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A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed. 比较肾功能生物标志物血清肌酐、原脑啡肽和胱抑素 C,以预测培美曲塞的清除率。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-04 DOI: 10.1007/s00280-024-04717-w
N de Rouw, R Beunders, O Hartmann, J Schulte, R J Boosman, H J Derijks, D M Burger, M M van den Heuvel, L B Hilbrands, P Pickkers, R Ter Heine

Introduction: For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed.

Methods: We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C.

Results: The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively.

Conclusions: In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.

简介对于治疗窗口较窄的药物来说,疗效和毒性之间存在着微妙的平衡,因此,从首次给药开始就使用正确的剂量至关重要。培美曲塞是一种用于肺癌治疗的细胞毒性药物,其暴露量受肾功能的影响。为了优化培美曲塞的剂量,准确预测药物清除率至关重要。因此,本研究旨在探讨肾功能生物标志物血清肌酐、胱抑素 C 和原烯脑啡肽在预测培美曲塞清除率方面的性能:我们使用两个临床试验的数据集进行了群体药代动力学分析,其中包含培美曲塞的药代动力学数据和所有三种生物标志物的测量值。对数据拟合了不含协变量的三室模型,并将获得的培美曲塞清除率个体经验贝叶斯估计值视为 "真实 "值(Ctrue)。随后,测试了以下作为培美曲塞清除率协变量的算法:使用肌酐的慢性肾脏病流行病学协作方程(CKD-EPICR)、胱抑素 C(CKD-EPICYS)、两者的组合(CKD-EPICR-CYS)、作为绝对值的原脑啡肽或与年龄和血清肌酐的组合算法,以及原脑啡肽与胱抑素 C 的组合:数据集由 66 名受试者组成,对所有三种肾功能生物标志物进行了配对观察。将 CKD-EPICR-CYS 作为培美曲塞清除率的协变量可使模型拟合效果最佳,目标函数(p CR-CYS 预测培美曲塞清除率的归一化均方根误差和平均预测误差分别为 19.9% 和 1.2%)下降幅度最大:总之,本研究表明,CKD-EPICR-CYS 组合在预测培美曲塞的药代动力学方面表现最佳。尽管存在假设的缺点,但在临床实践中,肌酐仍是预测培美曲塞清除率的一个合适且易于使用的指标。
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引用次数: 0
Successful desensitization in a patient with metastatic colorectal cancer presenting with regorafenib-mediated fix drug eruption. 成功对一名出现瑞戈非尼介导的固定药物爆发的转移性结直肠癌患者进行脱敏治疗。
IF 4.6 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-19 DOI: 10.1007/s00280-024-04719-8
Hazal Kayikci, C Tuccar, E Damadoglu, G Karakaya, A F Kalyoncu

Introduction: Regorafenib is an oral protein kinase inhinitor approved fot the treatment of metastatic colorecral cancer. We present a first successful case of desensitization in regorafenib-related fix-drug eruption in the literature.

Case report: A 44-year-old female patient was diagnosed with metastatic colorectal adenocarcinoma. The patient received regorafenib treatment for malignancy recurrence. The patient was admitted to adult allergy clinic with developing recurrent fix drug eruption in the second cycle, on the 10th day of regorafenib treatment. The patient was given the third cycle of regorafenib treatment with a 6-day desensitization protocol, the first day of which consisted of 6 steps and and the third cycle was successfully completed.

Management and outcome: Regorafenib-mediated delayed hypersensitivity reactions occur less frequently and and regorafenib hypersensitivity reactions are difficult to manage and experience is limited. This is the first successful desensitization protocol developed by us for regorafenib-related fix drug eruption and more cases are needed to be reported to confirm the desensitization protocol.

Discussion: There is only one successful regorafenib desensitization protocol for severe delayed hypersensivity reaction in the literature, but there is no protocol developed for mild type delayed hypersensivity reaction. The management of fix-drug eruption primarily involves discontinuation and avoidance of the offending drug but our patient had a mild delayed-type reaction and there was no alternative to regarofenib treatment. We developed the rapid 6-step desensitization protocol (Day 1). According to this protocol, the patient was able to continue regorafenib treatment successfully.

