Herbal pharmacology and Drug interaction of the Herbs that Remove Blood Stasis For 2010 Acupuncture Continue Education Dr. Baisong Zhong Ph.D, L.Ac, M.D(China)

Herbal pharmacology and Drug Herbal pharmacology and Drug interaction of the Herbs that interaction of the Herbs that Remove Blood StasisRemove Blood Stasis

For 2010 Acupuncture Continue EducationFor 2010 Acupuncture Continue Education

Dr. Baisong Zhong Ph.D, L.Ac, Dr. Baisong Zhong Ph.D, L.Ac,

M.D(China)M.D(China) WWW: Easternbalancetcm.com WWW: Easternbalancetcm.com E-mail: E-mail: [email protected]@yahoo.com

Introduction of Herbal pharmacology Introduction of Herbal pharmacology and Drug Interaction of the Herbs and Drug Interaction of the Herbs that Remove Blood Stasis that Remove Blood Stasis

1. Actions of the herbs 1. Actions of the herbs (1,2,3)(1,2,3)

(1) Improve the microcirculation(1) Improve the microcirculationBlood stasis is the most common pathogenesis of Blood stasis is the most common pathogenesis of disorders of microcirculation, such as coronary disorders of microcirculation, such as coronary heart disease, cerebral diseases. This group herbs heart disease, cerebral diseases. This group herbs can improve the fluid, state, permeabilitycan improve the fluid, state, permeability of of microcirculation.microcirculation.

(2)Improve hematology and against (2)Improve hematology and against coagulationcoagulation

Blood stasis is related to thrombus Blood stasis is related to thrombus formation due to “thickness, stickiness, formation due to “thickness, stickiness, coagulation and accumulation” of blood in coagulation and accumulation” of blood in circulation. Most of the herbs that remove circulation. Most of the herbs that remove blood stasis have excellent function of blood stasis have excellent function of improving the tendency of “thickness, improving the tendency of “thickness, stickiness, coagulation and accumulation” stickiness, coagulation and accumulation” of blood in circulation. They have inhibitory of blood in circulation. They have inhibitory influence on thrombus formation, and are influence on thrombus formation, and are used in treatment of angina, embolism and used in treatment of angina, embolism and stroke. The herbs include Dan Shen(Radix stroke. The herbs include Dan Shen(Radix Salviae Mitiorrhizae), Chuan Salviae Mitiorrhizae), Chuan Xiong(Rhizoma Ligustici Chuanxiong), Hong Xiong(Rhizoma Ligustici Chuanxiong), Hong Hua(Flos Carthami). Hua(Flos Carthami).

(3)Dilate blood vessel and increase blood (3)Dilate blood vessel and increase blood perfusion to small vessels. perfusion to small vessels.

The herbs that dilate coronary arteries include Shui The herbs that dilate coronary arteries include Shui Zhi(Hirudo), E Zhu(Rhizoma Curcumae), Tao Zhi(Hirudo), E Zhu(Rhizoma Curcumae), Tao Ren(Semen Persicae), Chuan Xiong(Rhizoma Ren(Semen Persicae), Chuan Xiong(Rhizoma Ligustici Chuanxiong)Ligustici Chuanxiong)

(4)Antineoplastic: Some of the herbs can inhibit (4)Antineoplastic: Some of the herbs can inhibit the growth of cancer cells in vitro.the growth of cancer cells in vitro.

The examples are San Leng(Rhizoma Sparganii), The examples are San Leng(Rhizoma Sparganii), E Zhu(Rhizoma Curcumae), Sanqi (E Zhu(Rhizoma Curcumae), Sanqi (Panax Panax notoginsengnotoginseng).).

(5)Lower cholesterol (5)Lower cholesterol

The herbs are Sanqi (The herbs are Sanqi (Panax notoginsengPanax notoginseng), Dan Shen ), Dan Shen (Radix Salviae Mitiorrhizae), Pu Huang(Pollen (Radix Salviae Mitiorrhizae), Pu Huang(Pollen Typhae).Typhae).

2. Potential Herb-drug Interactions 2. Potential Herb-drug Interactions (3)(3)

(1)Antiplatelets and anticoagulants: The group herbs (1)Antiplatelets and anticoagulants: The group herbs may enhance the actions of antiplatelets and may enhance the actions of antiplatelets and anticoagulants medications, and prolong bleeding, anticoagulants medications, and prolong bleeding, such as warfarin, heparin, lepirudin, salicylate .such as warfarin, heparin, lepirudin, salicylate .

(2)Antihypertensives: Some of the group of (2)Antihypertensives: Some of the group of herbs may dilate the blood vessels, which may herbs may dilate the blood vessels, which may potentiate the effect of antihypertensiv potentiate the effect of antihypertensiv medications.medications.

ReferenceReference

1.Qian Xin-zhong. Chinese Materia Medica. People’s Medical 1.Qian Xin-zhong. Chinese Materia Medica. People’s Medical Publishing House. 2007.BeijingPublishing House. 2007.Beijing

2. Shen Yin-jun. Chinese Herbal Pharmacology. People’s 2. Shen Yin-jun. Chinese Herbal Pharmacology. People’s Medical Publishing House. 2000.BeijingMedical Publishing House. 2000.Beijing

3. John Chen, Tina T Chen. Chinese Medical Herbology and 3. John Chen, Tina T Chen. Chinese Medical Herbology and Pharmacology. Art of Medicine Press, Inc. 2009. City of Pharmacology. Art of Medicine Press, Inc. 2009. City of Industry, CA. Industry, CA.

