Beyond drug-drug interactions: effects of transporter inhibition on endobiotics,nutrients and toxins

Introduction: Membrane transport proteins play a central role in regulating the disposition of endobiotics, dietary nutrients and environmental toxins. The inhibition of transporters by drugs has potential physiologic consequences. The full extent of the effect of drugs on the function of transporters is poorly understood because only a small subset of the hundreds of transporters expressed in humans – primarily those mediating the rate-determining step in the elimination of specific drugs – are assessed during clinical development.

Areas covered: We provide a comprehensive overview of literature reports implicating the inhibition of transporters as the mechanism for off-target effects of drugs.

Expert opinion: Transporter inhibition, the mechanism of action of many marketed drugs, appears to play an underappreciated role in a number of side effects including vitamin deficiency, edema, dyslipidemia, cholestasis and gout. Cell systems more broadly expressing transporter networks and methods like unbiased metabolomics should be incorporated into the screening paradigm to expand our understanding of the impact of drugs on the physiologic function of transporters and to allow for these effects to be taken into account in drug discovery and clinical practice.     

缺血预处理对糖尿病大鼠心肌影响

目的研究糖尿病大鼠心肌缺血预处理(IPC)后其心肌超微结构改变、环磷酸腺苷(CAMP)含量及环磷酸腺苷依赖蛋白激酶(PKA)活性的变化。方法取糖尿病及非糖尿病SD大鼠各30只,设为糖尿病组和非糖尿病组。根据随机分组原则,将糖尿病组和非糖尿病组各分为Sham组、I/R组、IPC组3个亚组,每组各10只大鼠。比较各组心肌酶谱变化,心肌梗死范围、心肌cAMP含量及PKA活性变化。并通过电镜观察心肌线粒体结构变化。结果非糖尿病组大鼠:Sham组心肌酶谱含量明显低于IPC组,IPC组低于I/R组,组间比较,差异均有统计学意义(P<0.05);IPC组心肌梗死面积明显低于与I/R组(P<0.05);IPC组cAMP含量及PKA活性明显高于I/R组(P<0.05)。糖尿病组大鼠:Sham组心肌酶谱含量明显低于IPC组(P<0.05);IPC组与I/R组心肌酶含量、心肌梗死面积、cAMP含量及PKA活性变化比较,差异均无统计学意义(P>0.05)。结论 IPC对非糖尿病大鼠的心肌具有保护作用,而糖尿病大鼠心肌cAMP含量及PKA活性降低,cGMP信号传导不明显,降低了IPC对糖尿病组大鼠的心肌保护作用。     

丹参粉针佐治小儿病毒性肺炎疗效观察

目的 观察丹参粉针佐治小儿病毒性肺炎的的疗效。方法 将60例病毒性肺炎患儿分为治疗组和对照组,每组30例。两组患儿均接受常规支持对症治疗,对照组接受单磷酸阿糖腺苷静脉滴注,治疗组加用丹参粉针静脉滴注。比较两组临床疗效及两组患儿症状体征消失时间。结果 治疗组体温恢复正常时间、肺部啰音消失时间和咳嗽消失时间均较对照组显著缩短（P<0.05）;治疗组临床疗效明显优于对照组（P<0.05）。结论 丹参粉针辅佐治疗小儿病毒性肺炎有利于提高临床疗效,缩短主要症状、体征的消失时间。     

缺氧对乳鼠耳蜗螺旋神经节神经元外向电流的影响及其环磷酸腺苷、环磷酸鸟苷含量变化的研究

目的  观察缺氧时间对体外培养的耳蜗螺旋神经节神经元（SGNs）外向电流的影响及其细胞内第二信使环磷酸腺苷（cAMP）、环磷酸鸟苷（cGMP）含量变化。方法  体外原代培养新生1～3 d SD大鼠SGNs并进行免疫荧光鉴定。用膜片钳全细胞记录模式观察缺氧外液灌流SGNs时,外向电流的变化趋势和特点。用酶联免疫吸附实验检测缺氧5、15和20 min时SGNs内cAMP和cGMP的浓度变化。结果  ①酶解分离可获得生存状态良好的神经元,经免疫荧光鉴定为SGNs。②当电压钳制在-60 mV时,急性缺氧增强SGNs外向电流,主要增强0～+60 mV电压区间的激活电流幅度。缺氧5 min时,+60 mV激活电流幅度从（971.2±50.3）pA增强到（2361.0±207.4）pA,差异有统计学意义（P <0.01）。随后出现下降趋势,11～15 min时,增强的电流幅度与对照组基础电流比较,差异无统计学意义（P >0.05）。③分别检测缺氧5、15和20 min后SGNs中cAMP和cGMP的含量变化。缺氧5 min组与正常对照组比较,cAMP浓度升高,差异有统计学意义（P <0.01）。缺氧15 min组与正常对照组比较,cAMP浓度变化差异无统计学意义;缺氧20 min组与正常组对照组比较,cAMP浓度水平下降（P <0.01）。cGMP浓度随着缺氧时间的延长,总体呈下降趋势,但在20 min后有部分回升（缺氧15 min vs 缺氧20 min,P <0.01）。结论  在SGNs急性缺氧损伤过程中,外向电流增强,增强幅度随缺氧时间变化先升后降,推测在短期缺氧时细胞通过降低兴奋性,影响听觉信息的传导,且该过程与胞内第二信使cAMP和cGMP浓度的改变相关。

     

Metabolic clues regarding the enhanced performance of elite endurance athletes from orchiectomy-induced hormonal changes