简介瑞戈非尼是一种口服蛋白激酶抑制剂,被批准用于治疗转移性结肠癌。我们在文献中首次成功报道了一例瑞戈非尼相关固定药疹的脱敏治疗:病例报告:一名 44 岁的女性患者被诊断为转移性结直肠腺癌。患者因恶性肿瘤复发接受了瑞戈非尼治疗。在瑞戈非尼治疗的第 10 天,患者因在第二周期出现复发性固定药物疹而入住成人过敏门诊。患者在接受瑞戈非尼治疗的第三个周期时,接受了为期6天的脱敏方案,其中第一天包括6个步骤,并顺利完成了第三个周期的治疗:瑞戈非尼介导的迟发性超敏反应发生率较低,瑞戈非尼超敏反应难以处理,经验有限。这是我们针对瑞戈非尼相关固定药物爆发制定的首个成功脱敏方案,还需要更多病例的报道来证实该脱敏方案:讨论:文献中只有一个成功的瑞戈非尼脱敏方案用于重度迟发性过敏反应,但还没有针对轻度迟发性过敏反应的脱敏方案。固定药物疹的治疗方法主要是停用和避免使用违规药物,但我们的患者属于轻度延迟型反应,除了瑞戈非尼治疗外别无选择。我们制定了快速 6 步脱敏方案(第 1 天)。根据该方案,患者成功地继续接受了瑞戈非尼治疗。
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引用次数: 0
Phase I-II study of OBI-888, a humanized monoclonal IgG1 antibody against the tumor-associated carbohydrate antigen Globo H, in patients with advanced solid tumors. 针对肿瘤相关碳水化合物抗原 Globo H 的人源化单克隆 IgG1 抗体 OBI-888 在晚期实体瘤患者中的 I-II 期研究。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-23 DOI: 10.1007/s00280-024-04714-z
Apostolia Maria Tsimberidou, Axel Grothey, Darren Sigal, Heinz-Josef Lenz, Howard S Hochster, Yee Chao, Li-Yuan Bai, Chia-Jui L Yen, Dong Xu, M Wayne Saville

Purpose: OBI-888 is a humanized, monoclonal IgG1 antibody specific to the tumor-associated carbohydrate antigen Globo H. We conducted a phase I-II study of OBI-888 in patients with advanced cancer.

Methods: Patients were treated with OBI-888 5, 10, or 20 mg/kg IV weekly in Part A ("3 + 3" design) and 20 mg/kg IV weekly in Part B (Simon's 2-stage design) (1 cycle = 28 days).

Results: Overall, 54 patients were treated (Part A, n = 14; Part B, n = 40). OBI-888 was safe and well tolerated across the doses studied, with a low incidence of OBI-888-related treatment emergent adverse events. The maximum tolerated dose of OBI-888 was not reached. No dose-limiting toxicities were noted up to the 20 mg/kg dose level (recommended phase 2 dose). Stable disease (SD) was noted in 28.6% and 20% of Parts A and B, respectively, including three patients with SD for 6+, 7+, and 9 months. Antibody-dependent cellular cytotoxicity (ADCC) was induced after each OBI-888 treatment (average increase, 3.8-fold and 4.7-fold in Parts A and B, respectively), suggesting that ADCC induction is a potential mechanism of action of OBI-888.

Conclusions: OBI-888 was well tolerated. Prolonged SD was noted in three patients. ADCC was induced after each OBI-888 treatment.

目的:OBI-888是一种特异于肿瘤相关碳水化合物抗原Globo H的人源化单克隆IgG1抗体:方法:在A部分("3 + 3 "设计)中,患者每周接受5、10或20毫克/千克的OBI-888静脉注射治疗;在B部分(西蒙两阶段设计)中,患者每周接受20毫克/千克的OBI-888静脉注射治疗(1个周期=28天):共有54名患者接受了治疗(A部分,14人;B部分,40人)。在所有研究剂量中,OBI-888均安全且耐受性良好,与OBI-888相关的治疗突发不良事件发生率较低。未达到OBI-888的最大耐受剂量。在20毫克/千克剂量水平(第二阶段推荐剂量)以下,未发现剂量限制性毒性反应。A部分和B部分分别有28.6%和20%的患者病情稳定(SD),其中有3名患者病情稳定时间分别为6个月、7个月和9个月。每次OBI-888治疗后都会诱导抗体依赖性细胞毒性(ADCC)(A部分和B部分的平均增幅分别为3.8倍和4.7倍),这表明ADCC诱导是OBI-888的一种潜在作用机制:结论:OBI-888的耐受性良好。结论:OBI-888的耐受性良好,有3名患者的SD延长。每次OBI-888治疗后都能诱导ADCC。
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引用次数: 0
An intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors. 一项脑内微透析研究,旨在确定艾瑞布林在转移性或原发性脑肿瘤患者中的神经药代动力学。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-10-18 DOI: 10.1007/s00280-024-04711-2
Zeynep Eroglu, Timothy Synold, Behnam Badie, An Liu, Arnab Chowdhury, Julie Kilpatrick, Suzette Blanchard, Jana Portnow

Purpose: Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection.

