Pub Date : 2023-09-01DOI: 10.1007/s40268-023-00436-4
Yu Jeong Lee, Jinmi Kim, Youngmi Han, Kyuhyun Hwang, Byungkwan Choi, Tae Ryom Oh, Il Young Kim, Harin Rhee
Background and objective: Tramadol has been reported to cause hyponatremia but the evidence is conflicting. The risk of hyponatremia resulting from combination oral tramadol/acetaminophen (TA) therapy is thus unknown. This study examined whether, compared with acetaminophen (AA), TA use is associated with an increased risk of hyponatremia.
Methods: Hospital data compatible with the Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM; version 5.3) for 30,999 patients taking TA or AA from 2011 through 2020 were analyzed. New-onset hyponatremia was defined as a serum sodium level < 135 mEq/L within 10 days after drug initiation. The incidence rate ratio was calculated based on crude and 1:1 propensity-score-matched models. Subgroup analyses compared patients taking TA extended-release (TA-ER) and TA immediate-release (TA-IR) formulations.
Results: Among the 30,999 patients, 12,122 (39.1%) were aged > 65 years and 16,654 (53.7%) were male. Hyponatremia within 10 days developed in 1613 (8.4%) of the 19,149 patients in the TA group; the incidence rate was higher than in the AA group (4.2%; 493 out of 11,850 cases). In the propensity-score-matched model, the incidence rate of hyponatremia in the TA group was 6.8 per 1000 person-days (PD), which was 1.57-fold (1.31, 1.89) higher than that in the AA group (4.3 per 1000 PD). In both the crude and propensity-score-matched models, the incidence rate of hyponatremia was significantly higher in the TA-ER than TA-IR subgroup.
Conclusion: In this real-world study, hyponatremia was more frequently observed in the TA than AA group, and in the TA-ER than TA-IR subgroup. Therefore, it is imperative to prescribe tramadol cautiously and closely monitor electrolyte levels.
{"title":"Risk of Hyponatremia after Tramadol/Acetaminophen Single-Pill Combination Therapy: A Real-World Study Based on the OMOP-CDM Database.","authors":"Yu Jeong Lee, Jinmi Kim, Youngmi Han, Kyuhyun Hwang, Byungkwan Choi, Tae Ryom Oh, Il Young Kim, Harin Rhee","doi":"10.1007/s40268-023-00436-4","DOIUrl":"https://doi.org/10.1007/s40268-023-00436-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Tramadol has been reported to cause hyponatremia but the evidence is conflicting. The risk of hyponatremia resulting from combination oral tramadol/acetaminophen (TA) therapy is thus unknown. This study examined whether, compared with acetaminophen (AA), TA use is associated with an increased risk of hyponatremia.</p><p><strong>Methods: </strong>Hospital data compatible with the Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM; version 5.3) for 30,999 patients taking TA or AA from 2011 through 2020 were analyzed. New-onset hyponatremia was defined as a serum sodium level < 135 mEq/L within 10 days after drug initiation. The incidence rate ratio was calculated based on crude and 1:1 propensity-score-matched models. Subgroup analyses compared patients taking TA extended-release (TA-ER) and TA immediate-release (TA-IR) formulations.</p><p><strong>Results: </strong>Among the 30,999 patients, 12,122 (39.1%) were aged > 65 years and 16,654 (53.7%) were male. Hyponatremia within 10 days developed in 1613 (8.4%) of the 19,149 patients in the TA group; the incidence rate was higher than in the AA group (4.2%; 493 out of 11,850 cases). In the propensity-score-matched model, the incidence rate of hyponatremia in the TA group was 6.8 per 1000 person-days (PD), which was 1.57-fold (1.31, 1.89) higher than that in the AA group (4.3 per 1000 PD). In both the crude and propensity-score-matched models, the incidence rate of hyponatremia was significantly higher in the TA-ER than TA-IR subgroup.</p><p><strong>Conclusion: </strong>In this real-world study, hyponatremia was more frequently observed in the TA than AA group, and in the TA-ER than TA-IR subgroup. Therefore, it is imperative to prescribe tramadol cautiously and closely monitor electrolyte levels.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1c/90/40268_2023_Article_436.PMC10439094.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10420216","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}
Introduction: Despite rasburicase's proven efficiency in Caucasians, Japanese, and Koreans, studies evaluating the safety and effectiveness of rasburicase in Chinese pediatric patients with non-Hodgkin's lymphoma (NHL) and acute leukemia (AL) in particular are lacking.
