Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091151
Carlos Tamarit-Martínez, Lucía Bernat-Just, Carlos Bueno-López, Adrián M. Alambiaga-Caravaca, Virginia Merino, Alicia López-Castellano, Vicent Rodilla
Infections are one of the main complications in arthroplasties. These infections are difficult to treat because the bacteria responsible for them settle in the prosthesis and form a biofilm that does not allow antimicrobials to reach the infected area. This study is part of a research project aimed at developing 3D-printed spacers (temporary prostheses) capable of incorporating antibacterials for the personalized treatment of arthroplasty infections. The main objective of this research was to analyze the impact of the layer thickness of 3D-printed constructs based on polylactic acid (PLA) for improved treatment of infections in arthroplasty. The focus is on the following parameters: resistance, morphology, drug release, and the effect of antibacterials incorporated in the printed temporary prostheses. The resistance studies revealed that the design and layer thickness of a printed spacer have an influence on its resistance properties. The thickness of the layer used in printing affects the amount of methylene blue (used as a model drug) that is released. Increasing layer thickness leads to a greater release of the drug from the spacer, probably as a result of higher porosity. To evaluate antibacterial release, cloxacillin and vancomycin were incorporated into the constructs. When incorporated into the 3D construct, both antibacterials were released, as evidenced by the growth inhibition of Staphylococcus aureus. In conclusion, preliminary results indicate that the layer thickness during the three-dimensional (3D) printing process of the spacer plays a significant role in drug release.
感染是关节置换术的主要并发症之一。这些感染很难治疗，因为导致感染的细菌会在假体中定居并形成生物膜，使抗菌剂无法到达感染区域。本研究是一个研究项目的一部分，该项目旨在开发能够加入抗菌剂的 3D 打印垫片（临时假体），用于关节成形术感染的个性化治疗。本研究的主要目的是分析基于聚乳酸（PLA）的三维打印结构层厚度对改善关节置换术感染治疗的影响。重点是以下参数：抗性、形态、药物释放以及打印临时假体中加入抗菌剂的效果。抗性研究表明，打印垫片的设计和层厚度对其抗性性能有影响。打印层的厚度会影响亚甲蓝（用作模型药物）的释放量。增加层厚度会导致更多的药物从间隔物中释放出来，这可能是孔隙率增加的结果。为了评估抗菌释放情况，在构建物中加入了氯唑西林和万古霉素。在三维构建体中加入氯唑西林和万古霉素后，这两种抗菌药物都得到了释放，金黄色葡萄球菌的生长抑制作用就证明了这一点。总之，初步结果表明，三维（3D）打印过程中间隔物的层厚度对药物释放起着重要作用。
{"title":"An Antibacterial-Loaded PLA 3D-Printed Model for Temporary Prosthesis in Arthroplasty Infections: Evaluation of the Impact of Layer Thickness on the Mechanical Strength of a Construct and Drug Release","authors":"Carlos Tamarit-Martínez, Lucía Bernat-Just, Carlos Bueno-López, Adrián M. Alambiaga-Caravaca, Virginia Merino, Alicia López-Castellano, Vicent Rodilla","doi":"10.3390/pharmaceutics16091151","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091151","url":null,"abstract":"Infections are one of the main complications in arthroplasties. These infections are difficult to treat because the bacteria responsible for them settle in the prosthesis and form a biofilm that does not allow antimicrobials to reach the infected area. This study is part of a research project aimed at developing 3D-printed spacers (temporary prostheses) capable of incorporating antibacterials for the personalized treatment of arthroplasty infections. The main objective of this research was to analyze the impact of the layer thickness of 3D-printed constructs based on polylactic acid (PLA) for improved treatment of infections in arthroplasty. The focus is on the following parameters: resistance, morphology, drug release, and the effect of antibacterials incorporated in the printed temporary prostheses. The resistance studies revealed