Developmental pharmacology and therapeutics最新文献

{"title":"Supplementation and plasma levels of vitamin A in premature newborns at risk for chronic lung disease. Italian Collaborative Group on Preterm Delivery (ICGPD).","authors":"","doi":"10.1159/000457555","DOIUrl":"https://doi.org/10.1159/000457555","url":null,"abstract":"<p><p>Deficiency of vitamin A (retinol) has been suggested as an important contributing cause in the pathogenesis of bronchopulmonary dysplasia (BPD) in premature newborns with severe lung disease. Although the efficacy of vitamin A supplementation has yet to be clearly confirmed, it is widely employed, at different dosages and schedules, in neonatal intensive care units (NICU). Since in Italy today no suitable formulation of vitamin A is available, the present observational study was designed to define the profile of plasma vitamin A and retinol-binding protein (RBP) concentrations in supplemented infants at risk for BPD admitted to seven Italian NICU. Twelve babies (average 27 weeks of gestation, birth weight 1,008 g), supplemented with vitamin A, were observed with sequential measurements of retinol and RBP up to 28 days of age. At birth retinol and RBP plasma concentrations were both adequate in the infants and half their mothers' levels. During supplementation the levels rose with wide variability according to the differences in dosing and timing in the different units. Plasma levels of retinol and RBP were the same in infants who had BPD and those who did not. A routine standardized therapeutic approach using vitamin A supplementation in Italian NICU will be more than welcome.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18826978","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":"Relative contribution of endothelium-derived relaxation factor to vascular tone in the systemic, pulmonary, and cerebral circulations of piglets.","authors":"B Rudinsky,&nbsp;A Bell,&nbsp;R Hipps,&nbsp;W Meadow","doi":"10.1159/000457556","DOIUrl":"https://doi.org/10.1159/000457556","url":null,"abstract":"<p><strong>Unlabelled: </strong>We determined the contribution of endothelium-derived relaxation factor (EDRF) to vascular tone in the systemic, pulmonary, and cerebral circulations of piglets.</p><p><strong>Methods: </strong>11 piglets were anesthetized and mechanically ventilated. Systemic cardiac output was determined by an electromagnetic flow probe placed on the main pulmonary artery. Cerebral blood flow was assessed by determining unilateral internal carotid artery blood flow (ICBF) using a flow probe placed on the common carotid artery after ligation of the ipsilateral external carotid circulation. Progressive inhibition of EDRF was achieved by continuous infusion of the substituted L-arginine analog N-nitro-L-arginine (NNLA). Hemodynamic observations were compared at 0, 0.1, 1.0, 10, 30, and 80 mg/kg cumulative dose of NNLA.</p><p><strong>Results: </strong>At all NNLA doses > or = 1 mg/kg, both systemic blood pressure and systemic vascular resistance were elevated. At all NNLA doses > or = 10 mg/kg, systemic cardiac output was reduced. At all NNLA doses > or = 10 mg/kg, pulmonary artery pressure and pulmonary vascular resistance were elevated. Although cerebral vascular resistance was elevated at all NNLA doses > or = 10 mg/kg, ICBF was maintained at or near baseline values up to a dose of 80 mg/kg. At all levels of EDRF inhibition, both the pulmonary and systemic circulations demonstrated approximately equal magnitudes of vasoconstriction. In contrast, at 30 and 80 mg/kg cumulative dose of NNLA, the cerebral circulation was relatively less constricted by NNLA than was the systemic circulation. Systemic VO2 was significantly reduced at 30 mg/kg and 80 mg/kg cumulative NNLA dose, while cerebral VO2 was preserved at both NNLA doses.</p><p><strong>Conclusions: </strong>EDRF contributes to resting vasodilator tone in the systemic, pulmonary, and cerebral circulations in piglets. Progressive inhibition of EDRF constricts the systemic and pulmonary circulation equally. Inhibition of EDRF does not impair the ability of the brain to vary cerebral vascular resistance in order to redistribute blood flow towards itself during a period of reduced cardiac output.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18826979","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":"Comparison of acceptance of clinical versus basic studies on drugs and therapeutics in infants and children.","authors":"G Koren,&nbsp;N Klein","doi":"10.1159/000457557","DOIUrl":"https://doi.org/10.1159/000457557","url":null,"abstract":"<p><p>Many clinicians and clinician-scientists have serious concerns that clinical studies (i.e. studies with patients) are less favorably accepted than basic ('bench') projects by funding agencies and by promotion committees of university departments. However, this commonly held view has not been previously verified. To test whether bias exists against clinical studies, we compared the acceptance rate of clinical vs. basic studies