute vancomycin solution, and separate infusions of incompatible drugs were evaluated separately. The infusion line outlet was connected to a dynamic particle counter.
Results: Reducing the common volume, using multilumen medical devices, or spacing out the two incompatible drugs on the infusion line did not prevent the occurrence of a significant particulate load. Only dilution of the vancomycin solution was associated with a significantly lower particulate load and the absence of drug incompatibility.
Conclusions: Our results show that under specific conditions, it is possible to reduce particulate contamination considerably.
{"title":"Evaluation of the Impact of Infusion Set Design on the Particulate Load Induced by Vancomycin-Piperacillin/Tazobactam Incompatibility.","authors":"Laura Négrier, Bertrand Décaudin, Anthony Treizebré, Marie Guilbert, Pascal Odou, Anthony Martin Mena","doi":"10.3390/ph17091222","DOIUrl":"https://doi.org/10.3390/ph17091222","url":null,"abstract":"<p><strong>Introduction: </strong>Drug incompatibilities are among the most common medication errors in intensive care units. A precipitate can form and block the catheter or cause an adverse event in the patient. Intensive care units have implemented various strategies for limiting the occurrence of these incompatibilities, which have already been studied in vitro under standardized conditions. The objective of the present in vitro study was to continue these assessments by determining the impact of the infusion line geometry and the drugs' position in the infusion set-up on the prevention of vancomycin-piperacillin/tazobactam incompatibility.</p><p><strong>Methods: </strong>Infusion lines with a different common volume, a multilumen medical infusion device, a dilute vancomycin solution, and separate infusions of incompatible drugs were evaluated separately. The infusion line outlet was connected to a dynamic particle counter.</p><p><strong>Results: </strong>Reducing the common volume, using multilumen medical devices, or spacing out the two incompatible drugs on the infusion line did not prevent the occurrence of a significant particulate load. Only dilution of the vancomycin solution was associated with a significantly lower particulate load and the absence of drug incompatibility.</p><p><strong>Conclusions: </strong>Our results show that under specific conditions, it is possible to reduce particulate contamination considerably.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Muhammad Asif, Muhammad Fakhar-E-Alam, Muhammad Tahir, Farah Jamil, Hassan Sardar, Javed Rehman, Kholood A Dahlous
In this research, we developed undoped and aluminum-doped zinc oxide for antimicrobial and anticancer activities. This study focuses on the synthesis, characterization, and biological activities of zinc oxide nanoparticles (ZnO NPs) and aluminum-doped zinc oxide nanocomposites (Zn1-xAlxO NCs) at varying concentrations (x = 0, 0.25, 0.5, and 0.75 wt%) using the coprecipitation method. Various characterization techniques such as XRD, UV-Vis, FTIR, EDX, and SEM were performed to analyze the crystal structure, optical properties, functional group identification, elemental composition, and surface morphology. The antimicrobial activity test showed that Zn0.75Al0.25O NCs exhibited the strongest inhibition zone against Bacillus cereus compared to Staphylococcus aureus > Pasteurella multocida > Escherichia coli. Moreover, the cytotoxicity and cell viability of liver cancer (HepG-2), breast cancer (MCF-7), ovarian cancer (SKOV3), and normal liver cell lines) were evaluated using the MTT assay, demonstrating that Zn0.75Al0.25O NCs not only enhance cell destruction but also show low cytotoxicity and high biocompatibility at low concentrations. These results suggest that Zn0.75Al0.25O NCs could be a promising candidate for in vivo anticancer applications and should be further investigated.