Methods: After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24 h after surgery, a single dose of eribulin 1.4 mg/m2 was administered intravenously. Dialysate samples were collected continuously for 72 h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry.

Results: Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log2 scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%.

Conclusion: Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain.

Clinicaltrials:

Gov identifier: NCT02338037 (January 9, 2015).

目的:Eribulin 是一种微管动力学抑制剂。它不像紫杉类药物那样与蛋白质高度结合,在血脑屏障(BBB)中不易被P-糖蛋白挤出。这些特点预示着艾瑞布林可在治疗脑肿瘤方面发挥积极作用。事实上,已发表的少量临床数据表明,艾瑞布林对乳腺癌脑转移可能有一定疗效。为了更好地了解艾瑞布林治疗脑肿瘤的潜力,我们进行了一项脑内微透析研究,以确定艾瑞布林在接受肿瘤切除术的癌症患者中的神经药代动力学:肿瘤切除后,将两根微透析导管插入瘤周脑组织。手术后约 24 小时,静脉注射单剂量艾瑞布林 1.4 mg/m2。连续收集透析液样本72小时,同时收集血浆样本。通过串联质谱分析艾瑞布林的浓度:结果:7 名研究参与者的 12 个脑内微透析导管的透析液样本被纳入分析。在统计学上观察到,BBB受损与完好的脑组织中的麦角苷浓度存在显著差异,平均最大浓度的对数值相差3.37(std err = 0.59,p值 = 0.005)。尽管如此,大脑与血浆中的艾瑞布林总体比率仅为 0.13% 至 1.99%:结论:尽管我们可以在BBB被破坏的脑组织中检测到较高浓度的艾瑞布林,但脑内艾瑞布林水平不足以预测艾瑞布林对脑内肿瘤具有一致的临床意义:Gov 标识符:NCT02338037(2015年1月9日)。
{"title":"An intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in patients with metastatic or primary brain tumors.","authors":"Zeynep Eroglu, Timothy Synold, Behnam Badie, An Liu, Arnab Chowdhury, Julie Kilpatrick, Suzette Blanchard, Jana Portnow","doi":"10.1007/s00280-024-04711-2","DOIUrl":"10.1007/s00280-024-04711-2","url":null,"abstract":"<p><strong>Purpose: </strong>Eribulin is an inhibitor of microtubule dynamics. It is not as highly protein bound as the taxanes and is less vulnerable to extrusion by P-glycoprotein in the blood-brain barrier (BBB). These features predict that eribulin could play an active role in managing brain tumors. Indeed, the small amount of published clinical data indicates eribulin may have some efficacy against breast cancer brain metastases. To better understand the potential of eribulin for treating brain tumors, we performed an intracerebral microdialysis study to determine the neuropharmacokinetics of eribulin in cancer patients undergoing tumor resection.</p><p><strong>Methods: </strong>After tumor removal, two microdialysis catheters were inserted into peritumoral brain tissue. Approximately 24 h after surgery, a single dose of eribulin 1.4 mg/m<sup>2</sup> was administered intravenously. Dialysate samples were collected continuously for 72 h, with plasma samples collected in parallel. Eribulin concentrations were analyzed by tandem mass spectrometry.</p><p><strong>Results: </strong>Dialysate samples from 12 intracerebral microdialysis catheters placed in 7 study participants were included in the analysis. A statistically significant difference was observed between eribulin concentrations in brain tissue where BBB was disrupted versus intact, with a difference in mean maximum concentrations on log<sub>2</sub> scale of 3.37 (std err = 0.59, p-value = 0.005). Nonetheless, overall brain to plasma ratios of eribulin only ranged from 0.13 to 1.99%.</p><p><strong>Conclusion: </strong>Although we could detect higher concentrations of eribulin in brain tissue where BBB was disrupted, intracerebral eribulin levels were not sufficient to predict eribulin would have consistent clinically meaningful activity against tumors in the brain.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT02338037 (January 9, 2015).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"807-813"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458677","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
Hypoalbuminemia in children with acute lymphoblastic leukemia: relation to asparaginase therapy and impact on high dose methotrexate elimination. 急性淋巴细胞白血病患儿的低白蛋白血症:与天冬酰胺酶疗法的关系以及对大剂量甲氨蝶呤消除的影响。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-12-01 Epub Date: 2024-09-21 DOI: 10.1007/s00280-024-04713-0
Sophie Rex Christensen, Christina Friis Jensen, Jesper Heldrup, Zachary Taylor, Laura B Ramsey, Steen Rosthøj

