Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study

Purpose: The purpose of the present study was to formulate and evaluate nanosuspension of Valsartan (VAL), a poorly water soluble and low bioavailable drug (solubility of 0.18?mg?mL^?1; 23% of oral bioavailability) with the aim of improving the aqueous solubility thus the bioavailability and consequently better anti-hypertensive activity.

Methods: Valsartan nanosuspension (VAL-NS) was prepared using high-pressure homogenization followed by lyophilisation. The screening of homogenization factors influencing nanosuspension was done by 3-factorial, 3-level Box-Behnken statistical design. Model suggested the influential role of homogenization pressure and cycles on drug nanosizing. The optimized formulation containing Poloxamer^?188 (PXM 188) was homogenized for 2 cycles at 500 and 1000?bar, followed by 5 cycles at 1500 bars.

Results: The size analysis and transmission electron microscopy showed nanometric size range and uniform shape of the nanosuspension. The in vitro dissolution showed an enhanced release of VAL from nanosuspension (VAL-NS) compared to physical mixture with PXM 188. Pharmacodynamic results showed that, oral administration of VAL-NS significantly lowered (p?≤?0.001) blood pressure in comparison to non-homogenized VAL (VAL-Susp) in Wistar rat. The level of VAL in rat plasma treated with VAL-NS showed significant difference (p?≤?0.005) in C_max (1627.47?±?112.05?ng?mL^?1), T_max (2.00?h) and AUC_0→24 (13279.2?±?589.426?ng?h?mL^?1) compared to VAL-Susp that was found to be 1384.73?±?98.76?ng?mL^?1, 3.00?h and 9416.24?±?218.48?ng?h?mL^?1 respectively. The lower T_max value, proved the enhanced dissolution rate of VAL.

Conclusion: The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.     

从风论治血管痉挛性心绞痛

血管痉挛性心绞痛(vasospastic angina,VSA)发作时疼痛部位不固定,或者表现为牙痛、头痛、腹痛等,疼痛时发时止,病位不固定,与风邪"善行"特点相符;VSA发病急骤,轻重不一,变化无常,与风邪"数变"特点相符。善行数变是风邪致病的特点,风邪外侵是VSA重要的病因。风邪包括外风、内风,VSA的发病病机为正虚邪中,由脏腑虚弱,风邪内侵而致,常因感受风寒邪气或在季节更替时诱发或加重,可见,外风是VSA的重要致病因素。内风与VSA也密切相关,肝为风木之脏,肝病则风从内生,肝风内动,风邪乘于心,心脉痉挛,卒发VSA。基于治病必求于本,中医治疗本病应重视运用风药,风药是指具有发散风邪、祛风、解痉功能的一类药物。现代药理研究表明,绝大多数祛风药均具有解除血管痉挛、扩张血管、改善血液循环、抗血小板聚集、抗凝、改善末梢循环、止痛等多方面的作用,是治疗VSA的有效中药。     

益气类中药及其复方制剂对心力衰竭细胞线粒体自噬调节作用的研究进展

导致心力衰竭发生发展的基本机制是心室重构,即心肌细胞的结构、功能在一系列复杂的分子和细胞机制作用下发生改变。线粒体作为心肌细胞中重要的细胞器,是参与心室重构的重要环节,它通过自噬机制选择性地清除受损的线粒体,因此,线粒体自噬对于维持心肌细胞的稳态非常重要。线粒体自噬在心力衰竭整个疾病发展过程中长期存在,通过调节自噬功能来改善心肌能量代谢,从而治疗心力衰竭、维持心脏正常生理功能至关重要。益气类中药及其复方制剂对衰竭心肌细胞具有保护作用,但现阶段研究对象多为中药单体活性成分或中药复方,而中医"整体观念、辨证论治"的基本理论依据不足,因此,该类药物对线粒体自噬细胞功能的调控机制,包括药效物质基础、配伍、用量等方面仍有待今后进一步深入研究。     

中医外治法治疗痛风性关节炎研究进展

痛风性关节炎为本虚标实之证,机体正气不足,脾肾亏虚为本,痰湿瘀血阻滞为标,治疗当标本兼顾。常用的中医外治法有中药外敷、中药熏洗、中药穴位贴敷、针灸疗法、刮痧疗法、推拿疗法和其他综合疗法。依据病情或单用一种外治法,或多种外治法联用。中医外治法具有操作简单、效果显著且无毒副作用等特点,但目前的研究仍存在较多不足,如相关研究样本量较小,科学规范性不足,作用机制和作用靶点的研究较少。今后应该更加科学、系统地研究中西医结合治疗痛风性关节炎的作用机制及作用靶点。     

中药外用治疗乳腺增生研究进展

乳腺增生为女性乳房多发疾病,其病情缠绵难愈,近年来中药外用治疗效果肯定,同时具有操作简便、见效快、病程短、安全性高等优点.从近10年的相关文献看,中药外用的传统形式包括膏药、油膏、箍围药、草药、掺药等,依托于现代技术的有巴布剂、凝胶膏剂、橡胶膏剂、离子导入等.中药外用治疗乳腺增生的机制主要有调节内分泌代谢和激素受体水平...     

