顶空气相色谱法测定坎地沙坦酯中残留溶剂

目的建立顶空气相色谱法测定坎地沙坦酯中有机溶剂甲醇、乙醇、二氯甲烷、乙酸乙酯和甲苯含量的方法。方法以DB-624毛细管柱为分离柱,采用程序升温,检测器为FID。结果 5个成分的线性关系良好,方法精密度、重复性均符合要求。结论该方法可用于测定坎地沙坦酯原料中残留溶剂甲醇、乙醇、二氯甲烷、乙酸乙酯和甲苯的含量。     

降血压药坎地沙坦的合成

以3-硝基-2-乙氧甲酰氨基苯甲酸甲酯为原料,经Curtius重排、还原、环化、取代、水解反应,制得坎地沙坦(1),总收率54.3%。该工艺原料价廉易得、合成路线短、产率提高、成本降低。     

人工神经网络模型在坎地沙坦酯片生物等效性研究中的应用

目的：评价中国健康受试者单次口服坎地沙坦酯片受试制剂和参比制剂的人体生物等效性,并建立人工神经网络模型,预测人体口服坎地沙坦酯片的血药浓度,为临床合理用药提供依据。方法：筛选32例中国健康受试者在空腹或餐后条件下单次口服8 mg坎地沙坦酯片受试制剂或参比制剂,进行生物等效性研究。利用坎地沙坦生物等效性研究结果,采用MATLAB软件构建反向传播人工神经网络模型,对模型进行内部和外部验证,用于预测人体口服坎地沙坦片后的血药浓度。结果：空腹试验和餐后条件下,受试制剂Cmax、AUC0-t、AUC0-∞均在参比制剂80.00%～125.00%的等效区间内,两制剂生物等效。利用MATLAB软件构建的坎地沙坦血药浓度预测模型,性能验证结果均方差为0.000 781,梯度幅度为0.000 432,验证检查次数为0,训练组、验证组、预测组的相关系数均大于0.99。结论：受试制剂与参比制剂在空腹和餐后服用的情况下均具有生物等效性,建立的坎地沙坦血药浓度预测模型能准确预测人体口服坎地沙坦酯片的血药浓度,可为临床合理用药提供依据。     

Charge-Conversional Binary Drug Delivery Polymeric Micelles for Combined Chemotherapy of Cervical Cancer

Candesartan-g-polyethyleneimine-cis-1,2-cyclohexanedicarboxylic anhydride (CD-g-PEI-HHPA, CPH) polymer-drug conjugates based on charge-conversional delivery, enhanced buffering capacity, amidase-triggered drug release, and combined cancer chemotherapy strategies were successfully synthesized for simultaneous and effective codelivery of CD and paclitaxel (PTX) to treat cervical cancer. The CPH polymer-drug conjugates could self-assemble into core-shell structure micelle of around 100 nm in diameter with negative surface charge and were employed to load PTX to formulate binary drug delivery system. The CPH polymeric micelles could mediate quick endosomal escape and amidase-responsive drug-release manners. In vitro cytotoxicity and in vivo investigations confirmed CPH binary drug delivery system exerted strong antitumor efficacy.     

Preparation,characterization and ex vivo–in vivo assessment of candesartan cilexetil nanocrystals via solid dispersion technique using an alkaline esterase activator carrier

The objective of this study was to improve candesartan cilexetil (CC) efficacy by formulating nanocrystals via solid dispersion (SD) technique using tromethamine (Tris). SD was prepared by solvent evaporation at different drug carrier ratios, evaluated for particle size, vitro dissolution studies, TEM, FTIR, and X-ray powder diffraction. Ex vivo, in vivo pharmacokinetic parameters were conducted on selected formulae compared to drug suspension and marketed product. Size analysis demonstrated formation of particles in the nanorange lower than 300?nm. A burst drug release followed by an improved dissolution was observed indicating instant formation of nanocrystals along with amorphization as confirmed by X-ray diffraction. FTIR studies suggested the absence of chemical interaction between Tris and CC. TEM revealed formation of irregular oval nanoparticles. SD-1:5 has higher apparent permeability coefficient compared to CC suspension. Furthermore, the pharmacokinetic results proved the ability of the formed nanoparticles to enhance the efficacy of CC compared to drug suspension and marketed product. In conclusion, using of Tris as alkaline esterase activator carrier could be a promising tool to bypass the controversial effect of esterase enzymes that may be a source for inter-individual variations affecting ester prodrug candidates’ efficacy.     

Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers

Candesartan is a long-acting and selective nonpeptide AT₁ subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16?mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16?mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0–36?h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUC_last, AUC_inf and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUC_last in the reference and the test drug were 1530.1?±?434.6 and 1315.7?±?368.6 ng·h/mL. The mean for AUC_inf in the reference and the test drug were 1670.0?±?454.5 and 1441.2?±?397.8 ng·h/mL. The mean value for C_max in the reference and the test drug was 142.6?±?41.0 and 134.9?±?41.4?ng/mL. The 90% confidence intervals for the AUC_last, AUC_inf and C_max were in the range of log 0.81–log 0.91, log 0.81–log 0.91 and log 0.88–log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16?mg of candesartan cilexetil hydrochloride.     

