Tan-Shen and Fondaparinux: Interaction Details

a) A 62-year-old man had been stabilized on warfarin 5 mg orally daily for mechanical valve prosthesis with an associated International Normalized Ratio (INR) of 3.0. The patient was also taking digoxin 0.25 mg, captopril 75 mg and furosemide 40 mg daily. Follow-up visits at 2 weeks and 4 weeks required no warfarin dose adjustment. At 6 weeks, he was admitted through the emergency room for massive right pleural effusion and an INR of 8.4. A detailed history revealed that he had begun taking tan-shen tea for "mending his heart" approximately two weeks prior to admission. With warfarin and tan-shen discontinuation, administration of 6 units of fresh frozen plasma and 7 units of packed red blood cells, and drainage of 4.5 L of nonclotted blood from a right pleural drain, the INR was brought down to 2.0 and the patient was stabilized ¹.

b) In a letter-to-the-editor in response to the ¹ report, it was noted that tan-shen, the root of Salvia miltiorrhiza, is not only available for oral intake but also is inhaled. It has been incorporated into some Chinese cigarettes ².

c) A 48-year-old woman with rheumatic heart disease with atrial fibrillation and mitral stenosis since age 26 underwent percutaneous transvenous mitral valvuloplasty with subsequent warfarin administration. Warfarin required frequent dose adjustments over the ensuing 14 months. One month prior to admission, INR was 1.35 and the warfarin dose was increased to 4 mg daily. The patient reported to the emergency room with dyspnea and atrial fibrillation with a prothrombin time (PT) exceeding 60 seconds and INR 5.62. The patient admitted to using tan-shen every day for the month preceding admission. The clotting abnormality persisted for 5 days. With resumption of warfarin at 3 mg daily, her INR stabilized at 2.5. Tan-shen was not reintroduced ³.

d) A 66-year-old male stabilized on warfarin with an International Normalized Ratio (INR) of approximately 2 experienced bleeding complications following use of methyl salicylate medicated oil and tan-shen. On admission, the INR was greater than 5.5, activated partial thromboplastin time was 43.7 seconds, and hemoglobin was 7.6 grams/deciliter. The patient had been experiencing melena for the previous two days. Other medications were digoxin 0.25 mg daily and propranolol 5 mg twice daily. Nine days prior to admission, the patient began treating non-specific left-sided chest wall pain with "Kwan Loong Medicated Oil" containing 15% methyl salicylate topically two to three times daily. Five and three days prior to admission, he drank a decoction of tan-shen. Gastroscopy revealed bleeding from a gastric carcinoma. Warfarin was stopped and 12 units of fresh frozen plasma and 7 units of packed cells were required to normalize the INR. This case of bleeding was attributed to an interaction between tan-shen, Kwan Loong Medicated Oil, and warfarin ⁴.

e) Tan-shen extract changed the concentration and effects of warfarin when given intraperitoneally to rats in doses of 5 grams/kg twice daily for 3 days followed by a single oral dose of 2 mg/kg racemic warfarin. Both R- and S-warfarin had increased rate of absorption, AUC, maximum concentration, and elimination half-life and decreased clearance and volume of distribution. This produced significantly increased plasma concentrations for 24 hours and prothrombin time for 2 days. The increased concentrations and prothrombin time also occurred with steady-state levels of racemic warfarin when it was given in doses of 0.2 mg/kg/day for 5 days and followed by tan-shen extract 2 g/kg twice daily for three days with warfarin treatment continuing ⁵.

f) Within 48 hours of a single warfarin dose in rats administered tan-shen, area under the curve (AUC) of warfarin was increased, half-life was decreased, and maximum concentration nearly doubled; prothrombin time was also increased. Tan-shen, authenticated pharmacognostically, was administered to 10 rats in a fixed dose of 5 g/kg twice daily intraperitoneally. Three days later a single oral dose of warfarin (2 mg/kg) was then administered. AUC increased from 154.8 mcg/mL/hr to 269.5 mcg/mL/hr (p less than 0.005), half-life decreased from 31.8 hr to 16.0 hr (p less than 0.001) and Cmax increased from 5500 ng/mL to 10,976 g/mL (p less than 0.001). Volume of distribution was significantly decreased from 142.5 mL to 54.4 mL (p less than 0.005). Clearance was nonsignificantly decreased from 3.53 mL/hr to 2.23 mL/hr. The authors concluded that tan-shen affected warfarin bioavailability initially and the shortened elimination half-life was due to the decrease in volume of distribution since the change in clearance was not considered significant. The prothrombin time when on warfarin alone was 41.1 seconds versus 49.9 seconds (p less than 0.001) with concomitant tan-shen administration ⁶.