基于中医传承辅助平台的老年性便秘用药规律分析

目的:基于现代文献分析中医药治疗老年性便秘的组方规律和用药特点。方法:检索中国期刊全文数据库(CNKI)中运用中成药及中医处方治疗老年性便秘的文献,运用中医传承辅助平台挖掘处方的组方规律和用药特点。结果:共纳入处方202首,使用中药156味,其中,用药频次≥19的高频药物有30味,排在前五位的药物为当归(121)、火麻仁(92)、白术(90)、肉苁蓉(79)、甘草(79);设置支持度个数为30,置信度为0.7,排在前五位的高频药对为当归-火麻仁(62),肉苁蓉-当归(61),黄芪-当归(55),白术-当归(55),当归-枳壳(53),最终演化得到核心组合18个,新处方9首。结论:中医药治疗老年性便秘的原则以润肠通便、益气养血为主,行(理)气、补肾、养阴为辅,这为临床治疗老年性便秘及开发治疗老年性便秘新药物提供了参考。     

The ideal blood pressure target to prevent cardiovascular disease in type 2 diabetes: A neutral viewpoint

Type 2 diabetes mellitus (T2DM) and essential hypertension are often associated, and retrospective data analyses suggest an association between lower blood pressure (BP) values and lower cardiovascular (CV) risk in patients with T2DM. However, the most recent intervention trials fail to demonstrate a further CV risk reduction, for BP levels <130/80 mm Hg, when compared to levels <140/90 mm Hg. Moreover, a J-shaped, rather than a linear, relationship of BP reduction with incident CV events has been strongly suggested. We here debate the main available evidences for and against the concept of ‘the lower the better’, in the light of the main intervention trials and meta-analyses, with a particular emphasis on the targets to be pursued in elderly patients. Finally, the most recent guidelines of the scientific societies are critically discussed.     

Optimising management of hypertension in primary care: the Valsartan Intensified Primary Care Reduction of Blood Pressure (Viper-Bp) study

Background

The Valstartan Intensified Primary CarE Reduction of Blood Pressure Study (VIPER-BP) Study is an open-label, randomised controlled trial comparing usual primary care management with an intensive BP management strategy using three forms of valsartan-based therapy (mono-therapy, thiazide diuretic or calcium channel blocker combinations) to achieve individualised BP control.

Methods

To identify the features of General Practitioner (GP) management of hypertension in Australia, we analyse the response to a case scenario-based survey of 500 GPs. We subsequently recruited a national cohort of GP Investigators to enrol up to 2500 patients into the VIPER-BP Study.

Results

GP responses clearly demonstrated that, compared to the VIPER-BP intervention, a heterogeneous approach to the primary care management of hypertension persists in Australia. By November 2010, 2157 hypertensive patients from 272 actively recruiting GP Investigators were enrolled into the study. Of these, 1965 (91%) patients were entered into a standardised “run-in” phase of 28 days of valsartan 80 mg/day. Subsequently, 1285 patients were randomised to usual care (n = 435) or the VIPER-BP intervention (n = 850). There was a predominance of males (62%), whilst 55% had pre-existing diabetes or cardiovascular disease and 63% had been previously treated for hypertension. Mean systolic and diastolic BP on randomisation for men and women, respectively, was 148 ± 15/88 ± 11 and 148 ± 18/87 ± 10 mm Hg.

Conclusions

In contrast to typical primary care management of hypertension, VIPER-BP combines more intensive and aggressive therapies with structured management to more rapidly attain and sustain individualised BP targets in hypertensive patients.     

四种抗高血压药物对单纯收缩期高血压患者短期降压疗效的研究

目的 探讨双氢克尿噻、阿替洛尔、硝苯地平缓释片、卡托普利在中国乡镇农村社区未治疗单纯收缩期高血压中的短期降压疗效.方法 442例单纯收缩期高血压患者随机分配4组：双氢克尿噻组（给予双氢克尿噻 12.5 mg/d,qd）113例;阿替洛尔组（给予阿替洛尔 12.5 mg/d,bid）66例;硝苯地平组（给予硝苯地平缓释片 10 mg/d,bid）130例;卡托普利组（给予卡托普利 12.5 mg/d,bid）133例,比较4周后四种抗高血压药物的降压疗效.结果 4周后收缩压、舒张压在各组中均明显下降.阿替洛尔降低收缩压作用低于双氢克尿噻（P=0.033）和硝苯地平缓释片（P=0.005）;双氢克尿噻降低舒张压作用明显低于硝苯地平缓释片（P=0.015）;双氢克尿噻降低脉压作用明显大于阿替洛尔（P=0.006）和卡托普利（P=0.019）;硝苯地平缓释片降低脉压作用明显高于阿替洛尔（P=0.026）.双氢克尿噻1年的费用约为11元.结论 从降压疗效及经济学上,双氢克尿噻是适合中国农民单纯收缩期高血压的首选一线药物.从降低血压各组分上,双氢克尿噻及硝苯地平缓释片优于阿替洛尔和卡托普利.     

“辛开苦降法”浅析

"辛开苦降"法系指将辛温与苦寒两类不同性味与功用的药物,相互配伍合用的一种常用独特的治疗方法,用以调畅气机、调和阴阳、平调寒热、分解湿热。就辛开苦降法的源流,组方特点及临床适应证进行阐述旨在加强对其深入研究与探讨,有利于中医药优势的进一步发挥。