that the design and layer thickness of a printed spacer have an influence on its resistance properties. The thickness of the layer used in printing affects the amount of methylene blue (used as a model drug) that is released. Increasing layer thickness leads to a greater release of the drug from the spacer, probably as a result of higher porosity. To evaluate antibacterial release, cloxacillin and vancomycin were incorporated into the constructs. When incorporated into the 3D construct, both antibacterials were released, as evidenced by the growth inhibition of Staphylococcus aureus. In conclusion, preliminary results indicate that the layer thickness during the three-dimensional (3D) printing process of the spacer plays a significant role in drug release.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091150
Hee Ra Park, Mudan Cai, Eun Jin Yang
We investigated the effects of epigenetic modifications on post-traumatic stress disorder (PTSD) using a novel combination of herbal medicines from Panax ginseng, Astragalus membranaceus, Atractylodes macrocephala, and Glycyrrhiza uralensis. The herbal formula extract (HFE) (250 mg/kg) was administered orally once daily for 14 days to determine its effects on PTSD in mice by combining prolonged stress and foot shock. The open field and Y-maze tests determined the effect of HFE on PTSD-induced anxiety and cognition. Hippocampal neuronal plastic changes and molecular mechanism were verified. Treatment with HFE decreased anxiety-like behavior and enhanced cognition. Moreover, it reduced the number of PTSD-related hilar ectopic granule cells in the dentate gyrus (DG). PTSD mice showed reduced neuronal plasticity of doublecortin+ cells in the DG, which was restored by HFE treatment. HFE reversed PTSD-induced inhibition of the Reelin/Dab1 pathway, a critical signaling cascade involved in brain development, and regulated Reelin methylation. Furthermore, DNA methylation, methyl-CpG binding protein 2, and DNA methyltransferase 1, which were elevated in the hippocampus of PTSD mice, were restored following HFE treatment. HFE increased the expression of synaptic plasticity-related factors in the hippocampus of PTSD mice. Our findings suggest that HFE can facilitate PTSD treatment by alleviating behavioral abnormalities through the restoration of hippocampal dysfunction via regulation of the Reelin/Dab-1 pathway and DNA methylation in the hippocampus.
我们研究了表观遗传修饰对创伤后应激障碍（PTSD）的影响，研究采用了人参、黄芪、白术和甘草的新型中药组合。小鼠口服中药配方提取物（HFE）（250 毫克/千克），每天一次，连续 14 天，通过长时间应激和足部冲击来确定其对创伤后应激障碍的影响。开阔地试验和Y-迷宫试验确定了HFE对创伤后应激障碍引起的焦虑和认知的影响。研究还验证了海马神经元的可塑性变化和分子机制。使用HFE治疗可减少焦虑样行为并提高认知能力。此外，它还减少了齿状回（DG）中与创伤后应激障碍相关的希氏异位颗粒细胞的数量。创伤后应激障碍小鼠的齿状回（DG）中双皮质素+细胞的神经元可塑性降低，而HFE治疗可恢复这种可塑性。HFE逆转了PTSD诱导的Reelin/Dab1通路抑制（Reelin/Dab1通路是参与大脑发育的关键信号级联），并调节了Reelin甲基化。此外，PTSD 小鼠海马中升高的 DNA 甲基化、甲基-CpG 结合蛋白 2 和 DNA 甲基转移酶 1 也在 HFE 治疗后得到恢复。HFE 增加了创伤后应激障碍小鼠海马中突触可塑性相关因子的表达。我们的研究结果表明，HFE可通过调节海马中的Reelin/Dab-1通路和DNA甲基化来恢复海马功能障碍，从而缓解行为异常，从而促进创伤后应激障碍的治疗。
{"title":"Herbal Formula Extract Ameliorates Anxiety and Cognitive Impairment via Regulation of the Reelin/Dab-1 Pathway in a Murine Model of Post-Traumatic Stress Disorder","authors":"Hee Ra Park, Mudan Cai, Eun Jin Yang","doi":"10.3390/pharmaceutics16091150","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091150","url":null,"abstract":"We investigated the effects of epigenetic modifications on post-traumatic stress disorder (PTSD) using a novel combination of herbal medicines from Panax ginseng, Astragalus membranaceus, Atractylodes macrocephala, and Glycyrrhiza uralensis. The herbal formula extract (HFE) (250 mg/kg) was administered orally once daily for 14 days to determine its effects on PTSD in mice by combining prolonged stress and foot shock. The open field and Y-maze tests determined the effect of HFE on PTSD-induced anxiety and cognition. Hippocampal neuronal plastic changes and molecular mechanism were verified. Treatment with HFE decreased anxiety-like behavior and enhanced cognition. Moreover, it reduced the number of PTSD-related hilar ectopic granule cells in the dentate gyrus (DG). PTSD mice showed reduced neuronal plasticity of doublecortin+ cells in the DG, which was restored by HFE treatment. HFE reversed PTSD-induced inhibition of the Reelin/Dab1 pathway, a critical signaling cascade involved in brain development, and regulated Reelin methylation. Furthermore, DNA methylation, methyl-CpG binding protein 2, and DNA methyltransferase 1, which were elevated in the hippocampus of PTSD mice, were restored following HFE treatment. HFE increased the expression of synaptic plasticity-related factors in the hippocampus of PTSD mice. Our findings suggest that HFE can facilitate PTSD treatment by alleviating behavioral abnormalities through the restoration of hippocampal dysfunction via regulation of the Reelin/Dab-1 pathway and DNA methylation in the hippocampus.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091152
Inês Rodrigues, Hugo Ribeiro, Carolina Costa, João Rocha-Neves, Marília Dourado
Appropriate pharmacological management is a cornerstone of quality in palliative care (PC), focusing on comfort and quality of life. Therapeutic review is crucial in PC, aiming to optimize symptom relief, reduce adverse effects, and manage drug interactions. This study aims to delve into the real-world pharmacological prescription practices within a Community Palliative Care Support Team (CPCST) in the northern region of Portugal, comparing practices at admission and at the last consultation before death. It is an observational, cross-sectional, retrospective study without intervention involving patients admitted to a CPCST in 2021. Data were obtained from clinical records, and the statistical analysis included descriptive and inferential measures. Sixty-four patients were included, with an average age of 77.34 years, referred mainly by a specialized Hospital Palliative Care Support Team (65.63%). Polypharmacy was present, with a significant increase in opioids, antipsychotics, prokinetics, antiemetics, antispasmodics, and local corticosteroids, and a reduction in drugs for peptic ulcer and gastroesophageal reflux treatment, antithrombotics, hypolipidemics, antihypertensives, and antidiabetics, among others. The oral route was preferred, decreasing between the two analyzed moments (85.5% versus 49.1%). Pro re nata (PRN) medications increased significantly (p ≤ 0.001). The prescription profile reflects a focus on symptom relief. The deprescription of drugs for chronic comorbidities suggests adaptation to care goals. At the end of life, PRN medications increase significantly (1.34 versus 3.26, p ≤ 0.001), administered as needed to soothe fluctuating symptoms. The pharmacological classes that have significantly increased are relevant in alleviating common symptoms in PC. The use of alternative routes for medication administration increases as instability of the oral route occurs, leading to a reduction in orally administered medications. Among these alternatives, the subcutaneous route shows the largest increase. The findings underscore the importance of flexible and responsive medication strategies in end-of-life care.