Dan Shen(Radix Dan Shen(Radix Salviae Salviae

Mitiorrhizae)Mitiorrhizae)

NewsNews

BEIJING, Aug. 7 (Xinhua) -- A China-made pill to treat BEIJING, Aug. 7 (Xinhua) -- A China-made pill to treat cardiovascular conditions has been tested safe and cardiovascular conditions has been tested safe and effective by the U.S. Food and Drug Administration effective by the U.S. Food and Drug Administration (FDA), and, hopefully, will be marketed in the U.S. as (FDA), and, hopefully, will be marketed in the U.S. as early as 2013, a pharmaceutical company said here early as 2013, a pharmaceutical company said here Saturday. Saturday. ((http://news.xinhuanet.com/english2010/china/2010-08/07/c_13434173.htmhttp://news.xinhuanet.com/english2010/china/2010-08/07/c_13434173.htm))

FDA reports: Dan Shen and Ge Gen are in clinical trial-FDA reports: Dan Shen and Ge Gen are in clinical trial-Phase II:Phase II:

Cardiovascular-Protective Effects of Herbal Medicine Cardiovascular-Protective Effects of Herbal Medicine DanshenDanshen-Gegen(http://clinicaltrials.gov/ct2/show/NCT01033630?term=Danshen&rank=1-Gegen(http://clinicaltrials.gov/ct2/show/NCT01033630?term=Danshen&rank=1 ))

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Dan Shen is the root and rhizome of salvia Dan Shen is the root and rhizome of salvia miltiorrhiza Bge., family Labiatae.miltiorrhiza Bge., family Labiatae.

Properties: Bitter and slightly coldProperties: Bitter and slightly coldChannels entered: Heart, pericardium, and liver Channels entered: Heart, pericardium, and liver

1. Actions and indications 1. Actions and indications (1)(1) Actions and indications in TCM Actions and indications in TCM (1) Invigorates the blood and breaks up blood (1) Invigorates the blood and breaks up blood

stasis:stasis: It is used for blood stasis disorders in lower abdomen such as dysmenorrhea, It is used for blood stasis disorders in lower abdomen such as dysmenorrhea,

amenorrhea, masses. It is also used for Chest pain.amenorrhea, masses. It is also used for Chest pain.

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Dan Dan

shenshen (2)Clears heat and smoothes irritability(2)Clears heat and smoothes irritability

It is used for restlessness, irritability, palpitation.It is used for restlessness, irritability, palpitation.

(3)Cools blood and expels pus(3)Cools blood and expels pusIt is used for heat in the blood level, skin sores due to It is used for heat in the blood level, skin sores due to

toxic heat.toxic heat.

2. Chemical Ingredients in 2. Chemical Ingredients in DanshenDanshen(2,3,4)(2,3,4)

Dan Shen has more than 50 compounds: Dan Shen has more than 50 compounds:

Tanshinone , Tanshinone A, Tanshinone B, Ⅰ Ⅱ ⅡTanshinone , Tanshinone A, Tanshinone B, Ⅰ Ⅱ ⅡCryptotanshinone, Cryptotanshinone, Cryptotanshinone, Cryptotanshinone, Danshensu(Salviania acid A), Isotanshinone , ⅠDanshensu(Salviania acid A), Isotanshinone , ⅠIsotanshinone , Isocryptotanshinone, Tanshinol , Ⅱ ⅠIsotanshinone , Isocryptotanshinone, Tanshinol , Ⅱ ⅠTanshinol . Methyl tanshinonate, hydroxytanshinone ⅡTanshinol . Methyl tanshinonate, hydroxytanshinone Ⅱ

B , Vitamine E.ⅡB , Vitamine E.Ⅱ

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3.Pharmacokinetics3.Pharmacokinetics(5)(5)

Major components absorbed rapidly Major components absorbed rapidly after oral administration after oral administration

Metabolized extensively by liver Metabolized extensively by liver Excreted from stool and urine, Excreted from stool and urine, Some components have low short Some components have low short

half life, low bioavailability, because half life, low bioavailability, because of extensive metabolism of extensive metabolism

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Dan ShenDan Shen4. Actions and indications in Herbal pharmacology4. Actions and indications in Herbal pharmacology

DanshensuDanshensu(6,7,8,9)(6,7,8,9)

Dilates coronary arteries, inhibits platelet Dilates coronary arteries, inhibits platelet aggregation, improves microcirculation, and aggregation, improves microcirculation, and protects the myocardium from reperfusion injury protects the myocardium from reperfusion injury of the ischemic heart.of the ischemic heart.

Mechanisms:Mechanisms: - prevent intracellular calcium increase - prevent intracellular calcium increase - remove oxygen free radicals - remove oxygen free radicals - Inhibit myocardial cell apoptosis - Inhibit myocardial cell apoptosis - protect the endothelial cells against - protect the endothelial cells against

homocysteinemia (risk factor for cardiovascular homocysteinemia (risk factor for cardiovascular diseases and atherosclerosis)diseases and atherosclerosis)

Salvianolic Acid BSalvianolic Acid B(10, 11)(10, 11)

Protect the brain from ischemia-reperfusion injuryProtect the brain from ischemia-reperfusion injuryMechanisms:Mechanisms:-Inhibit platelet aggregation and oxidative -Inhibit platelet aggregation and oxidative

modification of lowdensity lipoprotein(LDL), modification of lowdensity lipoprotein(LDL), leading to the prevention of the uptake of LDLleading to the prevention of the uptake of LDL (12,13).(12,13).

-Inhibit erythrocyte hemolysis and lipid peroxide -Inhibit erythrocyte hemolysis and lipid peroxide productionproduction(14)(14)

-Inhibit DNA synthesis of noncardiomyocytes and -Inhibit DNA synthesis of noncardiomyocytes and inhibit stress-activated protein kinase activity, inhibit stress-activated protein kinase activity, leading to protection of ischemia-reperfusion injury leading to protection of ischemia-reperfusion injury (15)(15)

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Tanshinone IIATanshinone IIAReduce myocardial infarct sizeReduce myocardial infarct size(16).(16).

-Inhibit LDL oxidation and angiotensin II -Inhibit LDL oxidation and angiotensin II activity, resulting in attenuation of cardiac activity, resulting in attenuation of cardiac cell hypertrophy.cell hypertrophy.

