Pharmacokinetic and pharmacodynamic interaction of Danshen-Gegen extract with warfarin and aspirin

Ethnopharmacological relevance

Danshen–Gegen (DG) product has clinically been proven to be an effective agent for heart-tonic efficacy by our previous research. In the mean time, herb–drug interactions between DG product and its commonly co-administered drugs, such as aspirin or warfarin need to be explored to ensure its safe clinical usage.

Aim of the study

Current study aims to investigate whether DG extract interacts with warfarin or aspirin when administered concomitantly to ensure the safety and efficacy of their usage.

Material and methods

Five groups of SD rats (n=6/group) received DG alone (0.15 g/kg, human relevant dose), warfarin alone (0.2 mg/kg), warfarin (0.2 mg/kg) in combination with DG (0.15 g/kg), aspirin alone (10.3 mg/kg), or aspirin (10.3 mg/kg) in combination with DG (0.15 g/kg), respectively. DG product was given twice daily for 5 day. Warfain or aspirin were given once daily for 5 day. DG morning doses were given 2 h post that of warfarin/aspirin. Following first dosing on day 5, plasma samples were collected at different time points. For the pharmacodynamic measurement, whole blood was collected at 30 min after DG dosing or at 2.5 h after warfarin/aspirin dosing, and the prothrombin time assay was conducted.

Results

Co-administration of DG with warfarin could significantly decrease the C_max, AUC and the prothrombin time of warfarin (p<0.05). In the mean time, the C_max and AUC of danshensu, the active bioavailable component of DG were significantly increased (p<0.01) in presence of warfarin. Co-administration of DG with aspirin could significantly increase the C_max and AUC of both aspirin (p<0.01) and its metabolite salicylic acid (p<0.01) and significantly decrease the prothrombin time of aspirin (p<0.05). However, the pharmacokinetics parameters of danshensu were not significantly affected by aspirin.

Conclusion

Our animal study indicated that co-administration of DG with warfarin/aspirin can cause significant pharmacokinetic and pharmacodynamic herb–drug interactions in rat.     

双氯芬酸钠缓释微丸在兔体内的药动学

 目的：测定双氯芬酸钠缓释微丸（DS-SRMP）在家兔体内药动学及相对生物利用度。方法：用紫外分光光度法测定家兔体内的血药浓度，研究DS-SRMP的吸收动力学及生物利用度。结果：DS-SRMP在体内0～8 h的吸收速度符合表观零级动力学过程，其Ka⁰=12.14％/h。结论：体内药动学研究表明，DS-SRMP缓释效果明显，给药后血药浓度较为平缓，持续作用时间长，可减少给药次数。该缓释制剂相对于其普通片剂具有释药稳定，生物利用度高，安全有效等制剂学意义。     

Morphological studies on crushed sciatic nerve of rabbits with electroacupuncture or diclofenac sodium treatment

Sciatic nerves of 15 rabbits were crushed by Halsted straight mosquito hemostat with 8-11 Newton force for 60 seconds on a point 5 mm above the knee joint, and then the rabbits were equally divided into three groups. The acupuncture group was treated by electroacupuncture on Huan Tiao and Wei Zhong points (25 minutes/day) for 7 days. The medicine group was treated with intramuscular administration of dicofenac sodium (15 mg) daily for 7 days. The control group was not treated. After treatment, the distal parts of crushed nerve were examined under light microscope, the densities of normal myelinated fibers in 0.126 mm2 were counted, and the diameters of 20 normal myelinated fibers were measured for each animal. The results showed that the mean densities were 176.2 +/- 5.953 in the acupuncture group, 118.2 +/- 10.878 in the medicine group and 101.4 +/- 8.548 in the control group. The mean values were significantly different between the acupuncture and medicine groups (p < 0.01) and highly significant difference between the acupuncture and control groups (p < 0.001); but there was no significant difference between the medicine and control groups (p > 0.05). There are more small myelinated fibers (0-9 microm) in the acupuncture group than in the medicine and control groups (p = 0.0028). The results revealed and confirmed that acupuncture promotes nerve regeneration; diclofenac sodium did not show such an effect. The present study demonstrates the positive effect of acupuncture on regeneration of a crushed sciatic nerve in the rabbits. And acupuncture is a better treatment for regeneration of crushed nerve than diclofenac sodium.     

