Blood-moving Herbs and Dan Shen

Monograph from Interactions: IBIS Guide to Drug-Herb and Drug-Nutrient Interactions (2000):

Blood-moving Herbs and Dan Shen

Summary

Dan Shen (Salvia miltiorrhiza) and Blood-Moving Herbs in Chinese Medicine

Blood-moving herbs: Summary: Herbs classified as "Blood-invigorating" in traditional Chinese herbal medicine were thought by ancient Chinese physicians to make "sluggish" or "stuck" Blood flow more freely. It is important to note that the Chinese physiological concept of the fluid "Xue," commonly translated as "Blood" is a functional term of broad implications which includes the anatomical "blood" of conventional biomedicine but is not restricted to such. A number of commonly used Chinese herbs are in this class and they have some general properties in common.

commonly prescribed formulae containing blood invigorating herbs: Shi Quan Da Bu Wan, Danshen Wan, Bu Zhong Yi Qi Tang, Xiao Yao San, Chuan Xiong Cha Tiao Wan, Ba Zhen Tang (Womens' Precious and common variations like Black Chicken Pills), Hai Hu Shu Gan Tang, Xue Fu Zhu Yu Tang, Du Huo Ji Sheng Tang and most formulae for any kind of chronic pain.

physiological action: Most of the herbs in this category have demonstrated anticoagulant, analgesic and/or anti-inflammatory properties.

proven or potential therapeutic uses: Angina, hepatitis, coronary artery disease, dysmenorrhea, rheumatoid arthritis, traumatic injury, tumors, depression, renal failure, stroke prevention and post-stroke syndrome.

overview of interactions involving "Blood-moving" herbs:
• drugs affected by herb group: Warfarin, Heparin, Ticlopidine

Commonly used "Blood-moving" herbs:
• Achyranthes bidentata
• Angelica sinensis
• Boswellia carteri
• Carthamus tinctorus
• Commiphora myrrha
• Curcuma longa
• Curcuma zedorai
• Leonorus heterophyllus
• Ligusticum wallichii
• Lycopus lucidus
• Millettia dielsiana
• Panax pseudoginseng
• Peony lactiflora
• Prunus persica
• Salvia miltiorrhiza
• Sparganium simplex

note: The commonly used Sage, officially known as Salvia officinalis, while a botanical relative of Salvia miltiorrhiza, is not considered a risk factor when using anticoagulant herbs. The two plants are quite distinct pharmacologically and clinically.

drugs affected by herb group: Warfarin, Heparin, Ticlopidine

• mechanism: Numerous animal and in vitro studies have shown blood invigorating herbs to have widespread receptor modulating effects, affecting calcium channels, dopamine, adrenergic, angiotensin II, benzodiazepine, endorphin and others. Human and animal studies demonstrate vasodilatation, protection of cardiac muscles from anoxia, increased blood flow, reduced platelet aggregation and thrombus formation. They reduce vascular permeability and increase phagocytosis, as well as speed healing time in fractures and other traumas. Several cases have appeared in the medical literature discussing the dangerous interaction which can result from the simultaneous use of warfarin and these Chinese herbs, either alone or in formulations. This reaction would be expected from the understanding of Blood-moving herbs and their clinical uses within the prescribing traditions of Chinese herbal medicine.
(Huang KC. 81; Zhou, JHG, Liu GZ. 200; Yu S, et al. J Tradit Chin Med 1998 Dec;18(4):292-299; Xing ZQ, et al. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1996 May;16(5):287-288; Ding Y, et al. J Osaka Univ Dent Sch 1995 Dec;35:21-27; Zhen Z, et al. Chung Hua I Hsueh Tsa Chih 1995 May;75(5):266-269, 318; Gu ZP, et al. Chung Hua Wai Ko Tsa Chih 1994 Nov;32(11):692-695; Wang Z, et al. Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao 1994 Apr;16(2):140-143 Liu J, et al. Chin Med Sci J 1992 Sep;7(3):142-147; Hu MZ.Chung Hua Wai Ko Tsa Chih 1993; Yang Y, et al.Hua Hsi I Ko Ta Hsueh Hsueh Pao 1993 Jun;24(2):143-146; Liu J. Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao 1993 Jun;15(3):201-205; Qin JZ, Wang XC. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1992 Jun;12(6):354-356, 325-326; Zheng XK. Chung Hsi I Chieh Ho Tsa Chih 1991 Dec;11(12):733-735, 710; Lei XL, Chiou GC. Am J Chin Med 1986;14(3-4):145-152; Wang Z, et al. Thromb Haemost 1982 Dec 27;48(3):301-306; Tam LS, et al. Aust NZ J Med 25 Jun, 258, 1995; Chan TY. Int J Clin Pharmacol Ther 1998 Jul;36(7):403-405; Cheng TO.Ann Thorac Surg. 1999 Mar;67(3):894.)