The other actions:The other actions: Prevent cancer metastasisPrevent cancer metastasis(17)(17)

Tanshinone II-A significantly inhibited in vivo metastasis of colon Tanshinone II-A significantly inhibited in vivo metastasis of colon carcinoma SW480 cells. It inhibited in vitro and in vivo invasion and carcinoma SW480 cells. It inhibited in vitro and in vivo invasion and metastasis of colon carcinoma cells by reducing levels of urokinase metastasis of colon carcinoma cells by reducing levels of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMP)-2 plasminogen activator (uPA) and matrix metalloproteinases (MMP)-2 and MMP-9, and by increasing levels of tissue inhibitor of matrix and MMP-9, and by increasing levels of tissue inhibitor of matrix metalloproteinase protein (TIMP)-1 and TIMP-2. Tanshinone II-A was metalloproteinase protein (TIMP)-1 and TIMP-2. Tanshinone II-A was also shown to suppress the nuclear factor-kappaB (NF-kappaB) signal.also shown to suppress the nuclear factor-kappaB (NF-kappaB) signal.

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Protect the liver injuryProtect the liver injury(18)(18)

Clinic researches:Clinic researches:1. Angina Pectoris1. Angina Pectoris-Danshen products were found to be better than isosorbide -Danshen products were found to be better than isosorbide

dinitrate(ISDN) for long term usedinitrate(ISDN) for long term use-None of the Danshen products was found to be superior in -None of the Danshen products was found to be superior in

efficiency to nitroglycerin, fewer side effects such as efficiency to nitroglycerin, fewer side effects such as headache were found in Danshen group compared to headache were found in Danshen group compared to that in the nitroglycerin groupthat in the nitroglycerin group(19).(19).

-Danshen dripping pill was found to achieve a higher rate of -Danshen dripping pill was found to achieve a higher rate of effectiveness in treating patients with angina pectoris in effectiveness in treating patients with angina pectoris in comparison to the Danshen Tablet.comparison to the Danshen Tablet.

-Fufang Danshen Spray and injection were similar or better -Fufang Danshen Spray and injection were similar or better efficacy when compared to ISDNefficacy when compared to ISDN(20)(20)

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-The improvement of exercise ECG from the -The improvement of exercise ECG from the Fufang Danshen Dripping Pill was found to Fufang Danshen Dripping Pill was found to be significantly better than ISDN.be significantly better than ISDN.

-The sublingual Fufang Danshen Dripping Pill -The sublingual Fufang Danshen Dripping Pill is at least as effective as sublingual ISDN and is at least as effective as sublingual ISDN and comparable to sublingual nitroglycerincomparable to sublingual nitroglycerin(21)(21)

2. Hyperlipidemia2. Hyperlipidemia(22)(22) -Danshen products can reduce the level of -Danshen products can reduce the level of

cholesterol, triglyceride, and LDL, and raised cholesterol, triglyceride, and LDL, and raised the level of HDL.the level of HDL.

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3. Acute Ischemic Stroke3. Acute Ischemic Stroke(23,24)(23,24)

-Improve the short-term effect of -Improve the short-term effect of acute stroke patientsacute stroke patients

-conducive to the recovery of patients -conducive to the recovery of patients with traumatic intracranial with traumatic intracranial hematoma (TICH)hematoma (TICH)

-improves the microcirculation of -improves the microcirculation of femoral head, which is beneficial to femoral head, which is beneficial to repair and reconstruction of femoral repair and reconstruction of femoral head.head.

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Side effectsSide effects(25)(25)

No major side effectsNo major side effects

Patients who are taking Fufang Danshen Patients who are taking Fufang Danshen Dripping Pill may felt thirsty(3/100), Dripping Pill may felt thirsty(3/100), dizziness, drowsiness, abdominal dizziness, drowsiness, abdominal discomfort(2/34), decrease appetite and discomfort(2/34), decrease appetite and itching.itching.

LD50 of water soluble extract was almost LD50 of water soluble extract was almost 4000 times higher in mice than the clinical 4000 times higher in mice than the clinical human oral dosage.human oral dosage.

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HERB-DRUG INTERACTIONHERB-DRUG INTERACTION1. The anticoagulant response to warfarin could be 1. The anticoagulant response to warfarin could be

exaggerated when coadministered with Danshen exaggerated when coadministered with Danshen (26,27).(26,27).

2. Salicylate in therapeutic concentration was reported 2. Salicylate in therapeutic concentration was reported to be significantly decrease free Danshen to be significantly decrease free Danshen concentration as measured by free-digoxin-like concentration as measured by free-digoxin-like activityactivity(28)(28)

DOSAGES:DOSAGES:1. Loose Danshen: 6-15g1. Loose Danshen: 6-15g2. Fufang Danshen Dripping Pill: 10 pills orally or sublingually each time, 3 2. Fufang Danshen Dripping Pill: 10 pills orally or sublingually each time, 3

times dailytimes daily3. Fufang Danshen Tablets 3 tablets orally each time, 3 times a day.3. Fufang Danshen Tablets 3 tablets orally each time, 3 times a day.

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1.Qian Xin-zhong. Chinese Materia Medica. People’s Medical 1.Qian Xin-zhong. Chinese Materia Medica. People’s Medical Publishing House. 2007.BeijingPublishing House. 2007.Beijing

2. Zhou L , Zuo Z , Chow MS . Danshen: an overview of its chemistry, 2. Zhou L , Zuo Z , Chow MS . Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use . J Clin Pharmacol . pharmacology, pharmacokinetics, and clinical use . J Clin Pharmacol . 2005;45(12):1345-1359.2005;45(12):1345-1359.

3. Wang X , Morris-Natschke SL , Lee KH . New developments in the 3. Wang X , Morris-Natschke SL , Lee KH . New developments in the chemistry and biology of the bioactive constituents of Tanshen . Med Res chemistry and biology of the bioactive constituents of Tanshen . Med Res Rev . 2007;27(1):133-148.Rev . 2007;27(1):133-148.

4. Jiang RW , Lau KM , Hon PM , Mak TC , Woo KS , Fung KP . Chemistry 4. Jiang RW , Lau KM , Hon PM , Mak TC , Woo KS , Fung KP . Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza and biological activities of caffeic acid derivatives from Salvia miltiorrhiza . Curr Med Chem . 2005;12(2):237-246.. Curr Med Chem . 2005;12(2):237-246.