Square-wave adsorptive stripping voltammetric determination of candesartan cilexetil in pharmaceutical formulations

A sensitive, simple and rapid square-wave adsorptive stripping voltammetric method was developed and validated for the determination of candesartan cilexetil in pharmaceutical formulations. The proposed method was based on electrochemical reduction of candesartan cilexetil at a hanging mercury drop electrode in phosphate buffer at pH 5.0. A well-defined reduction peak was observed at −1340 mV with 30 s of accumulation time and −1100 mV of accumulation potential. Under these optimized conditions, the square-wave adsorptive stripping voltammetric peak current showed a linear correlation on drug concentration over the range of 0.25–1.34 μg mL⁻¹ with a correlation coefficient of 0.9986 for the proposed method. The detection and quantitation limits for this method were 1 × 10⁻² and 2.5 × 10⁻¹ μg mL⁻¹, respectively. The results obtained for intra-day and inter-day precision (as RSD%) were between 1.10 and 3.90%. This method was applied successfully for the determination of candesartan cilexetil in its tablet dosage forms with mean recoveries of 101.13 ± 0.78% with RSD of 2.06% for 8 mg tablet and 99.84 ± 0.89% with RSD of 2.36% for 16 mg tablet. The results obtained from the developed square-wave adsorptive stripping voltammetric method were compared with those obtained by the analytical method reported in the literature.     

Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan,Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs.     

坎地沙坦对糖尿病肾病大鼠足细胞保护作用的研究

目的探讨糖尿病肾病（diabetic nephropathy,DN）大鼠足细胞超微结构及其相关分子nephrin表达的变化,以及坎地沙坦对其干预的影响,为DN的防治提供理论依据。方法选择健康雄性SD大鼠36只,按随机数字表法分为A组（正常对照组）、B组（DN组）和C组（DN＋坎地沙坦组）,每组12只。B、C组尾静脉注射链脲佐菌素（30 mg.kg-1）制备DN大鼠模型,于DN模型成模1周后将3组大鼠分别在代谢笼中喂养,C组给予坎地沙坦5 mg.kg-1.d-1灌胃,A组及B组给予等量生理盐水灌胃。用药后第4周和第7周检测各组大鼠的血糖、体质量2、4 h尿蛋白和内生肌酐清除率（Ccr）,于第7周取肾组织行光学显微镜及电子显微镜观察肾脏病理改变、RT-PCR法检测nephrin-mRNA表达。结果与A组比较：B组24 h尿蛋白排泄增多（P〈0.05）,Ccr在7周时下降（P〈0.05）;肾组织内nephrin-mRNA表达下调（P〈0.05）;肾组织足细胞足突宽度增加并出现融合,肾小球基底膜增厚。与B组比较：C组24 h尿蛋白排泄量降低（P〈0.05）,Ccr升高（P〈0.05）;肾组织内nephrin-mRNA表达增加（P〈0.05）,足细胞足突宽度及肾小球基底膜厚度变小。结论 DN时存在足细胞分子nephrin表达异常和超微结构改变,坎地沙坦对肾脏的保护作用机制可能是通过增加nephrin表达、改善足细胞超微结构而实现。     

Investigation of the candesartan cilexetil antihypertensive drug microencapsulation by PLA-PVP K30 biodegradable polymers: Experimental optimization and release kinetics modelling

Candesartan is an angiotensin receptor blocker (ARB) used to treat hypertension. However, its poor aqueous solubility and oral bioavailability have limited its therapeutic applications. In order to increase bioavailability and control the release of candesartan condensation, microspheres containing biodegradable polymers (polyvinylpyrrolidone [PVP K30] and polylactic acid [PLA]) in different ratios were prepared by the o/o solvent evaporation method using Span 80 as a surfactant. In addition, the impact of encapsulation parameters (i.e., PVP K30 and PLA concentrations) on the encapsulation ratio and release percentage was investigated by the mixed factorial design method. The release kinetics of the microspheres was simulated by combining two methods, the Dragonfly algorithm and a support vector machine (DA-SVM). The experimental data were in good agreement with the predicted data, with a coefficient of determination close to unity and a mean square error close to zero. Fourier-transfer infrared spectrometry (FTIR) analysis revealed the presence of condensation in all formulations without reporting distortion in the spectra. Scanning electron microscopy (SEM) confirmed the successful synthesis of microspheres, whose sizes were between 12 and 26 μm. Formulations with a PLA-drug ratio of 6:1 (N15, N17, and N18) showed the highest encapsulation efficiency (68%, 71%, and 70%, respectively), while formulations that do contain PVP K30, such as N5, N4, and N3, showed a higher release (83%, 84%, and 89%, respectively), indicating that the agent (PVP K30) enhanced the bioavailability and release of candesartan. Overall, N3 showed a higher drug release rate at 12 h and important encapsulation efficiency, making it the optimal formulation obtained in this study.