Pub Date : 2025-01-01DOI: 10.1016/j.clinthera.2024.10.016
Amita Datta-Mannan PhD , Brian Moser MS , Wen Xu PhD , Kimberley Jackson PhD , Jennifer Witcher PhD , April W. Armstrong MD MPH , Andrew Blauvelt MD, MBA , Peter A. Lio MD
Purpose
Lebrikizumab is a novel, high-affinity immunoglobulin G4 monoclonal antibody that targets interleukin-13, a central mediator in atopic dermatitis (AD). In previous studies in patients with moderate-to-severe AD, lebrikizumab, administered subcutaneously via a prefilled syringe with a needle safety device (PFS-NSD), demonstrated rapid and durable dose-dependent efficacy. We assessed the pharmacokinetics and safety of lebrikizumab using either a PFS-NSD or an investigational autoinjector. Such devices have been developed to make self-injection easier for patients, thus increasing adherence over long treatment durations.
Methods
The current study compared the pharmacokinetics and safety of 250 mg lebrikizumab (2 mL of a 125-mg/mL solution) administered subcutaneously at 1 of 3 different injection sites (abdomen, arm, or thigh) in 241 healthy participants using either a PFS-NSD (N = 122) or an investigational autoinjector (N = 119).
Findings
Statistical analysis demonstrated 2-mL (125 mg/mL) lebrikizumab autoinjector was bioequivalent to 2-mL (125 mg/mL) lebrikizumab PFS-NSD as 90% CIs of the geometric least squares means ratios for lebrikizumab AUC(0-tlast), AUC(0-∞), and Cmax were all completely contained within the prespecified confidence limits of 0.80 and 1.25. Injection-site location did not appear to impact lebrikizumab systemic exposure for either device. Lebrikizumab was well tolerated with no SAEs reported after PFS-NSD or autoinjector administration.
Implications
Bioequivalence was demonstrated between 250 mg lebrikizumab 2-mL autoinjector and prefilled syringe devices, showing both devices to be suitable options for administering lebrikizumab.
{"title":"Evaluation of Pharmacokinetics of Lebrikizumab in Healthy Individuals After Subcutaneous Administration Using a Prefilled Syringe or Autoinjector in a Phase 1 Randomized Study","authors":"Amita Datta-Mannan PhD , Brian Moser MS , Wen Xu PhD , Kimberley Jackson PhD , Jennifer Witcher PhD , April W. Armstrong MD MPH , Andrew Blauvelt MD, MBA , Peter A. Lio MD","doi":"10.1016/j.clinthera.2024.10.016","DOIUrl":"10.1016/j.clinthera.2024.10.016","url":null,"abstract":"<div><h3>Purpose</h3><div>Lebrikizumab is a novel, high-affinity immunoglobulin G4 monoclonal antibody that targets interleukin-13, a central mediator in atopic dermatitis (AD). In previous studies in patients with moderate-to-severe AD, lebrikizumab, administered subcutaneously via a prefilled syringe with a needle safety device (PFS-NSD), demonstrated rapid and durable dose-dependent efficacy. We assessed the pharmacokinetics and safety of lebrikizumab using either a PFS-NSD or an investigational autoinjector. Such devices have been developed to make self-injection easier for patients, thus increasing adherence over long treatment durations.</div></div><div><h3>Methods</h3><div>The current study compared the pharmacokinetics and safety of 250 mg lebrikizumab (2 mL of a 125-mg/mL solution) administered subcutaneously at 1 of 3 different injection sites (abdomen, arm, or thigh) in 241 healthy participants using either a PFS-NSD (<em>N</em> = 122) or an investigational autoinjector (<em>N</em> = 119).</div></div><div><h3>Findings</h3><div>Statistical analysis demonstrated 2-mL (125 mg/mL) lebrikizumab autoinjector was bioequivalent to 2-mL (125 mg/mL) lebrikizumab PFS-NSD as 90% CIs of the geometric least squares means ratios for lebrikizumab AUC<sub>(0-tlast)</sub>, AUC<sub>(0-∞)</sub>, and C<sub>max</sub> were all completely contained within the prespecified confidence limits of 0.80 and 1.25. Injection-site location did not appear to impact lebrikizumab systemic exposure for either device. Lebrikizumab was well tolerated with no SAEs reported after PFS-NSD or autoinjector administration.</div></div><div><h3>Implications</h3><div>Bioequivalence was demonstrated between 250 mg lebrikizumab 2-mL autoinjector and prefilled syringe devices, showing both devices to be suitable options for administering lebrikizumab.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 55-61"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784300","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 : 2025-01-01DOI: 10.1016/j.clinthera.2024.11.005
M. Marassi MD , G.P. Fadini MD, PhD
Purpose
Oral semaglutide is the first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) available for type 2 diabetes mellitus (T2DM) management, whose effectiveness and tolerability have extensively been demonstrated in the PIONEER clinical trial program. Nevertheless, data from real-world are crucial to evaluate treatment performance under routine care. The aim of this narrative review is to summarize available evidence regarding real-world utilization patterns of oral semaglutide, and discuss efficacy, safety, and dosing regimen data in routine scenarios.
Methods
We searched PubMed for real-world studies evaluating oral semaglutide up to August 2024, and specific search terms were: “oral semaglutide,” and “real-world studies” or “observational studies” or “retrospective studies”.