5. Ye G, Wang CS, Li YY, Ren H, Guo XM. Simultaneous determinationand 5. Ye G, Wang CS, Li YY, Ren H, Guo XM. Simultaneous determinationand pharmacokinetic studies on (3,4-dihydromxyphenyl)-lactic acid and pharmacokinetic studies on (3,4-dihydromxyphenyl)-lactic acid and protocatechuic aldehyde in rat serum after oral administration of Radix protocatechuic aldehyde in rat serum after oral administration of Radix Salvia miltiorrhiza extract. J Chromatogr Sci. 2003;41:327-330Salvia miltiorrhiza extract. J Chromatogr Sci. 2003;41:327-330

6.Dong ZT, Jiang WD, Effect of Danshen of isolated swine coronary artery 6.Dong ZT, Jiang WD, Effect of Danshen of isolated swine coronary artery perfusion preparation. Yaoxue Xuebao. 1982;17:226-228perfusion preparation. Yaoxue Xuebao. 1982;17:226-228

7. Li CZ, Yang SC, Zhao FD, et al. Anticoagulant Studies of Danshen. 7. Li CZ, Yang SC, Zhao FD, et al. Anticoagulant Studies of Danshen. Zhongxiyi Jiehe Zazhi.1983;3:297-299Zhongxiyi Jiehe Zazhi.1983;3:297-299

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8. Dong C, Wang Y, Zhu YZ. Asymmetric synthesis and biological evaluation of 8. Dong C, Wang Y, Zhu YZ. Asymmetric synthesis and biological evaluation of Danshensu derivatives as anti-myocardial ischemia drug candidates. Bioorg Med Danshensu derivatives as anti-myocardial ischemia drug candidates. Bioorg Med Chem. 2009 May 1;17(9):3499-507. Chem. 2009 May 1;17(9):3499-507.

9.Wu L, Qiao H, Li Y, Li L9.Wu L, Qiao H, Li Y, Li L.. Protective roles of puerarin and Danshensu on acute Protective roles of puerarin and Danshensu on acute ischemic myocardial injury in rats. Phytomedicine. 2007 Oct;14(10):652-8. Epub ischemic myocardial injury in rats. Phytomedicine. 2007 Oct;14(10):652-8. Epub 2007 Sep 17.2007 Sep 17.

10. Chen YH , Du GH, Zhang JT. Salvianolic acid B protects Brain against injuries 10. Chen YH , Du GH, Zhang JT. Salvianolic acid B protects Brain against injuries caused by ischemia-reperfusion in rats. ZhongGuo Xinyao Zazhi. 2000:21:463-caused by ischemia-reperfusion in rats. ZhongGuo Xinyao Zazhi. 2000:21:463-466.466.

11. He HB, Yang XZ, Shi MQ, et al. Comparison of cardioprotective effects of 11. He HB, Yang XZ, Shi MQ, et al. Comparison of cardioprotective effects of salvianolic acid B and benazepril on large myocardial infarction in rats. Pharmacol salvianolic acid B and benazepril on large myocardial infarction in rats. Pharmacol Rep. 2008 May-Jun;60(3):369-81.Rep. 2008 May-Jun;60(3):369-81.

12. Han JY, Fan JY, Horie Y, et al. Ameliorating effects of compounds derived from 12. Han JY, Fan JY, Horie Y, et al. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol Ther. 2008 Feb;117(2):280-95. injury by ischemia and reperfusion. Pharmacol Ther. 2008 Feb;117(2):280-95.

13. Tang MK, Ren DC, Zhang JT, et al. Effect of salvianolic acids from Radix Salviae 13. Tang MK, Ren DC, Zhang JT, et al. Effect of salvianolic acids from Radix Salviae miltiorrhizae on regional cerebral blood flow and platelet aggregation in rats. miltiorrhizae on regional cerebral blood flow and platelet aggregation in rats. Phytomedicine. 2002 Jul;9(5):405-9.Phytomedicine. 2002 Jul;9(5):405-9.

14. Yang TL, Lin FY, Chen YH, et al. Salvianolic acid B inhibits low-density 14. Yang TL, Lin FY, Chen YH, et al. Salvianolic acid B inhibits low-density lipoprotein oxidation and neointimal hyperplasia in endothelium-denuded lipoprotein oxidation and neointimal hyperplasia in endothelium-denuded hypercholesterolaemic rabbits. J Sci Food Agric. 2010 Sep 7hypercholesterolaemic rabbits. J Sci Food Agric. 2010 Sep 7 ..

15.Ouyang XS, Takahashi K , Komatsu K, et al. Protective effects of Salvia 15.Ouyang XS, Takahashi K , Komatsu K, et al. Protective effects of Salvia miltiorrhiza on angiotension II-indued hypertrophic responses in neonatal cardiac miltiorrhiza on angiotension II-indued hypertrophic responses in neonatal cardiac cells. Jpn J Phamarcol. 2001;87:289-296.cells. Jpn J Phamarcol. 2001;87:289-296.

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16. Wu TW, Zeng LH, Fung KP, et al. Effect of sodium tanshinone IIA sulfonate in the rabbit 16. Wu TW, Zeng LH, Fung KP, et al. Effect of sodium tanshinone IIA sulfonate in the rabbit myocardium and on human cardiomyocytes and vascular endothelial cells. Biochem myocardium and on human cardiomyocytes and vascular endothelial cells. Biochem Pharmacol. 1993;46:2327-2332. Pharmacol. 1993;46:2327-2332.

17. Shan YF, Shen X, Xie YK, et al. Inhibitory effects of tanshinone II-A on invasion and 17. Shan YF, Shen X, Xie YK, et al. Inhibitory effects of tanshinone II-A on invasion and metastasis of human colon carcinoma cells. Acta Pharmacol Sin.metastasis of human colon carcinoma cells. Acta Pharmacol Sin.

2009; 30:1537-1542.2009; 30:1537-1542.

