Clinical Pharmacology : Advances and Applications最新文献

{"title":"Pharmacotherapy for Obesity: Recent Updates.","authors":"Thomas Ward Fredrick, Michael Camilleri, Andres Acosta","doi":"10.2147/CPAA.S497904","DOIUrl":"10.2147/CPAA.S497904","url":null,"abstract":"<p><p>In this narrative review we describe the recent updates regarding anti-obesity medications as of February 2025. We describe the physiologic mechanisms underpinning the development of hunger, satiation, and maintenance of satiety to address targets for anti-obesity medications. The efficacy, mechanism, and additional beneficial effects of anti-obesity medications are then further detailed. For this review, we focus on FDA-approved medications for obesity and on select medications currently under development and undergoing Phase 2 and 3 trials. We start by focusing on the non-incretin anti-obesity medications orlistat, phentermine, phentermine-topiramate, and naltrexone-bupropion. We also highlight setmelanotide for heritable obesity. The mechanism of action and comparative efficacy of the GLP-1 receptor agonists liraglutide and semaglutide are reviewed. Tirzepatide, the GLP-1 and GIP-receptor dual agonist is described, and weight loss is compared to alternative anti-obesity medications. Additional incretin targets in the pipeline include dual co-agonists to glucagon and GLP-1 receptors, triple agonists targeting glucagon, GLP-1 and GIP, novel GLP-1 agonists, oral formulations of GLP-1 agonists, and amylin agonists. Finally, we provide best practices for adjuncts to pharmacologic treatments of obesity, monitoring efficacy of obesity treatments, and adjusting medication regimens for providers.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"305-327"},"PeriodicalIF":2.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive Compounds From Saudi Arabian Fungi: A Systematic Review of Anticancer Potential.","authors":"Sahar S Alghamdi, Jehan H Alamre, Arwa Alsubait, Abdullah R Alanzi, Bandar S Aldawish, Fares Althobiti, Mohammed Ibrahim Al Rudhyyan, Abdulrahman Majid Almadi, Afrah E Mohammed","doi":"10.2147/CPAA.S540060","DOIUrl":"10.2147/CPAA.S540060","url":null,"abstract":"<p><p>Cancer remains the second leading cause of death worldwide, highlighting the urgent need for novel therapeutic approaches. Fungi are a rich source of bioactive metabolites, some of which exhibit potent anticancer properties. This scoping review evaluates the current research on fungal metabolites with anticancer potential, focusing on species native to Saudi Arabia's unique ecosystem. Following PRISMA 2020 guidelines, a comprehensive literature search was conducted using PubMed, Google Scholar, and Web of Science. Out of approximately 14,000 records, 11 studies met the inclusion criteria (2000-2024). A total of 16 distinct fungal species were identified, with their metabolites tested against various human cancer cell lines. Compounds derived from <i>Penicillium sp. RO-11, Fusarium venenatum, Chaetomium globosum, Bipolaris sorokiniana</i>, and <i>Aspergillus sydowii</i> demonstrated notable cytotoxic effects. Reported IC₅₀ values ranged from as low as 0.2 µg/mL to over 600 µg/mL, indicating varying levels of potency. <i>Penicillium sp. RO-11</i> (emodin, IC₅₀ = 2 ± 7.6 µM) and <i>Fusarium venenatum</i> (IC₅₀ = 0.3779 µg/mL against HCT8 cells) emerged as the most potent candidates. These metabolites exerted their effects by inducing apoptosis, inhibiting proliferation, and disrupting oncogenic signaling pathways. The findings underscore the therapeutic potential of fungal-derived compounds and highlight the importance of further research to isolate and characterize the most effective strains for biomedical applications. Expanding investigations into Saudi Arabia's fungal diversity may yield promising candidates for future cancer treatments.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"291-304"},"PeriodicalIF":2.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Monascus purpureus</i> Red Yeast Rice: A Review of the in vitro and in vivo Pharmacological Activities, Studies in Humans, and Case Reports.","authors":"Resha Resmawati Shaleha, Anna Yuliana, Saeful Amin, Jutti Levita, Sri Adi Sumiwi","doi":"10.2147/CPAA.S542721","DOIUrl":"10.2147/CPAA.S542721","url":null,"abstract":"<p><p>Red yeast rice (RYR) is an Asian indigenous medicine that ferments <i>Oryza sativa</i> grains using the Monascus fungi, specifically <i>Monascus purpureus</i>. Monacolins, pigments, phenols, sterols, and benzopyrans, such as the mycotoxin citrinin, were proven to be present in RYR, contributing to its numerous effects. This study aims to provide a thorough overview of the in vitro and in vivo pharmacological activities of <i>M. purpureus</i> red