Objective: The aim was to evaluate the safety and effectiveness of rasburicase in Chinese pediatric patients with NHL and AL.
Methods: In this phase IV, open-label, non-randomized, single-arm, multi-center, interventional study (NCT04349306), children newly diagnosed with NHL or AL who received 0.20 mg/kg/day of rasburicase were included. The primary objective was to assess the safety of rasburicase by the incidence of adverse events (AEs). The secondary objective was to determine the effectiveness of rasburicase in the control of hyperuricemia.
Results: Out of 50 patients, 25 reported a total of 76 treatment-emergent adverse events (TEAEs), including eight TEAEs of grade ≥ 3 in 12 patients. A drug-related serious AE was reported in one patient, and there was no incidence of death. The response rate in the intent-to-treat population was 100.0% (95% confidence interval 82.4-100.0) in patients (n = 19) with baseline uric acid level of > 8.0 mg/dL. Similarly, the response rate was 86.2% (n = 25) among 29 patients (60.4%) with baseline uric acid levels of ≤ 8.0 mg/dL. The maximum mean percentage decrease of plasma uric acid level in the overall patients was 96.9%.
Conclusion: Rasburicase was well tolerated and effective in controlling hyperuricemia in Chinese pediatric patients with NHL and AL.
{"title":"Safety and Effectiveness of Rasburicase in the Control of Hyperuricemia in Pediatric Patients with Non-Hodgkin's Lymphoma and Acute Leukemia: An Open-Label, Single-Arm, Multi-center, Interventional Study.","authors":"Tianyou Wang, Xiaofan Zhu, Yumei Chen, Shuhong Shen, Yongmin Tang, Jingying Zhang, Yingyi He, Hui Zhang, Ju Gao, Jianpei Fang, Rong Liu, Xiaoyan Wu, Jinchuan Sun, Minlu Zhang","doi":"10.1007/s40268-023-00420-y","DOIUrl":"https://doi.org/10.1007/s40268-023-00420-y","url":null,"abstract":"<p><strong>Introduction: </strong>Despite rasburicase's proven efficiency in Caucasians, Japanese, and Koreans, studies evaluating the safety and effectiveness of rasburicase in Chinese pediatric patients with non-Hodgkin's lymphoma (NHL) and acute leukemia (AL) in particular are lacking.</p><p><strong>Objective: </strong>The aim was to evaluate the safety and effectiveness of rasburicase in Chinese pediatric patients with NHL and AL.</p><p><strong>Methods: </strong>In this phase IV, open-label, non-randomized, single-arm, multi-center, interventional study (NCT04349306), children newly diagnosed with NHL or AL who received 0.20 mg/kg/day of rasburicase were included. The primary objective was to assess the safety of rasburicase by the incidence of adverse events (AEs). The secondary objective was to determine the effectiveness of rasburicase in the control of hyperuricemia.</p><p><strong>Results: </strong>Out of 50 patients, 25 reported a total of 76 treatment-emergent adverse events (TEAEs), including eight TEAEs of grade ≥ 3 in 12 patients. A drug-related serious AE was reported in one patient, and there was no incidence of death. The response rate in the intent-to-treat population was 100.0% (95% confidence interval 82.4-100.0) in patients (n = 19) with baseline uric acid level of > 8.0 mg/dL. Similarly, the response rate was 86.2% (n = 25) among 29 patients (60.4%) with baseline uric acid levels of ≤ 8.0 mg/dL. The maximum mean percentage decrease of plasma uric acid level in the overall patients was 96.9%.</p><p><strong>Conclusion: </strong>Rasburicase was well tolerated and effective in controlling hyperuricemia in Chinese pediatric patients with NHL and AL.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/f2/40268_2023_Article_420.PMC10293550.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10224901","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}
Pub Date : 2023-06-01DOI: 10.1007/s40268-023-00419-5
Céline Gérard, Jean-Michel Foidart
Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.
{"title":"Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.","authors":"Céline Gérard, Jean-Michel Foidart","doi":"10.1007/s40268-023-00419-5","DOIUrl":"https://doi.org/10.1007/s40268-023-00419-5","url":null,"abstract":"<p><p>Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/06/55/40268_2023_Article_419.PMC10293541.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9760649","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}
Background: SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes.