{"title":"Synthesis, Characterization, and Evaluation of the Antimicrobial and Anticancer Activities of Zinc Oxide and Aluminum-Doped Zinc Oxide Nanocomposites.","authors":"Muhammad Asif, Muhammad Fakhar-E-Alam, Muhammad Tahir, Farah Jamil, Hassan Sardar, Javed Rehman, Kholood A Dahlous","doi":"10.3390/ph17091216","DOIUrl":"https://doi.org/10.3390/ph17091216","url":null,"abstract":"<p><p>In this research, we developed undoped and aluminum-doped zinc oxide for antimicrobial and anticancer activities. This study focuses on the synthesis, characterization, and biological activities of zinc oxide nanoparticles (ZnO NPs) and aluminum-doped zinc oxide nanocomposites (Zn<sub>1-x</sub>Al<sub>x</sub>O NCs) at varying concentrations (x = 0, 0.25, 0.5, and 0.75 wt%) using the coprecipitation method. Various characterization techniques such as XRD, UV-Vis, FTIR, EDX, and SEM were performed to analyze the crystal structure, optical properties, functional group identification, elemental composition, and surface morphology. The antimicrobial activity test showed that Zn<sub>0.75</sub>Al<sub>0.25</sub>O NCs exhibited the strongest inhibition zone against <i>Bacillus cereus</i> compared to <i>Staphylococcus aureus</i> > <i>Pasteurella multocida</i> > <i>Escherichia coli</i>. Moreover, the cytotoxicity and cell viability of liver cancer (HepG-2), breast cancer (MCF-7), ovarian cancer (SKOV3), and normal liver cell lines) were evaluated using the MTT assay, demonstrating that Zn<sub>0.75</sub>Al<sub>0.25</sub>O NCs not only enhance cell destruction but also show low cytotoxicity and high biocompatibility at low concentrations. These results suggest that Zn<sub>0.75</sub>Al<sub>0.25</sub>O NCs could be a promising candidate for in vivo anticancer applications and should be further investigated.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicole Beckert, Annabelle Dietrich, Jürgen Hubbuch
Lipid nanoparticles (LNPs) and their versatile nucleic acid payloads bear great potential as delivery systems. Despite their complex lipid composition, their quality is primarily judged by particle characteristics and nucleic acid encapsulation. In this study, we present a holistic reversed-phase (RP)-charged aerosol detection (CAD)-based method developed for commonly used LNP formulations, allowing for intensified LNP and process characterization. We used an experimental approach for power function value (PFV) optimization termed exploratory calibration, providing a single PFV (1.3) in an appropriate linearity range for all six lipids. Followed by the procedure of method calibration and validation, linearity (10-400 ng, R2 > 0.996), precision, accuracy, and robustness were effectively proven. To complement the commonly determined LNP attributes and to evaluate the process performance across LNP processing, the developed RP-CAD method was applied in a process parameter study varying the total flow rate (TFR) during microfluidic mixing. The RP-CAD method revealed a constant lipid molar ratio across processing but identified deviations in the theoretical lipid content and general lipid loss, which were both, however, entirely TFR-independent. The deviations in lipid content could be successfully traced back to the lipid stock solution preparation. In contrast, the observed lipid loss was attributable to the small-scale dialysis following microfluidic mixing. Overall, this study establishes a foundation for employing RP-CAD for lipid quantification throughout LNP processing, and it highlights the potential to extend its applicability to other LNPs, process parameter studies, or processes such as cross-flow filtration.
{"title":"RP-CAD for Lipid Quantification: Systematic Method Development and Intensified LNP Process Characterization.","authors":"Nicole Beckert, Annabelle Dietrich, Jürgen Hubbuch","doi":"10.3390/ph17091217","DOIUrl":"https://doi.org/10.3390/ph17091217","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) and their versatile nucleic acid payloads bear great potential as delivery systems. Despite their complex lipid composition, their quality is primarily judged by particle characteristics and nucleic acid encapsulation. In this study, we present a holistic reversed-phase (RP)-charged aerosol detection (CAD)-based method developed for commonly used LNP formulations, allowing for intensified LNP and process characterization. We used an experimental approach for power function value (PFV) optimization termed exploratory calibration, providing a single PFV (1.3) in an appropriate linearity range for all six lipids. Followed by the procedure of method calibration and validation, linearity (10-400 ng, <i>R</i><sup>2</sup> > 0.996), precision, accuracy, and robustness were effectively proven. To complement the commonly determined LNP attributes and to evaluate the process performance across LNP processing, the developed RP-CAD method was applied in a process parameter study varying the total flow rate (TFR) during microfluidic mixing. The RP-CAD method revealed a constant lipid molar ratio across processing but identified deviations in the theoretical lipid content and general lipid loss, which were both, however, entirely TFR-independent. The deviations in lipid content could be successfully traced back to the lipid stock solution preparation. In contrast, the observed lipid loss was attributable to the small-scale dialysis following microfluidic mixing. Overall, this study establishes a foundation for employing RP-CAD for lipid quantification throughout LNP processing, and it highlights the potential to extend its applicability to other LNPs, process parameter studies, or processes such as cross-flow filtration.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11435201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hugo Roux, Franck Touret, Pascal Rathelot, Patrice Vanelle, Manon Roche
Non-polio enteroviruses (NPEVs), namely coxsackieviruses (CV), echoviruses (E), enteroviruses (EV), and rhinoviruses (RV), are responsible for a wide variety of illnesses. Some infections can progress to life-threatening conditions in children or immunocompromised patients. To date, no treatments have been approved. Several molecules have been evaluated through clinical trials without success. To overcome these failures, the multi-target directed ligand (MTDL) strategy could be applied to tackle enterovirus infections. This work analyzes registered clinical trials involving antiviral drugs to highlight the best candidates and develops filters to apply to a selection for MTDL synthesis. We explicitly stated the methods used to answer the question: which solution can fight NPEVs effectively? We note the originality and relevance of this proposal in relation to the state of the art in the enterovirus-inhibitors field. Several combinations are possible to broaden the antiviral spectrum and potency. We discuss data related to the virus and data related to each LEAD compound identified so far. Overall, this study proposes a perspective on different strategies to overcome issues identified in clinical trials and evaluate the "MTDL" potential to improve the efficacy of drugs, broaden the antiviral targets, possibly reduce the adverse effects, drug design costs and limit the selection of drug-resistant virus variants.