yeast rice, its studies in humans, and a summary of recent case reports. A literature search was conducted on the PubMed database, using the keywords: \"pharmacology activity of red yeast rice\" filtered to free full text and articles published from 2014 to 2024 for in vitro and in vivo studies, to ensure the newest developments. In vitro and in vivo pharmacological activity studies of RYR and/or metabolites have confirmed antidyslipidemia, anti-inflammatory, and anticancer activities, whereas studies in humans have evidenced its activity in improving lipid profiles. Furthermore, case reports on red yeast rice supplements, published between 2020 and 2025, revealed Fanconi syndrome and kidney dysfunction as the main adverse events, mostly reported from Japan.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"269-289"},"PeriodicalIF":2.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12415105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomics Insights into the Benefits of SGLT2 Inhibitors in Type 2 Diabetes.","authors":"Artemis Kyriakidou, Theocharis Koufakis, Helen Gika, Kalliopi Kotsa","doi":"10.2147/CPAA.S497906","DOIUrl":"10.2147/CPAA.S497906","url":null,"abstract":"<p><strong>Background: </strong>Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an established class of agents in the treatment of type 2 diabetes mellitus (T2DM), with proven cardiovascular and renal benefits. However, their precise mechanisms of action remain incompletely understood. Metabolomics offers a powerful approach to uncovering drug-induced alterations in metabolic pathways.</p><p><strong>Aim: </strong>This narrative review summarizes the available human evidence on the metabolomic effects of SGLT2 inhibitors, with a focus on their potential implications for metabolic adaptation and cardiorenal protection.</p><p><strong>Methods: </strong>We performed a comprehensive literature search of human studies that applied metabolomic analyses to evaluate the effects of SGLT2 inhibitors in T2DM. Both targeted and untargeted metabolomic approaches were considered.</p><p><strong>Results: </strong>Across studies, SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates. Key metabolite changes include increases in ketone bodies, alterations in branched-chain amino acids, and modulation of intermediates of the tricarboxylic acid cycle.</p><p><strong>Conclusion: </strong>SGLT2 inhibitors consistently induce a metabolic shift away from glucose utilization toward more energy-efficient substrates, including ketone bodies, fatty acids, and certain amino acids. These metabolomic adaptations may underlie their observed cardiovascular and renal protective effects. While these findings support the \"thrifty fuel\" hypothesis, additional longitudinal studies with standardized methodologies and precision medicine approaches are needed to fully define the clinical significance of these metabolic adaptations.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"253-267"},"PeriodicalIF":2.5,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determination of 5-Fluorouracil in Dried Blood Spots for Therapeutic Drug Monitoring and Adverse Event Assessment in Breast Cancer Patients.","authors":"Muthia Hanifah, Yahdiana Harahap, Denni Joko Purwanto","doi":"10.2147/CPAA.S515595","DOIUrl":"10.2147/CPAA.S515595","url":null,"abstract":"<p><strong>Background: </strong>5-Fluorouracil (5-FU) is a chemotherapy drug used to treat breast cancer. Monitoring 5-FU levels in blood is essential due to its narrow therapeutic range, high individual variability, nonlinear pharmacokinetics, dosage calculations based on body surface area, and susceptibility to toxicity influenced by individual factors such as enzyme polymorphisms.</p><p><strong>Methods: </strong>An observational study was conducted in 2 types of patients: patients receiving intravenous 5-FU chemotherapy and those receiving oral chemotherapy with capecitabine as the 5-FU prodrug. 5-Fluorouracil blood levels in those patients were monitored using dried blood spots (DBS) as a biosampling method to correlate them with adverse events experienced by patients. Samples from DBS were analyzed using LC-MSMS which has been fully validated with propylthiouracil as an internal standard. All patients were also interviewed to determine adverse events experienced during 5-FU treatment. These adverse events were evaluated based on Common Terminology Criteria for Adverse Events version 5.0.