{"title":"Pharmacological Prescription at the End of Life: Quality Assessment in the Transition of Care to a Community Palliative Care Support Team","authors":"Inês Rodrigues, Hugo Ribeiro, Carolina Costa, João Rocha-Neves, Marília Dourado","doi":"10.3390/pharmaceutics16091152","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091152","url":null,"abstract":"Appropriate pharmacological management is a cornerstone of quality in palliative care (PC), focusing on comfort and quality of life. Therapeutic review is crucial in PC, aiming to optimize symptom relief, reduce adverse effects, and manage drug interactions. This study aims to delve into the real-world pharmacological prescription practices within a Community Palliative Care Support Team (CPCST) in the northern region of Portugal, comparing practices at admission and at the last consultation before death. It is an observational, cross-sectional, retrospective study without intervention involving patients admitted to a CPCST in 2021. Data were obtained from clinical records, and the statistical analysis included descriptive and inferential measures. Sixty-four patients were included, with an average age of 77.34 years, referred mainly by a specialized Hospital Palliative Care Support Team (65.63%). Polypharmacy was present, with a significant increase in opioids, antipsychotics, prokinetics, antiemetics, antispasmodics, and local corticosteroids, and a reduction in drugs for peptic ulcer and gastroesophageal reflux treatment, antithrombotics, hypolipidemics, antihypertensives, and antidiabetics, among others. The oral route was preferred, decreasing between the two analyzed moments (85.5% versus 49.1%). Pro re nata (PRN) medications increased significantly (p ≤ 0.001). The prescription profile reflects a focus on symptom relief. The deprescription of drugs for chronic comorbidities suggests adaptation to care goals. At the end of life, PRN medications increase significantly (1.34 versus 3.26, p ≤ 0.001), administered as needed to soothe fluctuating symptoms. The pharmacological classes that have significantly increased are relevant in alleviating common symptoms in PC. The use of alternative routes for medication administration increases as instability of the oral route occurs, leading to a reduction in orally administered medications. Among these alternatives, the subcutaneous route shows the largest increase. The findings underscore the importance of flexible and responsive medication strategies in end-of-life care.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091154
Feng Qu, Saloni Darji, David H. Thompson
High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics—Keytruda, Adstiladrin, and Anktiva —have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC.
{"title":"Recent Advances in Drug Delivery Strategies for High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: A Brief Review from 2018 to 2024","authors":"Feng Qu, Saloni Darji, David H. Thompson","doi":"10.3390/pharmaceutics16091154","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091154","url":null,"abstract":"High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) is a condition that is typically treated with Bacillus Calmette–Guérin (BCG) therapy. Unfortunately, NMIBC is characterized by high recurrence, with a significant percentage of BCG patients ultimately requiring radical cystectomy. As a consequence, the development of effective new therapies to avoid RC has become a rapidly evolving field to address this unmet clinical need. To date, three biologics—Keytruda, Adstiladrin, and Anktiva —have been approved by the FDA, and multiple drug modalities, particularly gene therapies, have shown promising results in clinical trials. Advances in drug delivery strategies, such as targeted delivery, sustained release, and permeabilization of protective layers, are critical in overcoming the challenges posed by therapeutic intervention in bladder cancer. This review focuses on high-risk BCG-unresponsive NMIBC therapies that have been or are currently being investigated in clinical trials, offering a broad overview of the delivery system designs and up-to-date clinical outcomes that have been reported as of July 2024. It aims to inform the development of future drug delivery systems for second-line therapies in high-risk BCG-unresponsive NMIBC.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091153
Agata Grzejdziak, Witold Brniak, Olaf Lengier, Justyna Anna Żarek, Dziyana Hliabovich, Aleksander Mendyk
Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification by coating or forming matrix systems. The aim of this study was to demonstrate the possibility of the formulation of prolonged-release minitablets with bromhexine hydrochloride (BHX) and bisoprolol fumarate (BFM) dedicated to pediatric patients. Minitablets with 3 mm diameter and 15 mg mass, containing 1 mg of active substance in 1 unit, were prepared by direct compression with hydroxypropyl methylcellulose (HPMC) of different grades, methylcellulose, sodium alginate, or polyvinyl alcohol (PVA) as a sustained-release polymer. Different amounts of polymers and different compression forces were evaluated. Analysis of minitablets included their uniformity, hardness, and dissolution tests. The kinetics of drug substance release were analyzed with dedicated software. The prepared minitablets met the pharmacopeial requirements with respect to the uniformity of mass and content. The compressibility of BFM was significantly better than that of BHX, yet all minitablets had good mechanical properties. Dissolution studies showed a strong relationship between the type of polymer and its amount in the mass of a tablet and the dissolution rate. Prolonged release of up to 8 h was achieved when HPMC of 4000 cP viscosity was used in the amount of 30% to 80%. Sodium alginate in the amount of 50% was also effective in prolonging dissolution, but PVA was much less effective. Studies on the release kinetics showed that dissolution from prolonged-release minitablets with BHX fit the best to Hopfenberg or Hixson–Crowell models, while in the case of BFM, the best fit was found for Hopfenberg or Korsmeyer–Peppas models.