• research: Salvia miltiorrhiza (Dan Shen) and other common blood invigorating herbs have been implicated in dangerously potentiating warfarin (coumadin) and heparin, including Angelica sinensis, Ligusticum wallichii, Prunus persica, Carthamus tinctorus. This is due to such herbs having anticoagulant actions themselves. While some physicians trained in Chinese herbal medicine may take advantage of this interaction to use lower doses of blood thinners in some cases, this should only be undertaken with close monitoring of bleeding times and appropriate dose reduction of pharmaceuticals under the supervision of the prescribing physician.
(Chen J. Oriental Medicine. Winter 1999; 16, 24; Yu CM, et al. J Intern Med. 1997 Apr; 241(4):337-339; Izzat MB, et al. Ann Thorac Surg. 1998 Sep; 66(3):941-942; Page RL 2nd; Lawrence JD. Pharmacotherapy. 1999 Jul;66(7):870-876; Chan TY. Int J Clin Pharmacol Ther. 1998 Jul;89(2):403-405.)

• discussion: Since Salvia, Angelica and Ligusticum are all contained in many commonly used Chinese health tonics, patients (especially Asians) should be queried about their herb use before instituting anticoagulant therapy. Several incidents have been noted regarding these interactions in Asian countries and overseas communities. This is particularly important as Asians are known to be more sensitive to coumadin and heparin than Caucasians, even when not taking herbs. While Salvia miltiorrhiza and Angelica sinensis have been implicated in an actual clinical cases of adverse reactions, the other herbs in this class are assumed to posses the same risk, given their common anticoagulant actions. Salvia and other Blood-invigorating herbs may be able to lower the doses of drugs like coumadin and in some cases replace them altogether. Unlike coumadin, which has a risky safety profile, the use of Blood-invigorating herbs without concurrent drug use is extremely safe in comparison. While Blood-invigorating herbs are thought to cause mild, reversible side effects if used for too long, in too large doses or when not indicated, the herbs mentioned are completely nontoxic in the sense that they do not cause adverse reactions even in dosages far above the therapeutic range. At this time, the safe use of Blood-invigorating herbs in combination with anticoagulant drugs has not yet been established. Patients are advised to seek the advice of their prescribing physician and/or a healthcare professional trained in herbal medicine before altering their medication or incorporating such herbs into their regimen.
(Yu HC, et al. QJM. 1996 Feb; 89(2):127-135; Yu CM. et al. QJM. 1997 Aug;90(8):535-543.)

References

Bensky D, Barolet R. Chinese Herbal Medicine: Formulas and Strategies. Seattle,WA: Eastland Press 1990.

Chan K, Lo AC, Yeung JH, Woo KS. The effects of Danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol 1995 May;47(5):402-406.
Abstract: The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats. After a single oral dose of racemic warfarin (2 mg kg-1), treatment with oral Danshen extract (5 g kg-1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0.2 mg kg-1 day-1 for 5 days) the 3-day treatment of Danshen extract (5 g kg-1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin. The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.

Chan TY. Drug interactions as a cause of overanticoagulation and bleedings in Chinese patients receiving warfarin. Int J Clin Pharmacol Ther. Jul 1998;89(2):403-405.
Abstract: Little is known about the incidence and consequences of drug interactions in patients receiving warfarin. Hence, drug interactions as a cause of overanticoagulation and bleedings were determined in Chinese patients admitted to our medical unit during a 9-month period in 1994/95. Only patients with an admission international normalized ratio (INR) of > 3.0 (target range 2.0-2.5) were included since the drug interactions, if present, were more likely to be of clinical significance. Of 35 patients reviewed, 7 had a predisposing condition such as peptic ulcer and 19 received drugs or folk medicines that can interact with warfarin. Based on the temporal relationship between the initiation of the interacting agent(s) and the rise in INR/onset of bleedings, drug-warfarin interactions were definitely (n = 6) or possibly (n = 1) responsible in 7 patients (drugs for common cold 2, piroxicam plus piroxicam gel 2, medicated oil (15% methyl salicylate) plus Salvia miltiorrhiza Bge 1, "analgesic balm" (50% methyl salicylate) 1, diclofenac gel 1). These agents were prescribed by their physicians (n = 1), family doctors (n = 1) and other specialists (n = 1) or bought over-the-counter (n = 2). One other patient used the drugs from previous consultations. Five of the 7 patients developed bleedings. Drug interactions accounted for 20% of all patients with an INR of > 3.0 and 5 (36%) of 14 patients with bleedings. Patients receiving warfarin should be warned about the danger of self-medication. When prescribing warfarin, physicians should be aware of other medications that their patients are taking.

