E. Mansilla, R. Martínez, G. Marín, I. Filho, E. Rivas, Jaime Rivas, K. Carvalho, M. Dayer, Ali Samadikuchaksaraei
{"title":"Macrolide-Clarithromycin Task-Force for the Treatment and Prophylaxis of Covid-19 as a Single Agent","authors":"E. Mansilla, R. Martínez, G. Marín, I. Filho, E. Rivas, Jaime Rivas, K. Carvalho, M. Dayer, Ali Samadikuchaksaraei","doi":"10.4236/pp.2020.116009","DOIUrl":"https://doi.org/10.4236/pp.2020.116009","url":null,"abstract":"SARS-CoV-2 is a novel RNA coronavirus responsible of \u0000a deadly pandemic: the clinical illness COVID-19. With only one authorized drug \u0000for emergency use in critically ill patients: Remdesivir, there is not any \u0000other approved drug or vaccine yet with proven potential to overcome this \u0000infection. We exposed here many scientific evidences to support our novel idea \u0000that a macrolide, basically Clarithromycin, could be effective as a single \u0000agent for treatment and prophylaxis of COVID-19. Clarithromycin could change \u0000the history of this pandemic. It could reduce the costs of treatment and the \u0000potential adverse effects when combining more than one drug such as with \u0000Hydroxychloroquine. Clarithromycin treatment and prophylaxis as a single agent \u0000could be much more simple, safe and cheaper as giving Chloroquine or \u0000Hydroxychloroquine alone or in combination with Azithromycin as well as other \u0000therapeutic options.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78927975","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}
Jamie L. McConaha, Phil Lunney, J. Kitzen, J. Pergolizzi, Robert W. Taylor, R. Raffa
{"title":"E-Cigarette Survey among Student Pharmacists Reveals Troubling Results","authors":"Jamie L. McConaha, Phil Lunney, J. Kitzen, J. Pergolizzi, Robert W. Taylor, R. Raffa","doi":"10.4236/pp.2020.116012","DOIUrl":"https://doi.org/10.4236/pp.2020.116012","url":null,"abstract":"The rise in “vaping”-associated deaths in the United \u0000States raises serious concerns. A justification for some level of risk is that \u0000e-cigarettes might provide a “reverse-gateway” from smoking traditional cigarettes to a less-harmful alternative. But are users actually smokers? We developed an electronic \u0000on-line survey to gather data regarding e-cigarette usage in a target study \u0000population of pharmacy students. The survey was created using Google Forms to \u0000collect the responses anonymously. We surveyed medical-savvy healthcare \u0000students about their e-cigarette use, and whether or not their healthcare \u0000providers were aware of their e-cigarette use. Although nearly one-fourth of a \u0000convenience sampling of 134 pharmacy-student respondents (23.9%) reported using \u0000e-cigarettes, only 2.0% reported prior regular cigarette use, 28% used \u0000cartridges containing nicotine and only 11.2% had tried and wanted to quit. The \u0000majority (64.1%) reported that their healthcare providers did not ask about \u0000such use, and respondents did not volunteer this information. The results of \u0000this pilot survey reveal a significant e-cigarette use among health-aware \u0000pharmacy students, and they do not support the notion that the respondents do \u0000so to quit smoking. The observation that most of the students’ healthcare \u0000providers did not inquire about their e-cigarette use, coupled with the finding \u0000that users did not volunteer their vaping behavior, suggests that the information should be included \u0000when getting a medical history. Further research is needed to determine what \u0000behavioral factors may play a role in this type of decision-making among \u0000student healthcare professionals.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77346598","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":"“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Development","authors":"R. Raffa, J. Pergolizzi, Robert Taylor","doi":"10.4236/pp.2020.111001","DOIUrl":"https://doi.org/10.4236/pp.2020.111001","url":null,"abstract":"Many therapeutic drugs are racemates; i.e. they are chiral molecules consisting of “left”- and “right-handed” \u0000enantiomers (stereoisomers that are mirror images \u0000of each other, and are non-superimposable). In some cases, both enantiomers \u0000of the drug contribute to some extent (or equally) to the therapeutic effect; in other cases they contribute not at all. The same is true for the \u0000adverse effects of racemate drugs: the adverse effects of a racemate drug can \u0000be greater-than, less-than, or equal to one or the other enantiomer. An unusual \u0000situation arises when a drug consists of “atropisomers”, stereoisomers arising \u0000because of hindered rotation about a single chemical bond. We summarize the \u0000concept of atropisomerism, and give examples.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84634700","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}
S. Paul, Md. Nur Islam, Md. Ashraf Ali, R. Barman, M. I. I. Wahed, B. M. Rahman