18. Chor SY, Hui AY, To KF, et al. Anti-proliferative and pro-apoptotic effects of herbal 18. Chor SY, Hui AY, To KF, et al. Anti-proliferative and pro-apoptotic effects of herbal medicine on hepatic stellate cell. J Ethnopharmacol. 2005 Aug 22;100(1-2):180-6.medicine on hepatic stellate cell. J Ethnopharmacol. 2005 Aug 22;100(1-2):180-6.

19. Wang YY, Wang H. comparison of dissolving compound Salvia miltiorrhiza in mouth and 19. Wang YY, Wang H. comparison of dissolving compound Salvia miltiorrhiza in mouth and dissolving nitroglycerin in mouth to treat angina pectoris. Henan Zhigong Yixueyuan dissolving nitroglycerin in mouth to treat angina pectoris. Henan Zhigong Yixueyuan Xuebao. 2004;16:227-229.Xuebao. 2004;16:227-229.

20.Guan ZX, Zhang XQ. Curative effects of composite Salvia miltiorrhiza bunge complex 20.Guan ZX, Zhang XQ. Curative effects of composite Salvia miltiorrhiza bunge complex aerosol on ischemic angina pectoris. Zhonggou Zhongxiyi Jiehe Zazhi. 2000;4:284.aerosol on ischemic angina pectoris. Zhonggou Zhongxiyi Jiehe Zazhi. 2000;4:284.

21. Ding XM, Lia LZ, Wang CH. Curative effect of Danshen composite on stable angina 21. Ding XM, Lia LZ, Wang CH. Curative effect of Danshen composite on stable angina ppectoris. Zhongguo Linchuang Yixue.1999;6:21-22.ppectoris. Zhongguo Linchuang Yixue.1999;6:21-22.

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22. Shao M. Clinic observation of Salvia miltiorrhiza injection on ubstable 22. Shao M. Clinic observation of Salvia miltiorrhiza injection on ubstable anginapectoris. Anhui Zhongyi Xueyuan Xuebao. 2003;22:13-15anginapectoris. Anhui Zhongyi Xueyuan Xuebao. 2003;22:13-15

23. Sun M, Zhang JJ, Shan JZ, et al. Clinical observation of Danhong Injection (herbal 23. Sun M, Zhang JJ, Shan JZ, et al. Clinical observation of Danhong Injection (herbal TCM product from Radix Salviae miltiorrhizae and Flos Carthami tinctorii) in the TCM product from Radix Salviae miltiorrhizae and Flos Carthami tinctorii) in the treatment of traumatic intracranial hematoma. Phytomedicine. 2009 treatment of traumatic intracranial hematoma. Phytomedicine. 2009 Aug;16(8):683-9Aug;16(8):683-9

24. Huang X, Jian H, Liu D, et al. Implantation of calcium phosphate cement/Danshen 24. Huang X, Jian H, Liu D, et al. Implantation of calcium phosphate cement/Danshen drug delivery system for avascular necrosis of femoral head. Zhongguo Xiu Fu drug delivery system for avascular necrosis of femoral head. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2008 Mar;22(3):307-10.Chong Jian Wai Ke Za Zhi. 2008 Mar;22(3):307-10.

25. Zhou JZ, Xiong P. Clinical observation of composite Danshen dipping pill on 100 25. Zhou JZ, Xiong P. Clinical observation of composite Danshen dipping pill on 100 patients with coroary heart disease. Linchuang Yi yao Shijiang Zazhi. patients with coroary heart disease. Linchuang Yi yao Shijiang Zazhi. 2003;12:264-265.2003;12:264-265.

26. Liu J, Wang X, Cai Z, et al. 26. Liu J, Wang X, Cai Z, et al. Effect of tanshinone IIA on the noncovalent interaction Effect of tanshinone IIA on the noncovalent interaction between warfarin and human serum albumin studied by electrospray ionization mass between warfarin and human serum albumin studied by electrospray ionization mass

spectrometry. J Am Soc Mass Spectrom. 2008; Oct: 1568-75spectrometry. J Am Soc Mass Spectrom. 2008; Oct: 1568-75 27. Chan TY. Interaction between warfarin and Danshen. Ann Pharmacother. 27. Chan TY. Interaction between warfarin and Danshen. Ann Pharmacother.

2001;35:501-504.2001;35:501-504.28. Gupta D, Jalali M, Wells A, et al. Drug-herb interactions: unexpected suppression 28. Gupta D, Jalali M, Wells A, et al. Drug-herb interactions: unexpected suppression

on free Danshen concentrations by salicylate. J Clin Lab Anal.2002;16:290-294on free Danshen concentrations by salicylate. J Clin Lab Anal.2002;16:290-294

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Sanqi (Sanqi (Panax Panax notoginsengnotoginseng))

SanqiSanqi

The root of Panax NotoginsengThe root of Panax Notoginseng It is the largest ingredient in It is the largest ingredient in 云南白药 云南白药 ((

Yunnan Yunnan BaiBai Yao Yao), a famous hemostatic herbal ), a famous hemostatic herbal remedy remedy

Sweet and slightly bitter in taste, and Sweet and slightly bitter in taste, and nontoxic.nontoxic.

The dose in decoction for clinical use is 5-10 The dose in decoction for clinical use is 5-10 g. It can be ground to powder for swallowing g. It can be ground to powder for swallowing directly or taking mixed with water: the dose directly or taking mixed with water: the dose in that case is usually is 1-3 grams. in that case is usually is 1-3 grams.

SanqiSanqi

1. Action and Indications in 1. Action and Indications in TCMTCM

(1) Stops bleeding and transforms (1) Stops bleeding and transforms blood stasis:blood stasis:

Used for internal and external Used for internal and external bleedingbleeding

(2) Reduces swelling and alleviates (2) Reduces swelling and alleviates pain: pain:

SanqiSanqi

2. Chemical constituents.2. Chemical constituents. Saponins derivatives (PNS), which is a Saponins derivatives (PNS), which is a

mixture of more than 20 types of mixture of more than 20 types of saponins, four or five of them are saponins, four or five of them are considered as the principle active onesconsidered as the principle active ones Notoginenoside R1, ginsenoside Rg1, Rd, Notoginenoside R1, ginsenoside Rg1, Rd,

Re and Rb1 (75-80% total PNS)Re and Rb1 (75-80% total PNS) Flavonoids et al. Flavonoids et al.

