The pharmacokinetics of milbemycin oxime was investigated in dogs following oral(per os, PO) and intravenous(IV) administration. Three groups of dogs received milbemycin oxime tablets as a single PO dose equal to 0.25...The pharmacokinetics of milbemycin oxime was investigated in dogs following oral(per os, PO) and intravenous(IV) administration. Three groups of dogs received milbemycin oxime tablets as a single PO dose equal to 0.25, 0.5 and 1.0 mg · kg-1 of milbemycin oxime, respectively, another group received a single IV dose of 0.5 mg · kg-1. Blood samples were collected at predetermined times after drug administration and the milbemycin oxime concentrations in plasma were determined by LC-MS/MS. The drug protein binding in dog plasma in vitro was determined by equilibrium dialysis at concentrations spanning the range of values observed in vivo in dog plasma. After PO administration at doses of 0.25, 0.5 and 1.0 mg · kg-1, milbemycin oxime was slowly absorbed and eliminated, the time to reach the maximum plasma concentration(Tmax) was 4.14±0.20, 4.27±0.14 and 4.06±0.13 h, the mean absorption time(MAT) was 19.06, 13.67 and 11.77 h, the terminal rate half-life(t1/2λz) was 15.06±0.37, 11.09±0.54 and 9.76±0.89 h and the total body clearance(Cl) was 1.15±0.05, 1.18±0.03 and 1.17±0.07 m L · min-1 · kg-1, respectively. The maximum plasma concentration(Cmax, 36.50±1.40, 76.11±2.77 and 182.05±7.20 ng · m L-1, respectively) and the area under the first-moment curve(AUC-10→∞, 985.83±49.46, 1 663.12±51.42 and 3 558.04±197.88 mg · h · L, respectively) increased accordingly to the administered dose rates; the oral bioavailabilities were estimated to be 88.61%, 74.75% and 79.96%, respectively. The values of fu were 0.12%, 0.14% and 0.13% in dog plasma, respectively. In conclusion, the pharmacokinetics of milbemycin oxime in dogs following oral administration revealed its higher oral bioavailability and advantageous pharmacokinetic properties, such as its lower total body clearance and longer elimination half-life, and indicated that the single oral dose of 0.50 mg · kg-1 of milbemycin oxime which was recommended in all the parasitological efficacy studies allowed an adequate concentration of the drug.展开更多
OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated ...OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.展开更多
Two mathematical models are developed in this paper to study the effectiveness of system administration efforts on the improvement of system availability, based on the assumption that there exists a transitional state...Two mathematical models are developed in this paper to study the effectiveness of system administration efforts on the improvement of system availability, based on the assumption that there exists a transitional state for a computer system in operation before it is brought down by some hardware or software problems and with intensified system administration efforts, it is possible to discover and fix the problems in time to bring the system back to normal state before it is down. Markov chain is used to simulate the transition of system states. A conclusion is made that increasing system administration efforts may be a cost-effective way to meet the requirements for moderate improvement on system availability, but higher demand on this aspect still has to be met by advanced technologies.展开更多
《公共行政评论》(Journal of Public Administration,JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准...《公共行政评论》(Journal of Public Administration,JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准,以学术品质为用稿标准,向国内外学术界、实务界热忱征集言之有物、论之有据、符合学术规范、遵守学术道德的论文、理论综述、书评、评论和博士学位论文摘要。展开更多
《公共行政评论》(Journal of Public Administration,JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准...《公共行政评论》(Journal of Public Administration,JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准,以学术品质为用稿标准,向国内外学术界、实务界热忱征集言之有物、论之有据、符合学术规范、遵守学术道德的论文、理论综述、书评、评论和博士学位论文摘要。展开更多
《公共行政评论》(Journal of Public Administration, JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标...《公共行政评论》(Journal of Public Administration, JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准,以学术品质为用稿标准,向国内外学术界、实务界热忱征集言之有物、论之有据、符合学术规范、遵守学术道德的论文、理论综述、书评、评论和博士学位论文摘要。展开更多
通过药物治疗使耳鸣减轻或消失是医患双方的共同期待,因而寻找有效治疗耳鸣的药物一直是耳鸣研究的重点之一。国内外学者在耳鸣的药物治疗方面进行着不懈的探索,所得结果不尽相同,尚未能形成药物治疗方面的共识[1~3];而且,至今没有任何...通过药物治疗使耳鸣减轻或消失是医患双方的共同期待,因而寻找有效治疗耳鸣的药物一直是耳鸣研究的重点之一。国内外学者在耳鸣的药物治疗方面进行着不懈的探索,所得结果不尽相同,尚未能形成药物治疗方面的共识[1~3];而且,至今没有任何药物被FDA（food and drug administration）或者EMEA（european medicines agency）标识为＂耳鸣治疗用药，医生始终在为没有疗效确切的药物可用于治疗耳鸣而苦恼。展开更多
