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Asciminib, a novel allosteric inhibitor of BCR‐ABL1, shows synergistic effects when used in combination with imatinib with or without drug resistance 阿西米尼是一种新型 BCR-ABL1 异源抑制剂,与伊马替尼联合使用时,无论有无耐药性,都能产生协同效应
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-21 DOI: 10.1002/prp2.1214
Naoki Okamoto, Kenta Yagi, Sayaka Imawaka, Mayu Takaoka, Fuka Aizawa, Takahiro Niimura, Mitsuhiro Goda, Koji Miyata, Kei Kawada, Yuki Izawa‐Ishizawa, Satoshi Sakaguchi, Keisuke Ishizawa
In the treatment of chronic myeloid leukemia (CML), resistance to BCR‐ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR‐ABL inhibitor asciminib and conventional BCR‐ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib‐resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST‐8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA‐seq and real‐time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR‐ABL inhibitors may improve the therapeutic efficacy of conventional BCR‐ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross‐resistance between BCR‐ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.
在慢性髓性白血病(CML)的治疗中,BCR-ABL 抑制剂的耐药性使治疗难以为继,并直接关系到患者的寿命。因此,阿昔米尼作为克服耐药性的有效药物被推向市场。虽然联合使用分子靶向药物有助于避免耐药,但新的 BCR-ABL 抑制剂 asciminib 和传统的 BCR-ABL 抑制剂原则上应作为单一疗法使用。因此,我们研究了阿西米尼和伊马替尼联合用药的协同效应和机制。我们利用人类CML细胞株K562生成了伊马替尼耐药细胞,利用WST-8试验检测了伊马替尼和阿西米尼暴露对细胞存活的影响,并利用RNA-seq和实时PCR全面分析了与耐药性相关的基因变异。在伊马替尼耐药或不耐药的情况下,伊马替尼和阿西米尼联合使用可观察到协同效应。提取了GRRP1、ESPN和NOXA1三个基因作为阿西米尼的作用位点。阿西米尼与BCR-ABL抑制剂联用可提高传统BCR-ABL抑制剂的疗效,并防止耐药性的产生。即使使用不会引起副作用的最小剂量,其剂量也可能有效。这一作用机制还需要进一步验证。此外,BCR-ABL 抑制剂与阿西米尼之间可能会产生交叉耐药性,这需要尽快通过进一步验证加以澄清。
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引用次数: 0
A novel and selective fluorescent ligand for the study of adenosine A2B receptors 用于研究腺苷 A2B 受体的新型选择性荧光配体
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-21 DOI: 10.1002/prp2.1223
Foteini Patera, Sarah J. Mistry, Nicholas D. Kindon, Eleonora Comeo, Joelle Goulding, Barrie Kellam, Laura E. Kilpatrick, Hester Franks, Stephen J. Hill
Fluorescent ligands have proved to be powerful tools in the study of G protein‐coupled receptors in living cells. Here we have characterized a new fluorescent ligand PSB603‐BY630 that has high selectivity for the human adenosine A2B receptor (A2BR). The A2BR appears to play an important role in regulating immune responses in the tumor microenvironment. Here we have used PSB603‐BY630 to monitor specific binding to A2BRs in M1‐ and M2‐like macrophages derived from CD14+ human monocytes. PSB603‐BY630 bound with high affinity (18.3 nM) to nanoluciferase‐tagged A2BRs stably expressed in HEK293G cells. The ligand exhibited very high selectivity for the A2BR with negligible specific‐binding detected at NLuc‐A2AR, NLuc‐A1R, or NLuc‐A3R receptors at concentrations up to 500 nM. Competition binding studies showed the expected pharmacology at A2BR with the A2BR‐selective ligands PSB603 and MRS‐1706 demonstrating potent inhibition of the specific binding of 50 nM PSB603‐BY630 to A2BR. Functional studies in HEK293G cells using Glosensor to monitor Gs‐coupled cyclic AMP responses indicated that PSB603‐BY630 acted as a negative allosteric regular of the agonist responses to BAY 60–6583. Furthermore, flow cytometry analysis confirmed that PSB603‐BY630 could be used to selectively label endogenous A2BRs expressed on human macrophages. This ligand should be an important addition to the library of fluorescent ligands which are selective for the different adenosine receptor subtypes, and will enable study of the role of A2BRs on immune cells in the tumor microenvironment.