{"title":"Improvement of Dissolution Rate of Gliclazide Using Solid Dispersions with Aerosil 380 and Its Effect on Alloxan Induced Diabetic Rats","authors":"S. Paul, Md. Nur Islam, Md. Ashraf Ali, R. Barman, M. I. I. Wahed, B. M. Rahman","doi":"10.4236/PP.2019.108030","DOIUrl":"https://doi.org/10.4236/PP.2019.108030","url":null,"abstract":"The main objective of this research is to conduct a comprehensive study for enhancing the aqueous solubility of poorly water soluble gliclazide using hydrophilic fumed silica particles (Aerosil® 380) and evaluating the influence of silica on drug release profile and pharmacological activity on alloxan induced diabetic rats. Solid dispersions (SD’s) of gliclazide were prepared using solvent evaporation method. The dissolution profiles and solid state characterization of the SD’s prepared were all evaluated. The dissolution rate of gliclazide in the SD’s with fumed silica (weight ratio, 1:1) was approximately 38%, which is about 10 fold higher than that of the pure drug after 30 min. After forming the SD’s, gliclazide changed into an amorphous state, which can infer from differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Fourier transform infrared spectroscopy (FTIR) also revealed the formation of weak hydrogen bonding through the interactions between the secondary amine groups of gliclazide and silanol groups of silica particles in the SD’s. The rapid dissolution rate from the SD’s might be attributed to the amorphization of drug, improved specific surface area and wettability than the original drug crystals. Further, we investigated the antidiabetic effects of SD’s of gliclazide in alloxan induced diabetic rats. The SD’s of gliclazide decrease the blood glucose level 64% whereas the conventional gliclazide decreases only 37% in diabetic rats. Lipid profiles, kidney and liver functions are remarkably improved in diabetic rat treated with SD’s of gliclazide than that of conventional gliclazide. These results suggest that SD’s of gliclazide have much more bioavailability and hence are more pharmacologically active than that of conventional gliclazide form.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90153576","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":"TNF Type-I Receptor Inhibitor, R-7050 Attenuates Acute Kidney Injury in a Mouse Model of Crush Syndrome","authors":"S. Mizuno, E. Osaki, Hiroyuki Ohnishi","doi":"10.4236/PP.2018.912043","DOIUrl":"https://doi.org/10.4236/PP.2018.912043","url":null,"abstract":"Crush syndrome (CS) is caused by severe and extensive muscular skeletal damages, and acute kidney injury (AKI) with hyperkalemia is one of the most lethal factors of this syndrome. Especially under natural disasters of earthquake, many persons die due to AKI and hyperkalemia-induced cardiac arrest, but there has been no pathogenesis-based drugs for preventing CS-induced AKI. Pro-inflammatory cytokines, such as TNF-α and IL-6, play a critical role for induction of AKI during CS development. Glycerol-injected mice are used as an experimental tool for reflecting pathological events of human CS. Using this popular model, we provide evidence to show that TNF type-I receptor (TNFR1) inhibitor, R-7050 significantly attenuates the onset of AKI after the muscular destruction. In this process, R-7050 treatment suppressed the NF-κB activation in the affected kidney, and this was associated with a decrease in blood IL-6, a downstream target of NF-κB. As a result, renal tubular apoptosis became milder in the R-7050-treated CS mice. These findings suggest that induction of IL-6 via sequential events of TNF-α a TNFR1 a NF-κB is contributable for renal tubular apoptosis, a histological hallmark of AKI. Thus, TNFR1-selective inhibition can be a pharmacological strategy to attenuate the onset of AKI immediately after the clinical manifestation of rhabdomyolysis.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80258620","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}
S. Kouakou, M. Ouattara, J. P. N'Guessan, S. Coulibaly, A. G. Irié-N’guessan, G. Kouakou-Siransy
{"title":"Antioxidant and Cytotoxicity Potential of Six Synthesized Chalcones","authors":"S. Kouakou, M. Ouattara, J. P. N'Guessan, S. Coulibaly, A. G. Irié-N’guessan, G. Kouakou-Siransy","doi":"10.4236/PP.2018.912042","DOIUrl":"https://doi.org/10.4236/PP.2018.912042","url":null,"abstract":"Background: Chalcones are open-chain flavonoids which display a large number of pharmacological activities such as cytotoxic, anti-inflammatory including antioxidant. The objective of this study was to assess antioxidant and cytotoxic activity of six synthesized chalcones. Methodology: For the current experiments, 1,3-diphenylpropenone (compound R) was used as molecular model to synthetize six compounds, namely three benzyl-benzimidazolyl-chalcones (U1, U2, WAC1) and three imidazopyridinyl-chalcones (V1, V2, V3). All the compounds were evaluated for their ability to scavenge the stable free ABTS.