Objective: This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin®) in healthy Chinese males.
Methods: This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3 mg/kg infusion of either SCT510 or bevacizumab and followed up for 99 days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC0-∞), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC0-t), and the maximum observed concentration (Cmax). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes.
Results: A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC0-∞, AUC0-t, and Cmax were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC0-∞, AUC0-t, and Cmax were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day 99 visit.
Conclusion: This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin®). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males.
{"title":"A Randomized, Double-Blind, Parallel-Controlled Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of SCT510 to Bevacizumab (Avastin<sup>®</sup>) in Healthy Chinese Males.","authors":"Jing Wu, Guolan Wu, Liangzhi Xie, Duo Lv, Chang Xu, Huili Zhou, Lihua Wu, Jingjing Zhang, Jianzhong Shentu","doi":"10.1007/s40268-023-00424-8","DOIUrl":"https://doi.org/10.1007/s40268-023-00424-8","url":null,"abstract":"<p><strong>Background: </strong>SCT510 is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), which is intended as a candidate biosimilar of bevacizumab that is approved for various metastatic cancers.Please confirm change in wording to match definition for VEGF belowYes.</p><p><strong>Objective: </strong>This study aimed to compare the pharmacokinetics profiles, safety, and immunogenicity of SCT510 to bevacizumab (Avastin<sup>®</sup>) in healthy Chinese males.</p><p><strong>Methods: </strong>This was a single-center, double-blind, parallel-group phase I study. A total of 84 participants were randomly assigned (1:1) to receive a single 3 mg/kg infusion of either SCT510 or bevacizumab and followed up for 99 days. Primary endpoints were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC<sub>0-∞</sub>), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUC<sub>0-t</sub>), and the maximum observed concentration (C<sub>max</sub>). Secondary endpoints included safety and immunogenicity.Kindly check and confirm the edit made in the article title.Yes.</p><p><strong>Results: </strong>A total of 82 subjects completed the study. Geometric means ratios (GMR) for AUC<sub>0-∞</sub>, AUC<sub>0-t</sub>, and C<sub>max</sub> were 0.88, 0.89, and 0.97, respectively, for SCT510 versus bevacizumab (USA). The 90% confidence intervals for GMRs of AUC<sub>0-∞</sub>, AUC<sub>0-t</sub>, and C<sub>max</sub> were all within the prespecified criteria (80-125%). No adverse events (AEs) led to study termination, and no serious adverse events (SAEs) were reported. None of the anti-drug antibodies (ADAs) identified were found to be neutralizing antibodies (NAbs), and only one subject from the SCT510 group tested positive for the ADA at the day 99 visit.</p><p><strong>Conclusion: </strong>This study demonstrated that the pharmacokinetics, safety, and immunogenicity of SCT510 were equivalent to bevacizumab (Avastin<sup>®</sup>). As a proposed biosimilar drug to bevacizumab, SCT510 was well tolerated in healthy Chinese males.</p><p><strong>Clinical trials registration: </strong>NCT05113511.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1e/17/40268_2023_Article_424.PMC10293153.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9706556","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}
Pub Date : 2023-06-01DOI: 10.1007/s40268-023-00421-x
André B P van Kuilenburg, Carla E M Hollak, Ana Travella, Melisa Jacobs, Lucas D Gentilini, René Leen, Karen M M Ghauharali-van der Vlugt, Femke S Beers Stet, Susan M I Goorden, Sanne van der Veen, Marcelo Criscuolo, Mariana Papouchado
Background and objective: Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta.
Methods: Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice.
Results: AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO.
Conclusion: These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development.
