Drug Research最新文献

{"title":"Maternal Mirtazapine Selectively Enhances Hippocampal LTP without Reversing Stress-Associated Alterations in Basal Transmission, Short-Term Plasticity, or Open Field Behaviour in Rat Offspring.","authors":"Zdenka Gasparova, Stanislava Bukatova, Michal Dubovicky","doi":"10.1055/a-2682-5112","DOIUrl":"10.1055/a-2682-5112","url":null,"abstract":"<p><p>Maternal stress during pregnancy has profound effects on offspring, disrupting brain development and behaviour. Mirtazapine, an antidepressant commonly prescribed for maternal depression, has an unclear impact on offspring neurophysiology and behaviour. We hypothesized that maternal mirtazapine treatment during pregnancy and lactation would influence locomotor activity, exploratory behaviour, and hippocampal synaptic plasticity in rat offspring, particularly in the context pre-gestational stress.Offspring from control or chronically stressed dams, treated with either vehicle or mirtazapine, were assessed. Behavioural responses were evaluated using the open field test, and the hippocampus was examined electrophysiologically to measure population spike (PS) amplitude of compound action potential, field excitatory postsynaptic potential (fEPSP) slope, short-term plasticity, and long-term potentiation (LTP).Maternal stress significantly reduced exploration of the central zone, indicating increased anxiety-like behaviour, although <i>post hoc</i> comparisons did not reach significance. Mirtazapine treatment did not reverse these behavioural alterations. PS amplitude was unaffected across groups, but fEPSP slope was significantly reduced in stressed offspring, with no recovery observed following mirtazapine treatment. Paired-pulse ratios across inter-pulse intervals (10-100 ms) were consistently decreased in the stressed group, indicating impaired short-term synaptic plasticity, which mirtazapine did not restore. In contrast, LTP showed a significant stress×treatment interaction (<i>p</i>=0.0201), suggesting that mirtazapine selectively enhanced long-term plasticity in stressed offspring.Mirtazapine did not reverse behavioural impairments or basal synaptic transmission deficits induced by maternal stress. It may selectively enhance long-term synaptic plasticity, suggesting its potential to modulate specific neurodevelopmental outcomes following prenatal stress exposure.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"308-319"},"PeriodicalIF":2.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinapic Acid Protects Mortality and Toxicity Induced by N-Ethyl-N-Nitrosourea, a Full Carcinogen Agent, in Mice.","authors":"Ahmad Salimi, Mahshad Pourgholi, Saleh Khezri, Shadi Haddadi, Bahare Asgari","doi":"10.1055/a-2687-0870","DOIUrl":"10.1055/a-2687-0870","url":null,"abstract":"<p><p>We investigated, in vivo, the chemopreventive efficacy of sinapic acid, as a known radical scavenger and antioxidant on mortality and toxicity in a N-ethyl-N-nitrosourea (ENU)-induced chronic lymphocytic leukemia (CLL) model in mice.Mice were divided into three groups: control (normal saline), ENU (80 mg/kg, i.p., single dose on day 31), and sinapic acid+ENU (pretreated with 30 mg/kg of sinapic acid, i.p., daily for 30 days, followed by 80 mg/kg of ENU). Body weight changes and mortality were monitored over 120 days. After this period, the animals were sacrificed, and lymphocytes, the target cells in CLL, were isolated and evaluated for various cellular parameters.Sinapic acid significantly (P<0.001) increased mouse survival up to 71%, delayed time of death, and prevented weight loss following ENU exposure. Additionally, sinapic acid inhibited the formation of reactive oxygen species (ROS) (P<0.001), lysosomal and mitochondrial dysfunction (P<0.001), and lipid peroxidation (P<0.05) in the isolated lymphocytes. These findings indicate a protective effect of sinapic acid against ENU-induced lethal toxicity.This study confirms that sinapic acid may serve as a promising chemopreventive agent against carcinogenicity induced by alkylating agents, primarily through the inhibition of oxidative stress and lysosomal/mitochondrial dysfunction.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"334-342"},"PeriodicalIF":2.