Journal of pharmacological and toxicological methods最新文献

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The efficient method to get better raw brain signal on rat anesthetics experiment 在大鼠麻醉实验中获取更佳原始大脑信号的有效方法。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-09-01 DOI: 10.1016/j.vascn.2024.107551
{"title":"The efficient method to get better raw brain signal on rat anesthetics experiment","authors":"","doi":"10.1016/j.vascn.2024.107551","DOIUrl":"10.1016/j.vascn.2024.107551","url":null,"abstract":"<div><p>This paper introduces an efficient methodology for conducting rat anesthesia experiments, aimed at enhancing the quality of raw brain signals obtained. The proposed approach enables the acquisition of animal brain signals during experiments without the confounding influence of muscle noise. Initially, the use of alpha-chloralose (a-c) in conjunction with Isoflurane is introduced to induce anesthesia in rats. Subsequently, Dexdomitor is administered to prevent muscular movements during the collection of brain signals, further refining the signal quality. Experimental outcomes conclusively demonstrate that our anesthesia method produces cleaner raw signals and exhibits improved robustness during data acquisition, outperforming existing methods that rely solely on Isoflurane or the Ketamine-Xylazine combination. Notably, this improved performance is achieved with minimal alterations to vital physiological parameters, including body temperature, respiration, and heart rates. Moreover, the efficacy of a-c in maintaining anesthesia for up to 7 h stands in contrast to the shorter durations achievable with continuous Isoflurane administration or the 30-min window offered by Ketamine-Xylazine, highlighting the practical advantages of our proposed method. Finally, post-experiment observations confirmed that the animals gradually returned to normal behavior without any signs of distress or adverse effects, indicating that our method was both effective and safe.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1056871924000613/pdfft?md5=b88f1f26d9ecf2ae4d735c241bb24bc6&pid=1-s2.0-S1056871924000613-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142157065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparative analysis of high-throughput RNA extraction kits in Naïve Non-Human Primate (NHP) tissues for downstream applications utilizing Xeno Internal Positive Control (IPC) 利用 Xeno 内部阳性对照 (IPC) 对用于下游应用的非人灵长类 (NHP) 组织中的高通量 RNA 提取试剂盒进行比较分析。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-09-01 DOI: 10.1016/j.vascn.2024.107549
{"title":"Comparative analysis of high-throughput RNA extraction kits in Naïve Non-Human Primate (NHP) tissues for downstream applications utilizing Xeno Internal Positive Control (IPC)","authors":"","doi":"10.1016/j.vascn.2024.107549","DOIUrl":"10.1016/j.vascn.2024.107549","url":null,"abstract":"<div><p>Ribonucleic acid (RNA) extraction and purification play pivotal roles in molecular biology and cell and gene therapy, where the quality and integrity of RNA are critical for downstream applications. Automated high-throughput systems have gained interest due to their potential for scalability and reduced labor requirements compared to manual methods. However, ensuring high-throughput capabilities, reproducibility, and reliability while maintaining RNA yield and purity remains challenging.</p><p>This study evaluated and compared the performance of four commercially available high-throughput magnetic bead-based RNA extraction kits across six types of naïve non-human primate (NHP) tissue matrices: brain, heart, kidney, liver, lung, and spleen. The assessment focused on RNA purity, yield, and extraction efficiency (EE) using Xeno Internal Positive Control (IPC) spiking.</p><p>Samples (∼50 mg) were homogenized via bead-beating and processed according to the manufacturer's protocol on the KingFisher Flex platform in eight replicates. RNA purity and yield were measured using a NanoDrop® spectrophotometer, while EE was evaluated via real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR).</p><p>The findings indicate consistent high RNA purity across all tested extraction kits, yet substantial variation in RNA yield. Extraction efficiency exhibited variations across tissue types, with decreasing trends observed from brain to lung tissues. These results underscore the importance of careful kit selection and method optimization for achieving reliable downstream applications. The MagMAX™ <em>mir</em>Vana™ Total RNA Isolation Kit stands out as the most accurate and reproducible, making it the preferred choice for applications requiring high RNA quality and consistency. Other kits, such as the Maxwell® HT simplyRNA Kit, offer a good balance between cost and performance, though with some trade-offs in precision. These findings highlight the importance of selecting the appropriate RNA isolation method based on the specific needs of the research, underscoring the critical role of accurate nucleic acid extraction in gene and cell therapy research.