Chen J. Recognition and Prevention of Herb-Drug Interaction. Oriental Medicine. Winter 1999; 16, 24.

Cheng TO. Warfarin danshen interaction. Ann Thorac Surg. 1999 Mar;67(3):894. (Letter)

Ding Y, Soma S, Takano-Yamamoto T, Matsumoto S, Sakuda M. Effects of salvia miltiorrhiza bunge (SMB) on MC3T3-E1 cells. J Osaka Univ Dent Sch 1995 Dec;35:21-27.
Abstract: In previous research, we found that the Salvia Miltiorrhiza Bunge (SMB), a traditional Chinese medicinal herb, accelerates orthodontic tooth movement. In the present study, to characterize the actions of SMB on bone remodeling, we investigated the effect of SMB on DNA synthesis and alkaline phosphatase activity of murine osteoblast like cell-clone, MC3T3-E1 cells in vitro. Treatment of the cells with SMB for 72 hours caused significant increase in ALPase activity. It was found that SMB increased ALPase activity in a dose-dependent manner, and up to maximum at the concentration of 5.0 mg/ml. At that concentration, ALPase activity was about 135% greater than that of control. SMB at 5.0 mg/ml significantly stimulated ALPase activity of the cells in multilayer on day 8 or calcification stage on day 16, but inhibited it in the sparse stage on day 2 or subconfluency stage on day 4. SMB had no effect on DNA synthesis in any stage of culture. ALPase activity significantly increased at 48 hours and was up to 300% greater than that of control activity at 96 hours. These findings suggest that SMB directly stimulates ALPase activity of MC3T3-E1 cells in multilayer stage or calcification stage without any effect on proliferation. Locally administrated SMB may affect the differentiation of osteoblasts in vivo.

Gu ZP, Ma CX, Zhang BX. The effects of injection salviae miltiorrhizae in preventing and treating fat embolism syndrome.Chung Hua Wai Ko Tsa Chih 1994 Nov;32(11):692-695.
Abstract: This study was to examine the effects and mechanisms of injectio salviae miltiorrhizae (ISM) in preventing and treating fat embolism syndrome (FES), which was simulated by intravenous injection of homologous bone marrow fat in 16 dogs. PaO2, free fatty acids (FFAs), TXA2/PGI2, SOD/MDA were measured in different times combined with X-ray, conjunctiva microcirculation observation, radioisotope scanning and histologic examination. It was found that in the control group there were a significant fall in PaO alpha and rise in FFAs and MDA; blood clot stained with oil red O showed many fat droplets; radioisotope scanning revealed mild hypoperfusion or perfusion defects. In the treatment group, arterial oxygen levels were maintained, serum level of FFAS and MDA was reduced significantly. It is concluded that there is damage induced by oxygen-derived radicals in FES, LSM is an effective therapy for the FES, and 99mTc radioisotope scanning is a promising technique for noninvasive identification of FES in the early stage.

Huang KC.The Pharmacology of Chinese Herbs, Ann Arbor, MI: CRC Press 1993.

Hu MZ. [Effect of radix salviae miltiorrhizae on the mitotic activity of osteoblast-like cells isolated from chicken embryo calvariae cultured in vitro.Chung Hua Wai Ko Tsa Chih. 1993 Apr;31(4):251-253. [Article in Chinese]
Abstract: Chicken embryo calvariae cultured in vitro, could yield 3 types of osteoblast-like cells, which differed in morphology. They were the spindle-shaped cells, globular cells, and squamous cells. Of these, the squamous cell was the chief cellular component, while both the spindle-shaped cells and the globular cells gradually transformed into squamous cells. Administration of Radix Salviae Miltiorrhizae rendered more rapid growth of the osteoblast-like cells in the early stage of culture. After 17-day of culture, when both the control group cells and the treated, group cells became quite confluent, 3H-Thymidine labelling and radioautographic study revealed a very statistically significant increase in the number of cells, bearing silver grains over the nucleus area in the treated group, as compared with the control (P

Izzat MB; Yim AP; El-Zufari MH. A taste of Chinese medicine! Ann Thorac Surg,1998 Sep. 66(3):941-942 .
Abstract: We report a case of profound anticoagulation caused by interaction between warfarin and danshen, a widely used Chinese herbal medicine, in a patient who had undergone mitral valve replacement. Patients taking warfarin should be warned not to take this herb. In addition, physicians should be alert to the possibility of an interaction with herbal medicine when anticoagulation control becomes difficult and no other causes are apparent.