事实证明,荧光配体是研究活细胞中 G 蛋白偶联受体的有力工具。在这里,我们鉴定了一种新型荧光配体 PSB603-BY630,它对人类腺苷 A2B 受体(A2BR)具有高选择性。A2BR 似乎在调节肿瘤微环境中的免疫反应方面发挥着重要作用。在这里,我们使用 PSB603-BY630 来监测与源自 CD14+ 人类单核细胞的 M1- 和 M2-like 巨噬细胞中 A2BR 的特异性结合。PSB603-BY630 与稳定表达在 HEK293G 细胞中的纳米荧光素酶标记的 A2BR 具有高亲和力(18.3 nM)。该配体对 A2BR 具有极高的选择性,在浓度高达 500 nM 时,与 NLuc-A2AR、NLuc-A1R 或 NLuc-A3R 受体的特异性结合可忽略不计。竞争结合研究显示了 A2BR 与 A2BR 选择性配体 PSB603 和 MRS-1706 的预期药理作用,显示了 50 nM PSB603-BY630 与 A2BR 特异性结合的强效抑制作用。在 HEK293G 细胞中使用 Glosensor 监测 Gs 偶联环 AMP 反应的功能研究表明,PSB603-BY630 是 BAY 60-6583 激动剂反应的负异位调节剂。此外,流式细胞仪分析证实,PSB603-BY630 可用于选择性标记人巨噬细胞上表达的内源性 A2BR。这种配体是对不同腺苷受体亚型具有选择性的荧光配体库的重要补充,有助于研究 A2BR 在肿瘤微环境中对免疫细胞的作用。
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引用次数: 0
Not first-line antihypertensive agents, but still effective-The efficacy and safety of imidazoline receptor agonists: A network meta-analysis. 不是一线降压药,但仍然有效-咪唑啉受体激动剂的疗效和安全性:网络荟萃分析。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1002/prp2.1215
András Érszegi, Réka Viola, Muh Akbar Bahar, Barbara Tóth, Imola Fejes, Anna Vágvölgyi, Dezső Csupor

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first-line medications are recommended, while imidazoline receptor agonists are not first-line antihypertensives. Our goal was to conduct a network meta-analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta-analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45-30.15; DBP MD: 10.90; 95% CI: 8.45-13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: -2.60-8.80; DBP MD: 1.30; 95% CI: -1.25-3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70-18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85-49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17-2.31). Imidazoline receptor agonists were nearly as effective as the first-line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first-line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.

心血管疾病是世界上最主要的死亡原因。许多器官疾病(肾脏、心脏和大脑)在高血压患者身上更容易发生。在高血压的治疗中,推荐使用一线药物,而咪唑啉受体激动剂并非一线降压药。我们的目标是进行网络荟萃分析,评估咪唑啉受体激动剂的疗效和安全性。荟萃分析遵循 PRISMA 指南,采用 PICOS 格式,并考虑了 CONSORT 建议。研究收集自四个数据库:PubMed、Cochrane Library、Web of Science 和 Embase。共找到 5960 篇文章。经过筛选,仍有 27 项研究符合网络荟萃分析的条件。与安慰剂相比,莫索尼定在治疗 8 周后显著降低了坐位血压(SBP MD:23.80;95% CI:17.45-30.15;DBP MD:10.90;95% CI:8.45-13.35)。此外,莫索尼定比依那普利更有效地降低血压,但差异并不显著(SBP MD:3.10;95% CI:-2.60-8.80;DBP MD:1.30;95% CI:-1.25-3.85)。所有咪唑啉受体激动剂都有口干的副作用。治疗 8 周后,与安慰剂相比,氯硝柳胺的口干发生率最高(OR:9.27 95% CI:4.70-18.29),利美尼定的口干发生率最低(OR:6.46 95% CI:0.85-49.13)。与利美尼啶相比,莫索尼定的嗜睡发生率较低(OR:0.63 95% CI:0.17-2.31)。在所考察的研究中,咪唑啉受体激动剂与一线药物几乎同样有效。然而,由于其副作用,它们作为降压药的作用有限。因此,它们不是一线降压药,不应作为单一疗法使用。然而,在耐药性高血压的情况下,它们是一种可行的选择。根据我们的研究结果,从安全性和有效性的角度来看,莫索尼定似乎是咪唑啉受体激动剂中的最佳选择。
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引用次数: 0
Exogenous melatonin's effect on salivary cortisol and amylase: A randomized controlled trial. 外源性褪黑素对唾液皮质醇和淀粉酶的影响:随机对照试验
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1002/prp2.1205
Praewpat Pachimsawat, Piyanee Ratanachamnong, Nattinee Jantaratnotai