3. Pharmacokinetics 3. Pharmacokinetics

Oral administration, most Saponins Oral administration, most Saponins derivatives (powder) tested in rats, derivatives (powder) tested in rats, reached peak concentration in plasma reached peak concentration in plasma rapidly within about 0.75 h - rapidly within about 0.75 h - hint their hint their absorption were quick. absorption were quick.

Maximum concentration in rat plasma Maximum concentration in rat plasma were lowwere low indicated that it may be poorly absorbed indicated that it may be poorly absorbed

and / or extensive metabolized (intestinal and / or extensive metabolized (intestinal microflora, liver) microflora, liver)

Sanqi

Half time was changed from 1 to 20 hrs Half time was changed from 1 to 20 hrs in rat plasma after oral administration in rat plasma after oral administration of the constituents of the constituents

IvIv in rats, most constituents were in rats, most constituents were cleared quickly except a couple of PNS cleared quickly except a couple of PNS the pharmacokinetic profile diversities of the pharmacokinetic profile diversities of

these constituents are probably one of the these constituents are probably one of the mechanisms of the multiple pharmacology mechanisms of the multiple pharmacology activities activities

San-qi

(1)Hemostatic (1)Hemostatic effecteffect

San-qi and a saponin (PNS) extract San-qi and a saponin (PNS) extract provide hemostatic effects. External provide hemostatic effects. External application reduces bleeding timeapplication reduces bleeding time(1).(1).

San-qi

4. Actions and indications in Herbal pharmacology

(2)Thrombogenicity effects(2)Thrombogenicity effects

PNS reduces platelet PNS reduces platelet activation, adhesion and activation, adhesion and aggregationaggregation(2).(2).

Prevent thrombosis and Prevent thrombosis and improve microcirculation in improve microcirculation in patients with blood patients with blood hyperviscosicity syndromehyperviscosicity syndrome(3).(3).

San-qi

(3)Thrombogenicity effects (3)Thrombogenicity effects

PNS iv or oral 200 mg/kg PNS iv or oral 200 mg/kg need 20 days to appearneed 20 days to appearhint a slow effect compare hint a slow effect compare to hemostatic to hemostatic

San-qi

(4)Fibrinolytic effects (4)Fibrinolytic effects

Sanqi (Sanqi (the extract as the extract as notoginsenoside R1notoginsenoside R1) ) increased the fibrnolytic increased the fibrnolytic potential in potential in in vivoin vivo lab test, lab test, which may be beneficial to which may be beneficial to cardiovascular diseasecardiovascular disease(4)(4)

San-qi

(5)Cardiovascular effects (5)Cardiovascular effects

Dilate the coronary artery, Dilate the coronary artery, increase coronary blood flow, increase coronary blood flow, providing more blood to the heart providing more blood to the heart musclemuscle

Improves micro-circulation in Improves micro-circulation in and around damaged heart tissue and around damaged heart tissue

Reduces cardiac load, lowers Reduces cardiac load, lowers arterial pressurearterial pressure(5)(5)

San-qi

Decrease the size of myocardial Decrease the size of myocardial infarction infarction

Anti-arrhythmiaAnti-arrhythmia PNS increases PGI2 and reduces PNS increases PGI2 and reduces

thromboxane A2 in platelets – thromboxane A2 in platelets – correct the unbalance between correct the unbalance between the two prostaglandins the two prostaglandins

San-qi

(6)Anti-atherosclerotic (6)Anti-atherosclerotic effect effect It helps lower cholesterol and It helps lower cholesterol and

triglycerides, to prevent the triglycerides, to prevent the progression of atherosclerotic lesion. progression of atherosclerotic lesion. PNS possess anti-hyperglycemic and PNS possess anti-hyperglycemic and anti-obese activities by improving anti-obese activities by improving insulin- and leptin sensitivity, and insulin- and leptin sensitivity, and Rb1 is responsible for the anti-Rb1 is responsible for the anti-hyperglycemic effect among the five hyperglycemic effect among the five saponins in KK-Ay micesaponins in KK-Ay mice .(6, 7).(6, 7)

San-qi

(7)Effects on brain(7)Effects on brain Protect ischaemic brain damageProtect ischaemic brain damage(8).(8).

Ginsenoside Rb(3) could markedly protected OGD-Ginsenoside Rb(3) could markedly protected OGD-Rep induced ischemic injury and the mechanisms Rep induced ischemic injury and the mechanisms maybe related to its suppression of the maybe related to its suppression of the intracellular Ca(2+) elevation and inhibition of intracellular Ca(2+) elevation and inhibition of apoptosis and caspase activity. Ginsenoside Rb(3) apoptosis and caspase activity. Ginsenoside Rb(3) could be a promising candidate in the development could be a promising candidate in the development of a novel class of anti-ischemic agent. of a novel class of anti-ischemic agent.

Decrease brain edema, infarct size and neuron Decrease brain edema, infarct size and neuron damage damage

Inhibit uptake calcium by neuron cells isolated Inhibit uptake calcium by neuron cells isolated from ratsfrom rats

Protect cultured rat cortical neuron from Protect cultured rat cortical neuron from glutamate neurotoxicityglutamate neurotoxicity(9)(9)

San-qi

(8)Tumor Radio-sensitivity (8)Tumor Radio-sensitivity

Taiwanese scientists studied the Taiwanese scientists studied the sensitization effect of Panax sensitization effect of Panax notoginseng extract and purified notoginseng extract and purified Saponin (Rb1) on the radiation Saponin (Rb1) on the radiation response of an experimental tumor response of an experimental tumor (KHT sarcoma) in comparison with its (KHT sarcoma) in comparison with its effects on a normal tissue (bone effects on a normal tissue (bone marrow) in mice. marrow) in mice.