Lei XL, Chiou GC. Cardiovascular pharmacology of Panax notoginseng (Burk) F.H. Chen and Salvia miltiorrhiza. Am J Chin Med 1986;14(3-4):145-152.
Abstract: The cardiovascular pharmacology of two Chinese herbs, Salvia miltiorrhiza (SM) and Panax notoginseng (Burk) F. H. Chen (PNG) were studied both in vivo and in vitro. Extracts of both herbs suppressed systemic blood pressure in albino rats and rabbits, an effect which was blocked or reversed by atropine, propranolol, and chlorpheniramine plus cimetidine. This reversed hypertension was blocked by phenoxybenzamine. These results indicate that these herbs have multiple effector sites in the cardiovascular system. This could be due to an increased utilization of extracellular calcium ions since the activity of SM on isolated blood vessels of rabbits was enhanced by 2 mM Ca++. The effects of aqueous extract of SM and purified active principles of SM (tanshinones) on rat and rabbit blood vessels in vitro were very similar both qualitatively and quantitatively. Both caused vasodilation of coronary arteries at all concentrations tested but induced vasodilation of renal, mesenteric and femoral arteries only at low concentrations. At higher concentrations, vasoconstriction was induced in these vessels. These results indicate that an economical decoction of SM is as efficacious as the more expensive isolated tanshinones. Both SM and PNG would be useful as antianginal agents since they dilate coronary vessels. Their use in hypertension is questionable since they induce both vasodilation and vasoconstriction depending on dose and target vessel.

Lei XL, Chiou GC. Studies on cardiovascular actions of Salvia miltiorrhiza. Am J Chin Med 1986;14(1-2):26-32.
Abstract: Cardiovascular actions of S. miltiorrhiza (SM) were studied on systemic blood pressure in the rat. Langendorff cardiac preparation in the guinea pig, and four types of vasculature in the dog, including coronary, renal, femoral, and mesenteric arteries. SM induced dose-related hypotension without changing heart rate. The hypotension was antagonized by atropine, propranolol, and chlorpheniramine plus cimetidine. In the isolated whole-heart preparation, SM increased coronary blood flow significantly for 15 min and positive inotropic action for 3 min after pulse injection. SM relaxed all arteries at low concentration (3.0 mg/ml) and contracted all but the coronary artery at higher concentration (10.0 mg/ml). The coronary artery relaxed at all doses of SM tested.

Liu SY, Xu YY, Zhu JY. The effects of Salvia miltiorrhizae Bge and Ligustrazine on thromboxane A2 and prostacyclin in pregnancy induced hypertension.Chung Hua Fu Chan Ko Tsa Chih 1994 Nov;29(11):648-650, 697.
Abstract: The clinical efficiency and mechanism of traditional Chinese medicinal herb Salvia Miltiorrhizae Bge (SMB) and Ligustrazine (L) on pregnancy induced hypertension (PIH) were studied in 30 patients. Before and after the administration of SMB and L, the following parameters: mean arterial pressure (MAP), proteinuria, levels of Thromboxane A2 (TXA2) and Prostacyclin (PGI2) were observed. TXA2 and PGI2 were measured by their stable hydration products Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by an established radioimmunoassay. The results of treatment were compared with the base line values and showed as follows: MAP and proteinuria decreased significantly (P

Liu J, Kuang P, Wu W, Zhang F, Liu J, Wan F, Huang Y, Ding A.Radix Salviae miltiorrhizae protects rat hippocampal neuron in culture from anoxic damage. Tradit Chin Med 1998 Mar;18(1):49-54.
Abstract: Radix Salviae Miltiorrhizae (RSM), a well-known traditional Chinese medicinal herb, has been used to improve blood circulation and resolve blood stasis. We have previously found that RSM has neuroprotective effect on ischemia and/or ischemia-reperfusion rats. The purpose of this study was to obtain further information on the mechanism of the RSM-induced neuroprotection and to examine the neuroprotective effect on neurons exposed to anoxia. The effect of RSM on anoxic damage in cultured hippocampal neurons of neonatal rat was investigated by using morphological changes and heat shock protein 70 kD (HSP70) expression as indicators. RSM given 0.5 h before 2 h-anoxia followed by 48 hours reoxygenation could significantly increase survival rate of hippocampal neurons and number of HSP70 positive cells. The results suggest that RSM has a direct neuroprotective effects on anoxic damage in hippocampal neurons.