</p><p><strong>Results: </strong>Among the five patients who received intravenous 5-FU, only one patient had concentrations within the target range of 2-3 µg/mL, two patients were below the target range, and two patients were slightly above the target range. For the patients receiving oral capecitabine, 5-FU concentrations were detectable in only 3 out of 8 patients, with values near the LLOQ. The most common adverse events observed in intravenous chemotherapy patients were constipation, fatigue, and alopecia. Hand-foot syndrome was the most common syndrome in patients receiving oral chemotherapy.</p><p><strong>Conclusion: </strong>The validated DBS method can be applied for therapeutic drug monitoring of 5-FU, offering advantages such as reduced invasiveness compared to traditional venipuncture. However, no significant relationship was found between the administered drug dosage, 5-FU blood levels, and adverse events. This study's limitations include its small sample size, which requires further research with larger cohorts to validate these observations and their clinical relevance.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"243-251"},"PeriodicalIF":2.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent Checkpoint Inhibitor-Related Pneumonitis Refractory to Corticosteroid Treatment: A Case Report and Literature Review.","authors":"Jinyu Yu, Xuanjun Liu, Xingjiao Ma, Li Liang, Yan'e Liu, Wencheng Yin, Qian Li, Baoshan Cao, Wei Liu","doi":"10.2147/CPAA.S534323","DOIUrl":"10.2147/CPAA.S534323","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are antibodies that activate the immune system to kill tumor cells and have been widely used in oncology. However, dysregulated immune activation may result in the attack of normal tissues and organs, leading to immune-related adverse events (irAEs). Corticosteroid-refractory irAE pneumonitis severely threatens patient survival and is characterized by a lack of high-level evidence-based management guidelines, highlighting the need for increased scrutiny in this area.</p><p><strong>Case presentation: </strong>This article presents the diagnosis and treatment of a patient with lung squamous cell carcinoma who developed recurrent corticosteroid-refractory grade 3 checkpoint inhibitor- related pneumonitis (CIP) during treatment with the ICI tislelizumab. The management approach included the use of intravenous immunoglobulin (IVIG) and mycophenolate mofetil (MMF). The case is thoroughly analyzed and discussed, accompanied by a review of relevant literature.</p><p><strong>Conclusion: </strong>IVIG and MMF showed effectiveness in corticosteroid-refractory CIP, and further investigation is warranted to establish standardized guideline and to optimize therapeutic drug monitoring for immunosuppressive agents.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"235-242"},"PeriodicalIF":2.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing Antimicrobial Use in Japan: Strategies for Dosage, Combination Therapy, De-Escalation, Oral Switching, Duration, and Guideline Adherence.","authors":"Masafumi Seki","doi":"10.2147/CPAA.S539674","DOIUrl":"10.2147/CPAA.S539674","url":null,"abstract":"<p><p>Antimicrobial stewardship has gained momentum in Japan, prompting the adoption of various strategies to optimize antimicrobial use. Key recommendations include individualized dosing, dosing intervals, and treatment regimens tailored to the patient's condition, causative pathogens, and affected organs. Combination therapy is advised for empiric treatment of severe infections and suspected multidrug-resistant organisms. Early initiation of antimicrobial therapy followed by de-escalation may enhance clinical outcomes and reduce resistance development. Additionally, while clear criteria for intravenous-to-oral switch therapy remain undefined, its implementation could play a crucial role in optimizing antimicrobial administration. The duration of therapy should be guided by disease pathophysiology rather than isolated inflammatory markers, including C-reactive protein, with adherence to established guidelines and clinical recommendations. These strategies have been incorporated at the bedside, and optimized antibiotics use are now advanced in Japan.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"227-233"},"PeriodicalIF":2.5,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose Optimization of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.","authors":"Jiali Chen, Yidan Zhu, Yinyu Zhao, Nan Guo, Yuxuan Yao, Xingxian Luo, Lin Huang","doi":"10.2147/CPAA.S532263","DOIUrl":"10.2147/CPAA.S532263","url":null,"abstract":"<p><p>With the advent of newer treatments such as new molecular targeted agents and immunotherapies, the model that selects therapeutic doses on the basis of the maximum tolerated dose is no longer relevant. The emergence of tyrosine kinase inhibitor (TKI) therapy has changed the treatment prospects for chronic myeloid leukemia (CML) and prolonged the long-term survival of CML patients. However, long-term