This study aimed to examine the effect of acute exogenous melatonin administration on salivary cortisol and alpha-amylase (sCort and sAA) as representatives of the HPA axis and the sympathetic nervous system, respectively. A single-dose prolonged-release melatonin (2 mg) or a placebo tablet was given to healthy volunteers (n = 64) at 20:00 h in a crossover design. The saliva was collected at six time points (20:00, 21:00, awakening, 30 min after awakening, 10:00, and 12:00 h) and was measured for sCort, sAA, and salivary melatonin (sMT) levels. Pulse rates and sleep parameters were also collected. Melatonin was effective in improving sleep onset latency by 7:04 min (p = .037) and increasing total sleep time by 24 min (p = .006). Participants with poor baseline sleep quality responded more strongly to melatonin than participants with normal baseline sleep quality as they reported more satisfaction in having adequate sleep (p = .017). Melatonin administration resulted in higher sCort levels at awakening time point (p = .023) and a tendency of lower sAA levels but these were not significant. Melatonin ingestion at 20:00 h resulted in a marked increase in sMT levels at 21:00 h and remained higher than baseline up to at least 10:00 h (p < .001). Melatonin increases sCort levels at certain time point with a tendency to lower sAA levels. These opposing effects of melatonin suggested a complex interplay between melatonin and these biomarkers. Also, the results confirmed the positive acute effect of a single-dose melatonin on sleep quality.

本研究旨在探讨急性外源性褪黑素给药对唾液皮质醇和α-淀粉酶(sCort 和 sAA)的影响,这两种物质分别代表 HPA 轴和交感神经系统。采用交叉设计,在 20:00 时给健康志愿者(64 人)服用单剂量缓释褪黑素(2 毫克)或安慰剂片剂。在六个时间点(20:00、21:00、唤醒、唤醒后 30 分钟、10:00 和 12:00)收集唾液,测量 sCort、sAA 和唾液褪黑素 (sMT) 水平。同时还收集了脉搏率和睡眠参数。褪黑素能有效改善睡眠开始潜伏期 7:04 分钟(p = .037),增加总睡眠时间 24 分钟(p = .006)。与基线睡眠质量正常的参与者相比,基线睡眠质量较差的参与者对褪黑激素的反应更强烈,因为他们对拥有充足睡眠的满意度更高(p = .017)。服用褪黑素后,唤醒时间点的 sCort 水平会升高(p = .023),sAA 水平也有降低的趋势,但并不显著。在 20:00 时摄入褪黑素会导致 21:00 时的 sMT 水平显著升高,并且至少在 10:00 时仍高于基线水平(p = 0.017)。
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引用次数: 0
Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed-dose combination tablets versus the use of single-component tablets in healthy subjects. 健康受试者服用马西替坦/他达拉非 10/20 固定剂量复方片剂与服用单组分片剂的生物等效性和食物效应。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1002/prp2.1202
Jennifer Lynn Ford, Ahad Sabet, Jaya Natarajan, Hans Stieltjes, Daniel L Chao, Navin Goyal, Denes Csonka

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

研究的主要目的是证明10/20毫克单片马西替坦/他达拉非固定剂量复方制剂(FDC)与这两种药物的游离复方制剂之间的生物等效性,并评估食物对10/20毫克固定剂量复方制剂的影响。在这项以健康成年参与者为对象的单中心、随机、开放标签、3路交叉、单剂量1期研究中,马西替坦/他达拉非以10/20毫克FDC制剂给药,并与马西替坦和他达拉非的自由组合进行比较。此外,还评估了食物对 FDC 的影响。进行了药代动力学采样(216 小时)。治疗 A(FDC,空腹)与治疗 C(游离复方制剂,空腹)的最大观察血浆分析物浓度几何平均比(Cmax)和血浆分析物浓度-时间曲线下面积(AUC)的 90% 置信区间(CIs)均在生物等效性范围内,表明 FDC 制剂可被视为与游离复方制剂具有生物等效性。治疗方案 B(FDC,进食)与治疗方案 A(FDC,空腹)的 Cmax 和 AUC 几何平均比的 90% CI 均在生物等效性范围内,表明不存在食物效应。健康参试者服用 10/20 毫克 FDC 总体安全,耐受性良好。这项研究表明,在健康参试者中,马西替坦/他达拉非(10/20 毫克)单片剂 FDC 与这两种药物的自由组合具有生物等效性,而且 FDC 与单个成分类似,可以在不考虑食物的情况下服用。FDC总体上安全且耐受性良好。
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引用次数: 0
Incidence and management of the main serious adverse events reported after COVID-19 vaccination. 接种 COVID-19 疫苗后报告的主要严重不良事件的发生率和处理情况。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1002/prp2.1224
Teresa Padilla-Flores, Alicia Sampieri, Luis Vaca

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2n first appeared in Wuhan, China in 2019. Soon after, it was declared a pandemic by the World Health Organization. The health crisis imposed by a new virus and its rapid spread worldwide prompted the fast development of vaccines. For the first time in human history, two vaccines based on recombinant genetic material technology were approved for human use. These mRNA vaccines were applied in massive immunization programs around the world, followed by other vaccines