Current pharmaceutical design最新文献

{"title":"Ranking the Diabetes-related Safety Profile of Different Statin Drugs.","authors":"Dongsheng Zheng, Jinsuai Ren, Duo Lv, Qingwei Zhao, Dongsheng Hong","doi":"10.2174/0113816128430202250902074509","DOIUrl":"https://doi.org/10.2174/0113816128430202250902074509","url":null,"abstract":"<p><strong>Introduction: </strong>Statins are widely prescribed for cardiovascular disease prevention, but their potential to increase diabetes risk has prompted regulatory warnings. Different statin drugs have varying physicochemical properties, yet comprehensive comparative assessments of their individual diabetes-related safety profiles remain limited in post-marketing surveillance data. Therefore, this study aimed to evaluate and compare the risk of diabetes-related adverse events among different statin drugs using pharmacovigilance data.</p><p><strong>Methods: </strong>We analyzed adverse event reports from the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2022. Diabetes-related adverse events were identified using relevant MedDRA Preferred Terms. Four pharmacovigilance algorithms-Reporting Odds Ratio (ROR), Medicines and Healthcare products Regulatory Agency (MHRA) standard method, Bayesian Confidence Propagation Neural Network, and Multi-Item Gamma Poisson Shrinkage-were employed to detect signals. Positive signals were defined when all four methods showed significance. Outcome severity and time-to-event were also analyzed.</p><p><strong>Results: </strong>Among 13,438,409 ADE reports, 63,583 identified statins as primary suspect drugs, with 11,562 reporting diabetes-related events. Positive signals were detected for atorvastatin, rosuvastatin, simvastatin, pravastatin, and pitavastatin. Signal strength ranking showed atorvastatin had the strongest association (ROR 36.70; 95% CI 35.92-37.51), followed by rosuvastatin (ROR 9.63; 95% CI 9.10-10.19), pitavastatin (ROR 5.46; 95% CI 4.03-7.41), simvastatin (ROR 2.96; 95% CI 2.54-3.45), and pravastatin (ROR 2.82; 95% CI 2.14-3.71). In patients under 45, only atorvastatin showed a positive signal. Atorvastatin was associated with a higher risk of serious adverse events (PRR=1.37; 95% CI: 1.09-1.71) with a median time to event of 1,012 days.</p><p><strong>Discussion: </strong>Our findings revealed differences in diabetes-related risk profiles among statins, with atorvastatin demonstrating the strongest signals across different age groups. The observed risk hierarchy may be attributed to differences in lipophilicity, potency, and metabolic effects. The age-dependent patterns and extended timeto- event for diabetic events underscore the importance of long-term monitoring, complementing clinical trial data with post-marketing surveillance evidence for improved statin selection.</p><p><strong>Conclusion: </strong>Different statins demonstrate varying associations with diabetes-related adverse events, with atorvastatin showing the strongest signal across age groups. These findings may inform clinical decisionmaking when prescribing statins, particularly for patients with pre-existing diabetes risk factors.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130088","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}

{"title":"Preparation and Evaluation of Sodium Alginate Nanoparticles Containing Recombinant Diphtheria Toxoid (CRM197) and their Immunogenicity in Mice.","authors":"Samira Aghamiri, Mojtaba Noofeli, Hamid Reza Goudarzi, Parvaneh Saffarian, Zahra Salehi Najafabadi","doi":"10.2174/0113816128402345250905072744","DOIUrl":"https://doi.org/10.2174/0113816128402345250905072744","url":null,"abstract":"<p><strong>Introduction: </strong>Recombinant protein vaccines against infectious diseases, based on immunogenic antigen identification and employing polymeric nanoparticles as a delivery system, can provoke immune responses comparable to or better than traditional vaccines. The production of a safe and immunogenic vaccine against diphtheria was achieved by preparing sodium alginate nanoparticles containing recombinant diphtheria toxoid (CRM197).</p><p><strong>Methods: </strong>Alginate nanoparticles loaded with CRM197 were prepared using the ionic-gelation method and thoroughly characterized. Safety and immunogenicity studies were conducted in an animal model for comparison with commercial vaccines. Antibody responses were evaluated using both qualitative and quantitative measurements, as determined by the toxin neutralization test (TNT) and indirect ELISA, respectively. IgG subclasses in the sera of immunized mice and possible pathological lesions in vital tissues of all immunized mouse groups were investigated.</p><p><strong>Results: </strong>Nanoparticles with or without CRM197 were synthesized by the ionic gelation method. LE and LC measurements showed ˃80% and ˃20%, respectively, indicating stable and persistent release without a bursting pattern. In vivo studies showed safety and enhanced immunogenicity in mice immunized with the CRM197- loaded sodium alginate nanoparticles, with higher levels of total anti-CRM197 IgG and subclasses than those induced by conventional vaccines.</p><p><strong>Discussion: </strong>Reducing antigen usage in vaccine production while increasing immunogenicity and safety compared with traditional vaccines are the goals of new vaccine development, which were achieved in the current study.</p><p><strong>Conclusion: </strong>Engineered alginate nanoparticles loaded with recombinant diphtheria antigen (CRM197) demonstrated in vitro controlled and slow release, as well as safety and immunogenicity profiles against diphtheria in vivo. Nanoparticles containing CRM197 antigens equivalent to adult and children doses showed high levels of IgG1 and IgG2a, confirming the combined responses of the humoral and cellular immune systems.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111988","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}