Findings
19 real-world studies were included in the narrative review. In real-world settings, oral semaglutide provided significant glycemic (median HbA1c reduction at 6 months of 1%) and weight (median body weight reduction of 2 to 3 kg) benefits across the spectrum of T2DM, aligning with pre-clinical evidence from the PIONEER program. No new tolerability and safety issue has emerged from oral semaglutide administration in routine clinical practice.
Implications
Oral semaglutide constitutes an effective and safe option for T2DM management, and its increased acceptance has the potential to favor the early introduction of GLP-1RAs along the disease course. Nevertheless, continuous evaluation of real-world data is critical to better define the optimal positioning of oral semaglutide along T2DM trajectory and fully exploit its potential in everyday clinical practice.
{"title":"Real-world Evidence on Oral Semaglutide for the Management of Type 2 Diabetes. A Narrative Review for Clinical Practice","authors":"M. Marassi MD , G.P. Fadini MD, PhD","doi":"10.1016/j.clinthera.2024.11.005","DOIUrl":"10.1016/j.clinthera.2024.11.005","url":null,"abstract":"<div><h3>Purpose</h3><div>Oral semaglutide is the first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) available for type 2 diabetes mellitus (T2DM) management, whose effectiveness and tolerability have extensively been demonstrated in the PIONEER clinical trial program. Nevertheless, data from real-world are crucial to evaluate treatment performance under routine care. The aim of this narrative review is to summarize available evidence regarding real-world utilization patterns of oral semaglutide, and discuss efficacy, safety, and dosing regimen data in routine scenarios.</div></div><div><h3>Methods</h3><div>We searched PubMed for real-world studies evaluating oral semaglutide up to August 2024, and specific search terms were: “oral semaglutide,” and “real-world studies” or “observational studies” or “retrospective studies”.</div></div><div><h3>Findings</h3><div>19 real-world studies were included in the narrative review. In real-world settings, oral semaglutide provided significant glycemic (median HbA1c reduction at 6 months of 1%) and weight (median body weight reduction of 2 to 3 kg) benefits across the spectrum of T2DM, aligning with pre-clinical evidence from the PIONEER program. No new tolerability and safety issue has emerged from oral semaglutide administration in routine clinical practice.</div></div><div><h3>Implications</h3><div>Oral semaglutide constitutes an effective and safe option for T2DM management, and its increased acceptance has the potential to favor the early introduction of GLP-1RAs along the disease course. Nevertheless, continuous evaluation of real-world data is critical to better define the optimal positioning of oral semaglutide along T2DM trajectory and fully exploit its potential in everyday clinical practice.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 102-110"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767057","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 : 2025-01-01DOI: 10.1016/j.clinthera.2024.09.024
Chuka Udeze PharmD, MS , Nelly F. Ly PharmD, MScRes , Fiona C. Ingleby PhD , Sophia D. Fleming MSc , Sarah C. Conner PhD, MPH , Jo Howard MB BChir, MRCP, FRCPath , Nanxin Li PhD, MBA , Farrukh Shah MBBS, FRCP, FRCPath, MD
Purpose
Patients with transfusion-dependent β-thalassemia (TDT) have reduced levels of β-globin, leading to ineffective erythropoiesis and iron overload. Patients with TDT depend on regular red blood cell transfusions (RBCTs) and iron chelation therapy for survival and management of disease- and treatment-related clinical complications. This study describes the clinical and economic burden in patients with TDT in England.
Methods
This longitudinal, retrospective study linked the Clinical Practice Research Datalink (CPRD) database with secondary care data from the Hospital Episode Statistics database to identify patients with a diagnosis of β-thalassemia between July 1, 2008, and June 30, 2018. Included patients had a diagnosis of β-thalassemia prior to the index date, ≥8 RBCTs per year for ≥2 consecutive years, and ≥1 year of follow-up data available from the index date. Each eligible patient was exact matched with up to 5 controls in the CPRD. Proportions of deaths and rates of mortality, acute and chronic complications, and healthcare resource utilization (HCRU) were calculated during the follow-up period.
Findings
Of 11,359 identified patients with β-thalassemia, 237 patients with TDT met the eligibility criteria and were matched with 1184 controls. The mean age at the index date was approximately 25 years in the patient and control groups. The proportion of deaths (7.17% vs 1.18%; P < 0.05) and mortality rate (1.19 deaths per 100 person-years vs 0.20 deaths per 100 person-years) were higher among patients with TDT compared to controls. Endocrine complications and bone disorders were the most prevalent complications among patients with TDT (58.23%) and included osteoporosis (29.11%), diabetes mellitus (28.27%), and hypopituitarism (28.27%). Patients with TDT had a mean of 13.62 RBCTs per patient per year (PPPY). HCRU was substantially higher among patients with TDT, wherein patients with TDT had higher rates of prescriptions recorded in primary care (24.09 vs 8.61 PPPY), outpatient visits (16.69 vs 1.31 PPPY), and inpatient hospitalizations (17.41 vs 0.24 PPPY) than controls. Inpatient hospitalizations were primarily <1 day, with 16.62 events PPPY lasting <1 day and 0.79 events PPPY lasting ≥1 day. Patients with TDT aged ≥18 years had increased rates of mortality, clinical complications, and HCRU than those aged <18 years.
Implications
Patients with TDT in England have higher mortality than matched controls, substantial disease-related clinical complications, and substantial HCRU. High mortality and clinical complications highlight the need for additional innovative therapies for TDT.
