The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products最新文献

{"title":"Criteria for Evaluation of Clinical Efficacy of Anticancer Medicines","authors":"A. V. Tikhomirova","doi":"10.30895/1991-2919-2019-9-1-34-40","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-1-34-40","url":null,"abstract":"Criteria for evaluation of clinical efficacy make it possible to assess the risk-benefit ratio of anticancer medicines that patients receive, in particular, for the treatment of solid malignant tumors. A medicine’s efficacy is assessed using special criteria called the endpoints of clinical efficacy, allowing most objective assessment of study results. It was demonstrated that nowadays clinical efficacy of anticancer drugs is assessed using «patient-centered» (overall survival and quality of life) and «tumor-centered» (response to therapy, progression-free survival, disease-free survival) endpoints. «Patient-centered» endpoints make it possible to evaluate the direct clinical benefit of chemotherapy in patients, while «tumor-centered» endpoints allow for evaluation of efficacy at earlier stages, without directly reflecting the clinical benefit. The analysis of the most suitable endpoints with the aim of making them interchangeable with the primary outcome measure – overall survival – is becoming more and more relevant in oncology. The choice of criteria of efficacy should be made taking into account the specific features of a particular oncological disease, study population and duration of therapy. The authors of the study analysed Russian and foreign literary sources containing information on criteria of efficacy of anticancer medicines and highlighted the advantages and disadvantages of these criteria. The study showed that clinical endpoints should be clinically significant, sensitive to therapy, easy to measure and interpret. It was demonstrated that comprehensive evaluation of outcome measures makes it possible to adequately assess the risk-benefit ratio of anticancer medicines.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78374397","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":"Conceptualisation of an Information Analytical Database of Reference Standards","authors":"D. P. Andreev, A. V. Kozlovich","doi":"10.30895/1991-2919-2019-9-1-49-53","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-1-49-53","url":null,"abstract":"The article summarises the main results of a study investigating integrated development and implementation of an information analytical database of reference standards in the Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of Russia (FSBI «SCEEMP»). The subject of the research is an information analytical database of reference standards designed to assess the quality, efficacy and safety of medicines. The aim of the study was to create the concept of an information analytical database of reference standards based on object-oriented approaches. The database was created in response to the need for improving the efficiency of certain types of activities of the FSBI «SCEEMP» which has already automated some of its processes. The paper discusses the key prerequisites for the creation of an integrated specialised information technology product as a way to improve overall performance. A general procedure for the development of an information and analytical database is presented, taking into account the tasks set and the established requirements for the functionality of the information and analytical system. The paper describes the implemented solutions, as well as strategies for their improvement. The operation algorithms of the information-analytical database of reference materials allow for its further modernisation, as well as greater automation of actions with documents and data, incorporation of new standardised reference books, ready-made templates, as well as modification  in case any changes are made to business processes, legislation or technical and technological aspects of using reference standards.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78897902","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":"Application of HPLC for Evaluation and Standardisation of Hawthorn Flower Herbal Substance","authors":"N. Antonova, E. Shefer, N. E. Semenova, A. Kalinin, S. S. Prokhvatilova, I. M. Morgunov","doi":"10.30895/1991-2919-2019-9-3-177-183","DOIUrl":"https://doi.org/10.30895/1991-2919-2019-9-3-177-183","url":null,"abstract":"The process of harmonisation of Russian and foreign approaches and requirements in the field of medicines quality assurance calls for revision of quality control procedures included in various regulations and guidelines. The monograph FS.2.5.0062.18 “Hawthorn flowers” of the State Pharmacopoeia of the Russian Federation XIV edition includes a test procedure for determination of flavonoids by a chromatospectrophotometric method. This procedure does not take into account current scientific capabilities and has a number of shortcomings, therefore it was necessary to revise the existing test procedure and develop a new approach to the standardisation of the hawthorn flower herbal substance.The objectiveof the studywas to develop an assay method for standardisation