Purpose: High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor.

Methods: To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L).

Results: Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%).

Conclusion: Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses.

目的:大剂量甲氨蝶呤(HDMTX)疗法是急性淋巴细胞白血病(ALL)治疗方案的重要组成部分。疗程与肾损伤风险、消除延迟和全身毒性增加有关。最近,低白蛋白血症被认为是另一个风险因素:为了研究血清白蛋白的影响,我们回顾了根据 NOPHO ALL 2008 方案接受治疗的 51 名儿童中的 325 个 HDMTX 5 g/m2 疗程,并将这些疗程分为四组,每组的基线白蛋白水平不同(A 结果:51%的疗程存在低白蛋白血症,主要发生在天冬酰胺酶治疗进行中的化疗早期,尤其是在用药后不到两周的情况下(78%)。低白蛋白血症对输注末血清 MTX 有显著影响,具体取决于低白蛋白血症的程度:在 A 组至 D 组中,MTX > 150 µM 的比例分别为 37%、32%、20% 和 8%:低血清白蛋白是由同时接受天冬酰胺酶治疗引起的,对 MTX 的处置有显著的临床影响。如果血清白蛋白偏低,可能需要调整 HDMTX 的用药指南。
{"title":"Hypoalbuminemia in children with acute lymphoblastic leukemia: relation to asparaginase therapy and impact on high dose methotrexate elimination.","authors":"Sophie Rex Christensen, Christina Friis Jensen, Jesper Heldrup, Zachary Taylor, Laura B Ramsey, Steen Rosthøj","doi":"10.1007/s00280-024-04713-0","DOIUrl":"10.1007/s00280-024-04713-0","url":null,"abstract":"<p><strong>Purpose: </strong>High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor.</p><p><strong>Methods: </strong>To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25-29 g/L, C 30-34 g/L and D ≥ 35 g/L).</p><p><strong>Results: </strong>Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%).</p><p><strong>Conclusion: </strong>Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"775-785"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280629","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
Combination of ionizing radiation and 2-thio-6-azauridine induces cell death in radioresistant triple negative breast cancer cells by downregulating CD151 expression. 电离辐射和 2-硫代-6-氮尿嘧啶联合使用可通过下调 CD151 的表达诱导耐放射性三阴性乳腺癌细胞死亡。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI: 10.1007/s00280-024-04709-w
Rakshmitha Marni, Manas Malla, Anindita Chakraborty, Murali Krishna Voonna, Partha Sarathi Bhattacharyya, Deepak Kgk, Rama Rao Malla

Background: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer and is frequently resistant to therapy, ultimately resulting in treatment failure. Clinical trials have demonstrated the potential of sensitizing radiation therapy (RT)-resistant TNBC through the combination of chemotherapy and RT. This study sought to explore the potential of CD151 as a therapy response marker in the co-treatment strategy involving ionizing radiation (IR) and the repurposed antiviral drug 2-Thio-6-azauridine (TAU) for sensitizing RT-resistant TNBC (TNBC/RR).

Methods: The investigation encompassed a variety of assessments, including viability using MTT and LDH assays, cell proliferation through BrdU incorporation and clonogenic assays, cell cycle analysis via flow cytometry, cell migration using wound scratch and Boyden chamber invasion assays, DNA damage assessment through γH2AX analysis, apoptosis evaluation through acridine-orange and ethidium bromide double staining assays, as well as caspase 3 activity measurement using a colorimetric assay. CD151 expression was examined through ELISA, flow cytometry and RT-qPCR.

