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61.
《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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63.
J.A. Hannam S.J. Mitchell D. Cumin C. Frampton A.F. Merry M.R. Moore C.J. Kruger 《British journal of anaesthesia》2019,122(2):198-205
Background
Etomidate is frequently selected over propofol for induction of anaesthesia because of a putatively favourable haemodynamic profile, but data confirming this perception are limited.Methods
Patients undergoing cardiac surgery were randomised to induction of anaesthesia with propofol or etomidate. Phase I (n=75) was conducted as open-label, whereas Phase II (n=75) was double blind. Mean arterial blood pressure (MAP) and boluses of vasopressor administered after induction were recorded. The primary endpoint was the area under the curve below baseline MAP (MAP-time integral) during the 10 min after induction. Secondary endpoints were the use of vasopressors over the same period, and the effect of blinding on the aforementioned endpoints. Groups were compared using regression models with phase and anaesthetist as factors.Results
The mean difference between etomidate and propofol in the MAP-time integral below baseline was 2244 mm Hg s (95% confidence interval, 581–3906; P=0.009), representing a 34% greater reduction with propofol. Overall, vasopressors were used in 10/75 patients in the etomidate group vs 21/75 in the propofol group (P=0.38), and in 20/74 patients during the blinded phase vs 11/76 during the open-label phase (P=0.31). The interaction between randomisation and phase (open-labelled or blinded) was not significant for either primary (P=0.73) or secondary endpoints (P=0.90).Conclusions
Propofol caused a 34% greater reduction in MAP-time integral from baseline after induction of anaesthesia than etomidate, despite more frequent use of vasopressors with propofol, confirming the superior haemodynamic profile of etomidate in this context. The proportion of patients receiving vasopressors increased slightly, albeit not significantly, in both groups in the blinded phase.Clinical trial registration
Australian and New Zealand Clinical Trials Registry, ACTRN12614000717651. 相似文献64.
《Journal of pharmaceutical sciences》2019,108(7):2500-2504
Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field. 相似文献
65.
范玲 《中华产科急救电子杂志》2020,9(3):133-135
远程胎儿监护是应用互连网及计算机技术,孕妇在家中或远程监护终端将胎心监护图形传输到中央监护站,医生即可通过电脑或手机APP远程判读。对高危孕妇实行远程监护,便于及时发现胎儿宫内缺氧情况和及时处理,改善围产儿结局。 相似文献
66.
《Ultrasound in medicine & biology》2015,41(12):3172-3181
Fetal activity parameters such as movements, heart rate and the related parameters are essential indicators of fetal wellbeing, and no device provides simultaneous access to and sufficient estimation of all of these parameters to evaluate fetal health. This work was aimed at collecting these parameters to automatically separate healthy from compromised fetuses. To achieve this goal, we first developed a multi-sensor–multi-gate Doppler system. Then we recorded multidimensional Doppler signals and estimated the fetal activity parameters via dedicated signal processing techniques. Finally, we combined these parameters into four sets of parameters (or four hyper-parameters) to determine the set of parameters that is able to separate healthy from other fetuses. To validate our system, a data set consisting of two groups of fetal signals (normal and compromised) was established and provided by physicians. From the estimated parameters, an instantaneous Manning-like score, referred to as the ultrasonic score, was calculated and was used together with movements, heart rate and the associated parameters in a classification process employing the support vector machine method. We investigated the influence of the sets of parameters and evaluated the performance of the support vector machine using the computation of sensibility, specificity, percentage of support vectors and total classification error. The sensitivity of the four sets ranged from 79% to 100%. Specificity was 100% for all sets. The total classification error ranged from 0% to 20%. The percentage of support vectors ranged from 33% to 49%. Overall, the best results were obtained with the set of parameters consisting of fetal movement, short-term variability, long-term variability, deceleration and ultrasound score. The sensitivity, specificity, percentage of support vectors and total classification error of this set were respectively 100%, 100%, 35% and 0%. This indicated our ability to separate the data into two sets (normal fetuses and pathologic fetuses), and the results highlight the excellent match with the clinical classification performed by the physicians. This work indicates the feasibility of detecting compromised fetuses and also represents an interesting method of close fetal monitoring during the entire pregnancy. 相似文献
67.