背景和目的:法布里病(FD)是一种罕见的溶酶体贮积症,由α-半乳糖苷酶a (aGal a)缺乏引起。自2001年以来,两种不同的酶替代疗法已被批准,在西方世界的大部分地区使用了α-半乳糖苷酶。目前,一些昂贵的酶疗法的生物仿制药正在开发中,以提高患者的可及性。我们提出了一种生物类似物开发的临床前结果,以琼脂苷酶β。方法:从中国仓鼠卵巢(CHO)细胞系统中制备的aGal a Biosidus (AGABIO)生物类似物,与aGal苷酶β在氨基酸序列、糖基化、α-半乳糖苷酶特异性活性、血浆稳定性以及对培养的人法布里成纤维细胞和法布里小鼠的影响等方面进行比较。结果:AGABIO与琼脂苷酶β具有相同的氨基酸组成、相似的糖基化、酶活性和稳定性。成纤维细胞摄取α-半乳糖苷酶A后,α-半乳糖苷酶A活性呈剂量依赖性增加,在24 h后达到最大摄取,并保持稳定至至少48 h。两种酶都定位于溶酶体。AGABIO和agalsidase - β对Fabry成纤维细胞中积累的球三烷基神经酰胺(Gb3)和溶酶体Gb3的减少表现出相似的剂量-反应曲线。在法布里基因敲除小鼠中,单次注射后,这两种酶都迅速从血浆中清除,并在组织和血浆鞘脂中显示出相同的减少。在大鼠身上进行的重复剂量研究没有引起任何安全问题。用琼脂苷酶治疗的FD患者的抗药物抗体对AGABIO具有相同的中和活性。结论:这些发现支持AGABIO与琼脂苷酶β的生物相似性。临床研究阶段目前正在开发中。
{"title":"Development of a Biosimilar of Agalsidase Beta for the Treatment of Fabry Disease: Preclinical Evaluation.","authors":"André B P van Kuilenburg, Carla E M Hollak, Ana Travella, Melisa Jacobs, Lucas D Gentilini, René Leen, Karen M M Ghauharali-van der Vlugt, Femke S Beers Stet, Susan M I Goorden, Sanne van der Veen, Marcelo Criscuolo, Mariana Papouchado","doi":"10.1007/s40268-023-00421-x","DOIUrl":"https://doi.org/10.1007/s40268-023-00421-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Fabry disease (FD) is a rare lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A (aGal A). Since 2001, two different enzyme replacement therapies have been authorized, with agalsidase beta being used in most parts of the Western world. Currently, biosimilars of several expensive enzyme therapies are under development to improve their accessibility for patients. We present the preclinical results of the development of a biosimilar to agalsidase beta.</p><p><strong>Methods: </strong>Produced in a Chinese hamster ovary (CHO)-cell system, the biosimilar aGal A Biosidus (AGABIO), was compared with agalsidase beta with respect to amino acid sequence, glycosylation, specific α-galactosidase activity, stability in plasma, and effects on cultured human Fabry fibroblasts and Fabry mice.</p><p><strong>Results: </strong>AGABIO had the same amino acid composition and similar glycosylation, enzymatic activity, and stability as compared with agalsidase beta. After uptake in fibroblasts, α-galactosidase A activity increased in a dose-dependent manner, with maximum uptake observed after 24 h, which remained stable until at least 48 h. Both enzymes were localized to lysosomes. Reduction of accumulated globotriaosylceramide (Gb3) and lysoGb3 in cultured Fabry fibroblasts by AGABIO and agalsidase beta showed comparable dose-response curves. In Fabry knockout mice, after a single injection, both enzymes were rapidly cleared from the plasma and showed equal reductions in tissue and plasma sphingolipids. Repeated dose studies in rats did not raise any safety concerns. Anti-drug antibodies from patients with FD treated with agalsidase beta showed equal neutralization activity toward AGABIO.</p><p><strong>Conclusion: </strong>These findings support the biosimilarity of AGABIO in comparison with agalsidase beta. The clinical study phase is currently under development.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/84/bf/40268_2023_Article_421.PMC10293523.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9709367","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}
Background and objective: Adult-onset Still's disease (AOSD) is an idiopathic systemic inflammatory disease of unknown aetiology. Some patients exhibit resistance to conventional treatment during long-term therapy. Janus kinase inhibitors (JAKinibs) may contribute to the improvement in AOSD symptoms via the JAK-signal transducer and activator of transcription (STAT) pathway. We aimed to explore the efficacy and safety of baricitinib in patients with refractory AOSD.
Methods: Patients were enrolled if they fulfilled the Yamaguchi AOSD classification criteria in China between 2020 and 2022. All patients were recognized as having refractory AOSD and were treated with oral baricitinib at a dosage of 4 mg once daily. A systemic score and prednisone dosage were used to evaluate the efficacy of baricitinib at months 1, 3, and 6 and at the last follow-up visit. The safety profiles were recorded and analysed at every assessment.