San-qi

Panax notoginseng extract at a Panax notoginseng extract at a concentration of concentration of 0.1-1000.1-100 mg/kg produced mg/kg produced an increase in tumor radiosensitivity. an increase in tumor radiosensitivity.

Rb1 at a concentration Rb1 at a concentration 0.001 to 1 mg/kg0.001 to 1 mg/kg produced an increase in tumor produced an increase in tumor radiosensitivity, with maximum effect at 1 radiosensitivity, with maximum effect at 1 mg/kg. mg/kg.

The effect was maximal at 10 mg/kg and The effect was maximal at 10 mg/kg and at 30 minutes after injection. at 30 minutes after injection.

Further purified or synthetic versions are Further purified or synthetic versions are useful in cancer therapy. useful in cancer therapy.

San-qi

(9)Anti-inflammatory effects and (9)Anti-inflammatory effects and

stop painstop pain San Qi can stop pain caused by San Qi can stop pain caused by

inflammation and trauma through anti-inflammation and trauma through anti-inflammation and disturbing the central inflammation and disturbing the central nervous system.nervous system.

5. Toxicity Low Low Esophagitis from consuming tablets Esophagitis from consuming tablets

(drink enough water) (drink enough water) may occurmay occur Allergic reactions including dermatitis, Allergic reactions including dermatitis,

shock, purpura, blisters, or other shock, purpura, blisters, or other idiosyncratic reactions. idiosyncratic reactions.

6. Clinical research6. Clinical research

(1)Coronary artery disease(1)Coronary artery disease

(2)Hyhercholesterolemia(2)Hyhercholesterolemia

(3)Bleedings: (3)Bleedings: Upper gastointerestinal bleedingUpper gastointerestinal bleeding Stomach bleedingStomach bleeding HemoptysisHemoptysis Pain Pain

Reference:Reference:1.Fan C, Song J, White CM.A comparision of the hemostatic effects of 1.Fan C, Song J, White CM.A comparision of the hemostatic effects of

notoginseng and yun nan bai yao to placebo control. J Herb Pharmacother. notoginseng and yun nan bai yao to placebo control. J Herb Pharmacother. 2005;5(2):1-5.2005;5(2):1-5.

2. Lau AJ, Toh DF, Chua TK, et al. Antiplatelet and anticoagulant effects of 2. Lau AJ, Toh DF, Chua TK, et al. Antiplatelet and anticoagulant effects of Panax notoginseng: comparison of raw and steamed Panax notoginseng Panax notoginseng: comparison of raw and steamed Panax notoginseng with Panax ginseng and Panax quinquefolium. J Ethnopharmacol. 2009 with Panax ginseng and Panax quinquefolium. J Ethnopharmacol. 2009 Sep 25;125(3):380-6. Epub 2009 Aug 7. Sep 25;125(3):380-6. Epub 2009 Aug 7.

3.Wang J, Xu J, Zhong JB. Effect of Radix notoginseng saponins on platelet 3.Wang J, Xu J, Zhong JB. Effect of Radix notoginseng saponins on platelet activating molecule expression and aggregation in patients with blood activating molecule expression and aggregation in patients with blood hyperviscosity syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004 hyperviscosity syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004 Apr;24(4):312-6.Apr;24(4):312-6.

4.Zhang WJ, Wojta J, Binder BR. Effect of notoginsenoside R1 on the 4.Zhang WJ, Wojta J, Binder BR. Effect of notoginsenoside R1 on the synthesis of components of the fibrinolytic system in cultured smooth synthesis of components of the fibrinolytic system in cultured smooth muscle cells of human pulmonary artery. Cell Mol Biol. 1997 muscle cells of human pulmonary artery. Cell Mol Biol. 1997 Jun;43(4):581-7.Jun;43(4):581-7.

5. Wu L, Zhang W, Tang YH, et al. Effect of total saponins of "panax 5. Wu L, Zhang W, Tang YH, et al. Effect of total saponins of "panax notoginseng root" on aortic intimal hyperplasia and the expressions of cell notoginseng root" on aortic intimal hyperplasia and the expressions of cell cycle protein and extracellular matrix in rats. Phytomedicine. 2010 cycle protein and extracellular matrix in rats. Phytomedicine. 2010 Mar;17(3-4):233-40. Mar;17(3-4):233-40.

Sanqi

6.Yang CY, Wang J, Zhao Y, et al. Anti-diabetic effects of Panax notoginseng 6.Yang CY, Wang J, Zhao Y, et al. Anti-diabetic effects of Panax notoginseng saponins and its major anti-hyperglycemic components. J Ethnopharmacol. 2010 saponins and its major anti-hyperglycemic components. J Ethnopharmacol. 2010 Jul 20;130(2):231-6.Jul 20;130(2):231-6.

7.Liu G, Wang B, Zhang J, et al. Total panax notoginsenosides prevent atherosclerosis 7.Liu G, Wang B, Zhang J, et al. Total panax notoginsenosides prevent atherosclerosis in apolipoprotein E-knockout mice: Role of downregulation of CD40 and MMP-9 in apolipoprotein E-knockout mice: Role of downregulation of CD40 and MMP-9 expression.J Ethnopharmacol. 2009 Nov 12;126(2):350-4.expression.J Ethnopharmacol. 2009 Nov 12;126(2):350-4.

8. Zhu JR, Tao YF, Lou S, et al. Protective effects of ginsenoside Rb(3) on oxygen and 8. Zhu JR, Tao YF, Lou S, et al. Protective effects of ginsenoside Rb(3) on oxygen and glucose deprivation-induced ischemic injury in PC12 cells. Acta Pharmacol Sin. glucose deprivation-induced ischemic injury in PC12 cells. Acta Pharmacol Sin. 2010 Mar;31(3):273-80. 2010 Mar;31(3):273-80.