Pharmacokinetic and pharmacodynamic study of interaction of Rhodiola rosea SHR-5 extract with warfarin and theophylline in rats

Significant pharmacokinetic/pharmacodynamic interactions between various herbal products and drugs being substrates of cytochrome P450 have recently been reported. The aim of this study was to determine whether Rhodiola rosea SHR-5 extract interacts with warfarin and theophylline when administered concomitantly. Thus, concomitant treatment of rats with theophylline and SHR-5 did not give rise to significant effects on the pharmacokinetics of theophylline. Simultaneous administration of SHR-5 and warfarin did not alter significantly the pharmacokinetics or the anticoagulant activity of warfarin. It is concluded that SHR-5 might be of value in the treatment of patients with mild or moderate depression, and that its interaction with co-administered drugs is likely to be negligible.     

双氯芬酸钠柔性脂质体的研究

目的 研究双氯芬酸钠柔性脂质体，为临床新制剂的开发提供参考。方法 以逆相蒸发－超声法制备双氯芬酸钠柔性脂质体，并对其性态、包封率、透过率、体外透皮以及抗炎药效学进行了试验。结果 双氯芬酸钠柔性脂质体平均粒径为81.5nm，平均包封率为73．12％；在0.3MPa外压作用下，柔性脂质体的透过速率平均达到水的90％；体外透皮实验中，24h累积透皮吸收百分率Q％为58．62％，优于普通脂质体和凝胶剂；对角叉菜胶所致的炎症有显著的抑制作用，比其凝胶剂作用持久。结论 双氯芬酸内柔性脂质体有望成为适于临床给药的一种新剂型。     

双氯灭痛滴眼液的研制

 拟定了双氯灭痛滴眼液的处方及其制备工艺，并制定了质量控制标准。用紫外分光光度法测定双氯灭痛的含量，结果于２７６ｎｍ处有最大吸收。同时对眼刺激性和溶液稳定性进行了试验，表明双氯灭痛滴眼液对眼无刺激，其有效期为２．６年。     

双氯芬酸钠及双氯芬酸赖氨酸在大鼠体内的药代动力学参数比较

 目的 比较双氯芬酸钠及双氯芬酸赖氨酸体内药代动力学参数。方法 20只Wister大鼠分成二组分别单次灌胃给予1.0 mmol·L^-11.4 ml双氯芬酸钠(DS)和双氯芬酸赖氨酸(DL),用高效液相色谱法测定血中DS及DL浓度。用3P87程序拟合计算药代动力学参数。结果与结论 经统计学方差分析,药-时曲线符合二室模型,两种双氯芬酸盐的 AUC,Vd,t_max,c_max,CL 无差异(P>0.05),两组t_1/2β有显著差异(P＜0.01)。     

双氯芬酸钠栓治疗带状疱疹神经痛研究

目的　探讨双氯芬酸钠栓对带状疱疹神经痛的治疗效果。方法　将 70例患者随机分为 2组 ,在常规抗病毒治疗的基础上 ,治疗组予双氯芬酸钠栓直肠给药 ,对照组予肠溶阿司匹林片口服 ,观察带状疱疹神经痛改善情况。结果　治疗组疼痛缓解程度优于对照组 ,两组比较有显著性差异 (P <0 .0 5 )。结论　双氯芬酸钠对带状疱疹神经痛有较好的治疗作用。     