Results: Seven female patients with refractory AOSD received baricitinib. The median age was 31 (IQR 10) years. Treatment was terminated in one patient due to progressive macrophage activation syndrome (MAS). Others continued baricitinib treatment until the last assessment. The systemic score decreased significantly at 3 months (p = 0.0216), 6 months (p = 0.0007), and the last follow-up visit (p = 0.0007) compared with baseline. One month after the initiation of baricitinib, the rates of improvement in fever, rash, sore throat, and myalgia symptoms were 71.4% (5/7), 40% (2/5), 80% (4/5), and 66.7% (2/3), respectively. Five patients remained symptom-free at the last follow-up visit. In most patients, their laboratory values had returned to normal by the last follow-up visit. A significant reduction in the levels of C-reactive protein (CRP) (p = 0.0165) and ferritin (p = 0.0047) was observed at the last visit compared with baseline. The daily prednisolone dosage significantly decreased from 35.7 ± 15.1 mg/day at baseline to 8.8 ± 4.4 mg/day by month 6 (p = 0.0256), and it was 5.8 ± 4.7 mg/day at the last assessment (p = 0.0030). Leukopenia due to MAS was noted in one patient. Except for mild abnormalities in lipid parameters, no other severe adverse events occurred during follow-up.
Conclusions: Our findings suggest that baricitinib therapy could provide rapid and durable clinical and laboratory improvement in patients with refractory AOSD. Treatment seemed to be well tolerated by these patients. The long-term efficacy and safety of baricitinib therapy for AOSD should be assessed further in prospective controlled clinical trials in the future.
Trial registration: Trial registration number (TRN): ChiCTR2200061599. Date of registration: 29 June 2022 (retrospectively registered).
{"title":"Efficacy of Baricitinib in Patients with Refractory Adult-Onset Still's Disease.","authors":"Ziyi Sun, Rongqi Li, Yingai Wang, Feng Han, Wei Wei, Xin Li","doi":"10.1007/s40268-023-00417-7","DOIUrl":"https://doi.org/10.1007/s40268-023-00417-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Adult-onset Still's disease (AOSD) is an idiopathic systemic inflammatory disease of unknown aetiology. Some patients exhibit resistance to conventional treatment during long-term therapy. Janus kinase inhibitors (JAKinibs) may contribute to the improvement in AOSD symptoms via the JAK-signal transducer and activator of transcription (STAT) pathway. We aimed to explore the efficacy and safety of baricitinib in patients with refractory AOSD.</p><p><strong>Methods: </strong>Patients were enrolled if they fulfilled the Yamaguchi AOSD classification criteria in China between 2020 and 2022. All patients were recognized as having refractory AOSD and were treated with oral baricitinib at a dosage of 4 mg once daily. A systemic score and prednisone dosage were used to evaluate the efficacy of baricitinib at months 1, 3, and 6 and at the last follow-up visit. The safety profiles were recorded and analysed at every assessment.</p><p><strong>Results: </strong>Seven female patients with refractory AOSD received baricitinib. The median age was 31 (IQR 10) years. Treatment was terminated in one patient due to progressive macrophage activation syndrome (MAS). Others continued baricitinib treatment until the last assessment. The systemic score decreased significantly at 3 months (p = 0.0216), 6 months (p = 0.0007), and the last follow-up visit (p = 0.0007) compared with baseline. One month after the initiation of baricitinib, the rates of improvement in fever, rash, sore throat, and myalgia symptoms were 71.4% (5/7), 40% (2/5), 80% (4/5), and 66.7% (2/3), respectively. Five patients remained symptom-free at the last follow-up visit. In most patients, their laboratory values had returned to normal by the last follow-up visit. A significant reduction in the levels of C-reactive protein (CRP) (p = 0.0165) and ferritin (p = 0.0047) was observed at the last visit compared with baseline. The daily prednisolone dosage significantly decreased from 35.7 ± 15.1 mg/day at baseline to 8.8 ± 4.4 mg/day by month 6 (p = 0.0256), and it was 5.8 ± 4.7 mg/day at the last assessment (p = 0.0030). Leukopenia due to MAS was noted in one patient. Except for mild abnormalities in lipid parameters, no other severe adverse events occurred during follow-up.</p><p><strong>Conclusions: </strong>Our findings suggest that baricitinib therapy could provide rapid and durable clinical and laboratory improvement in patients with refractory AOSD. Treatment seemed to be well tolerated by these patients. The long-term efficacy and safety of baricitinib therapy for AOSD should be assessed further in prospective controlled clinical trials in the future.</p><p><strong>Trial registration: </strong>Trial registration number (TRN): ChiCTR2200061599. Date of registration: 29 June 2022 (retrospectively registered).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/44/8b/40268_2023_Article_417.PMC10293510.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9705900","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}
Pub Date : 2023-06-01Epub Date: 2023-06-15DOI: 10.1007/s40268-023-00425-7
Paula Saz-Leal, Laura Zamorano-Domínguez, Jesús Frías, Pedro Guerra, Marc Saura-Valls, Ramón Roca-Juanes, Joaquín Nebot-Troyano, Eva García-Aguilar, Tatiana Vilchez, Katia Urso
Background: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules.