{"title":"Application of Hydrophilic Polymers to the Preparation of Prolonged-Release Minitablets with Bromhexine Hydrochloride and Bisoprolol Fumarate","authors":"Agata Grzejdziak, Witold Brniak, Olaf Lengier, Justyna Anna Żarek, Dziyana Hliabovich, Aleksander Mendyk","doi":"10.3390/pharmaceutics16091153","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091153","url":null,"abstract":"Minitablets have been extensively studied in recent years as a convenient pediatric form because they allow successful administration even in very young children. Their advantages include easy dose adjustment by multiplication of single units as well as the possibility of drug release modification by coating or forming matrix systems. The aim of this study was to demonstrate the possibility of the formulation of prolonged-release minitablets with bromhexine hydrochloride (BHX) and bisoprolol fumarate (BFM) dedicated to pediatric patients. Minitablets with 3 mm diameter and 15 mg mass, containing 1 mg of active substance in 1 unit, were prepared by direct compression with hydroxypropyl methylcellulose (HPMC) of different grades, methylcellulose, sodium alginate, or polyvinyl alcohol (PVA) as a sustained-release polymer. Different amounts of polymers and different compression forces were evaluated. Analysis of minitablets included their uniformity, hardness, and dissolution tests. The kinetics of drug substance release were analyzed with dedicated software. The prepared minitablets met the pharmacopeial requirements with respect to the uniformity of mass and content. The compressibility of BFM was significantly better than that of BHX, yet all minitablets had good mechanical properties. Dissolution studies showed a strong relationship between the type of polymer and its amount in the mass of a tablet and the dissolution rate. Prolonged release of up to 8 h was achieved when HPMC of 4000 cP viscosity was used in the amount of 30% to 80%. Sodium alginate in the amount of 50% was also effective in prolonging dissolution, but PVA was much less effective. Studies on the release kinetics showed that dissolution from prolonged-release minitablets with BHX fit the best to Hopfenberg or Hixson–Crowell models, while in the case of BFM, the best fit was found for Hopfenberg or Korsmeyer–Peppas models.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091148
Hoe-Myung Jung, Jung-Hye Ha, Mark Vincent C. dela Cerna, Joseph A. Burlison, Joonhyeok Choi, Bo-Ram Kim, Jeong Kyu Bang, Kyoung-Seok Ryu, Donghan Lee
Biliverdin IXβ reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, the direct application of OSA as a BLVRB inhibitor faces challenges, as it is prone to degradation into 5-aminosalicylic acid through cleavage of the diazenyl bond by abundant azoreductase (AzoR) enzymes in gut microbiota and eukaryotic cells. To overcome this obstacle, we devised olsalkene (OSK), an inhibitor where the diazenyl bond in OSA has been substituted with an alkene bond. OSK not only matches the efficacy of OSA but also demonstrates improved stability against degradation by AzoR, presenting a promising solution to this limitation. Furthermore, we have found that both OSK and OSA inhibit BLVRB, regardless of the presence of nicotinamide adenine dinucleotide phosphate, unlike other known inhibitors. This discovery opens new avenues for investigating the roles of BLVRB in blood disorders, including thrombocytopenia.