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pembrolizumab-associated hepatobiliary disorders: a real-world pharmacovigilance study using the FDA Adverse Events Reporting System (FAERS).","authors":"Likun Ding, Ning Ma, Meiyou Liu, Di Zhang, JuanLi Zhang, Tingting Fan, Jingwen Wang","doi":"10.1055/a-2662-9565","DOIUrl":"10.1055/a-2662-9565","url":null,"abstract":"<p><p>The aim of this study was to evaluate hepatobiliary disorders adverse events associated with pembrolizumab by using the Food and Drug Administration Adverse Event Reporting System (FAERS).We collected FAERS data from the first quarter of 2009 to the third quarter of 2024 and used reporting odds ratio (ROR) to detect pembrolizumab-associated hepatobiliary adverse events (AEs). A signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and≥5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale.A total of 20,225,379 AEs were reported in the FAERS database, of which 45,774 AEs listed pembrolizumab as the 'primary suspected' drug. Pembrolizumab treatment was significantly associated with hepatobiliary disorders. Among these AEs, 101 signals were detected at the preferred term (PT) levels, and 56 of them were identified as significant signals by using disproportionality analyses. The median time-to-onset (TTO) was 63 days. Notably, most hepatobiliary AEs occurred within three months after pembrolizumab therapy.Based on pharmacovigilance data from FAERS, different hepatobiliary AEs should be closely monitored and managed according to the indications for which pembrolizumab is used.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"320-325"},"PeriodicalIF":2.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing FDA-Approved Drugs as Fructosamine-3-Kinase Inhibitors: A Mechanistic and Translational Approach to Redox-Driven Cancer Therapy.","authors":"Erica Alves, Gurupadayya Bannimath, Prabitha Prabhakaran","doi":"10.1055/a-2677-4956","DOIUrl":"10.1055/a-2677-4956","url":null,"abstract":"<p><p>Fructosamine-3-kinase (FN3K), a deglycating enzyme originally studied in the context of diabetes, has recently emerged as a pivotal modulator of redox homeostasis and therapeutic resistance in cancer. FN3K catalyzes the removal of early glycation adducts, thereby stabilizing redox-sensitive proteins such as Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcriptional regulator of antioxidant defense. This review explores the evolving role of FN3K in tumor metabolism, highlighting its expression patterns across cancer types, structural features amenable to therapeutic targeting, and mechanistic interplay with the Nrf2 pathway. Emphasis is placed on FDA-approved drugs with FN3K-modulatory potential, evaluated through computational modeling, docking simulations, and structure - activity insights. The analysis reveals a dual opportunity: to repurpose redox-active agents as FN3K inhibitors and to exploit FN3K as a biomarker for redox stratification in precision oncology. Despite promising in silico data and preclinical correlations, challenges remain - particularly in achieving target selectivity, overcoming structural limitations, and validating pharmacodynamic markers. Addressing these barriers through integrated translational strategies could unlock FN3K as a tractable node in redox-driven cancer therapy.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"295-307"},"PeriodicalIF":2.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145023070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming Drug Therapy with Deep Learning: The Future of Personalized Medicine.","authors":"Altaf Osman Mulani, Minal Deshmukh, Vaishali Jadhav, Kalyani Chaudhari, Ammu Anna Mathew, Shweta Salunkhe","doi":"10.1055/a-2682-5167","DOIUrl":"10.1055/a-2682-5167","url":null,"abstract":"<p><p>Personalized medicine represents a paradigm shift in healthcare, aiming to tailor treatment strategies to the unique genetic, environmental, and lifestyle characteristics of individual patients. This approach holds immense potential for improving therapeutic efficacy and minimizing adverse drug reactions. With the rapid advancement of artificial intelligence, deep learning has emerged as a transformative tool in pharmacology, enabling precise modeling of complex biological data and uncovering hidden patterns in patient-specific information. This study investigates the application of deep learning techniques - such as Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), Transformer architectures, and Generative Adversarial Networks (GANs) - in optimizing personalized treatment strategies. Using a diverse dataset comprising electronic health records (EHRs), genomic sequences, and clinical indicators, we developed and trained deep learning models for tasks including drug response prediction, biomarker identification, and adverse drug reaction (ADR) forecasting. Among the models evaluated, Transformer-based architectures demonstrated superior performance, achieving an accuracy of 91.2% and an AUC-ROC of 0.92 in drug response prediction tasks. Moreover, the integration of deep learning models into the treatment pipeline resulted in a 20-30% improvement in drug-patient matching efficiency compared to traditional statistical methods. The findings underscore the potential of AI-powered systems to enhance clinical decision-making and enable precision pharmacotherapy. However, challenges such as data privacy, model interpretability, and regulatory compliance remain critical barriers to widespread adoption. The study also explores future directions, including the implementation of explainable AI (XAI) and federated learning, to address these limitations and facilitate the integration of deep learning into routine clinical practice.