based on more traditional approaches. Even though all vaccines were tested in clinical trials prior to their general administration, serious adverse events, usually of very low incidence, were mostly identified after application of millions of doses. Establishing a direct correlation (the cause-effect paradigm) between vaccination and the appearance of adverse effects has proven challenging. This review focuses on the main adverse effects observed after vaccination, including anaphylaxis, myocarditis, vaccine-induced thrombotic thrombocytopenia, Guillain-Barré syndrome, and transverse myelitis reported in the context of COVID-19 vaccination. We highlight the symptoms, laboratory tests required for an adequate diagnosis, and briefly outline the recommended treatments for these adverse effects. The aim of this work is to increase awareness among healthcare personnel about the serious adverse events that may arise post-vaccination. Regardless of the ongoing discussion about the safety of COVID-19 vaccination, these adverse effects must be identified promptly and treated effectively to reduce the risk of complications.

由严重急性呼吸系统综合征冠状病毒 2n 引起的 2019 年冠状病毒病(COVID-19)于 2019 年首次在中国武汉出现。不久后,世界卫生组织宣布其为大流行病。新病毒带来的健康危机及其在全球范围内的迅速传播促使疫苗的快速发展。人类历史上首次批准了两种基于基因重组材料技术的疫苗供人类使用。这些 mRNA 疫苗被应用于世界各地的大规模免疫计划中,随后其他疫苗也采用了更传统的方法。尽管所有疫苗在普遍使用前都经过了临床试验,但严重不良事件(通常发生率很低)大多是在使用数百万剂疫苗后发现的。事实证明,建立疫苗接种与不良反应出现之间的直接相关性(因果范式)具有挑战性。本综述重点关注接种疫苗后观察到的主要不良反应,包括过敏性休克、心肌炎、疫苗诱发的血栓性血小板减少症、格林-巴利综合征和横贯性脊髓炎,这些不良反应是在接种 COVID-19 疫苗的背景下报告的。我们重点介绍了这些不良反应的症状、适当诊断所需的实验室检查,并简要概述了针对这些不良反应的建议治疗方法。这项工作旨在提高医护人员对接种疫苗后可能出现的严重不良反应的认识。无论目前关于 COVID-19 疫苗接种安全性的讨论如何,这些不良反应都必须得到及时发现和有效治疗,以降低并发症的风险。
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引用次数: 0
Correction to "Pros and cons for statins use and risk of Parkinson's disease: An updated perspective". 他汀类药物的使用与帕金森病风险的利弊:最新观点"。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1002/prp2.1221
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引用次数: 0
Long-lasting, biochemically modified mRNA, and its frameshifted recombinant spike proteins in human tissues and circulation after COVID-19 vaccination. 接种 COVID-19 疫苗后,人体组织和血液循环中的长效生化修饰 mRNA 及其帧移位重组尖峰蛋白。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1002/prp2.1218
László G Boros, Anthony M Kyriakopoulos, Carlo Brogna, Marina Piscopo, Peter A McCullough, Stephanie Seneff

According to the CDC, both Pfizer and Moderna COVID-19 vaccines contain nucleoside-modified messenger RNA (mRNA) encoding the viral spike glycoprotein of severe acute respiratory syndrome caused by corona virus (SARS-CoV-2), administered via intramuscular injections. Despite their worldwide use, very little is known about how nucleoside modifications in mRNA sequences affect their breakdown, transcription and protein synthesis. It was hoped that resident and circulating immune cells attracted to the injection site make copies of the spike protein while the injected mRNA degrades within a few days. It was also originally estimated that recombinant spike proteins generated by mRNA vaccines would persist in the body for a few weeks. In reality, clinical studies now report that modified SARS-CoV-2 mRNA routinely persist up to a month from injection and can be detected in cardiac and skeletal muscle at sites of inflammation and fibrosis, while the recombinant spike protein may persist a little over half a year in blood. Vaccination with 1-methylΨ (pseudouridine