exposure to TKIs is accompanied by adverse events, which may lead to disease progression and even death. It can also increase economic pressure on patients and affect their health-related quality of life. In general, dose reduction is feasible and safe for most patients and can reduce the incidence of adverse events while ensuring efficacy, reduce the financial burden on patients and society, improve the quality of life of patients, and also as a prelude to an attempt at treatment-free remission (TFR). This review will classify the dose optimization of all approved TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib, radotinib) at different stages of treatment based on clinical trials and real-life studies, including dose optimization prior to attempting TFR. In addition, we briefly describe the application of therapeutic drug monitoring in dose optimization and the potential benefits of dose optimization on health-related quality of life.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"211-225"},"PeriodicalIF":2.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in Glioblastoma: An Overview of Current Status.","authors":"Zouina Sarfraz, Arun Maharaj, Vyshak Alva Venur, Justin D Lathia, Yazmin Odia, Manmeet S Ahluwalia","doi":"10.2147/CPAA.S497903","DOIUrl":"10.2147/CPAA.S497903","url":null,"abstract":"<p><p>Glioblastoma (GB) is an aggressive brain tumor with standard therapies offering limited but measurable survival benefit. Immunotherapy is expanding the treatment landscape for GB. Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have shown benefit in several cancers and are being studied in GB, with ongoing efforts to address the tumor's immunosuppressive environment. Chimeric Antigen Receptor (CAR) T-cell therapies are also being explored, with new approaches designed to overcome antigen variability and improve access across the blood-brain barrier. Cancer vaccines, especially dendritic cell-based platforms like DCVax-L, have shown promising survival outcomes in clinical trials. Advances in biomarker analysis and genomics are supporting more personalized immunotherapy approaches. In addition, combination strategies involving ICIs, CAR T-cells, vaccines, and oncolytic viruses are being developed to enhance immune response. This review outlines current immunotherapy approaches in GB, focusing on their mechanisms, clinical development, and future directions.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"185-209"},"PeriodicalIF":2.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12305673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in Gastrointestinal Cancers: Current Insights.","authors":"Xue Jiang, Yangyang Zhan, Dong-Hua Yang, Leilei Bao","doi":"10.2147/CPAA.S497836","DOIUrl":"10.2147/CPAA.S497836","url":null,"abstract":"<p><p>Gastrointestinal cancer is one of the most prevalent malignant tumors worldwide. The treatment landscape of gastrointestinal cancer has entered a new era with the advent of immunotherapy, which activates the immune system to identify and eliminate tumor cells. Immunotherapy has demonstrated high efficacy and tolerable toxicity profiles compared to conventional therapies. Immune checkpoint inhibitors including PD-1, PD-L1, CTLA-4 and LAG-3 in combination with targeted therapy or chemotherapy have been approved for the treatment of gastrointestinal tumors with good clinical patient benefit. In recent years, a variety of novel immunotherapeutic approaches have emerged. For example, adoptive T-cell therapy, such as claudin18.2-targeted CAR-T has achieved an objective remission rate of 48.6% in patients with advanced gastric cancer and gastroesophageal junction cancer. Oncolytic viruses inhibits tumor growth in both tumor lysis and immune activation, and is currently showing its efficacy against gastrointestinal tumors in some clinical trials. In addition, cancer vaccines, with their unique high degree of precision, have improved the effectiveness of individualized therapy. Personalized neoantigen vaccines combined with other immunotherapeutic drugs or chemotherapy, have shown some efficacy and safety in gastrointestinal patients. In this review, we summarize these recent advances in immunotherapy for the treatment of gastrointestinal tumors. Additionally, the challenges and limitations linked to immunotherapy were explored. This review will expand our understanding of clinical studies on immunotherapy in gastrointestinal cancer and assist in individualizing patient treatment strategies, maximizing therapeutic benefits, and improving patient prognosis.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"17 ","pages":"167-183"},"PeriodicalIF":2.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}