and evaluation of hawthorn flower using high performance liquid chromatography (HPLC).Materials and methods:the study was performed using samples of hawthorn flowers by Russian manufacturers. Quercetin (USP RS) and Hyperoside (HWI, primary standard) were used as the reference standards. The HPLC analysis was performed using an Infinity II 1260 DAD LC system (Agilent), and the UV spectra were recorded on a Cary 100 Varian spectrophotometer. A TLC Visualizer (CAMAG) was used to obtain digital images of thin layer chromatography plates.Results:the authors developed an HPLC test procedure for quantitative determination of total flavonoids, expressed as hyperoside, in hawthorn flowers. The developed procedure gives reliable and reproducible results and is characterised by high sensitivity and selectivity. The results of quantitative determination of the total flavonoid content in hawthorn flowers were used to propose the standard for the total content of flavonoids, expressed as hyperoside, of “not less than 0.5%”.Conclusions:the developed assay method for determination of active pharmaceutical ingredients in hawthorn flower products by HPLC can be recommended for inclusion into the Assay part of the “Hawthorn Flowers” monograph of the State Pharmacopoeia of the Russian Federation.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90257176","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":"MODERN ASPECTS OF HOMEOPATHIC MEDICINES STANDARDISATION","authors":"E. I. Sakanyan, N. Tereshina, M. N. Lyakina","doi":"10.30895/1991-2919-2018-8-3-145-150","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-3-145-150","url":null,"abstract":"The article describes the status of homeopathic medicines standardisation in the leading world pharmacopoeias. It reviews main requirements for raw materials of plant, animal, and mineral origin, which are used in the production of homeopathic medicines. It also considers requirements for homeopathic pharmaceutical substances, including technologies of obtaining homeopathic mother tinctures, homeopathic dilutions, triturations, etc., mono- and multi-component homeopathic medicines, as well as quality control of homeopathic substances and homeopathic medicines. The article analyses the nomenclature of homeopathic raw materials and homeopathic substances used by the leading world pharmacopoeias. It dwells upon the results of work devoted to the development of requirements for the following homeopathic dosage forms: homeopathic granules, homeopathic eye drops, homeopathic ointments, homeopathic infusions and decoctions,  homeopathic mother tinctures,  homeopathic solutions for injection,  homeopathic solutions and liquid dilutions,  homeopathic syrups, homeopathic mixtures,  homeopathic suppositories, homeopathic tablets, homeopathic triturations.  The article illustrates significant potential of using vibrational spectroscopy and Raman spectroscopy for the detection of distinctive features of homeopathic medicines at ultra-high dilutions. The article presents methodology for structuring pharmacopoeial standards for raw materials used in the production of pharmaceutical substances, for pharmaceutical substances that are used in homeopathic medicines, and for dosage forms, including specific aspects of production and standardisation of homeopathic medicines, which was implemented during preparation of draft monographs for the State Pharmacopoeia of the Russian Federation.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74342923","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":"CURRENT REQUIREMENTS FOR THE QUALITY OF HERBAL MEDICINAL PRODUCTS","authors":"E. I. Sakanyan, E. L. Kovaleva, L. N. Frolova, V. V. Shelestova","doi":"10.30895/1991-2919-2018-8-3-170-178","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-3-170-178","url":null,"abstract":"The article provides the results of a comparative analysis of requirements laid out in the State Pharmacopoeia of the USSR, XI ed. (SPh XI) and the State Pharmacopoeia of the Russian Federation, XIII ed. (SPh XIII) concerning  quality evaluation and standardization of herbal substances, herbal medicines and other herbal products. The article discusses requirements  for the criteria of herbal substances and herbal medicines quality control described in general chapters and monographs that were previously in force and that have recently been adopted. The article mentions new herbal substances that were included into the State Pharmacopoeia of the Russian Federation for the first time as well as herbal substances included into the State Pharmacopoeia of the USSR, X ed., not included into SPh XI, but included into SPh XIII. The article analyses the requirements described in the new general chapters that were recently included into SPh XIII: “Herbal substances. Herbal preparations”, “Determination of heavy metals and arsenic content in herbal substances and herbal medicinal  products”, “Determination of water absorption  factor for herbal substances”,  “Buds”, “Cut-pressed granules”. The article suggests ways to improve methods of analysis of herbal substances and herbal medicinal products in view of recent advances in pharmacopoeial analysis and the increasing requirements for its quality.