</p><p>In conclusion, this study highlights the critical factors influencing RNA extraction performance, emphasizing the need for researchers and practitioners to consider both kit performance and tissue characteristics when designing experimental protocols. These insights contribute to the ongoing efforts to enhance the reproducibility and reliability of RNA extraction methods in molecular biology and cell/gene therapy applications.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1056871924000595/pdfft?md5=710694baa0fad90506a661d8de218c74&pid=1-s2.0-S1056871924000595-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142142208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacokinetic profiles of methylcobalamin in rats after multiple administration routes by a simple LC-MS/MS assay with a small volume of plasma 通过一种简单的 LC-MS/MS 分析方法,在小容量血浆中测定多种给药途径后大鼠体内甲基钴胺的药代动力学特征。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-09-01 DOI: 10.1016/j.vascn.2024.107552
{"title":"Pharmacokinetic profiles of methylcobalamin in rats after multiple administration routes by a simple LC-MS/MS assay with a small volume of plasma","authors":"","doi":"10.1016/j.vascn.2024.107552","DOIUrl":"10.1016/j.vascn.2024.107552","url":null,"abstract":"<div><p>Methylcobalamin (MBL) is a vitamin B12 coenzyme and is effective for treating peripheral neuropathies. Little is known about pharmacokinetics (PK) of MBL in animals, we have developed a simple assay for MBL by using only 0.01 mL of plasma for PK of MBL in rats. Under minimal light exposure (&lt;5 lx), MBL was extracted by a simple protein precipitation using methanol and detected by liquid chromatography with tandem mass spectrometry. MBL in rat plasma at 20–10,000 ng/mL was quantified using only 0.01 mL of plasma. Relative error and relative standard deviation met the acceptance criteria in reproducibility assessments, indicating the robustness of the assay. PK of MBL was evaluated after intravenous, intramuscular, and subcutaneous administration. PK of MBL was dose proportional at 5–20 mg/kg in both intramuscular and subcutaneous administrations. Bioavailability after the two dosing routes was complete (ca. 100 %). The incurred sample reanalysis also supported that the assay is robust. The established assay was successfully applied to PK studies in rats to find that MBL showed high bioavailability after intramuscular and subcutaneous administrations.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142157064","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}
引用次数: 0
Understanding lymphatic drug delivery through chylomicron blockade: A retrospective and prospective analysis 通过乳糜微粒阻断了解淋巴给药:回顾性和前瞻性分析。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-08-02 DOI: 10.1016/j.vascn.2024.107548
{"title":"Understanding lymphatic drug delivery through chylomicron blockade: A retrospective and prospective analysis","authors":"","doi":"10.1016/j.vascn.2024.107548","DOIUrl":"10.1016/j.vascn.2024.107548","url":null,"abstract":"<div><p>Scientists have developed and employed various models to investigate intestinal lymphatic uptake. One approach involves using specific blocking agents to influence the chylomicron-mediated lymphatic absorption of drugs. Currently utilized models include pluronic L-81, puromycin, vinca alkaloids, colchicine, and cycloheximide. This review offers a thorough analysis of the diverse models utilized, evaluating existing reports while delineating the gaps in current research. It also explores pharmacokinetic related aspects of intestinal lymphatic uptake pathway and its blockage through the discussed models. Pluronic L-81 has a reversible effect, minimal toxicity, and unique mode of action. Yet, it lacks clinical reports on chylomicron pathway blockage, likely due to low concentrations used. Puromycin and vinca alkaloids, though documented for toxicity, lack information on their application in drug intestinal lymphatic uptake. Other vinca alkaloids show promise in affecting triglyceride profiles and represent possible agents to test as blockers. Colchicine and cycloheximide, widely used in pharmaceutical development, have demonstrated efficacy, with cycloheximide preferred for lower toxicity. However, further investigation into effective and toxic doses of colchicine in humans is needed to understand its clinical impact. The review additionally followed the complete journey of oral lymphatic targeting drugs from intake to excretion, provided a pharmacokinetic equation considering the intestinal lymphatic pathway for assessing bioavailability. Moreover, the possible application of urinary data as a non-invasive way to measure the uptake of drugs through intestinal lymphatics was illustrated, and the likelihood of drug interactions when specific blockers are employed in human subjects was underscored.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1056871924000583/pdfft?md5=fa29a2ac2b2f2cddf2c4a6c208fc204f&pid=1-s2.0-S1056871924000583-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Detection of contractility changes in the heart from arterial blood pressure data using symmetric Projection Attractor Reconstruction 利用对称投影吸引子重构从动脉血压数据中检测心脏收缩力变化