Results: The results showed a significant reduction in TNBC/RR cell viability following co-treatment. Moreover, the co-treatment reduced cell migration, induced apoptosis, downregulated CD151 expression, and increased caspase 3 activity in TNBC/RR cells. Additionally, CD151 was predicted to serve as a therapy response marker for co-treatment with TAU and IR.

Conclusion: These findings suggest the potential of combination treatment with IR and TAU as a promising strategy to overcome RT resistance in TNBC. Furthermore, CD151 emerges as a valuable therapy response marker for chemoradiotherapy.

背景三阴性乳腺癌(TNBC)是乳腺癌中最具侵袭性的亚型,经常对治疗产生耐药性,最终导致治疗失败。临床试验表明,通过化疗和 RT 的联合治疗,有可能使放射治疗(RT)耐药的 TNBC 增敏。本研究试图探索CD151在电离辐射(IR)和再利用抗病毒药物2-硫代-6-氮尿嘧啶(TAU)联合治疗策略中作为治疗反应标志物的潜力,以增敏RT耐药的TNBC(TNBC/RR):调查包括多种评估,其中包括使用 MTT 和 LDH 检测法评估细胞存活率;使用 BrdU 结合和克隆生成检测法评估细胞增殖;使用流式细胞仪分析细胞周期;使用伤口划痕和 Boyden 室侵袭检测法评估细胞迁移;使用 γH2AX 分析法评估 DNA 损伤;使用吖啶橙和溴化乙锭双重染色检测法评估细胞凋亡;以及使用比色法测量 Caspase 3 活性。通过酶联免疫吸附、流式细胞术和 RT-qPCR 检测 CD151 的表达:结果表明,联合治疗后 TNBC/RR 细胞活力明显降低。此外,联合处理还能减少 TNBC/RR 细胞的迁移、诱导细胞凋亡、下调 CD151 的表达和增加 caspase 3 的活性。此外,CD151被预测为TAU和IR联合治疗的治疗反应标志物:这些研究结果表明,IR和TAU联合治疗有望成为克服TNBC RT耐药的一种策略。此外,CD151还是化放疗的一个有价值的治疗反应标志物。
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引用次数: 0
Relative bioavailability and food effect of the galectin-3 inhibitor selvigaltin (GB1211) administered as a tablet in healthy participants (GALBA-1). 以片剂形式给健康参与者服用的galectin-3抑制剂selvigaltin(GB1211)的相对生物利用度和食物效应(GALBA-1)。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-21 DOI: 10.1007/s00280-024-04710-3
Vassilios Aslanis, Khalid Abd-Elaziz, Robert J Slack, Anne Brinch, Lise Gravelle, Wayne Morley, De Phung, Kimberly Herman, Ian Holyer, Karen Killerup Poulsen, Peter Dogterom, Susan Tantawi, Fredrik R Zetterberg, Brian Jacoby, Hans Schambye, Bertil Lindmark

Purpose: Overexpression of galectin-3, a β-galactoside-binding lectin, is associated with fibrotic diseases and cancer. Selvigaltin is an oral galectin-3 inhibitor, previously administered as a 50 mg capsule. This study aimed to evaluate the relative bioavailability and food effect of selvigaltin as a 100 mg tablet in healthy volunteers.

Methods: In this single-dose, randomized, three-period, crossover study (GALBA-1; NCT05747573), participants received selvigaltin as a 100 mg tablet (under fasted and fed conditions) or as two 50 mg capsules (under fasted conditions). Primary endpoints included plasma and urine pharmacokinetic (PK) parameters. Secondary endpoints were safety and tolerability.

Results: Of the 13 enrolled participants, 12 completed the study. Under fasted conditions, geometric mean maximum observed plasma concentration (Cmax) and systemic exposure (AUC0─inf) of selvigaltin were 161.0% and 84.0% higher, respectively, after administration of a tablet vs. capsules. Under fed vs. fasted conditions, geometric mean Cmax of the selvigaltin tablet was 20.0% lower, whereas AUC0─inf was unaffected. Geometric mean percentage of total dose of selvigaltin excreted in urine over 0─96 h was 30.3% and 35.9% for the tablet under fasted and fed conditions, respectively, and 14.5% for the capsules. No treatment-emergent severe or serious adverse events or study discontinuations due to a treatment-emergent adverse event were reported.

Conclusion: The tablet formulation of selvigaltin displayed higher bioavailability vs. the capsule formulation, with minimal effect of food on PK. Selvigaltin was well-tolerated during all treatments. These findings warrant further clinical development of the tablet formulation of selvigaltin without specific food restrictions.