{"title":"Clinical Burden and Healthcare Resource Utilization Associated With Managing Transfusion-dependent β-Thalassemia in England","authors":"Chuka Udeze PharmD, MS , Nelly F. Ly PharmD, MScRes , Fiona C. Ingleby PhD , Sophia D. Fleming MSc , Sarah C. Conner PhD, MPH , Jo Howard MB BChir, MRCP, FRCPath , Nanxin Li PhD, MBA , Farrukh Shah MBBS, FRCP, FRCPath, MD","doi":"10.1016/j.clinthera.2024.09.024","DOIUrl":"10.1016/j.clinthera.2024.09.024","url":null,"abstract":"<div><h3>Purpose</h3><div>Patients with transfusion-dependent <em>β</em>-thalassemia (TDT) have reduced levels of <em>β</em>-globin, leading to ineffective erythropoiesis and iron overload. Patients with TDT depend on regular red blood cell transfusions (RBCTs) and iron chelation therapy for survival and management of disease- and treatment-related clinical complications. This study describes the clinical and economic burden in patients with TDT in England.</div></div><div><h3>Methods</h3><div>This longitudinal, retrospective study linked the Clinical Practice Research Datalink (CPRD) database with secondary care data from the Hospital Episode Statistics database to identify patients with a diagnosis of <em>β</em>-thalassemia between July 1, 2008, and June 30, 2018. Included patients had a diagnosis of <em>β</em>-thalassemia prior to the index date, ≥8 RBCTs per year for ≥2 consecutive years, and ≥1 year of follow-up data available from the index date. Each eligible patient was exact matched with up to 5 controls in the CPRD. Proportions of deaths and rates of mortality, acute and chronic complications, and healthcare resource utilization (HCRU) were calculated during the follow-up period.</div></div><div><h3>Findings</h3><div>Of 11,359 identified patients with <em>β</em>-thalassemia, 237 patients with TDT met the eligibility criteria and were matched with 1184 controls. The mean age at the index date was approximately 25 years in the patient and control groups. The proportion of deaths (7.17% vs 1.18%; <em>P</em> < 0.05) and mortality rate (1.19 deaths per 100 person-years vs 0.20 deaths per 100 person-years) were higher among patients with TDT compared to controls. Endocrine complications and bone disorders were the most prevalent complications among patients with TDT (58.23%) and included osteoporosis (29.11%), diabetes mellitus (28.27%), and hypopituitarism (28.27%). Patients with TDT had a mean of 13.62 RBCTs per patient per year (PPPY). HCRU was substantially higher among patients with TDT, wherein patients with TDT had higher rates of prescriptions recorded in primary care (24.09 vs 8.61 PPPY), outpatient visits (16.69 vs 1.31 PPPY), and inpatient hospitalizations (17.41 vs 0.24 PPPY) than controls. Inpatient hospitalizations were primarily <1 day, with 16.62 events PPPY lasting <1 day and 0.79 events PPPY lasting ≥1 day. Patients with TDT aged ≥18 years had increased rates of mortality, clinical complications, and HCRU than those aged <18 years.</div></div><div><h3>Implications</h3><div>Patients with TDT in England have higher mortality than matched controls, substantial disease-related clinical complications, and substantial HCRU. High mortality and clinical complications highlight the need for additional innovative therapies for TDT.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 37-43"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564130","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 : 2025-01-01DOI: 10.1016/j.clinthera.2024.10.006
Xueting Xing , Weijie Ding , Yongzhe Tang , Jin Zhang , Yamin Liu , Junhong Ning , Jie Wang , Xiaoqing Zhang
Purpose
Docetaxel-based chemotherapy regimens (DBRs) are commonly used in the treatment of early-stage breast cancer (EBC). The prophylactic use of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been shown to reduce the incidence of neutropenia induced by DBRs. However, the clinical usage of PEG-rhG-CSF in EBC patients undergoing DBRs in China remains unclear.
Methods
This retrospective study was conducted in 137 EBC patients receiving DBRs from September 2022 to February 2024. We compared the incidence of chemotherapy-induced neutropenia (CIN) between patients who was treated with prophylactic PEG-rhG-CSF or not by complete blood counts, evaluating the effectiveness of PEG-rhG-CSF in preventing CIN. Prophylactic PEG-rhG-CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24–48 h following chemotherapy. Meanwhile, we also collected basic patient information, the area under time-concentration curve of docetaxel, and liver and kidney function indicators. Multivariate logistic regression and Receiver operating characteristic (ROC) curve analysis were employed to explore independent factors influencing neutropenia.
Findings
In this study, 87 of 137 EBC patients were administrated with prophylactic PEG-rhG-CSF, while 50 were not. Compared to patients who did not receive PEG-rhG-CSF, those who received prophylactic injections had a significantly lower incidence of grade 3–4 CIN (20% vs. 4.6%, P < 0.05). Higher body surface area (BSA), lower body mass index (BMI), elevated alanine aminotransferase (ALT), and nonprophylactic use of PEG-rhG-CSF were found to be positively correlated with CIN occurrence. ROC curve analysis indicated an area under the curve of 0.756 for predicting CIN in EBC patients when BSA was 1.66 m², BMI was 24.8 kg/m², and ALT was 41 U/L, with a sensitivity of 73.08% and specificity of 73.87%.
Implications
Prophylactic use of PEG-rhG-CSF significantly reduces the incidence of CIN, particularly grades 3 and 4. BSA, BMI, ALT, and PEG-rhG-CSF prophylaxis are independent influencing factors for the occurrence of neutropenia.