Liu J, Hua G, Liu W, Cui Y, Huang H, Zhao S, Chu Y, Yang C, Chen W. The effect of IH764-3 on fibroblast proliferation and function.Chin Med Sci J 1992 Sep;7(3):142-147.
Abstract: The effect of IH764-3, a potent component isolated from Salvia miltiorrhiza, on the proliferation and function of cultured fibroblasts was studied. It was found that the fibroblast growth curve had a dose-dependent relationship with IH764-3 concentration. The incorporation of 3H-TdR and 3H-proline into fibroblasts was significantly inhibited by IH764-3, and calmodulin, fibronectin and thrombospondin contents in the test group were obviously lower than those in the control group. Flow cytometry showed that in the IH764-3-treated group, the percentage of cells in G0/G1 phase was higher than that in the control. Electron microscopic observation (TEM and SEM) showed that in the treated group, collagen secretion was decreased. All of these results indicate that IH764-3 exerts a direct inhibitory effect on fibroblast proliferation and affects their ability to synthesize collagen.

Liu J. The effect of IH764-3 on proliferation and function of fibroblasts.Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao 1993 Jun;15(3):201-205.
Abstract: IH764-3, a potent component isolated from Salviae miltiorrhizae (a component of TML) was used to study the effect on proliferation and functions of cultured fibroblasts. The fibroblast growth curve demonstrated a dose-dependent relationship between growth and IH764-3 concentration. The incorporation of 3H-TdR and 3H-proline into fibroblasts was significantly inhibited by IH764-3. Calmodulin level, fibronectin and thrombospondin contents in the test group were obviously lower than those in the control group. Flow-cytometry showed that in the IH764-3 treated group, the percentage of cells in G0 + G1 phase was higher than that in the control. Electron microscopic observation (TEM and SEM) showed that in the treated group, the secretory function of collagen had decreased. All the results indicated that IH764-3 exerts a direct inhibitory effect on fibroblast proliferation and affects their ability to synthesize and secrete collagenous substances.

Lo AC, Chan K, Yeung JH, Woo KS. The effects of Danshen (Salvia miltiorrhiza) on pharmacokinetics and pharmacodynamics of warfarin in rats. Eur J Drug Metab Pharmacokinet 1992 Oct-Dec;17(4):257-262.
Abstract: Danshen is a Chinese folk medicine commonly used in the Chinese population. The effects of Danshen on the pharmacokinetics and pharmacodynamics of warfarin were studied in rats. In the pharmacokinetic study, single oral doses of warfarin were administered to rats or after 3 days treatment with Danshen intraperitoneally twice daily. Plasma warfarin concentrations were measured for 48 after each of two warfarin doses by high performance liquid chromatography (HPLC). In the pharmacodynamic study, the treatments were similar to the pharmacokinetic study, the prothrombin time (PT) was measured daily both in the Danshen treatment period and after the warfarin doses for 4 days. The absorption rate (Ka), volume of distribution (Vd) and elimination half-life (T1/2) of warfarin were significantly decreased while Cmax and Tmax were significantly increased after treatment with Danshen. There was no significant change in PT during the Danshen treatment period while the PTs were increased significantly in the first two days after warfarin doses. Our results suggested that Danshen can increase the initial bioavailability of warfarin and also affect the elimination of warfarin. It can also increase the PT further after the warfarin doses. The pharmacokinetic and pharmacodynamic interactions observed in this study indicate a clinically important interaction between Danshen and warfarin if these two agents are taken together.

Page RL 2nd; Lawrence JD. Potentiation of warfarin by dong quai.Pharmacotherapy, 1999 Jul 66(7):870-876.
Abstract: Dong quai is a Chinese herbal supplement touted for treatment of menstrual cramping, irregular menses, and menopausal symptoms. Phytochemical analyses found it to consist of natural coumarin derivatives, as well as constituents possessing antithrombotic, antiarrhythmic, phototoxic, and carcinogenic effects. A 46-year-old African-American woman with atrial fibrillation stabilized on warfarin experienced a greater than 2-fold elevation in prothrombin time and international normalized ratio after taking dong quai concurrently for 4 weeks. No identifiable cause was ascertained for the increase except dong quai. The patient's coagulation values returned to acceptable levels 1 month after discontinuing the herb. One animal study suggests a pharmacodynamic interaction between the product and warfarin, but the true mechanism remains unknown. Practitioners should be aware of the possibility of such an interaction and should inform patients of potential hazards of taking the two together.