in the early period of southern song,Emperor GaoZong and XiaoZong ages,the court tired to offer and support the war horses for his cavalries by breeding.So the emperors and government had erected some horse farm in di...in the early period of southern song,Emperor GaoZong and XiaoZong ages,the court tired to offer and support the war horses for his cavalries by breeding.So the emperors and government had erected some horse farm in different areas in order to propagate and breed horses but faced with a sea of troubles they finally had to give up after successive failures.The horse breeding was an important affair in horse administrations of southern song,the author of this article had make an general collection for the records of the topic and offered us a more comprehensive introduction.展开更多
The motor cortex plays a key role in motor control as its output directly generates movement.However,it is known that the motor cortex also exhibits a high degree of plasticity that may be important in both health and...The motor cortex plays a key role in motor control as its output directly generates movement.However,it is known that the motor cortex also exhibits a high degree of plasticity that may be important in both health and disease.Here I provide evidence to support that dopaminergic innervation arising from the midbrain plays critical roles in the process of acquiring novel motor skills as well as recovery of motor functions after ischemic stroke.Based on extracel ular multi-unit recordings from conscious freely moving rats,we investigated the dynamics of neurons in the output layer 5b(L5b)of the primary motor cortex during the training of a forelimb reaching for food task.We found a subpopulation of task-recruited layer 5b neurons that not only became more movement-encoding during motor learning,but their activities were also more temporally aligned to motor execution.These phenomena were accompanied by the emergence of reproducibleneurodynamics of the L5b neuronal ensemble and traininginduced long-term synaptic plasticity of inputs to these neurons,but were highly disrupted by local denervation of dopaminergic inputs originating from the ventral tegmental area.In another series of experiments based on rodent models of focal ischemic stroke,administration of L-DOPA,the precursor of dopamine,significantly promoted motor function recovery.Morphological and biochemical examination of the perilesioned area provided evidence that neuroplasticity markers,dendritic arborisation and synaptic plasticity were increased by the treatment.Further examination of neuronal activity through in vivo recording revealed that motor cortical regions adjacent to the infarct had restored capability for synaptic plasticity.Finally,pharmacological blockade of either D1 or D2 receptors at the perilesioned region abolished the beneficial effects.Together,our findings highlight the importance of the plasticity of the motor cortex in health and disease that are mediated by the mesocortical dopaminergic pathway.展开更多
基金Supported by Natural Science Fund of Heilongjiang Province(C201424)
文摘The pharmacokinetics of milbemycin oxime was investigated in dogs following oral(per os, PO) and intravenous(IV) administration. Three groups of dogs received milbemycin oxime tablets as a single PO dose equal to 0.25, 0.5 and 1.0 mg · kg-1 of milbemycin oxime, respectively, another group received a single IV dose of 0.5 mg · kg-1. Blood samples were collected at predetermined times after drug administration and the milbemycin oxime concentrations in plasma were determined by LC-MS/MS. The drug protein binding in dog plasma in vitro was determined by equilibrium dialysis at concentrations spanning the range of values observed in vivo in dog plasma. After PO administration at doses of 0.25, 0.5 and 1.0 mg · kg-1, milbemycin oxime was slowly absorbed and eliminated, the time to reach the maximum plasma concentration(Tmax) was 4.14±0.20, 4.27±0.14 and 4.06±0.13 h, the mean absorption time(MAT) was 19.06, 13.67 and 11.77 h, the terminal rate half-life(t1/2λz) was 15.06±0.37, 11.09±0.54 and 9.76±0.89 h and the total body clearance(Cl) was 1.15±0.05, 1.18±0.03 and 1.17±0.07 m L · min-1 · kg-1, respectively. The maximum plasma concentration(Cmax, 36.50±1.40, 76.11±2.77 and 182.05±7.20 ng · m L-1, respectively) and the area under the first-moment curve(AUC-10→∞, 985.83±49.46, 1 663.12±51.42 and 3 558.04±197.88 mg · h · L, respectively) increased accordingly to the administered dose rates; the oral bioavailabilities were estimated to be 88.61%, 74.75% and 79.96%, respectively. The values of fu were 0.12%, 0.14% and 0.13% in dog plasma, respectively. In conclusion, the pharmacokinetics of milbemycin oxime in dogs following oral administration revealed its higher oral bioavailability and advantageous pharmacokinetic properties, such as its lower total body clearance and longer elimination half-life, and indicated that the single oral dose of 0.50 mg · kg-1 of milbemycin oxime which was recommended in all the parasitological efficacy studies allowed an adequate concentration of the drug.
