Drugs in Research & Development最新文献

{"title":"Efficacy and Safety of Apatinib in Patients with Recurrent Glioblastoma.","authors":"Hao Lin,&nbsp;Xinli Zhou,&nbsp;Xiaofang Sheng,&nbsp;Xiaohua Liang","doi":"10.1007/s40268-023-00429-3","DOIUrl":"https://doi.org/10.1007/s40268-023-00429-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Glioblastoma is a cranial malignant tumor with a high recurrence rate after surgery and a poor response to chemoradiotherapy. Bevacizumab has demonstrated efficacy in the treatment of glioblastoma by inhibiting vascular endothelial growth factor, but the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors varies in treating glioblastoma. This single-arm prospective study aimed to explore the efficacy and safety of the vascular endothelial growth factor receptor tyrosine kinase inhibitor apatinib in treating recurrent glioblastoma after chemoradiotherapy.</p><p><strong>Methods: </strong>A total of 15 patients with recurrent glioblastoma (2016 World Health Organization grade IV) after chemoradiotherapy were enrolled in this study from September 2017 to September 2019 and treated with apatinib 500 mg once daily. Responses were evaluated according to the Response Assessment in Neuro-Oncology criteria, and adverse events were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.</p><p><strong>Results: </strong>The overall response rate was 33.3%, and the disease control rate was 66.6%. The median progression-free survival was 2 months, and the median overall survival was 6.5 months. The apatinib dose was adjusted in seven patients because of adverse events (46.6%). The most common adverse events were thrombocytopenia (53.3%), asthenia (40%), and hand-foot syndrome (33.3%).</p><p><strong>Conclusions: </strong>Apatinib might be effective in treating recurrent glioblastoma after chemoradiotherapy in terms of the overall response rate, but the efficacy is not durable and the clinical benefit is limited. The adverse effects of apatinib were acceptable.</p><p><strong>Clinical trial registration: </strong>ChiCTR-ONC-17013098, date of registration: 24 October, 2017.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"239-244"},"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/35/74/40268_2023_Article_429.PMC10439071.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10035581","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}

{"title":"Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.","authors":"Jan Hilpert, Esther Groettrup-Wolfers, Hristiyan Kosturski, Laura Bennett, Catriona L K Barnes, Kerstin Gude, Isabella Gashaw, Stefanie Reif, Thomas Steger-Hartmann, Christian Scheerans, Alexander Solms, Antje Rottmann, Guangping Mao, Charles Chapron","doi":"10.1007/s40268-023-00427-5","DOIUrl":"10.1007/s40268-023-00427-5","url":null,"abstract":"<p><strong>Introduction: </strong>BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa.</p><p><strong>Objective: </strong>This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period.</p><p><strong>Methods: </strong>Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated.</p><p><strong>Results: </strong>Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed.</p><p><strong>Conclusions: </strong>The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required.</p><p><strong>Clinical trial registration: </strong>NCT03373422 (date registered: November 23, 2017).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"221-237"},"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/58/73/40268_2023_Article_427.PMC10439066.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10035545","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}

{"title":"Bioavailability of Melatonin after Administration of an Oral Prolonged-Release Tablet and an Immediate-Release Sublingual Spray in Healthy Male Volunteers.","authors":"Samira Ait Abdellah,&nbsp;Véronique Raverot,&nbsp;Caroline Gal,&nbsp;Isabelle Guinobert,&nbsp;Valérie Bardot,&nbsp;Claude Blondeau,&nbsp;Bruno Claustrat","doi":"10.1007/s40268-023-00431-9","DOIUrl":"https://doi.org/10.1007/s40268-023-00431-9","url":null,"abstract":"<p><strong>Background: </strong>The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism.</p><p><strong>Objective: </strong>The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin.</p><p><strong>Methods: </strong>In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters.</p><p><strong>Results: </strong>The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (C_max: 2332 ± 950 pg/mL; T_max: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (C_max: 1151 ± 565 pg/mL; T_max: 64.2 ± 44.2 min; p < 0.001 for comparison of C_max and T_max) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC_0-540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated.</p><p><strong>Conclusions: </strong>The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.</p><p><strong>Trial registry: </strong>Registration number: NCT04574141.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"257-265"},"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/ad/83/40268_2023_Article_431.PMC10439092.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10044508","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}