双氯芬酸钠乳膏的制备及稳定性研究

目的:探讨双氯芬酸钠乳膏的制备及稳定性研究。方法:采用正交设计法对处方基质进行优选并进行初步稳定性考察。结果:得到最优基质配比:二甲硅油1.0%,十八醇0.5%,硬脂酸镁10.0%,蔗糖硬脂酸酯S-5 4.0%。结论:双氯芬酸钠乳膏性质稳定,达到了乳膏质量标准的要求。     

外用双氯芬酸钠凝胶治疗骨关节炎的临床研究

 目的：比较研究双氯芬酸钠凝胶（DSG）和吲哚美辛擦剂（IE）治疗骨关节炎的疗效和安全性。方法：DSG组54例，IE组46例，临床验证设计为随机、单盲、平行性和多中心的比较研究。方法为薄层涂布于患处，一日3次，总量不超过10g或10ml,疗程为2周。结果：DSG的总有效率为87.04%,不良反应发生率为1.85%；IE的总有效率为84.09%,不良反应发生率为80.43%。结论：DSG的疗效与IE相近，但不良反应发生率明显低于IE。     

双氯芬酸钠擦剂的制备及含量测定方法研究

 报道了双氯芬酸钠擦剂的研制及含量测定方法，采用紫外分光光度法测定双氯芬酸钠的含量，擦剂中其它成分不干扰测定，平均回收率为１００．６％±０．６６％，相对标准差为０．６６％（ｎ＝５），结果令人满意。     

双氯芬酸钠传递体的制备及质量评价

 目的：研制双氯芬酸钠传递体，并对其进行质量评价。方法：采用均匀设计法筛选最佳处方工艺，并对其质量控制、稳定性、变形性、以及皮肤刺激性进行评价。结果：制得的传递体为乳白色混悬液，平均包封率为73.12%，平均粒径81.5 nm，对光照稳定性好，但随温度升高变化较大，皮肤刺激性小。结论：双氯芬酸钠传递体的制备工艺可行，有望成为适于临床给药的一种新剂型。     

Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper methysticum Forst. f.)

Kava kava, a beverage or extract prepared from the rhizome of the kava plant (Piper methysticum Forst. f.), was used for many centuries as a traditional beverage in the Pacific Islands. During the past few decades, kava has also gained popularity in Western countries as well, due to its anxiolytic and sedative properties. However, in recent years, kava has been implicated in several liver failure cases which led to its ban in many countries and this has prompted wide discussion on its relative benefits and risks as a social beverage and a herbal remedy. Recently, it has been shown that several kavalactones, the assumed active principles of kava extracts, are potent inhibitors of several enzymes of the CYP 450 system (CYP1A2, 2C9, 2C19, 2D6, 3A4 and 4A9/11). This indicates that kava has a high potential for causing pharmacokinetic drug interactions with other herbal products or drugs, which are metabolised by the CYP 450 enzymes. In addition, several pharmacodynamic interactions have been postulated and indeed observed. Nevertheless, evidence of true pharmacokinetic and/or pharmacodynamic interactions remains unsubstantiated, and only few investigations of the potential of kava preparations to interact with specific drugs have been carried out. This review provides a critical overview of the existing data on interactions of kava with other drugs and concludes that there is an urgent need for further in vitro and in vivo investigations to fully understand clinically significant interactions with kava that have the potential to cause adverse effects or toxicity in kava users.     

伤湿解痛喷涂剂的临床与药效学研究

伤湿解痛喷涂剂系由红花、当归、冰片、细辛、防己等８味中药制成的外用制剂,治疗急性软组织损伤９５例,治愈５３例;显效２５例。总有效率为９３．７％。药效学实验显示,该制剂可明显提高小鼠足部接触热灼刺激的痛阈值（Ｐ＜０．０５）,显著减少小鼠因醋酸刺激的扭体次数（Ｐ＜０．０１）,对于二甲苯所致的小鼠耳廓肿胀具有显著抑制作用（Ｐ＜０．０５）。     