enriched) mRNA can elicit cellular immunity to peptide antigens produced by +1 ribosomal frameshifting in major histocompatibility complex-diverse people. The translation of 1-methylΨ mRNA using liquid chromatography tandem mass spectrometry identified nine peptides derived from the mRNA +1 frame. These products impact on off-target host T cell immunity that include increased production of new B cell antigens with far reaching clinical consequences. As an example, a highly significant increase in heart muscle 18-flourodeoxyglucose uptake was detected in vaccinated patients up to half a year (180 days). This review article focuses on medical biochemistry, proteomics and deutenomics principles that explain the persisting spike phenomenon in circulation with organ-related functional damage even in asymptomatic individuals. Proline and hydroxyproline residues emerge as prominent deuterium (heavy hydrogen) binding sites in structural proteins with robust isotopic stability that resists not only enzymatic breakdown, but virtually all (non)-enzymatic cleavage mechanisms known in chemistry.

据疾病预防控制中心称,辉瑞和 Moderna COVID-19 疫苗都含有核苷修饰的信使 RNA(mRNA),编码由电晕病毒引起的严重急性呼吸系统综合征(SARS-CoV-2)的病毒尖峰糖蛋白,通过肌肉注射给药。尽管核苷酸在全球范围内被广泛使用,但人们对核苷酸在 mRNA 序列中的修饰如何影响其分解、转录和蛋白质合成知之甚少。人们希望,被吸引到注射部位的常驻和循环免疫细胞会复制尖峰蛋白,而注射的 mRNA 会在几天内降解。据最初估计,mRNA 疫苗产生的重组尖峰蛋白可在体内存活数周。实际上,现在的临床研究报告显示,改良的 SARS-CoV-2 mRNA 在注射后通常会持续存在长达一个月,并可在炎症和纤维化部位的心肌和骨骼肌中检测到,而重组尖峰蛋白则可在血液中持续存在半年多一点。用 1-甲基Ψ(富含假尿嘧啶)mRNA 接种疫苗,可在主要组织相容性复杂的人群中激发对 +1 核糖体框架转换产生的肽抗原的细胞免疫。利用液相色谱串联质谱法对 1-甲基Ψ mRNA 进行翻译,发现了九种源自 mRNA +1 框架的肽。这些产物对目标外宿主 T 细胞免疫产生影响,包括增加新 B 细胞抗原的产生,从而产生深远的临床后果。例如,在接种疫苗长达半年(180 天)的时间里,发现接种疫苗的患者心肌 18-氟脱氧葡萄糖摄取量有非常明显的增加。这篇综述文章重点介绍了医学生物化学、蛋白质组学和脱氧核糖核酸组学原理,这些原理可以解释循环中持续存在的尖峰现象,即使在无症状的人身上也会出现与器官相关的功能损伤。脯氨酸和羟脯氨酸残基是结构蛋白质中重要的氘(重氢)结合位点,具有强大的同位素稳定性,不仅能抵抗酶分解,还能抵抗化学中已知的几乎所有(非)酶裂解机制。
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引用次数: 0
Pharmacist intervention to improve adherence to medication among heart failure patients at North East Ethiopia hospital 药剂师干预改善埃塞俄比亚东北部医院心力衰竭患者的服药依从性
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-30 DOI: 10.1002/prp2.1199
Abate Wondesen Tsige, Tsegaye Ababiya Kotiso, Kassahun Dires Ayenew, Siraye Genzeb Ayele
Heart failure (HF) is a major and growing medical problem and its management is still challenging due to the coexistence of complications, co‐morbidity, and medication non‐adherence. HF patients who are adherent to their medication have fewer HF exacerbations, improved survival, and lower healthcare expenditure. Adherence to HF medication plays a pivotal role in attaining maximal therapeutic outcomes. The aim was to assess the medication adherence of heart failure patients at Debre Berhan Comprehensive Specialized Hospital (DBCSH). A pre‐post interventional study was undertaken from July 1, 2022, to December 31, 2022, at the medical referral clinic of DBCSH. The educational interventions were provided for 6 months. Medication adherence was determined using the Morisky Green Levin Medication Adherence Scale (MGLS). The data was entered into Epidata version 4.2.0 and analyzed using SPSS version 25.0 statistical software. Descriptive statistics and binary logistic regression analysis were performed. The strength of the association between predictor variables and outcome variables was determined using a 95% confidence interval and adjusted odd ratio. In the pre‐intervention phase, 54.6% of patients had medium