{"title":"Biochemical Characterization of a New 10% IVIG Preparation [IgG Next Generation (BT595)/Yimmugo^®] Obtained from a Manufacturing Process Preserving IgA/IgM Potential of Human Plasma.","authors":"Christian Duellberg,&nbsp;Achim Hannappel,&nbsp;Steffen Kistner,&nbsp;Oliver Maneg","doi":"10.1007/s40268-023-00430-w","DOIUrl":"https://doi.org/10.1007/s40268-023-00430-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Human plasma is used for the generation of several life-saving drugs and contains valuable antibodies from the immunoglobulin classes IgG, IgM and IgA. Purified intravenous IgG solutions (IVIGs) form the majority of plasma-derived medicine to treat patients with various forms of immunodeficiencies. In conventional IVIG manufacturing processes, immunoglobulin classes IgM and IgA are often discarded as contaminants, but these antibody classes have been proven to be effective for the treatment of acute bacterial infections. Considering the increase in demand for human plasma-derived products and the ethical value of the raw material, a more resource-saving usage of human plasma is needed. Intensive research over the last decades showed that adverse reactions to IVIGs depend on the presence of thrombogenic factors, partially unfolded proteins, non-specific activation of the complement system, and blood group specific antibodies. Therefore, new IVIG preparations with reduced risks of adverse reactions are desirable.</p><p><strong>Method: </strong>A new manufacturing process that yields two biologics was established and quality attributes of the new IVIG solution (Yimmugo^®) obtained from this process are presented.</p><p><strong>Results: </strong>Here, we provide a biochemical characterization of Yimmugo^®, a new 10% IVIG preparation. It is derived from human blood plasma by a combined manufacturing process, where IgM and IgA are retained for the production of a new biologic (trimodulin, currently under investigation in phase III clinical trials). Several improvements have been implemented in the manufacturing of Yimmugo^® to reduce the risk of adverse reactions. Gentle and efficient mixing by vibration (called \"vibromixing\") during a process step where proteins are at risk to aggregate was implemented to potentially minimize protein damage. In addition, a dedicated process step for the removal of the complement system activator properdin was implemented, which resulted in very low anticomplementary activity levels. The absence of measurable thrombogenic activity in combination with a very high degree of functional monomeric antibodies predict excellent efficacy and tolerability.</p><p><strong>Conclusion: </strong>Yimmugo^® constitutes a new high quality IVIG preparation derived from a novel manufacturing process that takes advantage of the full therapeutic immunoglobulin potential of human plasma.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"245-255"},"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/59/c7/40268_2023_Article_430.PMC10439088.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10042548","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}

{"title":"Physicochemical and Functional Similarity Assessment Between Proposed Bevacizumab Biosimilar BAT1706 and Reference Bevacizumab.","authors":"Di Cao,&nbsp;Chunping Deng,&nbsp;Guangying Wang,&nbsp;Xiong Mei,&nbsp;Jianhua Xie,&nbsp;Yuanmei Liu,&nbsp;Yujie Liu,&nbsp;Yili Yang,&nbsp;Shengfeng Li,&nbsp;Cuihua Liu","doi":"10.1007/s40268-023-00432-8","DOIUrl":"https://doi.org/10.1007/s40268-023-00432-8","url":null,"abstract":"<p><strong>Background: </strong>BAT1706 is a proposed biosimilar of bevacizumab, a vascular endothelial growth factor A (VEGF-A)-targeting biologic used to treat several different cancers, including metastatic colorectal cancer. A comprehensive physicochemical and functional similarity assessment is a key component of demonstrating biosimilarity between a reference biologic and a proposed biosimilar. Here we report the physicochemical and functional similarity of BAT1706 and reference bevacizumab sourced from both the United States (US-bevacizumab) and the European Union (EU-bevacizumab).</p><p><strong>Method: </strong>A large range of product attributes, including primary and higher order structure, post-translational modifications, purity, stability, and potency, were characterized for BAT1706 and EU/US-bevacizumab using sensitive state-of-the-art analytical techniques. Up to 18 lots of US- and 29 lots of EU-bevacizumab, and 10 unique drug substance lots of BAT1706, were assessed.</p><p><strong>Result: </strong>BAT1706 was shown to have an identical amino acid sequence and an indistinguishable higher-order structure compared with EU/US-bevacizumab. BAT1706 and EU/US-bevacizumab also exhibited similar post-translational modifications, glycan profiles, and charge variants. Potency, assessed using a wide range of bioassays, was also shown to be comparable between BAT1706 and EU/US-bevacizumab, with statistical equivalence demonstrated for VEGF-A binding and neutralizing activity.</p><p><strong>Conclusion: </strong>Overall, this extensive comparability exercise demonstrated BAT1706 to match EU/US-bevacizumab in terms of all physicochemical and functional attributes assessed.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"267-288"},"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/d5/eb/40268_2023_Article_432.PMC10439073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10419756","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}