9. Cai BX, Li XY, Chen JH, et al. Ginsenoside-Rd, a new voltage-independent Ca2+ 9. Cai BX, Li XY, Chen JH, et al. Ginsenoside-Rd, a new voltage-independent Ca2+ entry blocker, reverses basilar hypertrophic remodeling in stroke-prone entry blocker, reverses basilar hypertrophic remodeling in stroke-prone renovascular hypertensive rats. Eur J Pharmacol. 2009 Mar 15;606(1-3):142-9.renovascular hypertensive rats. Eur J Pharmacol. 2009 Mar 15;606(1-3):142-9.

Sanqi

Chuan XiongChuan Xiong (Rhizoma Ligustici (Rhizoma Ligustici

Chuanxiong)Chuanxiong)

Chuanxiong is the root and rhizome of Ligusticum Chuanxiong is the root and rhizome of Ligusticum Chuangxiong HortChuangxiong Hort

Properties: Acrid, warm.Properties: Acrid, warm.

Channels entered: Liver, pericardium, and gallblader. Channels entered: Liver, pericardium, and gallblader.

1. Actions and indications in TCM 1. Actions and indications in TCM (1)(1) (1)Regulate Qi and invigorates the blood(1)Regulate Qi and invigorates the blood It is widely used for irregular menstruation, menorrhea, It is widely used for irregular menstruation, menorrhea,

dysmenorrhea, and headache due to qi stagnation and dysmenorrhea, and headache due to qi stagnation and blood stasis.blood stasis.

(2)Expel wind and relieve pain(2)Expel wind and relieve pain It is used for headache, aching body and Bi syndrome It is used for headache, aching body and Bi syndrome

due to wind cold. due to wind cold.

Chuan Xiong

2. Major Chemical Ingredients2. Major Chemical Ingredients(2)(2)

Alkaloids: Chuanxiongzine, Alkaloids: Chuanxiongzine, tetramethylprazine, tetramethylprazine,

Organic acid: Ferulic acid, sedanonic Organic acid: Ferulic acid, sedanonic acid,acid,

Essential oil: ethyl pentadecanoate,Essential oil: ethyl pentadecanoate,

3. Pharmacological effects3. Pharmacological effects(2,3)(2,3)

(1)Cardiovascular(1)Cardiovascular(4)(4)

Chuan Xiong dilates blood vessels, increases myocardial Chuan Xiong dilates blood vessels, increases myocardial blood flow and oxygen-supply, keeps myocardial oxygen blood flow and oxygen-supply, keeps myocardial oxygen balance. The mechanism is related to ChuanXiong decreases balance. The mechanism is related to ChuanXiong decreases invascular endothelial growth factor (VEGF) einvascular endothelial growth factor (VEGF) expressionxpression..

Chuan Xiong

(2). Improves the (2). Improves the circulationcirculation Dilates arteries: dilates the arteries Dilates arteries: dilates the arteries

of the heart, brain, lungs: for of the heart, brain, lungs: for example, increases blood perfusion example, increases blood perfusion to and reduce swelling of the brain. to and reduce swelling of the brain. Used for migraine, cerebral Used for migraine, cerebral ischemia, Alzheimer’s disease.ischemia, Alzheimer’s disease.

Antiplatelet and anticoagulant: Antiplatelet and anticoagulant:

Chuan Xiong

(3)Stop pain(3)Stop pain

Sedative: effects on the central Sedative: effects on the central nervous systemnervous system

Relaxes the spasm of musclesRelaxes the spasm of muscles

(4)(4)Others Others Decreases the side effects of Decreases the side effects of

kanamycin and cyclosporin Akanamycin and cyclosporin A Anti-radiotherapy:Anti-radiotherapy:

Chuan Xiong

4. Herb-drug 4. Herb-drug InteractionInteraction(2,3)(2,3)

Antiplatelet and anticoagulat: Though Antiplatelet and anticoagulat: Though this potential interaction has not this potential interaction has not been documented, it should be used been documented, it should be used with caution. Examples of antiplatelet with caution. Examples of antiplatelet are aspirin, dipyridamole(persantine), are aspirin, dipyridamole(persantine), and clopidogrel(plavix). Examples of and clopidogrel(plavix). Examples of anticoagulat are heparin, anticoagulat are heparin, wafarin(coumadin), and wafarin(coumadin), and enoxaprin(lovenox).enoxaprin(lovenox).

Chuan Xiong

5. Toxicology5. Toxicology(2,3)(2,3)

When continuous oral administrated When continuous oral administrated in mice with 5mg-10mg/kg for 4 in mice with 5mg-10mg/kg for 4 weeks, no abnormalities of liver, weeks, no abnormalities of liver, kidney, blood exam. and pathological kidney, blood exam. and pathological exam were observed.exam were observed.

The LD50 for it preparation in mice The LD50 for it preparation in mice was 66.42g/kg with intravenous was 66.42g/kg with intravenous injection.injection.

Chuan Xiong

6. Clinical Indication of 6. Clinical Indication of ResearchResearch HeadacheHeadache Diseases of the heart and brainDiseases of the heart and brain

Chuan Xiong

Reference:Reference:

1.Qian Xin-zhong. Chinese Materia Medica. People’s Medical Publishing 1.Qian Xin-zhong. Chinese Materia Medica. People’s Medical Publishing House. 2007.BeijingHouse. 2007.Beijing

2. Shen Yin-jun. Chinese Herbal Pharmacology. People’s Medical Publishing 2. Shen Yin-jun. Chinese Herbal Pharmacology. People’s Medical Publishing House. 2000.BeijingHouse. 2000.Beijing

3. John Chen, Tina T Chen. Chinese Medical Herbology and Pharmacology. 3. John Chen, Tina T Chen. Chinese Medical Herbology and Pharmacology. Art of Medicine Press, Inc. 2009. City of Industry, CA. Art of Medicine Press, Inc. 2009. City of Industry, CA.

4. Meng H, Guo J, Sun Jy, et al. Angiogenic effects of the extracts from 4. Meng H, Guo J, Sun Jy, et al. Angiogenic effects of the extracts from Chinese herbs: Angelica and Chuanxiong. Am J Chin Med. Chinese herbs: Angelica and Chuanxiong. Am J Chin Med. 2008;36(3):541-54.2008;36(3):541-54.

Chuan Xiong

Thank You !Thank You !