medication adherence, while in the post‐intervention phase, 36.4% of patients had high medication adherence and 61.9% of patients had medium medication adherence. Following the intervention, medication cost (120, 50%), inadequate availability of drugs (75, 31%), and forgetfulness (30, 13%) were the main reasons for medication non‐adherence. The presence of co‐morbidity and the number of co‐morbidity (p < .05) were significantly associated with the occurrence of decreased medication adherence in the pre‐intervention phase. Interventions by pharmacists to educate HF patients about the nature of their disease and providing brochures to increase awareness of their medications have been shown to improve medication adherence.
心力衰竭(HF)是一个日益严重的重大医疗问题,由于并发症、合并症和不遵医嘱用药等因素的同时存在,其治疗仍然充满挑战。坚持用药的心力衰竭患者心力衰竭加重的情况较少,生存率提高,医疗支出降低。坚持高血压药物治疗对获得最佳治疗效果起着至关重要的作用。该研究旨在评估德布雷伯汉综合专科医院(DBCSH)心衰患者的服药依从性。从2022年7月1日至2022年12月31日,在DBCSH的医疗转诊诊所开展了一项前后干预研究。教育干预为期 6 个月。采用莫里斯基-格林-列文用药依从性量表(MGLS)确定用药依从性。数据输入 Epidata 4.2.0 版,并使用 SPSS 25.0 版统计软件进行分析。对数据进行了描述性统计和二元逻辑回归分析。使用 95% 置信区间和调整后的奇数比来确定预测变量与结果变量之间的关联强度。在干预前阶段,54.6%的患者用药依从性中等,而在干预后阶段,36.4%的患者用药依从性高,61.9%的患者用药依从性中等。干预后,药费(120 人,50%)、药物供应不足(75 人,31%)和健忘(30 人,13%)是不坚持服药的主要原因。在干预前阶段,并发症的存在和并发症的数量(p <.05)与用药依从性下降的发生显著相关。药剂师对高血脂患者进行有关疾病性质的教育,并提供小册子以提高他们对药物的认识,这些干预措施已被证明可提高患者的用药依从性。
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引用次数: 0
Prediction of cell cycle distribution after drug exposure by high content imaging analysis using low‐toxic DNA staining dye 利用低毒 DNA 染色染料进行高含量成像分析,预测药物暴露后的细胞周期分布情况
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-29 DOI: 10.1002/prp2.1203
Kazuma Takeuchi, Yumiko Nishimura, Takayoshi Matsubara, Sho Isoyama, Asuka Suzuki, Masaaki Matsuura, Shingo Dan
Interference in cell cycle progression has been noted as one of the important properties of anticancer drugs. In this study, we developed the cell cycle prediction model using high‐content imaging data of recipient cells after drug exposure and DNA‐staining with a low‐toxic DNA dye, SiR‐DNA. For this purpose, we exploited HeLa and MCF7 cells introduced with a fluorescent ubiquitination‐based cell cycle indicator (Fucci). Fucci‐expressing cancer cells were subjected to high‐content imaging analysis using OperettaCLS after 36‐h exposure to anticancer drugs; the nuclei were segmented, and the morphological and intensity properties of each nucleus characterized by SiR‐DNA staining were calculated using imaging analysis software, Harmony. For the use of training, we classified cells into each phase of the cell cycle using the Fucci system. Training data (n = 7500) and validation data (n = 2500) were randomly sampled and the binary classification prediction models for G1, early S, and S/G2/M phases of the cell cycle were developed using four supervised machine learning algorithms. We selected random forest as the model with the best performance through 10‐fold cross‐validation; the accuracy rate was approximately 75%–87%. Regarding feature importance, variables expected to be biologically related to the cell cycle, for example, signal intensity and nuclear size, were highly ranked, suggesting the validity of the model. These results showed that the cell cycle can be predicted in cancer cells by simply exploiting the current prediction model using fluorescent images of DNA‐staining dye, and the model could be applied for the use of future ex vivo drug sensitivity diagnosis.