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-07-26 DOI: 10.1016/j.vascn.2024.107546
{"title":"Detection of contractility changes in the heart from arterial blood pressure data using symmetric Projection Attractor Reconstruction","authors":"","doi":"10.1016/j.vascn.2024.107546","DOIUrl":"10.1016/j.vascn.2024.107546","url":null,"abstract":"<div><p>The potential for unintended drug induced changes in cardiac contractility is a major concern in medicines development. Whilst direct left ventricular pressure (LVP) measurement is the gold standard for measuring cardiac contractility in vivo, it is resource intensive and poses a welfare burden on research animals. In contrast, arterial blood pressure (BP) measurement has fewer challenges. Symmetric Projection Attractor Reconstruction (SPAR) is a signal processing technique which transforms physiological time-series signals into a corresponding visual image (‘attractor’), amplifying morphology changes within physiological waveforms. It was hypothesized that SPAR analysis of BP signals would provide a surrogate measure of cardiac contractility by specifically amplifying the maximum slope of the systolic upstroke. BP (abdominal aorta) signals obtained from beagle dogs, treated with positive and negative inotropes, were retrospectively analysed to identify signal features that correlated with the maximum upslope of the LVP signal from simultaneously acquired LVP recordings. SPAR transformation of BP signals quantified drug induced changes in the maximum slope of the systolic upstroke. We identified key SPAR metrics that provided &gt;0.8 correlation with the LVP maximum upslope, outperforming the BP systolic upstroke alone. This was observed for all 4 different drugs, doses and time points evaluated across studies. Thus, we conclude that the SPAR measures derived from the BP signal could be used as a first pass in vivo screen to flag any risk of drug induced changes in cardiac contractility during the conduct of non-clinical medicines development, potentially reducing or replacing the need to perform direct left ventricular measurements.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S105687192400056X/pdfft?md5=8e0a0c5e71d9db51cee6e01697634e4b&pid=1-s2.0-S105687192400056X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Development and validation of an LC-MSMS method for the quantitation of pacritinib; application of kinetics in rabbits 开发和验证用于定量检测帕克替尼的 LC-MSMS 方法;在兔子身上应用动力学方法。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-07-26 DOI: 10.1016/j.vascn.2024.107547
{"title":"Development and validation of an LC-MSMS method for the quantitation of pacritinib; application of kinetics in rabbits","authors":"","doi":"10.1016/j.vascn.2024.107547","DOIUrl":"10.1016/j.vascn.2024.107547","url":null,"abstract":"<div><h3>Background</h3><p>Accurate and selective LC/ESI-MSMS method development and validation for the quantitation of pacritinib is the primary goal of this study to perform kinetic studies in the healthy rabbit.</p></div><div><h3>Methods</h3><p>Chromatographic resolution was accomplished with a hypersil/ODS (50 mm × 4.6 mm, 3 μ) analytical C<sub>18</sub> column and a mobile phase composition of 0.1% formic acid and ACN in the proportion of 25:75 with a 0.6 ml/min flow of the mobile phasic system from the analytical column. The method was employed by monitoring the established ionic transitions of <em>m</em>/<em>z-</em>473.25/98.09 for Pacritinib and 506.18/57.12 for the internal standard (Amprenavir) in multiple reaction monitoring.</p></div><div><h3>Results</h3><p>The calibration plot regression line was y = 0.0002× + 0.007, with a correction coefficient (r<sup>2</sup>) of 0.9989. The CV outcomes for the matrix effect at low-QC and high-QC levels were 4.79% and 4.91%, respectively. The percentage average recoveries for Pacritinib in High-QC (12.70 μg/ml), MQC (8.50 μg/ml), and Low-QC (1.19 μg/ml) were 95.87%, 103.64%, and 94.32%, respectively. The obtained values were found between 2.98 and 5.07% for the QC (1.19, 8.50, and 12.70 μg/ml) samples. The established procedure was subjected to kinetics study of Pacritinib after oral administration in rabbits. C<sub>max,</sub> T<sub>max,</sub> and T<sub>1/2,</sub> of the Pacritinib tablets were 247.25 ± 3.32 ng/ml, 6.0 ± 0.03 h, and 12.24 ± 0.53 h, respectively. AUC<sub>0-∞</sub> infinity for Pacritinib tablets was 1691.74 ± 3.67 ng h/ml.</p></div><div><h3>Conclusion</h3><p>After oral administration of Pacritinib to healthy rabbits, pharmacokinetic characteristics were presented, and the established technique was effectively verified.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790662","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}