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"326-333"},"PeriodicalIF":2.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144946690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and Therapeutic Assessment of Phytomediated Silver Nanoparticles Produced from the Stem Bark of Bombax ceiba.","authors":"Narendhar Dharavath, Mahendar Porika, Radhika Tippani, Anand Kishore Kola, Tomy Murigingayil Joseph, Maxim Shevtsov, Shirish H Sonawane","doi":"10.1055/a-2695-0339","DOIUrl":"https://doi.org/10.1055/a-2695-0339","url":null,"abstract":"<p><p>The study aims to develop an environmentally friendly method of producing silver nanoparticles using an extract from <i>Bombax ceiba</i> stem bark (<i>Bc</i>-AgNPs) and to investigate their potential medical applications, such as preventing blood cell damage, combating oxidation, and lowering inflammation. The synthesized <i>Bc</i>-AgNPs were characterized using UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy, and transmission electron microscopy (TEM). The zeta potential examination revealed a highly stable colloidal solution of <i>Bc</i>-AgNPs with a surface charge of-14 mV. The synthesized <i>Bc</i>-AgNPs had a face-centred cubic structure with a crystalline size of 26 nm and an average grain size of 59.8 nm, as seen in the TEM images. <i>Bc</i>-AgNPs showed no hemolysis at varied concentrations, but <i>B. ceiba</i> stem bark extract at 100 µg/mL caused 16.8±1.9% hemolysis, and Triton X-100 (0.1%; positive control) caused 99.1±0.4% hemolysis. <i>B. ceiba</i>'s aqueous extract contained flavonoid and phenolic components, which enhanced <i>Bc</i>-AgNPs' antioxidant capacity. The relative IC50 values were 28.03±0.98 µg/mL and 33.7±0.38 µg/mL. When compared to a reference medication, <i>Bc</i>-AgNPs demonstrated a moderate antiinflammatory effect, with IC50 values of 42.26±0.74 µg/mL for BSA and 50.93±1.07 µg/mL for egg albumin assay. According to the study, bio/hemocompatible <i>Bc</i>-AgNPs may be a viable treatment choice for antiinflammatory and antioxidant treatments.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lasmiditan in Migraine Management: An Advanced Review of Its Pharmacological Paradigm, Clinical Applications, Safety Considerations, Drug Interaction Spectrum, and Regulatory Approval.","authors":"Krutuja R Chougule, Archana S Patil, Swapnil Patil","doi":"10.1055/a-2695-0263","DOIUrl":"https://doi.org/10.1055/a-2695-0263","url":null,"abstract":"<p><p>This review offers an in-depth evaluation of Lasmiditan, a novel and selective 5-HT1F receptor agonist, representing a significant breakthrough in migraine pharmacotherapy. Unlike existing reviews, this article consolidates all critical aspects of Lasmiditan into a single, authoritative source encompassing both extensive literature analysis and original findings from our laboratory to provide researchers and clinicians with streamlined access to essential data and minimize the need for exhaustive literature searches.The review provides a comprehensive assessment of Lasmiditan, highlighting its physicochemical properties, pharmacological profile, mechanism of action, clinical efficacy and safety, drug interactions, and emerging insights from cell line studies. Lasmiditan's solubility influences its bioavailability and efficacy. It acts centrally without vascular constriction, unlike traditional therapies. Clinical trials confirm its rapid, effective migraine relief with mild side effects. Minimal drug interactions support its use in polypharmacy. Cell studies reveal its receptor activity and transport mechanisms, enhancing therapeutic understanding.Lasmiditan represents a groundbreaking addition to migraine therapeutics, providing a targeted, non-vasoconstrictive alternative. Its safety, tolerability, and efficacy make it a strong alternative for patients unsuitable for traditional treatments, with ongoing research likely to expand its clinical relevance.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic Induction of Apoptosis and Cell Cycle Arrest against Breast Cancer Cells by Combined Kaempferol and Paclitaxel.","authors":"Toofan Aghazadeh, Fatemeh Ramezani, Nuredin Bakhtiari, Isa Abdi Rad","doi":"10.1055/a-2637-1672","DOIUrl":"10.1055/a-2637-1672","url":null,"abstract":"<p><p>The study investigates the potential of combining Kaempferol (KAE) and Paclitaxel (PAC) to enhance anti-cancer effects and induce apoptosis in MDA-MB-468 triple-negative breast cancer cells and human normal foreskin fibroblast cells.For this porpose, the cells were treated with PAC, KAE, and their combination for 24, 48, and 72 hours. Cytotoxicity was assessed via MTT assay, and synergy was evaluated using Combination Index analysis. Apoptosis was quantified via Annexin V/PI staining and DAPI staining. Flow cytometry analyzed cell cycle arrest, while qPCR assessed apoptotic gene expression.The combination of KAE and PAC exhibited a