Tam LS. Chan TY. Leung WK. Critchley JA. Warfarin interactions with Chinese traditional medicines: danshen and methyl salicylate medicated oil. Aust NZ J Med 25 Jun, 258, 1995. (Letter)
Abstract: A case report has been described of a 66-year-old man with a past history of atrial fibrillation and cerebral embolism who was admitted to a Hong Kong hospital because of melaena for two days (Tam, L S and co-workers: Australian and New Zealand Journal of Medicine 25, 258, 1995). He had been taking 2.0 to 2.5mg warfarin daily for the past 14 months with an international normalised ratio (INR) stabilised at around 2.0. His other regular medications were digoxin 0.25 mg daily and propanolol 5 mg twice daily. For the treatment of chest wall pain he applied a Chinese medicated oil (15% methyl salicylate). On the recommendation of a Chinese herbalist he also drank a decoction of Salvia miltiorrhiza root 5 and 3 days before admission. On admission, he had a greatly prolonged INR of 5.5 and an activated partial thromboplastin time of 43.7. His haemoglobin concentration was only 7.6 g/dL and his platelet count was low. Gastroscopy revealed the presence of adenocarcinoma. His plasma salicylate concentration at 9 hours after admission was less than levels known to cause hypoprothrombinaemia. The authors felt that the greatly prolonged INR (anticoagulant effect) was due to the Salvia miltiorrhiza intake. They cited recent studies on rats which suggested that while this herb does not have a direct anticoagulant effect, it can decrease the elimination of warfarin. Hence the interaction is likely to have a pharmacokinetic basis. Comment: Some texts already suggest that Salvia miltiorrhiza is contraindicated in patients taking warfarin. This possible adverse drug interaction report reinforces this caution. Unfortunately, the dose of Salvia miltiorrhiza decoction consumed by the patient was not given.

Qin JZ, Wang XC. Effect of radix Salviae miltiorrhizae on calcium, zinc, copper content in serum, callus and bony tissue in early stage of healing process in rat closed tibial fracture. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1992 Jun;12(6):354-356, 325-326.
Abstract: Changes of calcium, zinc, copper contents in serum, callus and bony tissue in the early stage of the healing process of rat closed tibial fracture, also the changes of them with radix Salviae miltiorrhizae (RSM) treatment were studied. It was found that calcium, zinc contents and Zn/Cu ratio increased significantly and the rise of serum copper content was inhibited by the administration of RSM after fracture. Zn/Cu ratio in fracture callus was correlated to the calcium content in fracture callus. These findings suggested that the effect of the promotion of RSM on fracture healing was related to the increased zinc content in serum, also related to the acceleration of mobilization of zinc in fractured bone, and to the acceleration of fracture callus formation and mineralization process by the increased zinc and Zn/Cu ratio in the callus of the fracture.

Wang Z, Zhang H, You H. The effect of 764-3 on platelet aggregation and the activity of enzymes in arachidonic acid metabolism. Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao 1994 Apr;16(2):140-143.
Abstract: 764-3 is a purified compound extracted from Chinese herb Salvia miltiorrhizae. It was found to inhibit human and rabbit platelet aggregation induced by AA or ADP. Using AA as the substrate and pig lung microsome to provide enzymes, low doses of 764-3 (5-100 micrograms/ml) promoted the generation of 6-keto-PGF1 alpha in a dose-dependent manner. At a dose of 500 micrograms/ml, both TXB2 and 6-keto-PGF1 alpha production were inhibited. The results suggest that low dose of 764-3 may be able to bring a balance between TXB2 and 6-keto-PGF1 alpha.

Wang L, Huang X, Ding Z, Chen H, Peng R, Yuan G, Zhou D. The effects of Salvia miltiorrhiza and polysaccharide sulphate on the adhesion of erythrocytes of the patients with cerebral thrombosis to cultured endothelial cells. Hua Hsi I Ko Ta Hsueh Hsueh Pao 1995 Dec;26(4):381-385.
Abstract: Salvia miltiorrhiza and polysaccharide sulphate are commonly prescribed for curing cerebral vascular diseases. In this study, we found that the adhesion of erythrocytes of the patients with cerebral thrombosis to cultured human umbilical vein endothelial cells was decreased in number and intensity after the erythrocytes were treated with salvia miltiorrhiza and polysaccharide sulphate in flow field. Moreover we found that polysaccharide sulphate was more effective than salvia miltiorrhiza in preventing adherence in common doses. The two drugs' effects of preventing adherence might be an important mechanism for curing the patients with cerebral thrombosis.