Objectives: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo.
Methods: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug.
Results: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h.
Conclusion: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.
{"title":"Bioavailability of Cariban<sup>®</sup> Capsules: A Modified-Release Fixed-Dose Combination of Doxylamine and Pyridoxine to Relieve Nausea and Vomiting During Pregnancy.","authors":"Paula Saz-Leal, Laura Zamorano-Domínguez, Jesús Frías, Pedro Guerra, Marc Saura-Valls, Ramón Roca-Juanes, Joaquín Nebot-Troyano, Eva García-Aguilar, Tatiana Vilchez, Katia Urso","doi":"10.1007/s40268-023-00425-7","DOIUrl":"10.1007/s40268-023-00425-7","url":null,"abstract":"<p><strong>Background: </strong>Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban<sup>®</sup> is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules.</p><p><strong>Objectives: </strong>In the present study, we aimed to characterize the bioavailability performance of Cariban<sup>®</sup> in vitro and in vivo.</p><p><strong>Methods: </strong>An in vitro dissolution test was performed to evaluate the release profile of Cariban<sup>®</sup>, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban<sup>®</sup> administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug.</p><p><strong>Results: </strong>Cariban<sup>®</sup> capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h.</p><p><strong>Conclusion: </strong>Cariban<sup>®</sup> behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/42/40268_2023_Article_425.PMC10293548.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10084391","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}
Pub Date : 2023-06-01DOI: 10.1007/s40268-023-00415-9
Raphael Allgaier, Arne Kandulski, Karsten Gülow, Lars Maier, Martina Müller, Hauke Christian Tews
Background and objective: Metamizole is a non-opioid ampyrone sulfonate compound with potent analgesic, antipyretic, and spasmolytic effects. Agranulocytosis is a rare life-threatening complication of metamizole.
Case: Here, we present the case of a 62-year-old patient who developed agranulocytosis as well as hemolysis after a single administration of metamizole.
Conclusion: This case illustrates the inherent allergic potential of metamizole and its effects on different hematopoietic cell types.
{"title":"Case Report: Simultaneously Induced Neutropenia and Hemolysis After a Single Metamizole Dose.","authors":"Raphael Allgaier, Arne Kandulski, Karsten Gülow, Lars Maier, Martina Müller, Hauke Christian Tews","doi":"10.1007/s40268-023-00415-9","DOIUrl":"https://doi.org/10.1007/s40268-023-00415-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Metamizole is a non-opioid ampyrone sulfonate compound with potent analgesic, antipyretic, and spasmolytic effects. Agranulocytosis is a rare life-threatening complication of metamizole.</p><p><strong>Case: </strong>Here, we present the case of a 62-year-old patient who developed agranulocytosis as well as hemolysis after a single administration of metamizole.</p><p><strong>Conclusion: </strong>This case illustrates the inherent allergic potential of metamizole and its effects on different hematopoietic cell types.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/47/97/40268_2023_Article_415.PMC10293139.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082156","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}
Background and objective: For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC.
Methods: Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy.
Results: In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%.
Conclusions: These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.
Clinical trial registration: ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.