非脊髓灰质炎肠道病毒(NPEVs),即柯萨奇病毒(CV)、埃可病毒(E)、肠道病毒(EV)和鼻病毒(RV),可导致多种疾病。在儿童或免疫力低下的患者中,有些感染可发展为危及生命的疾病。迄今为止,还没有治疗方法获得批准。通过临床试验对几种分子进行了评估,但都没有成功。为了克服这些失败,多靶点定向配体(MTDL)策略可用于解决肠病毒感染问题。这项工作分析了已登记的抗病毒药物临床试验,以突出最佳候选药物,并开发了过滤器,用于选择 MTDL 合成。我们明确阐述了用于回答以下问题的方法:哪种方案能有效对抗 NPEV?我们注意到这一建议在肠病毒抑制剂领域的独创性和相关性。可以通过几种组合来扩大抗病毒谱和效力。我们讨论了与病毒有关的数据以及迄今发现的每种 LEAD 化合物的相关数据。总之,本研究从不同的角度提出了克服临床试验中发现的问题的策略,并评估了 "MTDL "在提高药物疗效、拓宽抗病毒靶点、减少不良反应、降低药物设计成本和限制耐药病毒变种的选择方面的潜力。
{"title":"From the \"One-Molecule, One-Target, One-Disease\" Concept towards Looking for Multi-Target Therapeutics for Treating Non-Polio Enterovirus (NPEV) Infections.","authors":"Hugo Roux, Franck Touret, Pascal Rathelot, Patrice Vanelle, Manon Roche","doi":"10.3390/ph17091218","DOIUrl":"https://doi.org/10.3390/ph17091218","url":null,"abstract":"<p><p>Non-polio enteroviruses (NPEVs), namely coxsackieviruses (CV), echoviruses (E), enteroviruses (EV), and rhinoviruses (RV), are responsible for a wide variety of illnesses. Some infections can progress to life-threatening conditions in children or immunocompromised patients. To date, no treatments have been approved. Several molecules have been evaluated through clinical trials without success. To overcome these failures, the multi-target directed ligand (MTDL) strategy could be applied to tackle enterovirus infections. This work analyzes registered clinical trials involving antiviral drugs to highlight the best candidates and develops filters to apply to a selection for MTDL synthesis. We explicitly stated the methods used to answer the question: which solution can fight NPEVs effectively? We note the originality and relevance of this proposal in relation to the state of the art in the enterovirus-inhibitors field. Several combinations are possible to broaden the antiviral spectrum and potency. We discuss data related to the virus and data related to each LEAD compound identified so far. Overall, this study proposes a perspective on different strategies to overcome issues identified in clinical trials and evaluate the \"MTDL\" potential to improve the efficacy of drugs, broaden the antiviral targets, possibly reduce the adverse effects, drug design costs and limit the selection of drug-resistant virus variants.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11434921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tariq M Aljarba, Fatma M Abdel Bar, Asmaa E Sherif, Engy Elekhnawy, Galal Magdy, Reham M Samra
Background/Objectives: Bacterial resistance and virulence are challenges in treating bacterial infections, especially in Klebsiella pneumoniae. Plants of the Launaea Cass. genus are used traditionally to address a variety of diseases, including infections, but the potential bioactive compounds are unknown. Our goals were to verify the potential contribution of two major polyacetylene glycosides isolated from our previous study, (3S,6E,12E)-6,12-tetradecadiene-8,10-diyne-1-ol 3-O-β-D-glucopyranoside (1) and bidensyneoside A (syn. gymnasterkoreaside A) [(3R,8E)-3-hydroxy-8-decene-4,6-diyn-1-yl β-D-glucopyranoside] (2), to the anti-infective properties of Launaea capitata and to develop a dependable HPLC method for their quantification; Methods: On a panel of K. pneumoniae clinical isolates, the antibacterial action of 1, 2, and the methanol extract of the whole L. capitata plant were evaluated by broth microdilution assay, while their antibiofilm action was evaluated by the crystal violet assay. qRT-PCR investigated luxS, mrkA, wzm, and wbbm genes that encode biofilm formation and quorum sensing (QS). The antibacterial activity of 1 was revealed by employing mice infection. Chromatographic separation was conducted using isocratic elution on a Hypersil BDS C18 column using a photodiode array (PDA) detector; Results: Compound 1 showed antibacterial activity with MIC values of 16-128 µg/mL. It remarkably reduced strong and moderate biofilm-forming bacterial isolates from 84.21% to 42.1% compared with the extract (68.42%) and 