{"title":"The Efficacy Research of Prophylactic PEG-rhG-CSF in Preventing Neutropenia in Early-Stage Breast Cancer Patients Treated With Docetaxel-Based Chemotherapy: A Retrospective Analysis","authors":"Xueting Xing , Weijie Ding , Yongzhe Tang , Jin Zhang , Yamin Liu , Junhong Ning , Jie Wang , Xiaoqing Zhang","doi":"10.1016/j.clinthera.2024.10.006","DOIUrl":"10.1016/j.clinthera.2024.10.006","url":null,"abstract":"<div><h3>Purpose</h3><div>Docetaxel-based chemotherapy regimens (DBRs) are commonly used in the treatment of early-stage breast cancer (EBC). The prophylactic use of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been shown to reduce the incidence of neutropenia induced by DBRs. However, the clinical usage of PEG-rhG-CSF in EBC patients undergoing DBRs in China remains unclear.</div></div><div><h3>Methods</h3><div>This retrospective study was conducted in 137 EBC patients receiving DBRs from September 2022 to February 2024. We compared the incidence of chemotherapy-induced neutropenia (CIN) between patients who was treated with prophylactic PEG-rhG-CSF or not by complete blood counts, evaluating the effectiveness of PEG-rhG-CSF in preventing CIN. Prophylactic PEG-rhG-CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24–48 h following chemotherapy. Meanwhile, we also collected basic patient information, the area under time-concentration curve of docetaxel, and liver and kidney function indicators. Multivariate logistic regression and Receiver operating characteristic (ROC) curve analysis were employed to explore independent factors influencing neutropenia.</div></div><div><h3>Findings</h3><div>In this study, 87 of 137 EBC patients were administrated with prophylactic PEG-rhG-CSF, while 50 were not. Compared to patients who did not receive PEG-rhG-CSF, those who received prophylactic injections had a significantly lower incidence of grade 3–4 CIN (20% vs. 4.6%, <em>P</em> < 0.05). Higher body surface area (BSA), lower body mass index (BMI), elevated alanine aminotransferase (ALT), and nonprophylactic use of PEG-rhG-CSF were found to be positively correlated with CIN occurrence. ROC curve analysis indicated an area under the curve of 0.756 for predicting CIN in EBC patients when BSA was 1.66 m², BMI was 24.8 kg/m², and ALT was 41 U/L, with a sensitivity of 73.08% and specificity of 73.87%.</div></div><div><h3>Implications</h3><div>Prophylactic use of PEG-rhG-CSF significantly reduces the incidence of CIN, particularly grades 3 and 4. BSA, BMI, ALT, and PEG-rhG-CSF prophylaxis are independent influencing factors for the occurrence of neutropenia.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 21-28"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616382","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}
Increasing medical device usage raises concerns regarding unexpected, potentially life-threatening events that pose public health risks. Such events are reported to the Food and Drug Administration (FDA), and cataloged in the Manufacturer and User Facility Device Experience (MAUDE) database, a vital tool for post market surveillance that requires information of high quality and integrity, particularly concerning reporting sources.
Purpose
To analyze reporting behavior among different reporters, including manufacturers, distributors, and user facilities, by examining differences in reported factors, namely: (1) device types, (2) product problem attribution, and (3) selection of Device Problem Codes (DPCs) associated with the root causes of events.
Methods
Data spanning from 2005 to 2022 was retrieved from the MAUDE database using Python. Reports were grouped by reporter type and divided according to device type, and the reporter's indication of association with a product problem. Furthermore, events were classified by their respective DPCs, which were manually grouped into four categories: device issues, user issues, clinical issues, or unknown.
Findings
The analysis revealed significant variations among reporters across all examined aspects (P < 0.00001 in all comparisons according to the proportion test). Manufacturers predominantly focused on infusion pumps (10.1%) and Implant, Endosseous, Root-Form (IER) devices (7.6%), with a product problem indication rate of 29.2% in their reports. Device issues codes were the most frequently observed category in their reports, comprising 36.3%, followed by unknown codes (32%) and clinical codes (19.3%). Distributors, on the other hand, primarily reported on IER devices (89%) and exhibited the lowest product problem indication rate at 2.7%. Clinical issues codes predominated in their reports, constituting 85.7%, followed by unknown codes (6.7%). User facilities concentrated on intravascular sets (4.7%), Electrosurgical, Cutting & Coagulation & Accessories (4.2%), and Ventricular (Assist) Bypass (4.1%). Remarkably, their product problem indication rate was the highest at 56.7%. They predominantly reported device issues codes (54.3%), followed by use codes (30.8%), and unknown codes (11.4%)
Implications
The notable variation among different reporters underscores the importance of incorporating diverse sources when analyzing the database, particularly in cases where majority of reports originate from manufacturers. Decision-makers must approach database information comprehensively, considering data sources and diverse perspectives to inform regulatory decisions effectively. Developing strategies that encourage various reporters to contribute their unique and complementary viewpoints is advisable.
