In Search of a 24 Hours Per Day Artificial Kidney

Wearable, 24 hrs per day, 7 days per week artificial kidneys are being developed. Patients will benefit from more even control of physiologic parameters than can be obtained with conventional intermittent dialysis. Improvement in economic and social circumstances will result. Both hemodialysis and peritoneal dialysis techniques are being miniaturized. Small REDY cartridges containing urease, zirconium phosphate, hydrous zirconium oxide and activated carbon are being utilized to regenerate dialysate. Hemodialyzers will be worn on the forearm and include long, wide, low resistance series blood flow paths to reduce the potential for thrombosis. Peritoneal effluent is regenerated and filtered by the sorbent cartridge and automatically cycled back into the peritoneal cavity.     

基于CYP3A4酶探讨灯盏花素对洛伐他汀的药动学的影响及机制

目的 探究灯盏花素与洛伐他汀联用对大鼠体内药动学的影响,从代谢酶的角度揭示灯盏花素对洛伐他汀药动学产生影响的机制。方法 采用探针药物法及RT-HPLC法测定咪达唑仑在肝微粒体孵育体系中的浓度,评价灯盏花素与洛伐他汀联用对CYP3A4酶活性的影响。通过RT-PCR反应来检测CYP3A4酶mRNA基因表达,采用Western blot法,从蛋白翻译水平上分析灯盏花素与洛伐他汀联用对大鼠肝脏CYP3A4蛋白表达的影响。结果 洛伐他汀与灯盏花素联合用药后,洛伐他汀在大鼠体内的血药浓度显著升高,从0.39 mg?L-1 上升到1.08 mg?L-1 ,清除率从3.36L?h-1?kg-1降低到1.08L?h-1?kg-1,药物半衰期从5.0h延长到6.2h,联合给药后洛伐他汀的AUC从2.42mg?L-1?h-1上升到4.22mg?L-1?h-1。洛伐他汀组与空白组比较CYP3A4酶活性均没有明显变化;灯盏花素组及灯盏花素联合洛伐他汀组与空白组比较发现均抑制CYP3A4酶活性;灯盏花素与灯盏花素联合洛伐他汀组CYP3A4酶mRNA 表达量均较空白组显著降低;CYP3A4酶蛋白含量结果表明,洛伐他汀组与灯盏花素联合洛伐他汀组与空白组比较CYP3A4酶蛋白含量均没有明显变化。结论 洛伐他汀与灯盏花素联用,灯盏花素通过抑制其基因转录水平抑制CYP3A4的活性,使大鼠体内药动学过程发生变化,洛伐他汀药物的代谢减慢。     

脂必泰胶囊中红曲的含量测定

目的建立测定脂必泰胶囊红曲中洛伐他汀含量的高效液相色谱法。方法色谱柱为Dionex C18柱(250 mm×4.6 mm,5μm),流动相为甲醇-水(75∶25),流速为1 mL/min,柱温为22℃,检测波长为236 nm,进样量为10μL。样品以75%乙醇超声提取10 min后进样测定,定量方法采用峰面积外标法。结果洛伐他汀质量浓度在0.011 83～0.473 2 g/L范围内与峰面积积分值线性关系良好(r=0.999 9),方法平均回收率为99.07%,RSD=1.77%(n=6)。结论该方法简单、快速、准确,适用于测定脂必泰胶囊红曲中洛伐他汀的含量。     

洛伐他汀与二氢吡啶类药物相互作用研究

目的研究5种二氢吡啶类药物对洛伐他汀代谢的影响。方法采用大鼠肝微粒体体外代谢模型,洛伐他汀分别与不同浓度的硝苯地平、非洛地平、拉西地平、乐卡地平和尼莫地平置于一定量的鼠肝微粒体中,于37℃预孵5min后．加β—NADP／NADPH的0．1％NaHC03溶液启动反应,并开始记时,37℃下孵育20min后,加入一定量冰乙腈沉淀蛋白并终止反应,高速离心后,上清液进HPLC分析,并分别计算硝苯地平、非洛地平、拉西地平、乐卡地平和尼莫地平对洛伐他汀代谢抑制IC50值。结果不同结构的二氢吡啶类药物对洛伐他汀代谢的影响亦不同,其中硝苯地平的抑制作用最小（IC50值为53．98umol·L-1）,尼莫地平的抑制作用最大（IC50值为2．01umol·L-1）,通过结构参数分析表明油水分配系数（LogP）对抑制作用影响较大成正相关,而分子量、表面积亦对抑制作用产生影响,成负相关。结论对于患有高血压合并血脂异常的患者联合使用二氢吡啶类降压药与洛伐他汀时,产生药物相互作用的可能性较大。为避免不良反应发生．宜选用LogP值较大,而分子量、表面积较小的硝苯地平和非洛地平等。     