+ radical cation, according to the method develop by Choong et al. In addition, the cytotoxicity test described by Price et al., was performed using healthy human cell line, then in human malignant cell lines (HEP-2, A549). Results: All synthesized chalcones reduced the ABTS.+ radical cation. Indeed, benzyl benzimidazolyl compounds WAC1, U1, U2, by developing respectively 39.61%, 66.09%, and 84.20% percentages of reduction, showed an antioxidant effect 6, 11 and 14 times greater than the compound R (6.14%). As a result, imidazopyridinyl-chalcones compounds, namely V1, V2 and V3 reduced the ABTS.+ radical cation at 91.62%, 99.84% and 97.45% respectively, being 15 and 16 times more active than the compound R. About cytotoxicity, V2 inhibited not significantly HEP-2 malignant cells growth at 48.64%, compared to the standard product, i.e. doxorubicin that inhibited the growth of the same cells at 42.37%. WAC1 inhibited significantly the growth of A549 malignant cells at 89.53%, more than doxorubicin which percentage of growth inhibition was 71.58%. Conclusion: The presence of the α, β-unsaturated carbonyl system (or 1,3-diphenylpropenone) along with a benzimidazole or imidazopyridine heterocyclic ring is likely to contribute to both cytotoxic and antioxidant activities of these compounds.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76884649","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":"Study of Factors Affecting Medical Incident: 1. Dispensing","authors":"Yuka Miyachi, Chika Nakayama, Kazuyo Nagashiba, K. Kinoshita, Masayuki Takeuchi, Masafumi Ohnishi, Hiroko Saito, Taeyuki Oshima","doi":"10.4236/PP.2018.912041","DOIUrl":"https://doi.org/10.4236/PP.2018.912041","url":null,"abstract":"In recent years, medical institutions have taken a \u0000variety of measures to prevent medical incident. In addition, progress has been \u0000made toward the development of a fully automated system for the purpose of \u0000medicine dispensing. However, automating the dispensing, or having it replaced \u0000by artificial intelligence (AI) will not, eradicate human error. Thus, measures \u0000against human error will continue to serve as an important topic. Therefore, \u0000hospitals are required to improve the efficiency of the pharmacy department. \u0000For these purposes, attention has now shifted to Supply Processing and \u0000Distribution (SPD). In this study, we measured for the gaze of the pharmacist \u0000and SPD, and examined the factors affecting dispensing error; moreover, we \u0000examined prevention of the human error. In the results of the eye tracking, SPD \u0000members tended to spend a greater number of gaze time and gaze counts, for each \u0000medicine, on “medicines” and “picking lists,” than pharmacists. On the other \u0000hand, when pharmacists picking medicines, they performed various work \u0000operations in parallel, such as checking the prescription and looking the next \u0000shelf location. It was conjectured that SPD members had more clearly defined \u0000items to check when picking, compared to pharmacists. This may have possibly \u0000led to a lower chance of dispensing errors being introduced by SPD members. \u0000These results suggest that the process of selection is not a mandatory \u0000requirement of pharmacists during the action of dispensing. Instead, SPD \u0000members, pharmacy assistants, or automatic dispensing devices could serve as \u0000substitutes for picking. It is suggested that pharmacists should spend more \u0000time and effort on prescription inspection, medicines checking and dosing \u0000operations.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73158285","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":"Onset Time Profiles for Syncope Associated with α 1 -Adrenoceptor Blockers in Males: Analysis of a Spontaneous Adverse Drug Event Database","authors":"K. Ohyama, Masaya Furumoto, M. Sugiura","doi":"10.4236/PP.2018.912040","DOIUrl":"https://doi.org/10.4236/PP.2018.912040","url":null,"abstract":"Background: α1-Adrenoceptor blockers (α1Bs) are used for the treatment of benign prostatic hyperplasia and hypertension, but they are known to cause hypotension-related adverse events. The objective of the present study was to evaluate the onset time profiles for syncope associated with the use of α1Bs. Methods: We analyzed the data obtained from the Japanese Adverse Drug Event Report (JADER) database for a period from April 2004 until November 2016 and calculated reporting odds ratios (RORs) for eight α1Bs available on the Japanese market, using disproportionality analysis. Moreover, time information recorded in the JADER database was analyzed to evaluate the onset times of adverse events. Results: In total, 186,724 reports for males older than 20 years were analyzed. Significant RORs for syncope, with 95% confidence intervals, were obtained for naftopidil (2.53, 1.81 - 3.53), silodosin (4.24, 2.37 - 5.20), and tamsulosin (2.22, 1.75 - 2.81). The median onset times of syncope for naftopidil, silodosin, and tamsulosin were 37, 26, and 108 days, respectively. The shape parameters obtained by fitting the data for the three α1Bs to the Weibull distribution were all less than 1.0, indicating that all these drugs could be classified as the early failure type. The cumulative incidence rates showed that the onset times of syncope tended to be similar among the three α1Bs. Conclusions: Patients treated with selective α1Bs should be closely monitored for 100 days, especially in the first 20 to 40 days after initiation of silodosin or naftopidil. This information may be useful for patients and healthcare professionals in preventing syncope due to the use of selective α1Bs.