{"title":"Understanding Variation Among Medical Device Reporting Sources: A Study of the MAUDE Database","authors":"Meital Mishali , Nadav Sheffer , Oren Mishali , Maya Negev","doi":"10.1016/j.clinthera.2024.10.004","DOIUrl":"10.1016/j.clinthera.2024.10.004","url":null,"abstract":"<div><h3>Background</h3><div>Increasing medical device usage raises concerns regarding unexpected, potentially life-threatening events that pose public health risks. Such events are reported to the Food and Drug Administration (FDA), and cataloged in the Manufacturer and User Facility Device Experience (MAUDE) database, a vital tool for post market surveillance that requires information of high quality and integrity, particularly concerning reporting sources.</div></div><div><h3>Purpose</h3><div>To analyze reporting behavior among different reporters, including manufacturers, distributors, and user facilities, by examining differences in reported factors, namely: (1) device types, (2) product problem attribution, and (3) selection of Device Problem Codes (DPCs) associated with the root causes of events.</div></div><div><h3>Methods</h3><div>Data spanning from 2005 to 2022 was retrieved from the MAUDE database using Python. Reports were grouped by reporter type and divided according to device type, and the reporter's indication of association with a product problem. Furthermore, events were classified by their respective DPCs, which were manually grouped into four categories: device issues, user issues, clinical issues, or unknown.</div></div><div><h3>Findings</h3><div>The analysis revealed significant variations among reporters across all examined aspects (<em>P</em> < 0.00001 in all comparisons according to the proportion test). Manufacturers predominantly focused on infusion pumps (10.1%) and Implant, Endosseous, Root-Form (IER) devices (7.6%), with a product problem indication rate of 29.2% in their reports. Device issues codes were the most frequently observed category in their reports, comprising 36.3%, followed by unknown codes (32%) and clinical codes (19.3%). Distributors, on the other hand, primarily reported on IER devices (89%) and exhibited the lowest product problem indication rate at 2.7%. Clinical issues codes predominated in their reports, constituting 85.7%, followed by unknown codes (6.7%). User facilities concentrated on intravascular sets (4.7%), Electrosurgical, Cutting & Coagulation & Accessories (4.2%), and Ventricular (Assist) Bypass (4.1%). Remarkably, their product problem indication rate was the highest at 56.7%. They predominantly reported device issues codes (54.3%), followed by use codes (30.8%), and unknown codes (11.4%)</div></div><div><h3>Implications</h3><div>The notable variation among different reporters underscores the importance of incorporating diverse sources when analyzing the database, particularly in cases where majority of reports originate from manufacturers. Decision-makers must approach database information comprehensively, considering data sources and diverse perspectives to inform regulatory decisions effectively. Developing strategies that encourage various reporters to contribute their unique and complementary viewpoints is advisable.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 76-81"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616387","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}
Pub Date : 2025-01-01DOI: 10.1016/j.clinthera.2024.11.009
Vandana Mathur MD, FASN , Michael Walker PhD , Steve Hasal PhD , Guru Reddy PhD , Shalabh Gupta MD
Purpose
Phosphate binders (PB) are integral to hyperphosphatemia management in patients with end-stage kidney disease. PB efficacy is adversely affected by nonadherence and limited phosphate-binding capacity relative to dietary intake. Oxylanthanum carbonate is an investigational novel nanotechnology product that combines lanthanum, which has the highest binding capacity of available PBs, with a smaller pill size that is swallowed with water rather than chewed. This study's objective was to demonstrate the pharmacodynamic equivalence of orally administered oxylanthanum carbonate to lanthanum carbonate (LC) in healthy subjects.
Methods
In this phase one, single-center, randomized, open-label study, healthy subjects were treated with oxylanthanum carbonate swallowable tablets 1000 mg three times/day and LC chewable tablets 1000 mg three times/day in a two-way crossover design. The primary pharmacodynamic variable was the least squares mean (LSM) change in urinary phosphate excretion from baseline to the evaluation period (Days 1–4 of treatment).
Findings
A total of 80 subjects were randomized and 75 received all doses. The LSM change in urinary phosphate excretion from Baseline to the Evaluation (Treatment) Period was similar for both oxylanthanum carbonate (–320.4 mg/day [90% CI: –349.7, –291.0]) and LC (–324.0 mg/day [90% CI: –353.3, –294.7]); the between-group LSM difference was 3.6 [90% CI: –37.8, 45.1] mg/day. Both drugs were well tolerated with an equal incidence of adverse events.
Implications
Thus, oxylanthanum carbonate was bioequivalent to LC in healthy subjects and well tolerated. Oral oxylanthanum carbonate may provide an option for patients with chronic kidney disease and hyperphosphatemia for whom chewing tablets is disliked, inconvenient, or difficult.