dealing with drugs and therapeutics in children, which were submitted to a large scientific meeting. Of 197 abstracts reporting on drug/therapeutic studies, submitted to the Society for Pediatric Research in 1993, there were 133 clinical and 64 basic studies. Fifty-nine (44.3%) of the clinical studies were accepted, significantly less than the basic projects (n = 47 or 73.4%, p < 0.0001). A basic paper was 66% more likely to be accepted (95% CI 50.7-82.6%). This trend was consistent for different groups of drugs/therapeutics, including analgesics, surfactants, corticosteroids, vaccines, hormones, and antiasthmatics. To examine whether the lower rate of acceptance of clinical papers is the result of lower scientific standard, all papers were scored for their quality by raters who were blinded to their acceptance or rejection status. In general, rejected clinical papers scored significantly higher than rejected basic papers (16 +/- 1.8 vs. 14.8 +/- 1.0, p < 0.05). Our study supports the commonly held but previously unproven view that there is a bias against clinical research, in the context of patient-based studies, when compared to basic (bench) research.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457557","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18826980","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":"Developmental differences in the electrophysiological response of isolated canine Purkinje fibers to adrenergic stimulation during simulated ischemia.","authors":"A Fenrich,&nbsp;M Hamra","doi":"10.1159/000457543","DOIUrl":"https://doi.org/10.1159/000457543","url":null,"abstract":"<p><p>Developmental differences in adrenergic responsiveness may cause age-related changes in the cellular response to ischemia. Standard microelectrode techniques were used in isolated young and adult canine Purkinje fibers to determine the effect of simulated ischemia ([K+]o = 10 mM, pH 6.7, pO2 < 25 mm Hg) alone or with adrenergic stimulation on the rhythmic activity in spontaneously beating Purkinje fibers and on transmembrane potentials and delayed afterdepolarizations in paced Purkinje fibers (basic cycle length = 800-300 ms). The adrenergic agonists used were phenylephrine (5 x 10(-8) M) and isoproterenol (1 x 10(-6) M). For all automatic fibers studied, the control maximum diastolic potential in adults (-96 +/- 1 mV, n = 37) and in the young (-98 +/- 1 mV, n = 36) went to -62 +/- 1 mV during ischemia in both groups and returned to -96 +/- 2 mV with reperfusion. The incidence of rhythmic activity (expressed as percent) during ischemia alone was similar at both ages: adults, 22%; young, 25%. The incidence of ectopic activity with phenylephrine superfusion during ischemia for adults was 63%, an effect blocked by prazosin (1 x 10(-6) M) but not by propranolol (2 x 10(-7) M); the incidence for the young was 25%. Isoproterenol caused ectopic rhythms in 86% of young fibers and 17% of adult fibers (p < 0.05 young vs. adult). During reperfusion the return to control rhythm was slower in adults after ischemia alone or ischemia + alpha-adrenergic stimulation with phenylephrine. There were no age-related differences in the transmembrane potential response of paced fibers to ischemia or reperfusion, and there were no delayed afterdepolarizations with interruption of pacing at 800, 500, or 300 ms in either group. These data suggest that age-related differences in adrenergic responses alter the cellular response to an ischemic insult. To the extent that an ectopic beat may initiate an abnormal rhythm, these differences in sensitivity to adrenergic agonists may lead to developmental differences in arrhythmogenic potential during ischemia.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457543","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18921690","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":"Pharmacokinetics of amikacin in neonates.","authors":"E M Padovani,&nbsp;C Pistolesi,&nbsp;V Fanos,&nbsp;A Messori,&nbsp;N Martini","doi":"10.1159/000457558","DOIUrl":"https://doi.org/10.1159/000457558","url":null,"abstract":"<p><p>Only a few data have thus far been published on the pharmacokinetics of amikacin in neonates. To gain further information on this issue, we studied a series of 32 neonates who were treated with amikacin for suspected or documented bacterial infection. Nineteen neonates were preterm (mean gestational age = 32.0 +/- 3.6 weeks, mean body weight = 1.74 +/- 0.81 kg) while the remaining 13 were full-term (mean body weight = 3.19 +/- 0.82 kg). The 32 neonates were given amikacin by intramuscular route. A total of 121 concentrations were measured (average number of concentrations per patient = 3.8; range 3-6). To estimate amikacin pharmacokinetic parameters, the serum concentration values of the drug were fitted to the one-compartment pharmacokinetic model. The calculated pharmacokinetic parameters were the following (mean +/- SD): clearance = 64.6 +/- 30.8 ml/h/kg; volume of distribution = 0.655 +/- 0.414 liters/kg; half-life = 7.6 +/- 4.4 h. These results are similar to the values reported previously, with the important exception of the volume of distribution, which was considerably higher in our study. The intraindividual variability of amikacin pharmacokinetics was evaluated by the standard two-stage method yielding an intraindividual variability coefficient of 28.9%. No previous estimate of this parameter has as yet been published. The population parameters of amikacin in neonates, derived from the present study (i.e. coefficient for intraindividual variability and means +/- SD for clearance and volume of distribution), can be applied to a further series of neonates to facilitate the prospective use of the bayesian method for individualizing amikacin dosage.