Wang Z, Roberts JM, Grant PG, Colman RW, Schreiber AD. The effect of a medicinal Chinese herb on platelet function.Thromb Haemost 1982 Dec 27;48(3):301-306.
Abstract: We investigated the effect of the Chinese herb Injectio Salvia Miltiorrhizae (ISM) on human platelet function in vitro. ISM inhibited platelet aggregation and serotonin release induced by either ADP or epinephrine in a dose dependent manner. This effect of ISM was observed with both gel-filtered platelets (ID50 = 8-30 micrograms ISM/ml gel-filtered platelets) and platelets in plasma (ID50 = 400-900 micrograms ISM/ml of platelet-rich plasma). The active molecule(s) in ISM was heat stable, resistant to acid, base and proteolysis and fractionated on Sephadex 6-25 at MW approximately 280. ISM did not interact with the platelet alpha-adrenergic receptor, but increased cAMP in intact platelets. The results are consistent with the concept that ISM inhibition of platelet aggregation and release is mediated by an increase in platelet cAMP. The exact mechanism whereby ISM increases platelet cAMP appears to be that of inhibition of cyclic AMP phosphodiesterase. The effect of ISM on platelet function is one mechanism which might explain the therapeutic effect of ISM in experimental and clinical coronary artery disease.

Yu CM, Chan JCN, Sanderson JE. Chinese herbs and warfarin potentiation by "danshen". J Intern Med Apr;241(4) :337-339.
Abstract: Drug interactions with warfarin can be dangerous and although common drug interactions are now well recognized those with Chinese herbs are not widely appreciated. 'Danshen' is a herbal medicine often used for various complaints, particularly cardiovascular, in the Chinese community. We report a case of danshen-induced overcoagulation with severe and dangerous abnormalities of clotting in a patient with rheumatic heart disease.

Xu ZC. Effect of injection Salvia miltiorrhizae on peritoneal dialysis. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1993 Feb;13(2):74-76, 67.
Abstract: Effective volume of blood flow of peritoneal capillary is an important factor influencing the efficiency of peritoneal dialysis. Injection of Salvia miltiorrhizae (ISM) could dilate the blood vessels and improve microcirculation. The effect of peritoneal dialysis with three kinds of dialytic fluid was studied. The dialysate of first group contained ISM, the second used dialysate only, the third contained dopamine. The result found that ISM could markedly increase the clearance rate and ultrafiltration rate of the peritoneum to creatinine, urea nitrogen and uric acid. Three concentrations of ISM (4%, 6%, 8%) were also compared. This comparison showed that 6% injection of ISM was the optimal concentration.

Yang Y, Wang L, Li L, Chen H. The effects of salvia miltiorrhiza, polysaccharide sulphate, dextran 40 and mannitol on the viscoelasticity properties of red blood cell suspension.Hua Hsi I Ko Ta Hsueh Hsueh Pao 1993 Jun;24(2):143-146.
Abstract: In vitro, the effects of Dextran 40(DX40), mannitol, salvia miltiorrhiza and polysaccharide Sulphate (PSS) on the viscoelasticity properties of red cell suspensions were studied. The results demonstrated that when the concentration of the drugs increased, mannitol increased eta 5 x 96, eta 51 x 2, eta', eta" and G', and DX 40 increased the values of eta' eta" and G', but it had no obvious effect on eta 5 x 96 and eta 51 x 2; salvia miltiorrhiza and PSS had no obvious effect on eta 5 x 96, eta 51 x 2, eta', eta'' and G'. However, the average values of eta', eta'' and G' of Salvia miltiorrhiza and PSS groups were lower than those of DX 40 and Mannitol groups. Clinically, these four drugs in treatment doses might improve viscoelasticity properties of whole blood. For treating the ischemic cerebral vascular diseases and hyperviscosity syndromes, Salvia miltiorrhiza and PSS could be infused faster, but DX40 and mannitol should be infused slowly.