synergistic anti-proliferative effect, significantly reducing MDA-MB-468 cell viability compared to monotherapies. Annexin V/PI staining revealed an increased apoptotic rate (73%) in co-treated cells, with enhanced chromatin condensation and nuclear fragmentation observed via DAPI staining. Flow cytometry indicated a marked increase in SubG1 phase cells, confirming apoptosis induction. Gene expression analysis demonstrated upregulation of pro-apoptotic BAD and downregulation of anti-apoptotic Bcl-2 and Mcl-1, highlighting the activation of apoptosis pathways.The combination of PAC and KAE enhances cytotoxicity, promotes apoptosis, and alters key apoptotic gene expressions in MDA-MB-468 cells while sparing normal fibroblast cells. These findings suggest a promising therapeutic strategy for triple-negative breast cancer.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"281-289"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of Prolonged Treatment with Pemafibrate plus an HMG-CoA Reductase Inhibitor in Japanese Patients with Type 2 Diabetes Mellitus.","authors":"Masataka Kusunoki, Fumiya Hisano, Shin-Ichi Matsuda, Akiko Kusunoki, Kazuhiko Tsutsumi, Tetsuro Miyata","doi":"10.1055/a-2560-9750","DOIUrl":"10.1055/a-2560-9750","url":null,"abstract":"<p><p>It has been suggested that caution should be exercised when using HMG-CoA reductase inhibitor (statin) in combination with a drug of the fibrate family because of the potentially elevated risk of development of hepatic function impairment and myopathy. We conducted this present study to evaluate the efficacy and safety of treatment with a statin plus pemafibrate (a new fibrate) versus treatment with pemafibrate alone in Japanese patients with type 2 diabetes mellitus.In this study, a total of 23 Japanese patients with type 2 diabetes mellitus were divided into two groups: a group that received pemafibrate alone and a group that received pemafibrate+a statin for a period of 3 years, respectively. Blood levels of lipids and hepatic and renal function parameters were measured before and one and three years after the start of treatment.The pemafibrate-alone group showed reduction of the blood lipid levels, but no adverse changes of the hepatic or renal function parameters were observed. Similarly, the combined pemafibrate+statin treatment group also showed lowering of the blood lipid levels without any adverse changes of the parameters.Improvement of the blood lipid profile was observed in patients who received prolonged treatment with pemafibrate. Similarly, improvement of the blood lipid profile without any adverse changes of the hepatic or renal function parameters was also observed in patients who received prolonged combined pemafibrate+statin treatment. Thus, our findings confirm the safety and efficacy of pemafibrate administered either alone or in combination with a statin.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"275-280"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin in Type 2 Diabetes Mellitus: A Natural Approach to Modulating Metabolic Dysfunction.","authors":"Rufaida Wasim, Sumaiya Azmi, Mohammad Owais, Aamir Anwar","doi":"10.1055/a-2604-4115","DOIUrl":"10.1055/a-2604-4115","url":null,"abstract":"<p><p>A complex and multifaceted metabolic disease, type 2 diabetes mellitus (T2DM) is becoming a significant public health concern. Due to their many biological characteristics, bioactive compounds from herbal medicine have been shown in multiple studies to have positive benefits on the prevention and control of type 2 diabetes. The scientific community is becoming more interested in curcumin, one of these therapeutic herbs. The plant Curcuma longa, often known as turmeric, has a bioactive compound called curcumin in its rhizome. Antioxidant, cardio-protective, anti-inflammatory, anti-microbial, nephro-protective, anti-neoplastic, hepato-protective, immunomodulatory, hypoglycemic, and anti-rheumatic effects are among the various pharmacological and biological effects of curcumin that have been reported by both in vitro and in vivo studies. Curcumin extract increases -cell functioning, delays the onset of diabetes, inhibits -cell death, and lowers insulin resistance in animal models. Recent preclinical studies and clinical trials have shown strong evidence of curcumin's vital roles in preventing type 2 diabetes via a number of pathways. Thus, the antidiabetic action of curcumin and its many mechanisms are comprehensively summarized in this study. The findings indicated that curcumin's anti-inflammatory, anti-oxidant, antihyperglycemic, antiapoptotic, and antihyperlipidemic properties, among others, account for its success in treating type 2 diabetes. These findings suggest that curcumin could be a potential option for T2DM prevention and management.</p>","PeriodicalId":11451,"journal":{"name":"Drug Research","volume":" ","pages":"251-260"},"PeriodicalIF":2.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}