This article examines the metabolic performance of an elite cyclist, Lance Armstrong, before and after his diagnosis with testicular cancer. Although a champion cyclist in 1-day events prior to his diagnosis of testicular cancer at age 25, he was not a contender in multi-day endurance cycle races such as the 3-week Tour de France. His genetic makeup and physiology (high VO2max, long femur, strong heavy build) coupled with his ambition and motivation enabled him at an early age to become one of the best 1-day cyclists in the world. Following his cancer diagnosis, he underwent a unilateral orchiectomy, brain surgery and four cycles of chemotherapy. After recovering, he returned to cycling and surprisingly excelled in the Tour de France, winning this hardest of endurance events 7 years running. This dramatic transformation from a 1-day to a 3-week endurance champion has led many to query how this is possible, and under the current climate, has led to suggestions of doping as to the answer to this metamorphosis. Physiological tests following his recovery indicated that physiological parameters such as VO2max were not affected by the unilateral orchiectomy and chemotherapy. We propose that his dramatic improvement in recovery between stages, the most important factor in winning multi-day stage races, is due to his unilateral orchiectomy, a procedure that results in permanent changes in serum hormones. These hormonal changes, specifically an increase in gonadotropins (and prolactin) required to maintain serum testosterone levels, alter fuel metabolism; increasing hormone sensitive lipase expression and activity, promoting increased free fatty acid (FFA) mobilization to, and utilization by, muscles, thereby decreasing the requirement to expend limiting glycogen stores before, during and after exercise. Such hormonal changes also have been associated with ketone body production, improvements in muscle repair and haematocrit levels and may facilitate the loss of body weight, thereby increasing power to weight ratio. Taken together, these hormonal changes act to limit glycogen utilization, delay fatigue and enhance recovery thereby allowing for optimal performances on a day-to-day basis. These insights provide the foundation for future studies on the endocrinology of exercise metabolism, and suggest that Lance Armstrong's athletic advantage was not due to drug use.     

UHILIC-MS/MS法同时测定复方三维右旋泛酸钙糖浆中5种维生素的含量

目的 建立一种超高效亲水作用色谱串联三重四极杆质谱法（UHILIC-MS/MS）,同时测定复方三维右旋泛酸钙糖浆中维生素B₁、维生素B₂、维生素B₆、烟酰胺和泛酸钙的含量。方法 采用超高效液相色谱仪,Waters ACQUITY BEHHILIC Amide色谱柱（2.1 mm×100 mm,1.7 μm）,以90%乙腈（含0.5%甲酸）-10 mmol/L甲酸铵水（含0.5%甲酸）为流动相,进行梯度洗脱,流速0.30 ml/min;在电喷雾（ESI）正离子模式下,用多反应监测（MRM）模式进行含量测定。结果 在5 min内,样品中5种维生素分别在各自考察的浓度范围内呈良好的线性关系,相关系数（r）均大于0.998 4;整体加样回收率在93.27%~100.39%之间,RSD为1.41%~4.96%;10批样品中维生素B₁、维生素B₂、维生素B₆、烟酰胺、泛酸钙的含量测定结果分别为32.40~38.91、7.002~8.462、9.677~11.17、33.64~39.58、3.276~3.771 mg/250 g。结论 本研究建立的UHILIC-MS/MS方法可快速实现对复方三维右旋泛酸钙糖浆中5种维生素类成分定性鉴定或定量检测,为复方三维右旋泛酸钙糖浆的开发利用和质量评价提供了可靠的技术检测方法。     

脑震荡大鼠海马CA1区P-CREB的表达

目的观察磷酸化CREB（p-CREB）在脑震荡大鼠海马区的表达。方法在多聚甲醛固定的海马脑薄片上，用免疫组化法观察p-CREB在海马CA1区的表达。结果p-CREB在脑震荡大鼠海马结构CA1区的表达，1～72h增多（P〈0．05），7d后降至正常。结论p-CREB在脑震荡大鼠海马内伤后早期表达增多，P-CREB可能具有神经保护因子的作用。     

慢律升颗粒对慢性心律失常模型大鼠血浆环磷酸腺苷和环磷酸鸟苷的影响

目的:研究慢律升颗粒对慢性心律失常模型大鼠血浆环磷酸腺苷(cAMP)、环磷酸鸟苷(cGMP)的影响。方法:将30只SD大鼠随机分为对照组、普萘洛尔组、乙酰胆碱组、普萘洛尔联合慢律升组、乙酰胆碱联合慢律升组,每组各6只。对照组大鼠灌胃0.9%氯化钠溶液,普萘洛尔组大鼠灌胃盐酸普萘洛尔,乙酰胆碱组大鼠灌胃乙酰胆碱,普萘洛尔联合慢律升组灌胃普萘洛尔、慢律升颗粒,乙酰胆碱联合慢律升组大鼠灌胃乙酰胆碱、慢律升颗粒。各组大鼠均连续灌胃7 d。治疗后记录各组大鼠的肛温、心率以及血清中cAMP、cGMP水平。结果:与对照组比较,普萘洛尔组、乙酰胆碱组大鼠的肛温均低(均P<0.05),普萘洛尔联合慢律升组、乙酰胆碱联合慢律升组的肛温均高(均P<0.05)。与对照组比较,普萘洛尔组、乙酰胆碱组大鼠的心率均低,普萘洛尔联合慢律升组、乙酰胆碱联合慢律升组的心率均高(均P<0.05)。与对照组比较,普萘洛尔组和乙酰胆碱组大鼠的cAMP均降低,而cGMP均高、cAMP/cGMP比值均低(均P<0.05)。与对照组比较,普萘洛尔联合慢律升组、乙酰胆碱联合慢律升组的cAMP均高、cGMP均低、cAMP/cGMP比值均高(均P<0.05)。结论:慢律升颗粒对普萘洛尔和乙酰胆碱诱导的慢性心律失常模型大鼠的肛温、心率及血清中cAMP、cGMP水平具有良好的改善作用。