基金The project supported by the National Training Program of Innovation and Entrepreneurship for Undergraduates(201610439108)
文摘OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.
基金This project was supported by the National Key program of Science and Technology(99-A29-0101).
文摘Two mathematical models are developed in this paper to study the effectiveness of system administration efforts on the improvement of system availability, based on the assumption that there exists a transitional state for a computer system in operation before it is brought down by some hardware or software problems and with intensified system administration efforts, it is possible to discover and fix the problems in time to bring the system back to normal state before it is down. Markov chain is used to simulate the transition of system states. A conclusion is made that increasing system administration efforts may be a cost-effective way to meet the requirements for moderate improvement on system availability, but higher demand on this aspect still has to be met by advanced technologies.
文摘《公共行政评论》(Journal of Public Administration,JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准,以学术品质为用稿标准,向国内外学术界、实务界热忱征集言之有物、论之有据、符合学术规范、遵守学术道德的论文、理论综述、书评、评论和博士学位论文摘要。
文摘《公共行政评论》(Journal of Public Administration,JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准,以学术品质为用稿标准,向国内外学术界、实务界热忱征集言之有物、论之有据、符合学术规范、遵守学术道德的论文、理论综述、书评、评论和博士学位论文摘要。
文摘《公共行政评论》(Journal of Public Administration, JPA)采用严格的匿名评审制度,致力于为国内外所有有志于公共管理研究的人士构建平等的交流平台,营造一个温暖的精神家园。现不拘作者专业、身份与地域,以聚焦公共管理领域为征稿标准,以学术品质为用稿标准,向国内外学术界、实务界热忱征集言之有物、论之有据、符合学术规范、遵守学术道德的论文、理论综述、书评、评论和博士学位论文摘要。
文摘通过药物治疗使耳鸣减轻或消失是医患双方的共同期待,因而寻找有效治疗耳鸣的药物一直是耳鸣研究的重点之一。国内外学者在耳鸣的药物治疗方面进行着不懈的探索,所得结果不尽相同,尚未能形成药物治疗方面的共识[1~3];而且,至今没有任何药物被FDA（food and drug administration）或者EMEA（european medicines agency）标识为＂耳鸣治疗用药，医生始终在为没有疗效确切的药物可用于治疗耳鸣而苦恼。
文摘in the early period of southern song,Emperor GaoZong and XiaoZong ages,the court tired to offer and support the war horses for his cavalries by breeding.So the emperors and government had erected some horse farm in different areas in order to propagate and breed horses but faced with a sea of troubles they finally had to give up after successive failures.The horse breeding was an important affair in horse administrations of southern song,the author of this article had make an general collection for the records of the topic and offered us a more comprehensive introduction.
基金The project supported by NSFC grant(SZRIA0314025)SRFDP-HKRGC grant(2900703)+1 种基金HKGRF grant(2140903)HMRF grant(02130976)
文摘The motor cortex plays a key role in motor control as its output directly generates movement.However,it is known that the motor cortex also exhibits a high degree of plasticity that may be important in both health and disease.Here I provide evidence to support that dopaminergic innervation arising from the midbrain plays critical roles in the process of acquiring novel motor skills as well as recovery of motor functions after ischemic stroke.Based on extracel ular multi-unit recordings from conscious freely moving rats,we investigated the dynamics of neurons in the output layer 5b(L5b)of the primary motor cortex during the training of a forelimb reaching for food task.We found a subpopulation of task-recruited layer 5b neurons that not only became more movement-encoding during motor learning,but their activities were also more temporally aligned to motor execution.These phenomena were accompanied by the emergence of reproducibleneurodynamics of the L5b neuronal ensemble and traininginduced long-term synaptic plasticity of inputs to these neurons,but were highly disrupted by local denervation of dopaminergic inputs originating from the ventral tegmental area.In another series of experiments based on rodent models of focal ischemic stroke,administration of L-DOPA,the precursor of dopamine,significantly promoted motor function recovery.Morphological and biochemical examination of the perilesioned area provided evidence that neuroplasticity markers,dendritic arborisation and synaptic plasticity were increased by the treatment.Further examination of neuronal activity through in vivo recording revealed that motor cortical regions adjacent to the infarct had restored capability for synaptic plasticity.Finally,pharmacological blockade of either D1 or D2 receptors at the perilesioned region abolished the beneficial effects.Together,our findings highlight the importance of the plasticity of the motor cortex in health and disease that are mediated by the mesocortical dopaminergic pathway.