Clinical trial registration: NCT05747573; February 28, 2023.

目的:galectin-3 是一种 β-半乳糖苷结合凝集素,它的过度表达与纤维化疾病和癌症有关。Selvigaltin是一种口服galectin-3抑制剂,以前以50毫克胶囊的形式给药。本研究旨在评估健康志愿者服用 100 毫克片剂塞尔维加尔汀的相对生物利用度和食物效应:在这项单剂量、随机、三期交叉研究(GALBA-1;NCT05747573)中,参与者服用的是 100 毫克片剂(空腹和进食条件下)或两粒 50 毫克胶囊(空腹条件下)。主要终点包括血浆和尿液药代动力学(PK)参数。次要终点为安全性和耐受性:结果:13 名参加者中,12 人完成了研究。在空腹条件下,服用片剂与胶囊相比,舍维加尔汀的几何平均最大观察血浆浓度(Cmax)和全身暴露量(AUC0─inf)分别高出161.0%和84.0%。在进食与禁食条件下,舍维加尔汀片剂的几何平均Cmax降低了20.0%,而AUC0─inf则不受影响。在空腹和进食条件下,片剂在0-96小时内从尿液中排出的舍维加尔汀占总剂量的几何平均百分比分别为30.3%和35.9%,胶囊则为14.5%。未报告因治疗引起的严重不良事件或研究中止:结论:与胶囊剂相比,片剂的生物利用度更高,食物对PK的影响最小。在所有治疗过程中,塞尔维加尔汀的耐受性都很好。这些研究结果证明,在没有特定食物限制的情况下,可以进一步临床开发舍维加尔汀片剂:临床试验注册:NCT05747573;2023年2月28日。
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引用次数: 0
Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects. 新型ALK酪氨酸激酶抑制剂[14C]envonalkib(TQ-B3139)在中国健康受试者中的药代动力学、质量平衡和代谢。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-03-20 DOI: 10.1007/s00280-024-04647-7
Sheng Ma, Xin Wang, Shu Yan, Liyan Miao, Xiaojing Wan, Dawei Ding, Ding Yu, Xingxing Diao, Xunqiang Wang, Hua Zhang

Purpose: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects.

Methods: A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification.

Results: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study.

Conclusion: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.

目的:Envonalkib(TQ-B3139)是一种新型、强效的无性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂,用于治疗ALK阳性的非小细胞肺癌。这项 I 期质量平衡研究调查了中国健康男性受试者体内 14C 放射性标记的恩沃纳克的药代动力学、代谢和排泄情况:方法:健康男性受试者在空腹状态下单次口服 600 毫克(150 µCi)[14C]envonalkib。收集血液、尿液和粪便样本,定量测定总放射性和未改变的烯沃纳基布,并对代谢物进行鉴定:结果:用药后,血浆中放射性的中位Tmax为4小时,平均t1/2为65.2小时。血浆中总放射性的暴露量远高于未改变的恩沃那昔。在给药后的504小时内,放射性标记剂量的平均总回收率为93.93%,其中尿液中的回收率为15.23%,粪便中的回收率为78.71%。恩沃那昔经过大量代谢,在血浆、尿液和粪便中总共发现了15种代谢物。未发生变化的恩沃那昔及其主要代谢物M315是血浆中的主要成分,分别占血浆总放射性的20.37%和33.33%。在尿液中,O-脱烷基代谢物 M315 是主要成分,占剂量的 7.98%。在粪便中,16.01%的剂量以半胱氨酸共轭物M434-1的形式排出。恩沃那麒耐受性良好,研究中未发现严重不良反应:结论:恩沃那珂布在排泄前被广泛代谢,主要以代谢物的形式经粪便排出体外。
{"title":"Pharmacokinetics, mass balance, and metabolism of [<sup>14</sup>C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects.","authors":"Sheng Ma, Xin Wang, Shu Yan, Liyan Miao, Xiaojing Wan, Dawei Ding, Ding Yu, Xingxing Diao, Xunqiang Wang, Hua Zhang","doi":"10.1007/s00280-024-04647-7","DOIUrl":"10.1007/s00280-024-04647-7","url":null,"abstract":"<p><strong>Purpose: </strong>Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of <sup>14</sup>C-radiolabeled envonalkib in healthy Chinese male subjects.</p><p><strong>Methods: </strong>A single oral dose of 600 mg (150 µCi) [<sup>14</sup>C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification.</p><p><strong>Results: </strong>After dosing, the median T<sub>max</sub> of radioactivity was 4 h and the mean t<sub>1/2</sub> was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study.</p><p><strong>Conclusion: </strong>Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"647-657"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173845","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
Selinexor targeting XPO1 promotes PEG3 nuclear accumulation and suppresses cholangiocarcinoma progression. 以 XPO1 为靶点的 Selinexor 可促进 PEG3 的核积累并抑制胆管癌的进展。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-05 DOI: 10.1007/s00280-024-04704-1
Deng Xiang, Min Wang, Huajun Wu, Xi Chen, Tianxiang Chen, Dongshan Yu, Lei Xiong, Han Xu, Ming Luo, Shouhua Zhang, Linquan Wu, Jinlong Yan

