Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats

Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of -rat atrial natriuretic peptide (-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of -rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.     

Bile Salt–Fatty Acid Mixed Micelles as Nasal Absorption Promoters of Peptides. I. Effects of Ionic Strength,Adjuvant Composition,and Lipid Structure on the Nasal Absorption of [D-Arg2]Kyotorphin

Bile salts and synthetic surfactants have been used to promote nasal absorption of peptide drugs. Although a marked increase in nasal absorption has been achieved, this may not be adequate and the possibility of adjuvant-induced membrane toxicity exists. The present study employs a rat in situ nasal perfusion technique and mixed micelles between sodium glycocholate (NaGC) and various lipids as potential nasal absorption enhancers of a stable model dipeptide, [D-Arg²]kyotorphin. NaGC alone enhanced the nasal absorption of the dipeptide in a concentration-dependent manner. When linoleic acid was added to form mixed micelles with NaGC, the absorption was further enhanced (P < 0.01). The effect of mixed micelles was synergistic and much greater than with single adjuvants. Increasing ionic strength was found to increase the adjuvant activity of both NaGC and NaGC–lipid mixed micelles. Structure of the lipid component of the mixed micelles also affected the adjuvant potency. Oleic acid, a cis-unsaturated fatty acid, was more effective than elaidic acid, the trans-isomer, whereas cis-linoleic acid and trans-linolelaidic acid were equally effective ( = 0.05). Mixed micelles of mono-glycerides such as monoolein and monolinolein were also more effective than NaGC alone ( = 0.05). Micellar solubilization of these polar lipids by NaGC appears to be important for nasal absorption enhancement to occur. Reversal of the membrane permeability was also observed within approximately 20–40 min after removal of the adjuvants from the rat nasal cavity. These observations are similar to the effects of mixed micelles on the rectal mucosa and may involve the same mechanism.     

混配农药中氰戊菊酯在小鼠体内的代谢和分布

目的　了解混配农药中氰戊菊酯在小鼠体内的代谢和分布。方法　以14 C -氰戊菊酯为示踪剂 ,静脉注射给药。给药后 0 .5～ 12 0min之间采 9次血样 ,8～ 96 0min之间分别对脑、心脏、肝脏和肺脏采 8次样品。样品用 β闪烁计数仪测量 ,并换算成化学浓度。用残数法计算毒代动力学参数。结果　混配农药中的氰戊菊酯的代谢符合二室开放模型。分布相T1/ 2 α为 2 .7min ,消除相T1/ 2 β为 10 6 .6min ,表观分布容积为 2 .9L/kg ,正向扩散系数k12 (0 .17min-1)大于逆向扩散系数k2 1(0 .0 77min-1)。分布浓度肺脏中最高 ,其次为肝脏、心脏、脑。结论　肺脏优势参与了氰戊菊酯的代谢过程 ,应重视此类农药的肺脏毒性。     

多普勒血流仪引导注射治疗内痔

目的：介绍新的更有效的内痔注射方式。方法：用多普勒血流仪引导注射治疗内痔出血与脱出,与单纯注射治疗对照观察。结果：一年后出血复发率治疗组为１０％,对照组为１１９．１７％（Ｐ〈０．０５）;内痔脱出复发率治疗组为１８．２５％,对照组为２５％。结论：用多普勒血流仪引导注射治疗内痔能更有效的闭塞痔动脉。     

交叉排列结扎术治疗环状混合痔

探讨环状混合痔的手术治疗方法。方法：采用交叉排列结扎术并尽量保留肛管移行区（ＡＴＺ）治疗环状混合痔,选择１６例进行式探讨及疗效观察。肛门麻醉后用胃幽门螺杆菌美蓝「（ＨＰ）ＭＢ」染色液对肛缘至齿线上５．０ｃｍ处染色,ＡＴＺ呈淡蓝色,直肠粘膜深蓝色,肛管皮肤不染色。对内外痔各分为３－５个部位交叉排列式贯穿结扎,结扎点在不同平面上,术中尽量保留淡蓝色的ＡＴＺ,使痔结扎点是保保留的粘膜桥与皮桥呈网状。结果     

危重患者心脏手术后氧代谢监测的价值

目的 探讨心脏直视术后危重患氧供需平衡的重要性和临床价值。指导救治,三疗效及预后,预防多器功能衰竭（ＭＯＦ）的发生,使ＩＣＵ监测水平跨跃到细胞水平。方法 对１４８例,心脏直视术后危重入ＩＣＵ后,分阶段动态监测动脉,混合静脉血气,心输出量,胃粘膜ＰＨ值,对代谢这各项监测值之间相关关系进行分析。结果 动静脉血气及其差值的变化与循环,呼吸功能变化呈正在关系;ＡＰＡＣＨＥⅡ评分高,ＳｖＯ２低的极重患     