{"title":"A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma.","authors":"Takuji Okusaka, Manabu Morimoto, Yuichiro Eguchi, Shinichiro Nakamura, Shuichi Iino, Rie Kageyama","doi":"10.1007/s40268-023-00416-8","DOIUrl":"10.1007/s40268-023-00416-8","url":null,"abstract":"<p><strong>Background and objective: </strong>For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC.</p><p><strong>Methods: </strong>Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy.</p><p><strong>Results: </strong>In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%.</p><p><strong>Conclusions: </strong>These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9b/41/40268_2023_Article_416.PMC10293504.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9704732","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}
Pub Date : 2023-06-01DOI: 10.1007/s40268-023-00418-6
Zhao-Xin Wu, Chen-Jing Wang, Ping Shi, Yan-Ping Liu, Ting Li, Fei-Fei Sun, Yao Fu, Xiao-Meng Gao, Ya-Ping Ma, Yu Cao
Background and objective: Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioequivalence and pharmacokinetics of the reference and test formulations of abiraterone acetate tablets in healthy Chinese volunteers.
Methods: A single-center, open, single-dose, randomized, three-period, three-sequence, semi-repeat (only repeated reference formulations), and reference formulation-corrected fasting reference-scaled average bioequivalence test was conducted in 36 healthy volunteers included in this study. Volunteers were randomly assigned to one of three groups in a 1:1:1 ratio. There was a minimum 7-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of abiraterone acetate tablets was determined by liquid chromatography-tandem mass spectrometry, and adverse events were recorded.
Results: Under fasting conditions, the maximum plasma concentration (Cmax) was 27.02 ± 14.21 ng/mL, area under the concentration-time curve from time zero to time t (AUCt) was 125.30 ± 82.41 h·ng/mL, and AUC from time zero to infinity (AUC∞) was 133.70 ± 83.99 h·ng/mL. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of AUCt and AUC∞ were in the range of 0.8000-1.2500, and the coefficient of variation (CVWR) of Cmax was more than 30%. The Critbound result was - 0.0522, and the GMR was between 0.8000 and 1.2500.
Conclusion: Both test and reference formulations of abiraterone acetate tablets were bioequivalent in healthy Chinese subjects under fasting conditions.
{"title":"Pharmacokinetics and Bioequivalence of Abiraterone Acetate Tablets in Healthy Chinese Volunteers: An Open, Randomized, Single-Dose, Three-Period, Three-Sequence Crossover Study.","authors":"Zhao-Xin Wu, Chen-Jing Wang, Ping Shi, Yan-Ping Liu, Ting Li, Fei-Fei Sun, Yao Fu, Xiao-Meng Gao, Ya-Ping Ma, Yu Cao","doi":"10.1007/s40268-023-00418-6","DOIUrl":"https://doi.org/10.1007/s40268-023-00418-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioequivalence and pharmacokinetics of the reference and test formulations of abiraterone acetate tablets in healthy Chinese volunteers.</p><p><strong>Methods: </strong>A single-center, open, single-dose, randomized, three-period, three-sequence, semi-repeat (only repeated reference formulations), and reference formulation-corrected fasting reference-scaled average bioequivalence test was conducted in 36 healthy volunteers included in this study. Volunteers were randomly assigned to one of three groups in a 1:1:1 ratio. There was a minimum 7-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of abiraterone acetate tablets was determined by liquid chromatography-tandem mass spectrometry, and adverse events were recorded.</p><p><strong>Results: </strong>Under fasting conditions, the maximum plasma concentration (C<sub>max</sub>) was 27.02 ± 14.21 ng/mL, area under the concentration-time curve from time zero to time t (AUC<sub>t</sub>) was 125.30 ± 82.41 h·ng/mL, and AUC from time zero to infinity (AUC<sub>∞</sub>) was 133.70 ± 83.99 h·ng/mL. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of AUC<sub>t</sub> and AUC<sub>∞</sub> were in the range of 0.8000-1.2500, and the coefficient of variation (CV<sub>WR</sub>) of C<sub>max</sub> was more than 30%. The Critbound result was - 0.0522, and the GMR was between 0.8000 and 1.2500.</p><p><strong>Conclusion: </strong>Both test and reference formulations of abiraterone acetate tablets were bioequivalent in healthy Chinese subjects under fasting conditions.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier NCT04863105, registered 26 April 2021-retrospectively registered ( https://register.</p><p><strong>Clinicaltrials: </strong>gov/prs/app/action/SelectProtocol?sid=S000ARAA&selectaction=Edit&uid=U00050YQ&ts=2&cx=-vbtjri.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/10/21/40268_2023_Article_418.PMC10293147.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9708866","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}