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457558","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18826981","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":"Influence of sympathetic nervous system on dexamethasone-stimulated renal tubular transport of p-aminohippurate in young rats.","authors":"H Bräunlich,&nbsp;S Rössler,&nbsp;C Gerhardt","doi":"10.1159/000457544","DOIUrl":"https://doi.org/10.1159/000457544","url":null,"abstract":"<p><p>After simultaneous administration of dexamethasone together with 6-hydroxydopamine or adrenergic neuronal blocking agents (alpha-methyldopa, reserpine, guanethidine) the dexamethasone-stimulated increase in renal excretion of p-aminohippurate (PAH) is distinctly diminished. The same is true for dopamine. This depressive effect could be proved by measurement of transport rates of PAH in renal cortical slices in vitro. The increase in kidney weight and in the protein content of kidney tissue in dexamethasone-treated rats is lower in rats simultaneously treated with adrenergic neuronal blocking agents of 6-hydroxydopamine. Adrenoceptor agonists and antagonists (pholedrine, orciprenaline, phentolamine, propranolol) are without influence on the dexamethasone-stimulated increase in PAH transport.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18921691","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":"Effect of nimodipine on cerebral and organ blood flow in normal and posthypoxemic newborn piglets.","authors":"J P Odden,&nbsp;E B Roll,&nbsp;C Hall,&nbsp;D Bratlid","doi":"10.1159/000457548","DOIUrl":"https://doi.org/10.1159/000457548","url":null,"abstract":"<p><p>Using the isotope-labelled microsphere method, blood flow to the brain, the heart and the kidneys were studied in newborn piglets during nimodipine infusion. Twenty piglets were studied in two different groups. Group 1 (n = 8) was kept normoxic and given a continuous nimodipine infusion (15 micrograms/kg/min). Group 2 (n = 12) was made hypoxemic by breathing 10% O2 for 10 min followed by an identical nimodipine infusion as group 1. In spite of a significant systemic hypotension, nimodipine infusion alone significantly increased blood flow in the brain stem and right cardiac ventricle at 30-60 min of infusion, while blood flow to cerebellum, cerebrum and the left cardiac ventricle did not change. Blood flow to the kidneys decreased significantly. In posthypoxemic piglets nimodipine infusion gave almost similar flow patterns, however, the changes appeared at an earlier time. We conclude that in spite of a significant reduction in blood pressure, cerebral and cardiac blood flow is preserved both in normal and posthypoxemic animals even at high doses of nimodipine. However, because of the decreased blood flow to the kidneys further dose-response studies are needed before clinical use in asphyctic newborns.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457548","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18923010","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":"Mechanisms of increased sensitivity to A2 adenosine receptor stimulation in immature rabbit aortic rings.","authors":"G P Matherne,&nbsp;P W Girling,&nbsp;N L McDaniel","doi":"10.1159/000457552","DOIUrl":"https://doi.org/10.1159/000457552","url":null,"abstract":"<p><p>Adenosine receptor-mediated vasodilation is increased in immature vessels compared to mature vessels. To determine the mechanism of this increased sensitivity, isolated vascular rings from mature and immature rabbits were studied to evaluate the contribution of the endothelium and the contribution of adenosine-dependent 3',5'-cyclic monophosphate (cAMP) to adenosine receptor-mediated relaxation. Dose responses were measured in endothelial-intact and nonendothelialized aortic rings using 5'-(N-ethylcarboxamido)-adenosine (NECA), a nonhydrolyzable adenosine agonist. Immature rings were more sensitive to NECA than mature rings as demonstrated by a lower ED50 and steeper slope of the dose-response curve. There was no effect on endothelial removal in immature rings while there was a significant decrease in response in mature rings. Despite being more sensitive to NECA, immature rings had less increase in cAMP (percent change from basal level) at maximal vasodilation than mature rings although cAMP did not change in either age at the ED50. The lack of change with endothelial removal in immature vessels suggests that the endothelium is not involved in the increased sensitivity of immature rings to NECA. The cAMP data suggests that other mechanisms for vasodilation are important at the ED50 for NECA in both ages. Maximal vasodilation with NECA on the other hand was associated with increases in cAMP although they were lower in the immature rings.