2 (78.95%). Compound 1 also downregulated the QS genes, luxS, mrkA, wzm, and wbbm, and exhibited in vivo antibacterial action through the enhancement of the histological construction of the liver and spleen, decreased TNF-α immunoreaction, bacterial burden, and the inflammatory mediators IL-1β and IL-6. A successful HPLC-PDA approach was developed to separate the binary mixture of 1 and 2 in less than 10 min with high sensitivity, with detection limits down to 0.518 and 0.095 µg/mL for 1 and 2, respectively; Conclusions: Compound 1 exhibited remarkable antibacterial and antibiofilm properties and may contribute to the anti-infectious traditional uses of L. capitata, meriting further clinical studies and serving as a reliable quality control biomarker for the plant.
{"title":"HPLC-PDA Analysis of Polyacetylene Glucosides from <i>Launaea capitata</i> and Their Antibacterial and Antibiofilm Properties against <i>Klebsiella pneumoniae</i>.","authors":"Tariq M Aljarba, Fatma M Abdel Bar, Asmaa E Sherif, Engy Elekhnawy, Galal Magdy, Reham M Samra","doi":"10.3390/ph17091214","DOIUrl":"https://doi.org/10.3390/ph17091214","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Bacterial resistance and virulence are challenges in treating bacterial infections, especially in <i>Klebsiella pneumoniae</i>. Plants of the <i>Launaea</i> Cass. genus are used traditionally to address a variety of diseases, including infections, but the potential bioactive compounds are unknown. Our goals were to verify the potential contribution of two major polyacetylene glycosides isolated from our previous study, (3<i>S</i>,6<i>E</i>,12<i>E</i>)-6,12-tetradecadiene-8,10-diyne-1-ol 3-<i>O</i>-<i>β</i>-D-glucopyranoside (<b>1</b>) and bidensyneoside A (syn. gymnasterkoreaside A) [(3<i>R</i>,8<i>E</i>)-3-hydroxy-8-decene-4,6-diyn-1-yl <i>β</i>-D-glucopyranoside] (<b>2</b>), to the anti-infective properties of <i>Launaea capitata</i> and to develop a dependable HPLC method for their quantification; <b>Methods</b>: On a panel of <i>K. pneumoniae</i> clinical isolates, the antibacterial action of <b>1</b>, <b>2</b>, and the methanol extract of the whole <i>L. capitata</i> plant were evaluated by broth microdilution assay, while their antibiofilm action was evaluated by the crystal violet assay. qRT-PCR investigated <i>lux</i>S, <i>mrk</i>A, <i>wzm</i>, and <i>wbb</i>m genes that encode biofilm formation and quorum sensing (QS). The antibacterial activity of <b>1</b> was revealed by employing mice infection. Chromatographic separation was conducted using isocratic elution on a Hypersil BDS C18 column using a photodiode array (PDA) detector; <b>Results</b>: Compound <b>1</b> showed antibacterial activity with MIC values of 16-128 µg/mL. It remarkably reduced strong and moderate biofilm-forming bacterial isolates from 84.21% to 42.1% compared with the extract (68.42%) and <b>2</b> (78.95%). Compound <b>1</b> also downregulated the QS genes, <i>lux</i>S, <i>mrk</i>A, <i>wzm</i>, and <i>wbb</i>m, and exhibited in vivo antibacterial action through the enhancement of the histological construction of the liver and spleen, decreased TNF-<i>α</i> immunoreaction, bacterial burden, and the inflammatory mediators IL-1<i>β</i> and IL-6. A successful HPLC-PDA approach was developed to separate the binary mixture of <b>1</b> and <b>2</b> in less than 10 min with high sensitivity, with detection limits down to 0.518 and 0.095 µg/mL for <b>1</b> and <b>2</b>, respectively; <b>Conclusions</b>: Compound <b>1</b> exhibited remarkable antibacterial and antibiofilm properties and may contribute to the anti-infectious traditional uses of <i>L. capitata</i>, meriting further clinical studies and serving as a reliable quality control biomarker for the plant.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11434657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
David Sipos, Zsanett Debreczeni-Máté, Zsombor Ritter, Omar Freihat, Mihály Simon, Árpád Kovács