《中国现代医生》2020,58(34):60-63
目的 通过检测老年轻度认知障碍(MCI)患者血清瘦素(LEP)、甲状腺激素水平,分析其与局部脑血流量(rCBF)的关系。方法 选择本院收治的128 例老年MCI 患者,另选健康者128 例作为对照组。检测血清LEP、甲状腺激素、大脑各区域rCBF 水平并分析其相关性。结果 老年MCI 组患者左右侧额叶、右侧颞叶、左侧顶叶、左右侧基底节区域脑血流量[(43.81±8.62)mL/(100 g·min)、(43.24±7.93)mL/(100 g·min)、(45.14±6.98)mL/(100 g·min)、(45.86±6.77)mL/(100 g·min)、(67.95±8.52)mL/(100 g·min)、(68.36±8.34)mL/(100 g·min)]低于对照组[(46.39±8.31)mL/(100 g·min)、(46.52±8.56)mL/(100 g·min)、(47.37±7.04)mL/(100 g·min)、(48.25±6.98)mL/(100 g·min)、(70.34±8.96)mL/(100 g·min)、(70.58±8.57)mL/(100 g·min)](P<0.05)。老年MCI 组患者血清LEP、T3、FT3 水平[(4.87±1.56)μg/L、(1.21±0.16)nmol/L、(3.04±0.36)pmol/L]低于对照组[(11.45±3.92)μg/L、(1.68±0.21)nmol/L、(4.82±1.21)pmol/L](P<0.05),TSH 水平为(2.78±0.75)IU/mL,高于对照组的(1.13±0.38)IU/mL(P<0.05)。老年MCI 患者血清LEP 水平与左侧额叶、右侧颞叶、左侧顶叶rCBF 呈正相关(r=0.452、0.537、0.544,P 均<0.05),T3 水平与左侧额叶、右侧颞叶rCBF 呈正相关(r=0.427、0.521,P 均<0.05),FT3 水平与右侧颞叶rCBF 呈正相关(r=0.492,P<0.05),TSH 水平与左侧额叶、右侧颞叶rCBF 呈负相关(r=-0.463、-0.489,P 均<0.05)。结论 老年MCI 患者血清中LEP、T3、FT3 水平降低,TSH 水平升高,且与不同区域rCBF 有相关性,可通过调控脑血管功能影响rCBF 变化水平。 相似文献
68.
69.
黄芪始载于《神农本草经》,有补气升阳、益卫固表,利水消肿,托毒生肌之效。被誉为补气健脾之要药,临床上常用于气虚乏力、脾虚泄泻等疾病,已为医者所熟知。近年来,研究学者围绕其补气、健脾、利水功效机制已有较全面的认识。然陶弘景在《本草经集注》首载黄芪"逐五脏间恶血",表明本品兼有活血作用。目前,对于本品活血作用机制阐释,中医常基于"补气活血""气行血行"理论进行论证,但并不等同于本品无活血作用。通过梳理历代本草文献中对黄芪的记载,发现其活血作用应用广泛。综合传统方剂与现代方剂中有关其活血作用的应用,本品在方中行活血通络、活血利水、活血扶正作用,尤能体现其活血作用。且现代药理学研究在有关瘀血病理指标的分子机制中,黄芪有很好的调控作用,表明黄芪有活血作用,但未深入探究,存在研究价值。该文从历代文献对黄芪活血功效的论述、黄芪活血作用的临床应用及现代药理学研究深入探讨其活血作用机制,以期扩展黄芪的临床应用范围,为临床治疗提供理论指导。 相似文献
70.