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77994496","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}
Md Rashidur Rahman, Mohammad Ali, Mostakim Sharif, S. Sajon, M. Mannan, Md. Shahed-Al-Mahmud
{"title":"Antidepressant-Like Activity of Methanolic Extract of the Seeds of Trachysperum ammi in Swiss Albino Mice","authors":"Md Rashidur Rahman, Mohammad Ali, Mostakim Sharif, S. Sajon, M. Mannan, Md. Shahed-Al-Mahmud","doi":"10.4236/PP.2018.912039","DOIUrl":"https://doi.org/10.4236/PP.2018.912039","url":null,"abstract":"Trachysperum ammi has been traditionally used for the treatment of neurological disorders such as depression and anxiety. To date, T. ammi has reported for its chemical constituents in different diseases condition. The traditional evidence convinced us to perform the antidepressant-like activity of methanolic extract of Trachysperum ammi (META). The antidepressant activity of META assessed by using forced swimming test (FST), tail suspension test (TST), and locomotor activity test. The seed parts of META at doses level of 50, 100 and 200 mg/kg body weight administered orally to examine the CNS stimulants activity test in mice behavioral models. Here, we reported that META significantly reduced immobility time in the FST after repeated administration of 50, 100 and 200 mg/kg to mice for 14 days. The intensity of immobility significantly reduced at all of the doses (p < 0.05) whereas, we were found the strongest effect observed at 200 mg/kg. The antidepressant-like effect of META caused the reduction (p < 0.05) in the immobility in TST of mice when orally administered with 50, 100 and 200 mg/kg for 14 days, respectively. Additionally, we were executed locomotor activity test to check the motor stimulating activity. META has employed at a dosage of 50, 100 and 200 mg/kg for 14 days, the results have found that 50 mg/kg produced the locomotion effects as similar to the control group. Interestingly, the locomotion, rearing, and defecation significantly (p < 0.05) increased at the dosage of 100 and 200 mg/kg of META. Our present findings suggest that the seed parts of Trachysperum ammi may possess antidepressant-like activity which may use as a supportive treatment to management of neurological disorders.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75927917","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":"Surprising Separation of Cannabinoid Physical Dependence and Withdrawal in an Invertebrate Model","authors":"Wanhui Sheng, R. Raffa","doi":"10.4236/PP.2018.912038","DOIUrl":"https://doi.org/10.4236/PP.2018.912038","url":null,"abstract":"Planarians have mammalian-like neurotransmitter systems and have been established as a novel in vivo model for neuropharmacology. In previous research, planarians that have been exposed to the cannabinoid receptor (CB-R) agonist WIN 55,212-2 for 1 h displayed abstinence-induced withdrawal when tested in drug-free, but not in drug-containing, water. The goals of the present study were to extend previous work and to further establish a cannabinoid behavioral model with planarians. The results showed 1) four different CB-R antagonists (AM251, AM281, SLV319 and SR144528) dose-relatedly blocked development of physical dependence induced by two different CB-R agonists (WIN 55,212-2 and JWH251); 2) none of the same four antagonists (AM251, AM281, SLV319 or SR144528) precipitated withdrawal; 3) short wavelength (254 nm), but not long wavelength (366 nm), ultraviolet (UV) light attenuated abstinence-induced withdrawal from WIN 55,212-2, while short wavelength UV light induced moderate withdrawal behavior. The results confirm the use of a planarian model as a simple yet robust way to study development of physical dependence to cannabinoid agonists. The effect of UV irradiation adds to the evidence that the results are receptor-related. The results also give rise to the surprising suggestion, within the limitations of the methodology, that development of cannabinoid physical dependence and antagonist-induced precipitated withdrawal might be separable phenomena in planarians.","PeriodicalId":19875,"journal":{"name":"Pharmacology & Pharmacy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76492302","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}