{"title":"Predictive Potential of Acido-Basic Properties, Solubility and Food on Bioequivalence Study Outcome: Analysis of 128 Studies.","authors":"Dejan Krajcar,&nbsp;Rebeka Jereb,&nbsp;Igor Legen,&nbsp;Jerneja Opara,&nbsp;Iztok Grabnar","doi":"10.1007/s40268-023-00426-6","DOIUrl":"https://doi.org/10.1007/s40268-023-00426-6","url":null,"abstract":"<p><strong>Background and objectives: </strong>Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome.</p><p><strong>Methods: </strong>We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs. Bioequivalence study conditions and acido-basic/solubility characteristics of APIs were collected and their predictive potential on the study outcome was assessed using a set of univariate statistical analyses.</p><p><strong>Results: </strong>There was no difference in bioequivalence rate between fasting and fed conditions. The highest proportion of non-bioequivalent studies was for weak acids (10/19 cases, 53%) and neutral APIs (23/95 cases, 24%). Lower non-bioequivalence occurrence was observed for weak bases (1/15 cases, 7%) and amphoteric APIs (0/16 cases, 0%). The median dose numbers at pH 1.2 and pH 3 were higher and the most basic acid dissociation constant (pKa) was lower in the non-bioequivalent group of studies. Additionally, APIs with low calculated effective permeability (cPeff) or low calculated lipophilicity (clogP) had lower non-bioequivalence occurrence. Results of the subgroup analysis of studies under fasting conditions were similar as for the whole dataset.</p><p><strong>Conclusion: </strong>Our results indicate that acido-basic properties of API should be considered in bioequivalence risk assessment and reveal which physico-chemical parameters are most relevant for the development of bioequivalence risk assessment tools for immediate-release products.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"211-220"},"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/df/91/40268_2023_Article_426.PMC10439087.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10034996","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}

{"title":"Comparative Efficacy of Different Drugs for the Treatment of Dilated Cardiomyopathy: A Systematic Review and Network Meta-analysis.","authors":"Xinyu Tong, Lijuan Shen, Xiaomin Zhou, Yudan Wang, Sheng Chang, Shu Lu","doi":"10.1007/s40268-023-00435-5","DOIUrl":"10.1007/s40268-023-00435-5","url":null,"abstract":"<p><strong>Background and objective: </strong>At present, the therapies of dilated cardiomyopathy concentrated on the symptoms of heart failure and related complications. The study is to evaluate the clinical efficacy of a combination of various conventional and adjuvant drugs in treating dilated cardiomyopathy via network meta-analysis.</p><p><strong>Methods: </strong>The study was reported according to the PRISMA 2020 statement. From inception through 27 June 2022, the PubMed, Embase, Cochrane library, and Web of Science databases were searched for randomized controlled trials on medicines for treating dilated cardiomyopathy. The quality of the included studies was evaluated according to the Cochrane risk of bias assessment. R4.1.3 and Revman5.3 software were used for analysis.</p><p><strong>Results: </strong>There were 52 randomized controlled trials in this study, with a total of 25 medications and a sample size of 3048 cases. The network meta-analysis found that carvedilol, verapamil, and trimetazidine were the top three medicines for improving left ventricular ejection fraction (LVEF). Ivabradine, bucindolol, and verapamil were the top 3 drugs for improving left ventricular end-diastolic dimension (LVEDD). Ivabradine, L-thyroxine, and atorvastatin were the top 3 drugs for improving left ventricular end-systolic dimension (LVESD). Trimetazidine, pentoxifylline, and bucindolol were the top 3 drugs for improving the New York Heart Association classification (NYHA) cardiac function score. Ivabradine, carvedilol, and bucindolol were the top 3 drugs for reducing heart rate (HR).</p><p><strong>Conclusion: </strong>A combination of different medications and conventional therapy may increase the clinical effectiveness of treating dilated cardiomyopathy. Beta-blockers, especially carvedilol, can improve ventricular remodeling, cardiac function, and clinical efficacy in patients with dilated cardiomyopathy (DCM). Hence, they can be used if patients tolerate them. If LVEF and HR do not meet the standard, ivabradine can also be used in combination with other treatments. However, since the quality and number of studies in our research were limited, large sample size, multi-center, and high-quality randomized controlled trials are required to corroborate our findings.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"23 3","pages":"197-210"},"PeriodicalIF":2.2,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f4/d5/40268_2023_Article_435.PMC10439079.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10048252","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}

{"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,&nbsp;Jinmi Kim,&nbsp;Youngmi Han,&nbsp;Kyuhyun Hwang,&nbsp;Byungkwan Choi,&nbsp;Tae Ryom Oh,&nbsp;Il Young Kim,&nbsp;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":"23 3","pages":"289-296"},"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}

{"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":"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":"23 2","pages":"129-140"},"PeriodicalIF":2.1,"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}

{"title":"Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.","authors":"Céline Gérard,&nbsp;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":"23 2","pages":"77-92"},"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}