Mixed Hyperbranched/Triblock Copolymer Micelle Assemblies: Physicochemical Properties and Potential for Drug Encapsulation

Mixed micelles have numerous advantages while requiring little to no effort in preparation. This study aims to produce mixed micelle nanostructures from a linear triblock copolymer and a hyperbranched random copolymer, and is able to be loaded with the weakly water-soluble drugs curcumin and indomethacin. Different preparation techniques are employed to produce mixed micelles comprised of Pluronic F127 block copolymer, and hyperbranched poly[(ethylene glycol) methyl ether methacrylate-co-lauryl methacrylate], H-[P(OEGMA-co-LMA)], copolymer. Few studies have dabbled in these types of coassemblies, which provides insight into how structural differences of each copolymer can affect the formation of micelles. To determine the properties of the emerging nanostructures in aqueous environments, including their size, homogeneity, and surface charge, different physicochemical techniques are used, such as light scattering and spectroscopic methods. The results reveal that the copolymers combine, and spontaneously self-assemble into mixed micelle-like nanostructures in aqueous environments, whereas both systems of neat and drug-loaded nanostructures exhibit desirable properties such as small average micelle hydrodynamic radii and low size polydispersity indices. The nanostructures that result from the effective encapsulation of curcumin exhibit outstanding stability over 169 days. The fluorescent qualities of curcumin persist after encapsulation, making the novel nanostructures excellent candidates for bioimaging applications.     

Pharmacodynamic Analysis of Analgesic Clinical Trials Using Empirical Methods

Data from analgesic clinical trials have characteristics such as ordered categorical longitudinal responses with repeated measures, delay of effect with respect to analgesic plasma concentration, and right-hand censoring of response due to remedication. In order to determine the concentration-effect relationship of such data, we propose convolving an empirical function for plasma concentration, in the form of broken lines which connect each pair of neighboring observations, with a monoexponential function, to generate effect site concentration Effect site concentration and time are used, simultaneously, as independent variables in the fit of the model for the logit of the probability of having a specific pain relief (PR) score at each time point pre-remedication, via maximum likelihood. Using corresponding effect site concentration, the probabilities of having specific PR scores post-remedication are predicted via the concentration-response relationship established. The overall (pre- and post-remedication) predictions and corresponding standard errors for the responses are then estimated. Inference of the PR scoring, using a posterior method, is proposed. An illustration using real data is used to demonstrate these methods.     

非线性混合效应模型法估算癫(间)患者苯妥英群体药物动力学参数

目的 应用非线性混合效应模型法(NONMEM),估算癫癇患者苯妥英群体药物动力学参数,考察各因素对最大消除速率常数Vm(mg·d-1)及米氏常数Km(mg·L-1)的影响。方法 回顾性搜集56例门诊及住院癫癇患者服用苯妥英钠日剂量和血药浓度数据96对,并运行SAS程序进行计算。结果 患者的性别、年龄、体重、合并用药等对药物动力学参数均无显著性影响,Vm=(522.40±10.25)mg·d-1(513.14～630.63 mg·d-1),Km=(11.05±9.62)mg·L-1(1.90～34.83 mg·L-1)。血药浓度预测值与实测值相关性良好。结论 用非线性混合效应模型法估算癫癇患者苯妥英群体药物动力学参数方法可靠,值得推广。     

通络助孕方对慢性炎症大鼠输卵管的影响

目的 :观察中药通络助孕方对慢性炎症大鼠模型输卵管病理形态学和受孕率的影响 ,并探讨其疗效机理。方法 :用混合菌接种法制作大鼠慢性炎症动物模型 ,以不同剂量的通络助孕方和对照药妇炎康治疗后 ,观察用药前后光镜和电镜下输卵管病理形态学改变情况 ,并追踪大鼠受孕情况。结果 :通络助孕方和对照药能不同程度恢复模型大鼠输卵管病理形态学改变 ,并提高了受孕率。结论 :模型大鼠输卵管组织呈慢性炎症表现 ,混合菌接种法可以成功制作大鼠慢性炎症模型 ;通络助孕方能改善输卵管结构和功能 ,从而对大鼠炎性不孕具有很好的治疗作用