{"title":"Two-Way Randomized Crossover Study to Establish Pharmacodynamic Bioequivalence Between Oxylanthanum Carbonate and Lanthanum Carbonate","authors":"Vandana Mathur MD, FASN , Michael Walker PhD , Steve Hasal PhD , Guru Reddy PhD , Shalabh Gupta MD","doi":"10.1016/j.clinthera.2024.11.009","DOIUrl":"10.1016/j.clinthera.2024.11.009","url":null,"abstract":"<div><h3>Purpose</h3><div>Phosphate binders (PB) are integral to hyperphosphatemia management in patients with end-stage kidney disease. PB efficacy is adversely affected by nonadherence and limited phosphate-binding capacity relative to dietary intake. Oxylanthanum carbonate is an investigational novel nanotechnology product that combines lanthanum, which has the highest binding capacity of available PBs, with a smaller pill size that is swallowed with water rather than chewed. This study's objective was to demonstrate the pharmacodynamic equivalence of orally administered oxylanthanum carbonate to lanthanum carbonate (LC) in healthy subjects.</div></div><div><h3>Methods</h3><div>In this phase one, single-center, randomized, open-label study, healthy subjects were treated with oxylanthanum carbonate swallowable tablets 1000 mg three times/day and LC chewable tablets 1000 mg three times/day in a two-way crossover design. The primary pharmacodynamic variable was the least squares mean (LSM) change in urinary phosphate excretion from baseline to the evaluation period (Days 1–4 of treatment).</div></div><div><h3>Findings</h3><div>A total of 80 subjects were randomized and 75 received all doses. The LSM change in urinary phosphate excretion from Baseline to the Evaluation (Treatment) Period was similar for both oxylanthanum carbonate (–320.4 mg/day [90% CI: –349.7, –291.0]) and LC (–324.0 mg/day [90% CI: –353.3, –294.7]); the between-group LSM difference was 3.6 [90% CI: –37.8, 45.1] mg/day. Both drugs were well tolerated with an equal incidence of adverse events.</div></div><div><h3>Implications</h3><div>Thus, oxylanthanum carbonate was bioequivalent to LC in healthy subjects and well tolerated. Oral oxylanthanum carbonate may provide an option for patients with chronic kidney disease and hyperphosphatemia for whom chewing tablets is disliked, inconvenient, or difficult.</div></div><div><h3>Clinical Trial Registration Number</h3><div>NCT06218290.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 70-75"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766999","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 : 2025-01-01DOI: 10.1016/j.clinthera.2024.11.007
Juntao Tan , Yue Yu , Yuxin He , Jiangyuan Zheng , Qingzhu Tan , Xiao Zhang , Chao Wan , Zhengyu Zhang , Xiaoxin Wu , Rui Tan
Background
The purpose of this study was to employ the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to mine and analyze adverse events related to iodinated contrast media (ICM), explore the characteristics of adverse events (AEs) including their occurrence and correlation strength between AEs and drugs, and to provide valuable insights for clinical use.
Methods
The FAERS database was queried, data from Q1 of 2004 to Q2 of 2023 were extracted, and AE reports targeting 5 ICMs as the primary suspects were collected. Data mining and analysis were carried out on relevant reports using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), while the standardized medical dictionary for regulatory activities (MedDRA) queries (SMQ) was used for systematic classification.
Results
A total of 11,155,106 AE reports were retrieved from FAERS, with 2,412 for ioversol, 2,001 for iohexol, 987 for iodixanol, 1,154 for iopamidol, and 3,835 for iopromide. ICM-induced AE occurrence targeted 21 system organ classes (SOCs). A total of 329 significant disproportionality Preferred terms (PTs) conforming to the 4 algorithms were simultaneously retained. The results revealed that the medium and strong adverse drug reaction (ADR) signals of the 5 ICMs largely focused on “respiratory, thoracic and mediastinal disorders,” “general disorders and administration site conditions,” “immune system disorders,” and “skin and subcutaneous tissue disorders.” Ioversol (log2ROR = 1.21, Padj = 0.034) and iopromide (log2ROR = 1.32, Padj = 0.004) were both correlated with a higher incidence of a significant ADR signal, namely throat irritation, particularly in females. In addition, ioversol and iopromide also suggested that toxic nephropathy (log2ROR = −2.47, Padj < 0.001) and hyperhidrosis (log2ROR = −1.22, Padj = 0.001) were significant ADR signals, especially in males, respectively.
Conclusions
While the AE distribution of the 5 ICMs was consistent, there were variations in specific ADR signal characteristics, warranting further consideration and exploration.
{"title":"Data Mining and Analysis for Iodinated Contrast Media Adverse Event Signals Based on the Food and Drug Administration Adverse Event Reporting System Database","authors":"Juntao Tan , Yue Yu , Yuxin He , Jiangyuan Zheng , Qingzhu Tan , Xiao Zhang , Chao Wan , Zhengyu Zhang , Xiaoxin Wu , Rui Tan","doi":"10.1016/j.clinthera.2024.11.007","DOIUrl":"10.1016/j.clinthera.2024.11.007","url":null,"abstract":"<div><h3>Background</h3><div>The purpose of this study was to employ the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database to mine and analyze adverse events related to iodinated contrast media (ICM), explore the characteristics of adverse events (AEs) including their occurrence and correlation strength between AEs and drugs, and to provide valuable insights for clinical use.</div></div><div><h3>Methods</h3><div>The FAERS database was queried, data from Q1 of 2004 to Q2 of 2023 were extracted, and AE reports targeting 5 ICMs as the primary suspects were collected. Data mining and analysis were carried out on relevant reports using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), while the standardized medical dictionary for regulatory activities (MedDRA) queries (SMQ) was used for systematic classification.</div></div><div><h3>Results</h3><div>A total of 11,155,106 AE reports were retrieved from FAERS, with 2,412 for ioversol, 2,001 for iohexol, 987 for iodixanol, 1,154 for iopamidol, and 3,835 for iopromide. ICM-induced AE occurrence targeted 21 system organ classes (SOCs). A total of 329 significant disproportionality Preferred terms (PTs) conforming to the 4 algorithms were simultaneously retained. The results revealed that the medium and strong adverse drug reaction (ADR) signals of the 5 ICMs largely focused on “respiratory, thoracic and mediastinal disorders,” “general disorders and administration site conditions,” “immune system disorders,” and “skin and subcutaneous tissue disorders.” Ioversol (log<sub>2</sub>ROR = 1.21, P<sub>adj</sub> = 0.034) and iopromide (log<sub>2</sub>ROR = 1.32, P<sub>adj</sub> = 0.004) were both correlated with a higher incidence of a significant ADR signal, namely throat irritation, particularly in females. In addition, ioversol and iopromide also suggested that toxic nephropathy (log<sub>2</sub>ROR = −2.47, P<sub>adj</sub> < 0.001) and hyperhidrosis (log<sub>2</sub>ROR = −1.22, P<sub>adj</sub> = 0.001) were significant ADR signals, especially in males, respectively.</div></div><div><h3>Conclusions</h3><div>While the AE distribution of the 5 ICMs was consistent, there were variations in specific ADR signal characteristics, warranting further consideration and exploration.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 82-90"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767048","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}
Pub Date : 2025-01-01DOI: 10.1016/j.clinthera.2024.09.023
Chuka Udeze PharmD, MS , Nelly F. Ly PharmD, MScRes , Fiona C. Ingleby PhD , Sophia D. Fleming MSc , Sarah C. Conner PhD, MPH , Jo Howard MB BChir, MRCP, FRCPath , Nanxin Li PhD, MBA , Farrukh Shah MBBS, FRCP, FRCPath, MD
Purpose
Sickle cell disease (SCD) is an inherited red blood cell disease caused by a mutation in the gene encoding the β-subunit of adult hemoglobin that leads to hemolysis, anemia, vaso-occlusive crises (VOCs), morbidity, and mortality. This study provides a real-world assessment of the clinical burden and health care resource utilization (HCRU) associated with SCD with recurrent VOCs in England.