由于参与活性氧（ROS）机制，胆绿素 IXβ 还原酶（BLVRB）已成为治疗血小板减少症的有望靶点。在寻找针对 BLVRB 的抑制剂的过程中，奥沙拉秦（OSA）显然是最有效的候选药物之一。然而，将 OSA 直接用作 BLVRB 抑制剂面临着挑战，因为它很容易被肠道微生物群和真核细胞中大量的偶氮还原酶（AzoR）裂解重氮键，降解成 5-氨基水杨酸。为了克服这一障碍，我们设计出了邻苯二甲酸酐（OSK），这是一种将 OSA 中的重氮键替换为烯键的抑制剂。OSK 不仅具有与 OSA 相同的功效，而且还能提高稳定性，防止 AzoR 降解，有望解决这一限制。此外，我们还发现 OSK 和 OSA 都能抑制 BLVRB，无论是否存在烟酰胺腺嘌呤二核苷酸磷酸酯，这与其他已知的抑制剂不同。这一发现为研究 BLVRB 在血液疾病（包括血小板减少症）中的作用开辟了新的途径。
{"title":"An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation","authors":"Hoe-Myung Jung, Jung-Hye Ha, Mark Vincent C. dela Cerna, Joseph A. Burlison, Joonhyeok Choi, Bo-Ram Kim, Jeong Kyu Bang, Kyoung-Seok Ryu, Donghan Lee","doi":"10.3390/pharmaceutics16091148","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091148","url":null,"abstract":"Biliverdin IXβ reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, the direct application of OSA as a BLVRB inhibitor faces challenges, as it is prone to degradation into 5-aminosalicylic acid through cleavage of the diazenyl bond by abundant azoreductase (AzoR) enzymes in gut microbiota and eukaryotic cells. To overcome this obstacle, we devised olsalkene (OSK), an inhibitor where the diazenyl bond in OSA has been substituted with an alkene bond. OSK not only matches the efficacy of OSA but also demonstrates improved stability against degradation by AzoR, presenting a promising solution to this limitation. Furthermore, we have found that both OSK and OSA inhibit BLVRB, regardless of the presence of nicotinamide adenine dinucleotide phosphate, unlike other known inhibitors. This discovery opens new avenues for investigating the roles of BLVRB in blood disorders, including thrombocytopenia.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.3390/pharmaceutics16091149
Gentil Arthur Bentes, Juliana Rodrigues Guimarães, Eduardo de Mello Volotão, Natália Maria Lanzarini, Alexandre dos Santos da Silva, Noemi Rovaris Gardinali, Renato Sergio Marchevsky, José Paulo Gagliardi Leite, Jaqueline Mendes de Oliveira, Marcelo Alves Pinto
Immunoglobulins Y (IgY) purified from egg yolks of hens represents an attractive, cost-effective alternative for the development of new diagnostic and therapeutic platforms. In this study, we evaluated the therapeutic efficacy of rotavirus-specific IgY in a cynomolgus monkey (Macaca fascicularis) model. Animals were experimentally infected with human rotavirus Group A (RVA), the most common cause of severe acute diarrhoea among young children worldwide. Animals were administered human RVA (3.1 × 107 FFU/mL) by oral gavage, challenged with 2.5 mg of anti-RVA IgY orally, and monitored for five days according to clinical, haematological and biochemical parameters; serum electrolyte levels; viral shedding; and histopathological changes. Immunotherapy with anti-RVA IgY had a protective effect against severe rotavirus-induced enteritis in four of the ten treated monkeys, as evidenced by histopathological findings. Although only one animal had diarrhoea, all but one exhibited virus shedding regardless of the treatment.