Yu CM; Chan TY; Tsoi WC; Sanderson JE .Heparin therapy in the Chinese--lower doses are required.QJM, 1997 Aug 90(8 ):535-543.
Abstract : Warfarin requirements are lower in the Chinese, but it is not known if this applies to heparin. We investigated the optimal dose for heparin therapy in Chinese patients, and to assess relationship between i.v. heparin dosage and anticoagulation efficacy. One hundred Chinese patients requiring intravenous heparin therapy were given an initial bolus followed by continuous intravenous infusion. The main outcome measures were: (i) Efficacy of anticoagulation assessed by blood coagulation studies (APTT) compared to heparin dosage, (ii) Determinants of dosage variation-age, gender, body weight, height, indication for heparin therapy and number of medications, other disease, and serum albumin level. It was found that the mean therapeutic infusion dose requirement of heparin was 848.7 +/- 274.7 units/h, 79% required a dose of 1000 units/h or less. Heparin dose correlated negatively with age (r = -0.40; p

Yu HC; Chan TY; Critchley JA; Woo KS. Factors determining the maintenance dose of warfarin in Chinese patients. QJM 1996 Feb 89(2) :127-135.
Abstract: Chinese patients are reportedly more sensitive than Caucasians to the anticoagulant effect of warfarin. We examined warfarin dose requirements and their determinants in 151 Chinese out-patients on stable maintenance dose of warfarin with international normalized ratio of 2 to 2.5. Mean daily warfarin requirement was 3.3 +/- 1.4 mg, much lower than reported doses in Caucasian patients. The most important determinant was age (r = -0.43, p

Yu CM; Chan JC; Sanderson JE. Chinese herbs and warfarin potentiation by 'danshen'. J Intern Med 1997 Apr 241(4) :337-339.
Abstract: Drug interactions with warfarin can be dangerous and although common drug interactions are now well recognized those with Chinese herbs are not widely appreciated. 'Danshen' is a herbal medicine often used for various complaints, particularly cardiovascular, in the Chinese community. We report a case of danshen-induced overcoagulation with severe and dangerous abnormalities of clotting in a patient with rheumatic heart disease.

Zhen Z, Guo Y, Zhang Z. Microthrombi in coronary heart disease.Chung Hua I Hsueh Tsa Chih 1995 May;75(5):266-269, 318.
Abstract: Of 180 patients with coronary heart disease (CHD) 43 (23.9%) showed in microthrombi conjunctival microcirculation. We compared the healthy subjects with the patients with microthrombi and thrombi-free as well as with the patients with microthrombi pre- and post-treatment of heparin or salvia miltiorrhizae. The formation and the number of microthrombi in the CHD patients were closely related to symptoms, ECGS, plasma TXB2, 6-kero-PGF1a and other indexes on hemodynamics. Follow-up of the patients with microthrombi revealed that their death rate was higher than that of CHD patients without microthrombi, especially in the sudden deaths. We consider that microthrombi may be regarded as an important index of the state, therapeutic efficacy, and prognosis of the CHD patients. The use of heparin may certainly be based on the condition of the microthrombi in the microcirculation of CHD patients.

Zheng XK. Effects of Salvia miltiorrhizae composite injection on hypoxic pulmonary vasoconstriction in rabbitsChung Hsi I Chieh Ho Tsa Chih 1991 Dec;11(12):733-735, 710.
Abstract: In the present experiment, the hemodynamic effect of Salvia miltiorrhizae composite injection (SMCI) on pulmonary and systemic circulation during hypoxic pulmonary arterial hypertension was observed. The results showed that the pulmonary arterial pressure increased at first in both group, then decreased gradually, but in SMCI group decreased much more than in the control group. The pulmonary vascular resistance increased very significantly in the control group, but in SMCI group considerably decreased after administration, then keeping at a level little more than the normal. Difference between groups was very significant. The stroke volume increased slightly at first and then decreased persistently in the control group, but increased significantly and kept at a higher level in SMCI group. The protective effects of SMCI on hypoxic myocardium was studied by observing ST-segment on ECG. It was found that the ST-segment fell in both groups, but the degree of fall in SMCI was much less than in the control group. It was found that the PaO2 was 35.1 +/- 2.6 in the control group, 38.1 +/- 2.4 in SMCI group. Difference between groups was significant (P less than 0.05.) The above results suggest that SMCI can diminish hypoxic pulmonary vasoconstriction, improve PaO2 in hypoxic animal and protect hypoxic myocardium. Hence, SMCI can be used to prevent and treat hypoxic pulmonary arterial hypertension.

Zhou, JHG, Liu GZ. Recent Advances in Chinese Herbal Drugs, Beijing, China: Science Press 1991.

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