Methods
This retrospective study linked primary care records from the Clinical Practice Research Datalink database with secondary care records from the Hospital Episode Statistics database to identify patients with SCD with recurrent VOCs between July 1, 2008, and June 30, 2018. A VOC was defined as SCD with crisis, acute chest syndrome, or priapism. Eligible patients had SCD, ≥2 VOCs/year in any 2 consecutive years after a diagnosis of SCD, and ≥1 year of follow-up data from the index date. Patients were exact matched with 5 controls from the general population in the databases. Demographics were assessed at index. Mortality, clinical complications, and HCRU were summarized during follow-up.
Findings
After applying eligibility criteria, 1117 patients with SCD with recurrent VOCs and 5585 controls were included in the study. Mean age at index was 25 years in both groups. The proportion of deaths (3.67% vs 0.68%; P < 0.001) and mortality rate (0.78 deaths per 100 person-years vs 0.16 deaths per 100 person-years) were substantially higher in patients with SCD with recurrent VOCs versus matched controls. Mean (standard deviation [SD]) age of death in patients with SCD with recurrent VOCs who died during the follow-up period was 40.17 (14.09) years. The mean (SD) rate of VOCs for patients with SCD with recurrent VOCs was 5.84 (12.50) per patient per year (PPPY) during follow-up. Compared with matched controls, patients with SCD with recurrent VOCs had substantially higher mean [SD] rates PPPY of inpatient hospitalizations (7.59 [14.50] vs 0.32 [2.71]), prescriptions (31.06 [60.62] vs 7.58 [27.77]), and outpatient visits (9.60 [10.69] vs 1.78 [4.18]). Older patients and those with increased numbers of VOCs had increased mortality, frequency of clinical complications, and HCRU.
Implications
Despite currently available care, patients with SCD with recurrent VOCs in England have increased mortality, substantial clinical complications, and significant HCRU driven by VOCs and hospitalizations. Elevated mortality and clinical complications in patients with SCD with recurrent VOCs highlight the need for novel therapies in this space.
{"title":"Clinical Burden and Health Care Resource Utilization Associated With Managing Sickle Cell Disease With Recurrent Vaso-occlusive Crises in England","authors":"Chuka Udeze PharmD, MS , Nelly F. Ly PharmD, MScRes , Fiona C. Ingleby PhD , Sophia D. Fleming MSc , Sarah C. Conner PhD, MPH , Jo Howard MB BChir, MRCP, FRCPath , Nanxin Li PhD, MBA , Farrukh Shah MBBS, FRCP, FRCPath, MD","doi":"10.1016/j.clinthera.2024.09.023","DOIUrl":"10.1016/j.clinthera.2024.09.023","url":null,"abstract":"<div><h3>Purpose</h3><div>Sickle cell disease (SCD) is an inherited red blood cell disease caused by a mutation in the gene encoding the β-subunit of adult hemoglobin that leads to hemolysis, anemia, vaso-occlusive crises (VOCs), morbidity, and mortality. This study provides a real-world assessment of the clinical burden and health care resource utilization (HCRU) associated with SCD with recurrent VOCs in England.</div></div><div><h3>Methods</h3><div>This retrospective study linked primary care records from the Clinical Practice Research Datalink database with secondary care records from the Hospital Episode Statistics database to identify patients with SCD with recurrent VOCs between July 1, 2008, and June 30, 2018. A VOC was defined as SCD with crisis, acute chest syndrome, or priapism. Eligible patients had SCD, ≥2 VOCs/year in any 2 consecutive years after a diagnosis of SCD, and ≥1 year of follow-up data from the index date. Patients were exact matched with 5 controls from the general population in the databases. Demographics were assessed at index. Mortality, clinical complications, and HCRU were summarized during follow-up.</div></div><div><h3>Findings</h3><div>After applying eligibility criteria, 1117 patients with SCD with recurrent VOCs and 5585 controls were included in the study. Mean age at index was 25 years in both groups. The proportion of deaths (3.67% vs 0.68%; <em>P</em> < 0.001) and mortality rate (0.78 deaths per 100 person-years vs 0.16 deaths per 100 person-years) were substantially higher in patients with SCD with recurrent VOCs versus matched controls. Mean (standard deviation [SD]) age of death in patients with SCD with recurrent VOCs who died during the follow-up period was 40.17 (14.09) years. The mean (SD) rate of VOCs for patients with SCD with recurrent VOCs was 5.84 (12.50) per patient per year (PPPY) during follow-up. Compared with matched controls, patients with SCD with recurrent VOCs had substantially higher mean [SD] rates PPPY of inpatient hospitalizations (7.59 [14.50] vs 0.32 [2.71]), prescriptions (31.06 [60.62] vs 7.58 [27.77]), and outpatient visits (9.60 [10.69] vs 1.78 [4.18]). Older patients and those with increased numbers of VOCs had increased mortality, frequency of clinical complications, and HCRU.</div></div><div><h3>Implications</h3><div>Despite currently available care, patients with SCD with recurrent VOCs in England have increased mortality, substantial clinical complications, and significant HCRU driven by VOCs and hospitalizations. Elevated mortality and clinical complications in patients with SCD with recurrent VOCs highlight the need for novel therapies in this space.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 29-36"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603455","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}
Investigate the analgesia effects and pharmacokinetics of ropivacaine at different concentrations in Serratus Anterior Plane Block (SAPB) and assess the efficacy and safety.