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78779136","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":"ELIMINATION OF FALSE RESULTS OF MEDICINES MICROBIOLOGICAL TESTING","authors":"I. A. Buylova, N. Sakhno, G. M. Bulgakova, O. Gunar","doi":"10.30895/1991-2919-2018-8-3-187-192","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-3-187-192","url":null,"abstract":"The validity of medicines microbial quality testing relies on the adequacy of the test procedure employed. The aim of the study was to analyse factors triggering false results during microbial quality testing of non-sterile  medicinal products, as well as to find ways of their elimination.  Materials and methods: the study was focused on non-sterile  medicinal products tested for microbial quality: N-methylglucamine, L-Malic  acid, Xeroform, Fingolimod hydrochloride, Succinic  acid, Streptocide,  Aripiprazole, Doxazosin, Clopidogrel,  Moxonidine, Tilorone,  Mycophenolic acid, Folic acid, Gabapentin, Dutasteride, Imatinib,  Temozolomide. The study involved the use of the following test strains: Bacillus subtilis, Bacillus cereus, Candida albicans, Escherichia coli, Aspergillus brasiliensis, as well as of reagents and growth media. The methods  used were determination of antimicrobial  activity under conditions of microbial quality testing, and modified in-depth  testing of microbial quality of medicinal products according to the requirements of the State Pharmacopoeia of the Russian Federation, 13th edition. Results: the analysis of literature sources helped reveal the main factors causing false results of microbiological  testing and determine  ways of their elimination.  The article sets forth the results of experimental comparison of two ways of sample preparation  for solid formulations: the standard one described in the State Pharmacopoeia of the Russian Federation, 13th edition, and the one involving the use of a laboratory shaker. The article provides experimental data on specific aspects of elimination of antimicrobial activity against B. subtilis and B. cereus and the use of specific inactivators for particular medicinal products. Conclusions: a set of measures aimed at prevention of false-positive and false-negative testing results should include: sterility control of the growth media and reagents used, monitoring  of facilities; control of growth promotion  properties and selectivity of the growth media; selection of adequate incubation  conditions  and inoculation procedure with due regard to the dosage form; justification of the amount of sample, diluents and dilution factor used; consideration  of the antimicrobial activity of a medicinal product.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79878509","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":"ANALYSIS OF THE RESULTS OF USING AMINO, AMIDE AND NITRILE SORBENTS IN HYDROPHILIC INTERACTION LIQUID CHROMATOGRAPHY","authors":"A. S. Osipov, O. Popova, S. G. Larionova","doi":"10.30895/1991-2919-2018-8-3-162-170","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-3-162-170","url":null,"abstract":"The article summarises the results of studies of hydrophilic  interaction  liquid chromatography performed  from 2013 until 2017. The analysis of results obtained  during separation  of a number  of model mixtures of compounds  having different nature  helped to compare  the characteristics  of columns  packed with amino,  amide and nitrile sorbents. It was demonstrated that columns packed with amino sorbents could be used for the analysis of both hydrophilic compounds  and some hydrophobic compounds  containing acidic (4-hydroxybenzoic acid) and potentially acidic groups (nitro groups of nitro compounds;  phenolic hydroxyl groups of butylhydroxyanisole isomers and parabens). It was discovered that chromatographic columns packed with nitrile and amide sorbents have common properties and can be used for the analysis of hydrophilic compounds (hydroxycarbamide) and platinum coordination compounds, but cannot be used for the analysis of butylhydroxyanisole isomers, esters of p-hydroxybenzoic acid and nitrate  esters of isosorbide. The article offers hypotheses about possible mechanisms  of interaction  between test substances and sorbents. It was concluded  that the increase in the acetonitrile  content  in mobile phases, which increases the retention time of the test substances and results in better resolution between their peaks, illustrates the mechanism  of hydrophilic interaction  liquid chromatography.