Glioblastoma multiforme (GBM) remains one of the most aggressive and lethal forms of brain cancer, characterized by rapid proliferation and diffuse infiltration into the surrounding brain tissues. Despite advancements in therapeutic approaches, the prognosis for GBM patients is poor, with median survival times rarely exceeding 15 months post-diagnosis. An accurate diagnosis, treatment planning, and monitoring are crucial for improving patient outcomes. Core imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are indispensable in the initial diagnosis and ongoing management of GBM. Histopathology remains the gold standard for definitive diagnoses, guiding treatment by providing molecular and genetic insights into the tumor. Advanced imaging modalities, particularly positron emission tomography (PET), play a pivotal role in the management of GBM. Among these, 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) PET has emerged as a powerful tool due to its superior specificity and sensitivity in detecting GBM and monitoring treatment responses. This introduction provides a comprehensive overview of the multifaceted role of 18F-FDOPA PET in GBM, covering its diagnostic accuracy, potential as a biomarker, integration into clinical workflows, impact on patient outcomes, technological and methodological advancements, comparative effectiveness with other PET tracers, and its cost-effectiveness in clinical practice. Through these perspectives, we aim to underscore the significant contributions of 18F-FDOPA PET to the evolving landscape of GBM management and its potential to enhance both clinical and economic outcomes for patients afflicted with this formidable disease.
多形性胶质母细胞瘤(GBM)仍然是最具侵袭性和致命性的脑癌之一,其特点是快速增殖和向周围脑组织弥漫浸润。尽管治疗方法不断进步,GBM 患者的预后仍然很差,诊断后的中位生存时间很少超过 15 个月。准确的诊断、治疗计划和监测对改善患者预后至关重要。计算机断层扫描(CT)和磁共振成像(MRI)等核心成像模式在 GBM 的初步诊断和持续治疗中不可或缺。组织病理学仍是明确诊断的黄金标准,通过提供肿瘤的分子和基因信息指导治疗。先进的成像模式,尤其是正电子发射断层扫描(PET),在 GBM 的治疗中发挥着举足轻重的作用。其中,3,4-二羟基-6-[18F]-氟-L-苯丙氨酸(18F-FDOPA)PET 因其在检测 GBM 和监测治疗反应方面具有卓越的特异性和灵敏度而成为一种强大的工具。本介绍全面概述了 18F-FDOPA PET 在 GBM 中的多方面作用,包括其诊断准确性、作为生物标记物的潜力、与临床工作流程的整合、对患者预后的影响、技术和方法的进步、与其他 PET 示踪剂的比较效果以及在临床实践中的成本效益。通过这些视角,我们旨在强调 18F-FDOPA PET 对不断发展的 GBM 管理的重大贡献,以及它在提高这种可怕疾病患者的临床和经济疗效方面的潜力。
{"title":"Complex Diagnostic Challenges in Glioblastoma: The Role of <sup>18</sup>F-FDOPA PET Imaging.","authors":"David Sipos, Zsanett Debreczeni-Máté, Zsombor Ritter, Omar Freihat, Mihály Simon, Árpád Kovács","doi":"10.3390/ph17091215","DOIUrl":"https://doi.org/10.3390/ph17091215","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) remains one of the most aggressive and lethal forms of brain cancer, characterized by rapid proliferation and diffuse infiltration into the surrounding brain tissues. Despite advancements in therapeutic approaches, the prognosis for GBM patients is poor, with median survival times rarely exceeding 15 months post-diagnosis. An accurate diagnosis, treatment planning, and monitoring are crucial for improving patient outcomes. Core imaging modalities such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are indispensable in the initial diagnosis and ongoing management of GBM. Histopathology remains the gold standard for definitive diagnoses, guiding treatment by providing molecular and genetic insights into the tumor. Advanced imaging modalities, particularly positron emission tomography (PET), play a pivotal role in the management of GBM. Among these, 3,4-dihydroxy-6-[<sup>18</sup>F]-fluoro-L-phenylalanine (<sup>18</sup>F-FDOPA) PET has emerged as a powerful tool due to its superior specificity and sensitivity in detecting GBM and monitoring treatment responses. This introduction provides a comprehensive overview of the multifaceted role of <sup>18</sup>F-FDOPA PET in GBM, covering its diagnostic accuracy, potential as a biomarker, integration into clinical workflows, impact on patient outcomes, technological and methodological advancements, comparative effectiveness with other PET tracers, and its cost-effectiveness in clinical practice. Through these perspectives, we aim to underscore the significant contributions of <sup>18</sup>F-FDOPA PET to the evolving landscape of GBM management and its potential to enhance both clinical and economic outcomes for patients afflicted with this formidable disease.