Background: The role of selinexor, a targeted inhibitor of exportin 1 (XPO1), in the treatment of cholangiocarcinoma is not yet fully understood. This study conducted comprehensive in vitro and in vivo investigations to elucidate the effects of selinexor on cholangiocarcinoma, with a focus on its mechanistic relationship with the cellular localization of Paternally Expressed Gene 3 (PEG3).

Methods: A patient-derived xenograft (PDX) model was established using samples from a cholangiocarcinoma patient in immunodeficient mice to assess the in vivo effects of selinexor. Additionally, cholangiocarcinoma cell lines HuCC-T1 and BRE were cultured to evaluate selinexor's impact on cell proliferation, invasion, migration, cell cycle, and apoptosis. HuCC-T1 cells were also implanted in immunodeficient mice for further investigation. Immunofluorescence and Western blotting were employed to observe the expression and localization of the PEG3 protein.

Results: The results demonstrated that selinexor significantly inhibited tumor growth in the cholangiocarcinoma PDX model and promoted the accumulation of PEG3 protein within the nuclei of tumor cells. In vitro experiments showed that selinexor effectively suppressed cholangiocarcinoma cell proliferation, invasion, and migration, while also impeding the cell cycle and inducing apoptosis. Notably, selinexor markedly facilitated the nuclear accumulation of PEG3 protein in cholangiocarcinoma cells. However, when PEG3 expression was knocked down, the effects of selinexor on cholangiocarcinoma were significantly reversed.

Conclusion: These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.

背景:selinexor是一种输出蛋白1(XPO1)靶向抑制剂,它在治疗胆管癌中的作用尚未完全明了。本研究进行了全面的体外和体内研究,以阐明 selinexor 对胆管癌的影响,重点研究其与父系表达基因 3 (PEG3) 细胞定位的机理关系:方法:利用免疫缺陷小鼠中的胆管癌患者样本建立了患者衍生异种移植(PDX)模型,以评估selinexor的体内效应。此外,还培养了胆管癌细胞系 HuCC-T1 和 BRE,以评估 selinexor 对细胞增殖、侵袭、迁移、细胞周期和凋亡的影响。还将 HuCC-T1 细胞植入免疫缺陷小鼠体内进行进一步研究。采用免疫荧光和 Western 印迹技术观察 PEG3 蛋白的表达和定位:结果表明,selinexor能显著抑制胆管癌PDX模型的肿瘤生长,并促进PEG3蛋白在肿瘤细胞核内的积累。体外实验表明,selinexor能有效抑制胆管癌细胞的增殖、侵袭和迁移,同时还能阻碍细胞周期并诱导细胞凋亡。值得注意的是,selinexor 能明显促进 PEG3 蛋白在胆管癌细胞核内的积累。然而,当 PEG3 的表达被敲除时,selinexor 对胆管癌的影响就会明显逆转:这些研究结果表明,selinexor 通过靶向 XPO1 和促进 PEG3 蛋白的核积累,从而阻碍细胞周期并诱导细胞凋亡,从而抑制胆管癌的进展。
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引用次数: 0
Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer. 晚期癌症患者使用低剂量 nivolumab(相对于常规剂量)的药代动力学和临床疗效。
IF 2.7 4区 医学 Q3 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-26 DOI: 10.1007/s00280-024-04697-x
Khushboo A Gandhi, Aditi Shirsat, Sharat Kumar Hj, Ashish Chavan, Parnika Dicholkar, Saniya Shah, Nandini Menon, Vanita Noronha, Amit Joshi, Kumar Prabhash, Vijay Patil, Vikram Gota

Purpose: Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses.