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457552","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18826975","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":"Comparison of CNS adverse effects between astemizole and chlorpheniramine in children: a randomized, double-blind study.","authors":"A Shanon,&nbsp;W Feldman,&nbsp;L Leikin,&nbsp;A H Pong,&nbsp;R Peterson,&nbsp;V Williams","doi":"10.1159/000457568","DOIUrl":"https://doi.org/10.1159/000457568","url":null,"abstract":"<p><strong>Objective: </strong>To assess the central nervous system side effects of chlorpheniramine and astemizole in children.</p><p><strong>Design: </strong>Prospective, randomized, double-blind cross-over study.</p><p><strong>Setting: </strong>Children were recruited from the out-patient allergy clinic and from respondents to an advertisement in a local newspaper. The study was conducted in the outpatient clinics of the ambulatory care services of the Children's Hospital of Eastern Ontario.</p><p><strong>Patients, participants: </strong>Children 8-16 years of age, with isolated allergic rhinitis or hay fever, were eligible for the study. We excluded children with: (1) chronic conditions (specifically asthma, atopic dermatitis, learning disabilities, or current treatment with oral corticosteroid medication); (2) known allergy to the study medications; (3) recent use of any antihistamine medication. One hundred and three children entered the study and 92 completed it.</p><p><strong>Interventions: </strong>Children were stratified by age and randomly allocated to treatment with one of the two medication sequences. Over a period of 13 weeks both groups had 1 week of baseline studies, 3 weeks of one study medication, either chlorpheniramine or astemizole, a 6-week wash-out period and then 3 weeks of the other study medication for a second treatment period.</p><p><strong>Main outcome measures: </strong>Attention span (continuous performance test), short-term auditory and visual memory (visual aural digit span test), visual memory for geometric shapes (Benton visual retention test), motor coordination and visual-motor integration (grooved pegboard test), tapping speed and fine motor coordination (finger tapping test), physical side effects (such as sleepiness and dizziness), and compliance.</p><p><strong>Results: </strong>One hundred and three patients were enrolled in the study, 92 (89%) completed the study. There were no significant drug effects on the visual retention test and the continuous performance test. On the visual aural digit span test, patients treated with astemizole scored higher than at baseline. There were no clinical or statistical differences in adverse effects between the two medications or between each medication and baseline.</p><p><strong>Conclusions: </strong>The two antihistamines studied had no adverse effects on the performance of children.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457568","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18828155","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":"Age-related morphine kinetics in infants.","authors":"M L Pokela,&nbsp;K T Olkkola,&nbsp;T Seppälä,&nbsp;M Koivisto","doi":"10.1159/000457538","DOIUrl":"https://doi.org/10.1159/000457538","url":null,"abstract":"<p><p>The pharmacokinetics of morphine was studied in 27 infants receiving a single intravenous dose of 0.1 mg/kg morphine after surgery (n = 23) or during mechanical ventilation (n = 4). The pharmacokinetics of morphine varied greatly between the subjects, especially in the neonates. The clearance and half-life varied distinctly with postnatal age. The mean (+/- SD) half-life was 8.1 +/- 8.1 h in 10 neonates younger than 1 week, 5.4 +/- 3.4 h in 10 infants aged from 1 week to 2 months and 2.6 +/- 1.7 h in 7 infants aged from 2 to 6 months. Mean clearance increased significantly with age, being 8.7 +/- 5.8 ml/min/kg in the youngest age group, 11.9 +/- 5.1 ml/min/kg in those aged 1 week to 2 months and 28.0 +/- 8.9 ml/min/kg in those aged 2-6 months, and was also significantly lower in the critically ill infants. The clearance and half-life of morphine begin to approach adult values after the age of 1 month, but great individual variability exists even after that. In order to reduce the risk of overdosing or underdosing, the dose of morphine should be titrated individually.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1993-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18923013","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}