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11434841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recombinant AAV (rAAV) vectors are increasingly favored for gene therapy due to their useful features of vectorology, such as transfection of dividing and nondividing cells, the presence of tissue-specific serotypes, and biosafety considerations. This study investigates the impact of commonly used therapeutic drugs-acetaminophen, budesonide, and simvastatin-on rAAV transduction efficiency in HEK-293 cells. Cells were transduced with an AAV mosaic vector under the control of a cytomegalovirus (CMV) promoter encoding green fluorescent protein (GFP). Transduction efficiency was assessed by qPCR and fluorescent microscopy. Analysis of functional interactions between genes potentially involved in rAAV transduction in drug-exposed cells was also performed. This study showed a clear effect of drugs on rAAV transmission. Notably, acetaminophen enhanced transduction efficiency by 9-fold, while budesonide and simvastatin showed 2-fold and 3-fold increases, respectively. The gene analysis illustrates the possible involvement of genes related to cell membranes in the potentiation of rAAV transduction induced by the drugs under investigation. Attention should be paid to S100A8, which is a common drug-modified gene for drugs showing anti-inflammatory effects (budesonide and simvastatin), demonstrating an interaction with the gene encoding the receptor for AAV (HGFR). This study underscores the significance of assessing rAAV pharmacokinetics/pharmacodynamics (PKs/PDs) and drug-gene therapy interactions in optimizing gene therapy protocols.
{"title":"Gene Therapy in the Light of Lifestyle Diseases: Budesonide, Acetaminophen and Simvastatin Modulates rAAV Transduction Efficiency.","authors":"Żaneta Słyk, Natalia Stachowiak, Maciej Małecki","doi":"10.3390/ph17091213","DOIUrl":"https://doi.org/10.3390/ph17091213","url":null,"abstract":"<p><p>Recombinant AAV (rAAV) vectors are increasingly favored for gene therapy due to their useful features of vectorology, such as transfection of dividing and nondividing cells, the presence of tissue-specific serotypes, and biosafety considerations. This study investigates the impact of commonly used therapeutic drugs-acetaminophen, budesonide, and simvastatin-on rAAV transduction efficiency in HEK-293 cells. Cells were transduced with an AAV mosaic vector under the control of a cytomegalovirus (CMV) promoter encoding green fluorescent protein (GFP). Transduction efficiency was assessed by qPCR and fluorescent microscopy. Analysis of functional interactions between genes potentially involved in rAAV transduction in drug-exposed cells was also performed. This study showed a clear effect of drugs on rAAV transmission. Notably, acetaminophen enhanced transduction efficiency by 9-fold, while budesonide and simvastatin showed 2-fold and 3-fold increases, respectively. The gene analysis illustrates the possible involvement of genes related to cell membranes in the potentiation of rAAV transduction induced by the drugs under investigation. Attention should be paid to <i>S100A8</i>, which is a common drug-modified gene for drugs showing anti-inflammatory effects (budesonide and simvastatin), demonstrating an interaction with the gene encoding the receptor for AAV (HGFR). This study underscores the significance of assessing rAAV pharmacokinetics/pharmacodynamics (PKs/PDs) and drug-gene therapy interactions in optimizing gene therapy protocols.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11434873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}