引用次数: 0
Assessment of corrected JT-peak (JTpc) and Tpeak-to-Tend (TpTec) as proarrhythmia biomarkers in non-human primates: Outcome from a HESI consortium 在非人灵长类动物中评估作为前心律失常生物标志物的校正JT-峰值(JTpc)和Tpeak-to-Tend(TpTec):HESI 联合会的成果。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-07-15 DOI: 10.1016/j.vascn.2024.107543
{"title":"Assessment of corrected JT-peak (JTpc) and Tpeak-to-Tend (TpTec) as proarrhythmia biomarkers in non-human primates: Outcome from a HESI consortium","authors":"","doi":"10.1016/j.vascn.2024.107543","DOIUrl":"10.1016/j.vascn.2024.107543","url":null,"abstract":"<div><h3>Introduction</h3><p>Corrected QT interval (QTc)is an established biomarker for drug-induced Torsade de Pointe (TdP), but with concerns for a false positive signal. Clinically, JTpc and TpTec have emerged as ECG sub-intervals to differentiate predominant hERG <em>vs.</em> mixed ion channel blocking drugs that prolong QTc.</p></div><div><h3>Methods</h3><p>In a multicentric, prospective, controlled study, different proarrhythmic drug effects on QTc, JTpc and TpTec were characterized with cynomolgus monkeys using telemetry in a Lead II configuration for internal and external telemetry.Drugs and vehicle were administered orally (PO) to group size of 4 to 8 animals, in 4 laboratories.</p></div><div><h3>Results</h3><p>In monkeys, dofetilide (0.03–0.3 mg/kg) was associated with exposure dependent QTc and JTpc increase, but no significant TpTec effect. Similarly, quinidine (2–50 mg/kg) increased QTc and JTpc but did not change TpTec. Mexiletine (1–15 mg/kg) and verapamil (50 mg/kg) did not induce any significant effect on QTc, JTpc or TpTec.</p></div><div><h3>Discussion</h3><p>Clinically, predominant hERG blockers (dofetilide and quinidine) prolong QTc, JTpc and TpTec and are associated with increased risk for TdP. Results from this study demonstrate that ECG changes after dofetilide and quinidine administration to telemetered monkeys differ from the clinical response, lacking the expected effects on TpTec. Potential explanations for the lack of translation include physio-pharmacology species differences or ECG recording and analysis methodology variations. Mixed ion channel blockers verapamil and mexiletine administered to monkeys showed no significant QTc, JTpc or TpTec prolongation as expected based on the similar clinical response for these agents.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636351","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}
引用次数: 0
First-order compartment model solutions – Exponential sums and beyond 一阶区间模型解决方案--指数和及其他。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-07-01 DOI: 10.1016/j.vascn.2024.107534
Cyprian Świętaszczyk , Lars Jødal
{"title":"First-order compartment model solutions – Exponential sums and beyond","authors":"Cyprian Świętaszczyk ,&nbsp;Lars Jødal","doi":"10.1016/j.vascn.2024.107534","DOIUrl":"10.1016/j.vascn.2024.107534","url":null,"abstract":"<div><p>First-order compartment models are common tools for modelling many biological processes, including pharmacokinetics. Given the compartments and the transfer rates, solutions for the time-dependent quantity (or concentration) curves can normally be described by a sum of exponentials. This paper investigates cases that go beyond simple sums of exponentials. With specific relations between the transfer rate constants, two exponential rate constants can be equal, in which case the normal solution cannot be used. The conditions for this to occur are discussed, and advice is provided on how to circumvent these cases. An example of an analytic solution is given for the rare case where an exact equality is the expected result. Furthermore, for models with at least three compartments, cases exist where the solution to a real-valued model involves complex-valued exponential rate constants. This leads to solutions with an oscillatory element in the solution for the tracer concentration, i.e., there are cases where the solution is not a simple sum of (real-valued) exponentials but also includes sine and cosine functions. Detailed solutions for three-compartment cases are given. As a tentative conclusion of the analysis, oscillatory solutions appear to be tied to cases with a cyclic element in the model itself.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1056871924000443/pdfft?md5=f175badb789b2a97176662cc39201e98&pid=1-s2.0-S1056871924000443-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ultra-fast UPLC–MS/MS approach for estimating X-376 in human liver microsomes: Evaluation of metabolic stability via in silico software and in vitro analysis 用超快 UPLC-MS/MS 方法估算人肝微粒体中的 X-376:通过硅学软件和体外分析评估代谢稳定性。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-07-01 DOI: 10.1016/j.vascn.2024.107540