{"title":"Passive Immunotherapy of Cynomolgus Monkeys with Anti-Rotavirus IgY","authors":"Gentil Arthur Bentes, Juliana Rodrigues Guimarães, Eduardo de Mello Volotão, Natália Maria Lanzarini, Alexandre dos Santos da Silva, Noemi Rovaris Gardinali, Renato Sergio Marchevsky, José Paulo Gagliardi Leite, Jaqueline Mendes de Oliveira, Marcelo Alves Pinto","doi":"10.3390/pharmaceutics16091149","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091149","url":null,"abstract":"Immunoglobulins Y (IgY) purified from egg yolks of hens represents an attractive, cost-effective alternative for the development of new diagnostic and therapeutic platforms. In this study, we evaluated the therapeutic efficacy of rotavirus-specific IgY in a cynomolgus monkey (Macaca fascicularis) model. Animals were experimentally infected with human rotavirus Group A (RVA), the most common cause of severe acute diarrhoea among young children worldwide. Animals were administered human RVA (3.1 × 107 FFU/mL) by oral gavage, challenged with 2.5 mg of anti-RVA IgY orally, and monitored for five days according to clinical, haematological and biochemical parameters; serum electrolyte levels; viral shedding; and histopathological changes. Immunotherapy with anti-RVA IgY had a protective effect against severe rotavirus-induced enteritis in four of the ten treated monkeys, as evidenced by histopathological findings. Although only one animal had diarrhoea, all but one exhibited virus shedding regardless of the treatment.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.3390/pharmaceutics16091140
Zijian Ye, Huaizhi Chen, Harrie Weinans, Bart van der Wal, Jaqueline Lourdes Rios
Bacterial infections and antimicrobial resistance are posing substantial difficulties to the worldwide healthcare system. The constraints of conventional diagnostic and therapeutic approaches in dealing with continuously changing infections highlight the necessity for innovative solutions. Aptamers, which are synthetic oligonucleotide ligands with a high degree of specificity and affinity, have demonstrated significant promise in the field of bacterial infection management. This review examines the use of aptamers in the diagnosis and therapy of bacterial infections. The scope of this study includes the utilization of aptasensors and imaging technologies, with a particular focus on their ability to detect conditions at an early stage. Aptamers have shown exceptional effectiveness in suppressing bacterial proliferation and halting the development of biofilms in therapeutic settings. In addition, they possess the capacity to regulate immune responses and serve as carriers in nanomaterial-based techniques, including radiation and photodynamic therapy. We also explore potential solutions to the challenges faced by aptamers, such as nuclease degradation and in vivo instability, to broaden the range of applications for aptamers to combat bacterial infections.
{"title":"Novel Aptamer Strategies in Combating Bacterial Infections: From Diagnostics to Therapeutics","authors":"Zijian Ye, Huaizhi Chen, Harrie Weinans, Bart van der Wal, Jaqueline Lourdes Rios","doi":"10.3390/pharmaceutics16091140","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091140","url":null,"abstract":"Bacterial infections and antimicrobial resistance are posing substantial difficulties to the worldwide healthcare system. The constraints of conventional diagnostic and therapeutic approaches in dealing with continuously changing infections highlight the necessity for innovative solutions. Aptamers, which are synthetic oligonucleotide ligands with a high degree of specificity and affinity, have demonstrated significant promise in the field of bacterial infection management. This review examines the use of aptamers in the diagnosis and therapy of bacterial infections. The scope of this study includes the utilization of aptasensors and imaging technologies, with a particular focus on their ability to detect conditions at an early stage. Aptamers have shown exceptional effectiveness in suppressing bacterial proliferation and halting the development of biofilms in therapeutic settings. In addition, they possess the capacity to regulate immune responses and serve as carriers in nanomaterial-based techniques, including radiation and photodynamic therapy. We also explore potential solutions to the challenges faced by aptamers, such as nuclease degradation and in vivo instability, to broaden the range of applications for aptamers to combat bacterial infections.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.3390/pharmaceutics16091141
Luiza de Oliveira Macedo, Jéssica Fagionato Masiero, Nádia Araci Bou-Chacra
Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration.