干扰细胞周期进展一直是抗癌药物的重要特性之一。在本研究中,我们利用受体细胞暴露于药物并用低毒 DNA 染料 SiR-DNA 进行 DNA 染色后的高含量成像数据开发了细胞周期预测模型。为此,我们利用了导入了基于泛素化荧光细胞周期指示剂(Fucci)的 HeLa 和 MCF7 细胞。暴露于抗癌药物 36 小时后,使用 OperettaCLS 对表达 Fucci 的癌细胞进行高含量成像分析;对细胞核进行分割,并使用成像分析软件 Harmony 计算以 SiR-DNA 染色为特征的每个细胞核的形态和强度特性。为了进行训练,我们使用 Fucci 系统将细胞分为细胞周期的各个阶段。我们随机抽取了训练数据(n = 7500)和验证数据(n = 2500),并使用四种监督机器学习算法开发了细胞周期 G1、S 早期和 S/G2/M 期的二元分类预测模型。通过 10 倍交叉验证,我们选出了性能最佳的随机森林模型,准确率约为 75%-87%。在特征重要性方面,预计与细胞周期有生物学相关性的变量,如信号强度和核大小,排名靠前,这表明了模型的有效性。这些结果表明,只需利用目前使用DNA染色剂荧光图像的预测模型,就能预测癌细胞的细胞周期,该模型可用于未来的体内外药物敏感性诊断。
{"title":"Prediction of cell cycle distribution after drug exposure by high content imaging analysis using low‐toxic DNA staining dye","authors":"Kazuma Takeuchi, Yumiko Nishimura, Takayoshi Matsubara, Sho Isoyama, Asuka Suzuki, Masaaki Matsuura, Shingo Dan","doi":"10.1002/prp2.1203","DOIUrl":"https://doi.org/10.1002/prp2.1203","url":null,"abstract":"Interference in cell cycle progression has been noted as one of the important properties of anticancer drugs. In this study, we developed the cell cycle prediction model using high‐content imaging data of recipient cells after drug exposure and DNA‐staining with a low‐toxic DNA dye, SiR‐DNA. For this purpose, we exploited HeLa and MCF7 cells introduced with a fluorescent ubiquitination‐based cell cycle indicator (Fucci). Fucci‐expressing cancer cells were subjected to high‐content imaging analysis using OperettaCLS after 36‐h exposure to anticancer drugs; the nuclei were segmented, and the morphological and intensity properties of each nucleus characterized by SiR‐DNA staining were calculated using imaging analysis software, Harmony. For the use of training, we classified cells into each phase of the cell cycle using the Fucci system. Training data (<jats:italic>n</jats:italic> = 7500) and validation data (<jats:italic>n</jats:italic> = 2500) were randomly sampled and the binary classification prediction models for G1, early S, and S/G2/M phases of the cell cycle were developed using four supervised machine learning algorithms. We selected random forest as the model with the best performance through 10‐fold cross‐validation; the accuracy rate was approximately 75%–87%. Regarding feature importance, variables expected to be biologically related to the cell cycle, for example, signal intensity and nuclear size, were highly ranked, suggesting the validity of the model. These results showed that the cell cycle can be predicted in cancer cells by simply exploiting the current prediction model using fluorescent images of DNA‐staining dye, and the model could be applied for the use of future ex vivo drug sensitivity diagnosis.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"72 1","pages":""},"PeriodicalIF":2.6,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140830398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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Pharmacology Research & Perspectives
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