Methods
Thirty-six patients undergoing video-assisted thoracoscopic surgery (VATS) pulmonary resections were enrolled. Ultrasound-guided SAPB was induced with 3 mg/kg ropivacaine at different concentrations (0.25%, 0.5%, and 0.75%, referred to as Group L, Group M, and Group H, respectively). The concentration of ropivacaine in the plasma at 1, 15, 30, 45, 60 min, 2, 4, 8, 12, and 24 h after SAPB was determined by LC-MS/MS. Other evaluated measures included the Numerical Rating Scale (NRS) scores at rest and on movement, the frequency of dermatomes blocked, onset time and effective plane, Quality of Requirements(QoR)-15 scale, chronic postsurgical pain, and the level of IL-6 and IL-8.
Findings
The NRS scores were significantly higher in Group L than those in other groups (P < 0.05), indicating that the analgesic effect of Group L was the worst among the three groups. Group H had a lower effective plane of anesthesia and significantly higher incidence of chronic postsurgical pain. The IL-8 level was significantly lower in Group H than in other groups at 1 min, 1 h, and 24 h after SAPB. The ropivacaine concentrations were the highest in Group H, followed by Group M and Group L. The high blood concentration of ropivacaine in Group H may increase the risk of systemic toxicity from local anesthetics. Compared to Group L and Group H, Group M had superior analgesic effects and better safety. Among the three groups, Cmax, t1/2, and AUC0-∞ differed significantly.
Implications
For patients undergoing VATS, using 0.5% ropivacaine for SAPB is recommended.
{"title":"Analgesic Effects and Pharmacokinetics of Ropivacaine at Different Concentrations in Serratus Anterior Plane Block in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Prospective Randomized Trial","authors":"Lingkai Tang MSc , Caomei Xu MSc , Jianfen Xie B.S. , Jiahao Xu MSc , Chen Chen PhD , Jiang Shen B.S. , Nan Hu PhD , Lan Qiu PhD","doi":"10.1016/j.clinthera.2024.11.003","DOIUrl":"10.1016/j.clinthera.2024.11.003","url":null,"abstract":"<div><h3>Purpose</h3><div>Investigate the analgesia effects and pharmacokinetics of ropivacaine at different concentrations in Serratus Anterior Plane Block (SAPB) and assess the efficacy and safety.</div></div><div><h3>Methods</h3><div>Thirty-six patients undergoing video-assisted thoracoscopic surgery (VATS) pulmonary resections were enrolled. Ultrasound-guided SAPB was induced with 3 mg/kg ropivacaine at different concentrations (0.25%, 0.5%, and 0.75%, referred to as Group L, Group M, and Group H, respectively). The concentration of ropivacaine in the plasma at 1, 15, 30, 45, 60 min, 2, 4, 8, 12, and 24 h after SAPB was determined by LC-MS/MS. Other evaluated measures included the Numerical Rating Scale (NRS) scores at rest and on movement, the frequency of dermatomes blocked, onset time and effective plane, Quality of Requirements(QoR)-15 scale, chronic postsurgical pain, and the level of IL-6 and IL-8.</div></div><div><h3>Findings</h3><div>The NRS scores were significantly higher in Group L than those in other groups (<em>P</em> < 0.05), indicating that the analgesic effect of Group L was the worst among the three groups. Group H had a lower effective plane of anesthesia and significantly higher incidence of chronic postsurgical pain. The IL-8 level was significantly lower in Group H than in other groups at 1 min, 1 h, and 24 h after SAPB. The ropivacaine concentrations were the highest in Group H, followed by Group M and Group L. The high blood concentration of ropivacaine in Group H may increase the risk of systemic toxicity from local anesthetics. Compared to Group L and Group H, Group M had superior analgesic effects and better safety. Among the three groups, <em>C</em><sub>max</sub>, t<sub>1/2</sub>, and AUC<sub>0-∞</sub> differed significantly.</div></div><div><h3>Implications</h3><div>For patients undergoing VATS, using 0.5% ropivacaine for SAPB is recommended.</div></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":"47 1","pages":"Pages 62-69"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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