{"title":"Promising Targets and Drugs for Improving Head and Neck Cancer Response to Radiotherapy.","authors":"Faris Anad Muhammad, Ayat Hussein Adhab, Morug Salih Mahdi, Ashishkumar Kyada, Subbulakshmi Ganesan, Deepak Bhanot, K Satyam Naidu, Aseel Salah Mansoor, Usama Kadem Radi, Nasr Saadoun Abd, Munther Kadhim","doi":"10.2174/0113816128398373250910100446","DOIUrl":"https://doi.org/10.2174/0113816128398373250910100446","url":null,"abstract":"<p><p>Head and neck cancers, particularly Head and Neck Squamous Cell Carcinoma (HNSCC), encompass a diverse group of malignancies with intricate cellular landscapes. The Tumor Microenvironment (TME) is characterized by constant communication between cancer cells and their surrounding cells. Stromal components, immune infiltrates, and Extracellular Matrix (ECM) elements all play crucial roles in this process. These dialogues shape tumor behavior, spread, and treatment resistance. At the molecular level, DNA Damage Response (DDR) by tumoral cells can reduce cell elimination via Ionizing Radiation (IR). Human Papillomavirus (HPV) infection, in some cases, further complicates the picture. Recent findings highlight how these molecular responses, as well as immune modulation, remodeling cell metabolism, enhanced growth factors, and hypoxia in TME, can influence tumor responses to IR. These findings may lead to strategies for radiosensitizing head and neck cancers. Unraveling these interactions is key to developing more effective treatments. This review focuses on different mechanisms of radioresistance in head and neck cancers. Then, we provide an overview of different targets and potential adjuvants or drugs for radiosensitization of these malignancies.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111964","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}

{"title":"The Impact of Artificial Intelligence Techniques and Machine Learning on Colorectal Cancer Management.","authors":"Anahita Azinfar, Negar Namvar, Ibrahim Saeed Gataa, Majid Khazaei, Seyed Mahdi Hassanian, Mohammadreza Nassir, Gordon A Ferns, Hamid Naderi, Amir Avan","doi":"10.2174/0113816128377312250827213457","DOIUrl":"https://doi.org/10.2174/0113816128377312250827213457","url":null,"abstract":"<p><p>Bowel cancer, known as colorectal cancer (CRC), is among the most common types of newly diagnosed cancers and a leading cause of cancer-related deaths. Despite advances in medical technology and screening programs, gaps in the detection of colorectal cancer patients persist, leading to delayed diagnoses and poorer outcomes. Therefore, new approaches using artificial intelligence-based analysis with gene panels and traditional risk factors for risk prediction and identification of cases at high risk are urgently warranted. Artificial Intelligence (AI) has emerged as a promising tool to enhance early detection and screening efficacy. Moreover, early detection is crucial for successful treatment and improved survival rates. However, conventional screening methods, such as colonoscopy and fecal occult blood tests (FOBT), have their limitations, including cost, invasiveness, and patient compliance. As a result, many individuals go undiagnosed until the disease has progressed to an advanced stage. In aggregate, the integration of AI in CRC detection holds great promise for bridging the existing gaps and improving patient outcomes. As technology continues to evolve, AI algorithms will become even more sophisticated, accurate, and scalable. Collaboration between clinicians, researchers, and AI developers is essential to harness the full potential of AI for earlier detection and better management of CRC, ultimately saving lives and reducing the global burden of disease.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079784","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}