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85325534","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":"PLANNING AND EVALUATION OF BIOEQUIVALENCE STUDIES OF ATAZANAVIR PRODUCTS","authors":"Наталия Евгеньевна Уварова, Н. Н. Еременко, Г. В. Раменская, Дмитрий Владимирович Горячев","doi":"10.30895/1991-2919-2018-8-3-151-157","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-3-151-157","url":null,"abstract":"The Government of the Russian Federation approved the State strategy of combating the spread of HIV aimed at prevention of HIV epidemic. One of the goals of the Strategy is to increase the coverage of antiretroviral therapy for people infected with HIV, which includes extensive use of generic drugs. In order for a generic drug to be authorised, the applicant has to submit a report on the results of the bioequivalence studies in which the generic product was compared to the reference product. Atazanavir is an antiretroviral drug, which is also the drug of choice for the treatment and prevention of mother-to-child transmission of HIV. The aim of this study was to analyze the protocols and reports of atazanavir products bioequivalence studies, which were submitted for expert examination  to the FSBI “SCEEMP” of the Ministry of Health of the Russian Federation, and to prepare recommendations  for planning of bioequivalence studies of atazanavir products. The analysis of a number of studies revealed significant differences in the study design and number of subjects. The main reason for these differences is the conflicting data on the intrasubject coefficient of variation of atazanavir, which means that atazanavir may be considered a highly variable drug. The analysis helped to formulate  recommendations for the design of bioequivalence  studies of atazanavir products,  including studies of the maximum dose, studies under fed conditions, and consideration  of atazanavir variation when planning the study design.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85780693","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":"EXPERIMENTAL TESTING OF AN IN VIVO METHOD OF PHOTOTOXICITY EVALUATION","authors":"V. Vavilova, E. Shekunova, V. Kashkin, M. Makarova, V. Makarov, A. Y. Khaymenov","doi":"10.30895/1991-2919-2018-8-2-115-122","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-2-115-122","url":null,"abstract":"At present all new medicinal products and cosmetics that absorb medium-wavelength UVB, long-wavelength UVA, or visible light in the range 290–700 nm need to be tested for potential phototoxicity. phototoxicity is evaluated by both in vitro and in vivo methods. There are guidelines for in vitro phototoxicity evaluation, however, there are no formally validated protocols for in vivo phototoxicity evaluation. The purpose of this study was to test an economically viable and informative method for in vivo evaluation of tetracycline and ketorolac phototoxicity using outbred rats. Two medicinal products potentially capable of causing clinically established phototoxic reactions were used in this study: tetracycline (tablets, 200 mg/kg and 300 mg/kg) and ketorolac (gel, 13.4 mg/kg, 26.8 mg/kg and 40.3 mg/kg). The medicines were administered in both single and multiple doses. Ultraviolet irradiator OUFK-03 (OOO «Solnyshko», Russia) was used as a light source. The UV exposure (5 J/cm2 and 15 J/cm 2 ) was performed once 1 h after medicine administration. The skin reaction was evaluated 30 minutes and 24 hours after irradiation and then daily for 2 weeks. As a result, the following optimal parameters were determined for in vivo evaluation of phototoxic reactions caused by the medicines: radiation intensity — 15 J/cm 2 for single systemic administration and 5 J/cm 2 for single topical (dermal) administration; recommended period of skin reaction evaluation for outbred rats is not less than 7 days.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83740340","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":"EXPERIMENTAL TESTING OF THE MODIFIED METHOD OF INTRAVITREAL INJECTION IN THE RABBIT EYE","authors":"A. Kalatanova, A. Katelnikova, M. Makarova, V. Makarov","doi":"10.30895/1991-2919-2018-8-2-109-114","DOIUrl":"https://doi.org/10.30895/1991-2919-2018-8-2-109-114","url":null,"abstract":"the article describes theoretical foundations and successful experimental testing of a modified method of intravitreal injection (ivi) in the rabbit eye performed in the laboratory. the method needed modification because preoperative preparation described in available guidelines on ivi requires the use of medicines that are not suitable for use in vivariums in the russian federation. the ivi procedure for rabbits was modified by using an anesthetic regime reproducible in russia and available eye preparations. the anesthetics used were Zoletil 50 («virbac», france) at a dose of 1.1 mg/kg and rometar («Bioveta, a.s.», czech republic) at a single intravenous dose of 5.6 mg/kg. additional analgesia was achieved by a single intramuscular injection of Ketonal («lek d.d.», Slovenia) at a dose of 5 mg/kg. the local anesthetic used was inokain eye drops («promed exports pvt. ltd.», india), the antiseptic used was Betadine (JSc «eGiS pharmaceutical plant», hungary) diluted with water in the proportion of 1:10. the results of clinical examination of animals following ivi performed by lab researchers during unassisted skill training were analysed, and the results of assessment of adverse reactions associated with ivi were expressed as scores and reflected in primary records. the suggested method demonstrated good reproducibility and, therefore, may be recommended for use in preclinical studies of ophthalmic drug products in russia.","PeriodicalId":22286,"journal":{"name":"The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80140154","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}