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《Journal of pharmaceutical sciences》2019,108(10):3425-3433
This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation. 相似文献
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Rik C. Schoemaker Joop M. A. van Gerven Adam F. Cohen 《Journal of pharmacokinetics and pharmacodynamics》1998,26(5):581-593
The most widely applied model relating drug concentrations to effects is the Emax
model. In practice, concentration–effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side effects. The parameters for the Emax
model can only be estimated with reasonable precision if the curve shows sign of reaching a maximum, otherwise both EC50
and Emax
estimates may be extremely imprecise. This paper provides a solution by introducing a new parameter (S0
) equal to Emax/EC50
that can be used to characterize potency adequately even if there are no signs of a clear maximum. Simulations are presented to investigate the nature of the new parameter and published examples are used as illustration. 相似文献
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川芎嗪的药动-药效学研究近况 总被引:13,自引:0,他引:13
川芎嗪是一种活性生物碱,其在体内代谢迅速,排泄较快,临床应用广泛,综述了近几年的药效学及药动学研究成果,并提出存在问题和未来研究的前景。 相似文献
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The aqueous humor concentration of phenylephrine and its corresponding mydriatic response were measured over time in New Zealand albino rabbit eyes following a 10-µl topical instillation of a phenylephrine HC1 viscous solution (10%) or a phenylephrine oxazolidine (prodrug) suspension in sesame oil (1 and 10%). The bioavailability of a 1% prodrug suspension in the rabbit eye (AUC of aqueous humor concentration vs time) was 30% lower than that of a 10% phenylephrine solution (P < 0.1) with the exception that the peak time occurred 34 min earlier with the prodrug. A 10% prodrug suspension increased the aqueous humor bioavailability approximately eightfold but improved the mydriatic activity (AUC of mydriasis vs time) only fourfold. The pharmacokinetic parameters, apparent absorption, and elimination rate constants, of phenylephrine and the prodrug were determined from aqueous humor concentration–time and mydriasis–time profiles. The study showed that the kinetic parameters of phenylephrine estimated from its mydriasis profile do not accurately reflect the kinetics of drug distribution in the iris. These parameters also varied with the instillation of phenylephrine solution or prodrug suspensions. A mydriatic tolerance of the pupil response was apparent after the topical instillation of phenylephrine solution. The mydriatic tolerance may be due to the decrease in receptor number in the iris dilator muscle. 相似文献
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目的:对五虎汤制剂及其有效部位群的镇咳、平喘、化痰作用进行药效学比较。方法:采用二氧化硫引咳、枸橼酸引咳、组胺—乙酰胆碱引喘和气管酚红排泄实验进行研究。结果:二者能显著延长二氧化硫及枸橼酸引咳的潜伏期;能显著延长组胺-乙酰胆碱混合液喷雾所致豚鼠喘息发作的潜伏期。结论:有效部位群各剂量组的疗效与同剂量制剂组在止咳、平喘、化痰作用上基本相当。 相似文献
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The influence of different levels of enflurane anaesthesia on infusion requirements of vecuronium was studied in 40 adult surgical patients. Ninety percent neuromuscular block was maintained by computer controlled infusion of vecuronium. During the first 90 min study period all patients received fentanyl-nitrous oxide-oxygen (2:1) anaesthesia. For the following 90 min the patients were randomly assigned to receive enflurane at different end-tidal concentrations: group I, control, fentanyl-nitrous oxide anaesthesia; group II, enflurane 0.3%-nitrous oxide; group III, enflurane 0.6%-nitrous oxide; group IV, enflurane 0.9%-nitrous oxide. Every patient served as his/her own control and the changes of vecuronium infusion requirements were determined individually. When the administration of enflurane was started, vecuronium infusion requirements decreased progressively until 90 min. In group II the infusion rate lowered from 80±28 to 56±20 μg . kg-1 . h -1 , in group III from 61 ±29 to 34±17 μg . kg-1 . h-1 and in group IV from 65±20 to 30± 14 μg . kg-1 . h-1 . In the control group the infusion rate decreased during the three hour study period from 69± 17 (first 90 min period) to 59± 16 μg . kg-1 . h-1 (second 90 min period). Enflurane reduces the dose requirements of vecuronium administered by continuous infusion in a dose- and time-dependent manner. 相似文献
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Stijnen Annemiek M. Hovinga Suzanne Langemeijer Mariska W. E. Hoogerkamp Arendien van Bezooijen Cornells F. A. Danhof Meindert 《Pharmaceutical research》1993,10(7):1046-1051
The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg · L–1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.Suzanne Hovinga: Deceased January 30, 1991. 相似文献