更昔洛韦在家兔体内药动学研究

 目的：了解抗病毒药更昔洛韦静脉注射后在家兔体内的药动学特性。方法：采用高效液相色谱法浏定药物在兔血、尿、组织中浓度的经时变化。结果：家兔静注3种荆童更昔洛韦后血药浓度变化符合开放式三房室模型特征。消除半衰期1.7 h。药物在体内分布广泛，肾脏中血药浓度最高。AUC与剂量呈正相关。24 h尿中原型药物排出黄占给药贡的90.8%。结论：更昔洛韦在家兔体内消除较快，无明显蓄积。     

双氯芬酸搽剂的抗炎镇痛作用

 目的：观察双氯芬酸搽剂的抗炎镇痛作用。方法：配制含双氯芬酸的搽剂，以动物模型观察药物的作用。结果：双氯芬酸搽剂对甲醛及热幅射所致小鼠疼痛有明显的镇痛作用，对二甲苯所致急性炎症及棉球所致慢性肉芽组织增生有显著抑制作用。结论：双氯芬酸搽剂可用于炎症疼痛病人的治疗。     

Comparative clinical trial of castor oil and diclofenac sodium in patients with osteoarthritis

A randomized, double‐blind, comparative clinical study was conducted to compare the safety and efficacy of castor oil with diclofenac sodium in patients with knee osteoarthritis. Subjects with symptoms of knee osteoarthritis were given a castor oil capsule 0.9 mL (n = 50) thrice daily for 4 weeks or a capsule of diclofenac sodium (n = 50), 50 mg thrice daily for 4 weeks. The subjects completed an overall evaluation of symptom relief at 2 weeks and 4 weeks of completed treatment. The subjects were evaluated by clinical, routine laboratory and radiographic investigations for improvement of disease conditions and also for adverse drug reaction. On completion of 4 weeks treatment it was observed that both drugs were significantly effective in the treatment of knee osteoarthritis (p < 0.001) and adverse drug reactions were high with diclofenac sodium, whereas with castor oil there were no adverse effects reported. The present study indicates that castor oil can be used as an effective therapy in primary knee osteoarthritis. Copyright © 2009 John Wiley & Sons, Ltd.     

高效液相色谱法和分光光度法测定双氯芬酸钠乳膏含量的研究

 目的：研究和寻找精密而简便地测定双氯芬酸钠乳膏含量的方法。方法：采用高效液相色谱法和紫外分光光度法。结果：两种方法的平均回收率(X%)及变异系数(RSD%)分别为99.46±0.91和99.70±0.92。结论：结果表明，两种方法均可用于双氯芬酸钠乳膏的含量测定，但HPLC更适于成品含量测定和杂质检查。而UV法可用于生产过程中的半成品检验。     

普罗帕酮与奎尼丁在家兔体内药动学的相互作用

 目的探讨普罗帕酮和奎尼丁在家免体内的药动学特性及合用的相互作用。方法采用高效液色谱法测定家兔给药后不同时间的普罗帕酮和奎尼丁的血药浓度。药-时数据用3P97程序拟合,求得药动学参数。结果两药合用与单独用药时的药-时曲线基本一致,二者的药动学过程均呈二室模型,除普罗帕酮使奎尼丁的t_1/2β,V_c延长及增大外,其余药动学参数无统计学差异。结论两药合用时,普罗帕酮有减慢奎尼丁代谢的趋势,应注意血药浓度监测。     

Effect of olive oil on percutaneous of flubiprofen and diclofenac sodium in rats

目的 考察橄榄油对氟比洛芬和双氯芬酸钠透过大鼠腹部皮肤的作用.方法 以离体大鼠腹部皮肤为渗透屏障,采用扩散池装置,以预处理皮肤法考察橄榄油对药物透过皮肤的影响.结果 橄榄油可有效促进氟比洛芬的经皮透过率,增渗倍数为2.11,但对双氯芬酸钠的经皮透过率有抑制作用.结论 橄榄油能够促进氟比洛芬的经皮渗透,可能归因于其中油酸的存在,还可能含有某些成分对双氯芬酸钠的经皮渗透有抑制作用.