洛伐他汀对实验性家兔动脉粥样硬化形成及其相关癌基因表达作用的研究

本研究观察了洛伐他汀（ｌｏｖａｓｔａｔｉｎ，商品名：美降之）对高胆固醇饲喂的家兔动脉粥样硬化（ＡＳ）形成及其相关癌基因表达的影响。结果显示，洛伐他汀治疗组（Ｌ组）血脂水平、ＡＳ斑块面积与主动脉内膜面积的百分比、平均最大斑块厚度和平均最大斑块与中膜比值，均较动脉粥样硬化对照组（ＣＡＳ组）低（Ｐ＜０．０１）。ＣＡＳ组原癌基因Ｖ－ｓｉｓ、Ｃ－ｆｏｓ、Ｈ－ｒａｓ表达量分别是Ｌ组的２．４倍（Ｐ＜０．０１）、１．４倍、１．４倍（Ｐ＜０．０５）。提示洛伐他汀具有抗ＡＳ作用，其机制可能与降低血脂，抑制癌基因表达有关。     

低强度抗凝合用洛伐他汀预防房颤患者脑卒中的研究

目的前瞻性研究低强度华法林抗凝合用洛伐他汀对非瓣膜性心房颤动患者脑卒中的预防作用。方法将自愿接受脑卒中预防的628例非瓣膜性心房颤动患者随机分为实验组和对照组各314例。对照组维持目标抗凝强度凝血活酶臣际标准化比率（INR）2．0～3．0；实验组维持目标抗凝强度INR1．5～1．9．并加用洛伐他汀20mg／d，随访7～56个月。结果与对照组比较，实验组出血事件和缺血性卒中的发生率明显降低．5a生存率明显提高。结论低强度华法林抗凝合用洛伐他汀能有效降低非瓣膜性心房颤动患者脑卒中发生率，降低华法林抗凝引起出血的危险性，提高长期生存率。     

Controlling immune response and demyelination using highly potent bifunctional peptide inhibitors in the suppression of experimental autoimmune encephalomyelitis

In this study, we investigated the efficacy of new bifunctional peptide inhibitors (BPIs) in suppressing experimental autoimmune encephalomyelitis (EAE) in an animal model. BPI [e.g. proteolipid protein–cyclo(1,8)‐CPRGGSVC‐NH₂ (PLP‐cIBR)] is a conjugate between the PLP_139–151 peptide derived from proteolipid protein (PLP) and the cIBR7 peptide derived from domain‐1 (D1) of intercellular adhesion molecule‐1 (ICAM‐1). PLP–cIBR is designed to bind to major histocompatibility complex (MHC)‐II and leucocyte function‐associated antigen‐1 (LFA‐1) simultaneously to inhibit the formation of the immunological synapse and alter the differentiation and activation of a subpopulation of T cells, thus inducing immunotolerance. The results show that PLP–cIBR is highly potent in ameliorating EAE, even at low concentrations and less frequent injections. Mice treated with PLP–cIBR had a higher secretion of cytokines related to regulatory and/or suppressor cells compared to phosphate‐buffered saline (PBS)‐treated mice. In contrast, T helper type 1 (Th1) cytokines were higher in mice treated with PBS compared to PLP–cIBR, suggesting that it suppressed Th1 proliferation. Also, we observed significantly less demyelination in PLP‐cIBR‐treated mice compared to the control, further indicating that PLP–cIBR promoted protection against demyelination.     

Investigational drugs in early development for treating dengue infection

Introduction: Dengue has emerged as the most significant arboviral disease of the current century. A drug for dengue is an urgent unmet need. As conventional drug discovery efforts have not produced any promising clinical candidates, there is a shift toward re-positioning pre-existing drugs for dengue to fast-track dengue drug development.

Areas covered: This article provides an update on the current status of recently completed and ongoing dengue drug trials. All dengue drug trials described in this article were identified from a list of >230 trials that were returned upon searching the World Health Organization’s International Clinical Trials Registry Platform web portal using the search term ‘dengue’ on December 31^st, 2015.

Expert opinion: None of the handful of drugs tested so far has yielded encouraging results. Early trial experience has served to emphasize the challenge of drug testing in the short therapeutic time window available, the need for tools to predict ‘high-risk’ patients early on and the limitations of the existing pre-clinical model systems. Significant investment of efforts and resources is a must before the availability of a safe, effective and inexpensive dengue drug becomes a reality. Currently, supportive fluid therapy remains the only option available for dengue treatment.