{"title":"Drug Nanocrystals in Oral Absorption: Factors That Influence Pharmacokinetics","authors":"Luiza de Oliveira Macedo, Jéssica Fagionato Masiero, Nádia Araci Bou-Chacra","doi":"10.3390/pharmaceutics16091141","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091141","url":null,"abstract":"Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Immunotherapy combined with chemicals and genetic engineering tools is emerging as a promising strategy to treat triple-negative breast cancer (TNBC), which is more aggressive with poorer progress than other breast cancer subtypes. In this study, lipid-based nanoparticles (LNPs) possessed an NK cell-like function that could deliver tumor-specific therapeutics and inhibit tumor growth. LNPs fused with an NK cell membrane protein system (NK-LNP) have three main features: (i) hydrophilic plasmid DNA can inhibit TNBC metastasis when encapsulated within LNPs and delivered to cells; (ii) the lipid composition of LNPs, including C18 ceramide, exhibits anticancer effects; (iii) NK cell membrane proteins are immobilized on the LNP surface, enabling targeted delivery to TNBC cells. These particles facilitate the targeted delivery of HIC1 plasmid DNA and the modulation of immune cell functions. Delivered therapeutic genes can inhibit metastasis of TNBC and then induce apoptotic cell death while targeting macrophages to promote cytokine release. The anticancer effect is expected to be applied in treating various difficult-to-treat cancers with LNP fused with NK cell plasma membrane proteins, which can simultaneously deliver therapeutic chemicals and genes.
与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）更具侵袭性，进展较慢，而免疫疗法与化学和基因工程工具相结合，正在成为治疗三阴性乳腺癌的一种前景广阔的策略。在这项研究中，脂质纳米粒子（LNPs）具有类似于 NK 细胞的功能，可以递送肿瘤特异性治疗药物并抑制肿瘤生长。融合了 NK 细胞膜蛋白系统的 LNPs（NK-LNP）有三个主要特征：(i) 亲水性质粒 DNA 被包裹在 LNPs 内并输送到细胞中时，可抑制 TNBC 转移；(ii) LNPs 的脂质成分（包括 C18 神经酰胺）具有抗癌作用；(iii) NK 细胞膜蛋白被固定在 LNPs 表面，可定向输送到 TNBC 细胞。这些颗粒有助于 HIC1 质粒 DNA 的靶向递送和免疫细胞功能的调节。递送的治疗基因可抑制 TNBC 的转移，然后诱导细胞凋亡，同时靶向巨噬细胞促进细胞因子的释放。融合了 NK 细胞质膜蛋白的 LNP 可同时递送治疗化学物质和基因，其抗癌效果有望应用于治疗各种难以治疗的癌症。
{"title":"Lipid-Based Nanoparticles Fused with Natural Killer Cell Plasma Membrane Proteins for Triple-Negative Breast Cancer Therapy","authors":"Eun-Jeong Won, Myungchul Lee, Eui-Kyung Lee, Seung-Hoon Baek, Tae-Jong Yoon","doi":"10.3390/pharmaceutics16091142","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091142","url":null,"abstract":"Immunotherapy combined with chemicals and genetic engineering tools is emerging as a promising strategy to treat triple-negative breast cancer (TNBC), which is more aggressive with poorer progress than other breast cancer subtypes. In this study, lipid-based nanoparticles (LNPs) possessed an NK cell-like function that could deliver tumor-specific therapeutics and inhibit tumor growth. LNPs fused with an NK cell membrane protein system (NK-LNP) have three main features: (i) hydrophilic plasmid DNA can inhibit TNBC metastasis when encapsulated within LNPs and delivered to cells; (ii) the lipid composition of LNPs, including C18 ceramide, exhibits anticancer effects; (iii) NK cell membrane proteins are immobilized on the LNP surface, enabling targeted delivery to TNBC cells. These particles facilitate the targeted delivery of HIC1 plasmid DNA and the modulation of immune cell functions. Delivered therapeutic genes can inhibit metastasis of TNBC and then induce apoptotic cell death while targeting macrophages to promote cytokine release. The anticancer effect is expected to be applied in treating various difficult-to-treat cancers with LNP fused with NK cell plasma membrane proteins, which can simultaneously deliver therapeutic chemicals and genes.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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