Mohamed W. Attwa, Ali S. Abdelhameed, Adnan A. Kadi
{"title":"Ultra-fast UPLC–MS/MS approach for estimating X-376 in human liver microsomes: Evaluation of metabolic stability via in silico software and in vitro analysis","authors":"Mohamed W. Attwa,&nbsp;Ali S. Abdelhameed,&nbsp;Adnan A. Kadi","doi":"10.1016/j.vascn.2024.107540","DOIUrl":"10.1016/j.vascn.2024.107540","url":null,"abstract":"<div><p>X-376 is a novel anaplastic lymphoma kinase (ALK) inhibitor that is capable of penetrating the blood brain barrier. This makes it suitable for use in patients with ALK-positive non-small cell lung cancer (NSCLC) who have metastases in the central nervous system. This study developed a highly sensitive, fast, eco-friendly, and reliable UPLC-MS/MS approach to quantify X-376 in human liver microsomes (HLMs). This approach was used to evaluate X-376's metabolic stability in HLMs in vitro. The UPLC-MS/MS analytical technique validation followed US-FDA bio-analytical method validation guidelines. StarDrop software, containing P450 metabolic and DEREK modules, was utilized to scan X-376's chemical structure for metabolic lability and hazardous warnings. X-376 and Encorafenib (ENF as internal standard) were resoluted on the Eclipse Plus C18 column utilizing an isocratic mobile phase method. The X-376 calibration curve was linear from 1 to 3000 ng/mL. The precision and accuracy of this study's UPLC-MS/MS approach were tested for intra- and inter-day measurements. Inter-day accuracy was −1.32% to 9.36% while intra-day accuracy was −1.5% to 10.00%. The intrinsic clearance (Cl<sub>int</sub>) and in vitro half-life (t<sub>1/2</sub>) of X-376 were 59.77 mL/min/kg and 13.56 min. The high extraction ratio of X-376 supports the 50 mg twice-daily dose for ALK-positive NSCLC and CNS metastases patients. In silico software suggests that simple structural changes to the piperazine ring or group substitution in drug design may improve metabolic stability and safety compared to X-376.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602388","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}
引用次数: 0
Cutibacterium acnes induces acne-like lesions in hairless mice models - A comparative study 痤疮杆菌诱导无毛小鼠模型出现痤疮样皮损--一项比较研究。
IF 1.3 4区 医学
Journal of pharmacological and toxicological methods Pub Date : 2024-07-01 DOI: 10.1016/j.vascn.2024.107539
George Ladopoulos , Christina Barda , Konstantina Tsami , Andrea Vitsos , Nikos Asoutis Didaras , Dimitris Mossialos , Helen Skaltsa , Ioannis Sfiniadakis , G.Th. Papaioannou , Michail Ch. Rallis
{"title":"Cutibacterium acnes induces acne-like lesions in hairless mice models - A comparative study","authors":"George Ladopoulos ,&nbsp;Christina Barda ,&nbsp;Konstantina Tsami ,&nbsp;Andrea Vitsos ,&nbsp;Nikos Asoutis Didaras ,&nbsp;Dimitris Mossialos ,&nbsp;Helen Skaltsa ,&nbsp;Ioannis Sfiniadakis ,&nbsp;G.Th. Papaioannou ,&nbsp;Michail Ch. Rallis","doi":"10.1016/j.vascn.2024.107539","DOIUrl":"10.1016/j.vascn.2024.107539","url":null,"abstract":"<div><p>Acne vulgaris, a chronic inflammatory skin disease with a high prevalence worldwide, necessitates reliable preclinical models for both understanding its pathogenesis and evaluating potential anti-acne therapies. This study aims to establish a robust mouse model using intracutaneous injection of <em>Cutibacterium acnes</em> bacterial suspension. Three hairless mouse strains (SKH-hr1, SKH-hr2 brown, and SKH-hr2 + ApoE) were systematically compared to ascertain the stains most closely resembling acne in humans. Various assessments, including photo documentation, biophysical evaluation, blood analysis, and histopathology, were conducted. Despite all strains exhibiting acne-like lesions, SKH-hr1 mice emerged as the most suitable model, demonstrating the most satisfactory results across multiple criteria. This research underscores the significance of employing hairless mice strains as models in acne studies to enhance and facilitate the development of effective therapeutic interventions.</p></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141539159","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}
引用次数: 0
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