Methods: Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity.

Results: Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized Cmax and AUC0-t were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group.

Conclusion: Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.

目的:Nivolumab获批的剂量多种多样,包括3毫克/千克、240毫克和480毫克的平剂量以及不同的给药间隔。近年来,低剂量免疫疗法的概念正日益受到重视。然而,我们需要更好地了解低剂量时的药代动力学和临床效果:方法:根据医院的现行做法,根据患者的经济承受能力,为患者注射 40 毫克的固定剂量或 3 毫克/千克的 Q2W/Q3W 剂量。所有患者均在第 1 天住院,并在服用首剂尼夫单抗后的 0、0.5、1.0、6.0、24.0、72.0 h 和第 14 天采集药代动力学样本。通过酶联免疫吸附法测定血浆中的尼夫单抗水平。对患者的反应和毒性进行随访:研究共纳入了 25 名患者。14名患者接受了常规剂量(3毫克/千克)的尼伏单抗治疗,11名患者接受了低剂量(40毫克平片)的尼伏单抗治疗。接受常规剂量和低剂量nivolumab的患者的剂量归一化Cmax和AUC0-t的几何平均数相当(分别为0.28对0.23 µg/mL/mg和0.0014对0.0011 d/mL)。19名患者的反应可进行评估。接受常规剂量治疗的患者的ORR为5/11(45.5%),而低剂量队列中的ORR为4/9(44.4%)。常规剂量组的所有 14 名患者(100%)和低剂量组的 7/11 名患者(63.64%)都出现了治疗突发不良事件。常规剂量组有4/14例患者出现≥3级毒性反应,低剂量组无:结论:与常规剂量相比,低剂量nivolumab导致患者的暴露量更低,但低剂量的耐受性更好,而反应率与常规剂量相当。
{"title":"Pharmacokinetics and clinical outcomes of low-dose nivolumab relative to conventional dose in patients with advanced cancer.","authors":"Khushboo A Gandhi, Aditi Shirsat, Sharat Kumar Hj, Ashish Chavan, Parnika Dicholkar, Saniya Shah, Nandini Menon, Vanita Noronha, Amit Joshi, Kumar Prabhash, Vijay Patil, Vikram Gota","doi":"10.1007/s00280-024-04697-x","DOIUrl":"10.1007/s00280-024-04697-x","url":null,"abstract":"<p><strong>Purpose: </strong>Nivolumab is approved at various doses, including 3 mg/kg, 240 mg and 480 mg flat doses at various dosing intervals. The concept of low-dose immunotherapy is gaining traction in recent years. However, there is a need to better understand the pharmacokinetics and clinical outcomes at lower doses.</p><p><strong>Methods: </strong>Patients were either administered 40 mg flat dose or 3 mg/kg Q2W/Q3W, depending on affordability as per prevailing hospital practice. All patients were hospitalized on day 1 and pharmacokinetic samples were collected at 0, 0.5, 1.0, 6.0, 24.0, 72.0 h and day 14 following administration of the first dose of nivolumab. Plasma nivolumab levels were measured by ELISA. Patients were followed up for response and toxicity.</p><p><strong>Results: </strong>Twenty five patients were included in the study. Fourteen received nivolumab at conventional dose (3 mg/kg), while 11 patients received low-dose (40 mg flat). The geometric means of dose normalized C<sub>max</sub> and AUC<sub>0-t</sub> were comparable between those who received conventional dose and low-dose of nivolumab (0.28 versus 0.23 µg/mL/mg and 0.0014 versus 0.0011 d/mL respectively). Nineteen patients were evaluable for response. ORR among patients who received conventional dose was 5/11 (45.5%) whereas it was 4/9 (44.4%) in the low-dose cohort. All 14 (100%) patients in conventional dosing group and 7/11 patients (63.64%) in low-dose group had treatment emergent adverse events. Grade ≥ 3 toxicities were observed in 4/14 patients in conventional dose group and none in low-dose group.</p><p><strong>Conclusion: </strong>Low-dose nivolumab leads to lower exposure in patients as compared with conventional dose, but low-dose was better tolerated, while response rates were comparable to conventional dose.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":" ","pages":"659-668"},"PeriodicalIF":2.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765554","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
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Cancer Chemotherapy and Pharmacology
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