{"title":"Quantification and Engineering of Lipid Nanocapsule Formulations for the Delivery of Niclosamide as an Anti-Cancer Drug.","authors":"Hatice Demirtas, Kenan Can Tok, Mehmet Gumustas, Ceyda Tuba Sengel-Turk","doi":"10.2174/0113816128385620250829061535","DOIUrl":"https://doi.org/10.2174/0113816128385620250829061535","url":null,"abstract":"<p><strong>Introduction: </strong>Recent studies indicate that niclosamide demonstrates considerable promise as both an anthelmintic agent and a possible anticancer medication. Given the increasing interest in nano-sized drug delivery methods for cancer therapy, lipid nanocapsules (LNCs) have emerged as a viable approach to enhance the bioavailability of poorly soluble pharmaceuticals due to their beneficial properties. This research intends to develop niclosamide-loaded lipid nanocapsules (NIC-LNCs) using the phase inversion technique, followed by the optimization of these formulations via the Box-Behnken experimental design.</p><p><strong>Methods: </strong>A reverse-phase high-performance liquid chromatography (RP-HPLC) method was devised and validated for quantifying niclosamide in the LNC formulations. Optimal chromatographic separation was attained utilizing an Agilent Eclipse XDB-C18 column (150×4.6 mm, 5 μm i.d.) with a mobile phase of a 50:50 (v/v) mixture of acetonitrile and 0.1% H3PO4 phosphate buffer, at a flow rate of 1.2 mL/min. The detection wavelength was set at 335 nm, and the analysis was performed at 35°C. The developed analytical methodology was validated through a comprehensive evaluation of accuracy, linearity, precision, limit of detection, limit of quantitation, specificity, and stability.</p><p><strong>Results: </strong>The optimization of the NIC-LNC formulation through the Box-Behnken design resulted in an optimal formulation labeled LNC5, consisting of 4% niclosamide, 20% lipid, and 20% surfactant. The proven RPHPLC method enables accurate quantification of NIC in the LNC formulations. The refined NIC-LNC formulation exhibited developed attributes as assessed by the design.</p><p><strong>Conclusion: </strong>The findings indicate that LNC systems are a promising method for drug administration, especially for anticancer drugs with limited solubility in water.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063309","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}

{"title":"Nasal Microbiota as a Potential Therapeutic Target for Allergic Rhinitis: An Emerging Perspective.","authors":"Bing-Yu Liang, Yi-Pin Yang, Chun-Ya Pan, Fen-Fen Li, Ping-Ting Zhou, Zi-Yue Fu, Yan-Xun Han, Qin Wang, Hai-Feng Pan, Yu-Chen Liu","doi":"10.2174/0113816128388496250812102820","DOIUrl":"https://doi.org/10.2174/0113816128388496250812102820","url":null,"abstract":"<p><p>Allergic Rhinitis (AR) represents a significant global health challenge with extensive prevalence and profound impacts, necessitating the development of novel therapeutic approaches beyond conventional symptomatic treatment. Emerging research has elucidated the crucial role of nasal microbiota dysbiosis in both the pathogenesis and progression of AR. Although the dominant microbial phyla remain largely consistent, significant changes in microbial abundance, composition, and diversity are often observed. In addition, studies have shown a correlation between changes in nasal microbiota and immune markers such as immunoglobulin E levels, suggesting that microbiota changes can reflect the severity of AR. Therefore, targeted modulation of the aberrant nasal microbiota may offer a promising therapeutic approach for this disease. However, further research is crucial for elucidating the causal relationships between specific microbial characteristics, disease severity, and potential comorbidities. This article summarizes recent studies examining the pathogenic role of nasal microbiota dysbiosis, the differential microbial composition across nasal mucosal sites, and potential therapeutic targets in AR. The ultimate goal is to develop precision medicine-based therapeutic interventions that target the underlying pathophysiological mechanisms of AR through specific modulation of dysbiotic nasal microbiota, thereby potentially preventing disease progression and reducing the risk of associated comorbidities.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063699","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}

{"title":"Unraveling the Complexity of Polycystic Ovary Syndrome: Biomarkers for Diagnosis, Prognosis, and Treatment.","authors":"Saloni Upadhyay, Avijit Mazumder, Saumya Das","doi":"10.2174/0113816128382284250822045319","DOIUrl":"https://doi.org/10.2174/0113816128382284250822045319","url":null,"abstract":"<p><p>Polycystic ovary syndrome is distinguished by alterations in ovarian morphology, ovulatory failure, and increased androgen levels. The National Institutes of Health (NIH) defines it as ovulatory dysfunction accompanied by hyperandrogenism. Women with PCOS may have obesity, type 2 diabetes, anxiety, hypertension, insulin resistance, and pregnancy-related complications. PCOS is additionally linked with a greater chance of cardiovascular and metabolic disorders. Several factors, including LH/FSH ratio, FAI levels, and ovarian USG, should be considered when diagnosing PCOS. The Rotterdam criterion is employed to determine the condition when two of the three features are present and other etiologies are eliminated. Biomarkers have developed as a means of optimizing PCOS diagnosis and treatment results. This review has examined a number of biomarkers associated with PCOS, such as insulin, anti-Mullerian hormone, oxidative stress markers, inflammatory markers, and others. Controlling these disease-related markers may aid in lessening the symptoms of PCOS.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063430","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}

