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
We sought: 1) to investigate the relationship between vascular wall shear stress and flow-mediated dilation (FMD) in humans, and 2) to investigate whether this relationship could explain why FMD is greater in small arteries.
BACKGROUND
Arterial wall shear stress (WSS) is considered to be the primary stimulus for the endothelial-dependent FMD response. However, the relationship between WSS and FMD has not been investigated in humans. Furthermore, FMD is greater in small arteries, though the reasons for this phenomenon are unclear.
METHODS
Using phase-contrast magnetic resonance angiography (PMRCA), we measured hyperemic WSS and FMD in 18 healthy volunteers. Peak systolic WSS was calculated assuming a blunted parabolic velocity profile. Diameter by PCMRA and by ultrasound was compared in nine subjects.
RESULTS
Flow-mediated dilation was linearly proportional to hyperemic peak systolic WSS (r = 0.79, P = 0.0001). Flow-mediated dilation was inversely related to baseline diameter (r = 0.62, P = 0.006), but the hyperemic peak WSS stimulus was also inversely related to baseline diameter (r = 0.47, P = 0.049). Phase-contrast magnetic resonance angiography and ultrasound diameters were compared in nine subjects and correlated well (r = 0.84, p < 0.0001), but diameter by PCMRA was greater (4.1 ± 0.7 mm vs. 3.7 ± 0.5 mm, P = 0.009).
CONCLUSIONS
Arterial FMD is linearly proportional to peak hyperemic WSS in normal subjects. Thus, the endothelial response is linearly proportional to the stimulus. Furthermore, the greater FMD response in small arteries is accounted for, at least partially, by a greater hyperemic WSS stimulus in small arteries. By allowing the calculation of vascular WSS, which is the stimulus for FMD, and by imaging a fixed arterial cross-section, thus reducing operator dependence, PCMRA enhances the assessment of vascular endothelial function. 相似文献
目的探讨老年人全麻手术期间中心体温的变化规律及护理措施。方法选择符合美国麻醉医师协会分级(american society of anesthesiologists,ASA)Ⅰ~Ⅱ级择期行中上腹部手术的老年患者100例。随机分成两组,全麻复合硬膜外组(A组)和单纯全麻组(B组),以食管温度代表中心体温,记录麻醉诱导前(T0)、诱导后10(T10)、30(T30)、60(T60)、90(T90)、120(T120)min及手术结束(Tend)各个时间点的食管温度。结果麻醉诱导后两组的中心体温均有不同程度的下降,A组在诱导30min后的各个时间点体温下降幅度比B组大,两组比较,差异有统计学意义(P〈0.05)。结论老年人全麻复合硬膜外阻滞期间更容易导致低体温,术中应做好保温、保暖护理,以保证老年患者全麻手术期间的安全。 相似文献