{"title":"Flavonoids as Dual Inhibitors of MELK and LYN Kinases in Cervical Cancer: An In Silico Molecular Docking Analysis.","authors":"Khalid Zoghebi, Abdulmajeed M Jali","doi":"10.2174/0113816128387273250823102532","DOIUrl":"https://doi.org/10.2174/0113816128387273250823102532","url":null,"abstract":"<p><strong>Introduction: </strong>Cervical cancer (CC) is among the most prevalent cancers affecting women globally, with a substantial number of deaths reported annually. Despite advancements in treatment, the persistently high mortality rate underscores the urgent need for novel and effective therapeutic strategies.</p><p><strong>Methods: </strong>This study screened a library of 240 flavonoids against maternal embryonic leucine zipper kinase (MELK) and LYN using molecular docking methods to achieve precise calculations. These proteins play critical roles in CC progression, and their simultaneous inhibition could mark a significant step forward in multitargeted drug design.</p><p><strong>Results: </strong>Molecular docking revealed binding affinities ranging from -10.0649 to -8.14296 kcal/mol for MELK and -10.2748 to -8.5237 kcal/mol for LYN. The screening process was complemented by pharmacokinetics and interaction fingerprinting analyses, which confirmed that the flavonoids effectively bound to optimal sites, forming stable complexes through multiple interactions. Molecular dynamics simulations extended to 100 ns further validated the stability of these protein-ligand complexes.</p><p><strong>Discussion: </strong>The findings indicate that the top-ranked compounds exhibit strong binding affinities and stable interactions, highlighting their potential as multitargeted therapeutic agents against CC.</p><p><strong>Conclusion: </strong>These findings set the stage for future experimental and clinical studies to validate our results and facilitate the development of novel, flavonoid-based therapeutic strategies against cervical cancer, potentially revolutionizing the treatment landscape of this disease.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014124","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}

{"title":"Green Tea Catechins and COVID-19: Epidemiological Trends and Therapeutic Perspectives.","authors":"Maksim Storozhuk","doi":"10.2174/0113816128412495250824132514","DOIUrl":"https://doi.org/10.2174/0113816128412495250824132514","url":null,"abstract":"<p><strong>Introduction: </strong>Pharmacological studies in vitro demonstrate the preventive and therapeutic potential of green tea and its constituent epigallocatechin-3-gallate (EGCG) in the fight against coronavirus disease 2019 (COVID-19). Previously reported correlations between per capita green tea consumption and COVID-19 morbidity/mortality suggest similar effects in vivo. Considering that some recent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) sub-variants are less influenced by EGCG, this study aimed to determine whether this affects the aforementioned correlations, focusing on comparisons between the periods before (2021) and after (2022-2024) the emergence of the Omicron variant.</p><p><strong>Methods: </strong>Correlations between per capita green tea consumption and COVID-19 morbidity/mortality were calculated using multiple regression models accounting for several confounding factors in a subset (n=84) of countries/territories worldwide with Human Development Index (HDI) above 0.55.</p><p><strong>Results: </strong>Higher per capita green tea consumption was associated with lower COVID-19 morbidity and mortality. Statistically significant correlations were observed in 2021-2024. Compared with 2021, the strength of both correlations decreased; the relative decrease in the strength of the correlation between per capita green tea consumption and COVID-19 mortality was notably less pronounced.</p><p><strong>Discussion: </strong>This differential decrease at the epidemiological level supports the idea that green tea consumption may have not only preventive but also therapeutic value regarding COVID-19. This aligns with in vitro pharmacological evidence indicating that green tea constituents target distinct molecular pathways responsible for the entry of the virus and its replication.</p><p><strong>Conclusion: </strong>While promising, these findings require further assessment in observational and interventional studies focused on potential therapeutic benefits.</p>","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999839","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}

{"title":"Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Future Directions.","authors":"Marcio F Chedid, Jane Mattei","doi":"10.2174/0113816128436770250828043354","DOIUrl":"https://doi.org/10.2174/0113816128436770250828043354","url":null,"abstract":"","PeriodicalId":10845,"journal":{"name":"Current pharmaceutical design","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999868","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}