Warfarin

Brand Names: Coumadin

Clinical Names: Warfarin

Summary

generic name: Warfarin

trade name: Coumadin

type of drug: Anticoagulant.

used to treat: Venous thrombosis, pulmonary embolism, venous thrombosis, and other occurrences of inappropriate or excessive clotting; to decrease risks from blood clotting in individuals with atrial fibrillation; to prevent stroke.

overview of interactions:
• nutrient affecting drug performance and toxicity: Coenzyme Q10

• substance affecting drug performance: Aluminum

• nutrients affecting drug performance: Minerals such as Iron, Magnesium, and Zinc

• nutrient affecting drug performance and toxicity: Vitamin C (Ascorbic Acid)

• nutrient affecting drug performance and toxicity: Vitamin D

• nutrient affecting drug performance and toxicity: Vitamin E

• nutrient affecting drug performance and toxicity: Vitamin K

• plants/foods affecting drug performance: Edible Plants with High Levels of Vitamin K

Plants with relatively high levels of Vitamin K capable of potential Warfarin antagonism:
Beta vulgaris (Beet root and greens)
Brassica oleracea v. acephala (Collard leaves)
Brassica oleracea v. capita (Cabbage leaves)
Brassica oleracea v. fruticosa (Kale leaves)
Brassica oleracea v. gemmifera (Brussels sprouts buds)
Brassica oleracea v. italica (Broccoli flower buds)
Brassica campestris v. pekinensis (Chinese cabbage leaves)
Brassica rapa (Turnip leaves)
Capsella bursa-pastoris (Shepherd’s purse)
Lactuca sativa (Lettuce leaves)
Medicago sativa (Alfalfa plant)
Nasturtium officinale (Watercress)
Petroselinum crispum (Parsley leaves)
Plantago major (Plantain leaves)
Polygonum hydropiper, Polygonum punctatum (Smartweed plant)
Spinacea oleracea (Spinach leaves)
Urtica spp. (Stinging nettles plant)
Zea mays (Corn silk stigmas)

• substance affecting drug performance and toxicity: Alcohol

• diet affecting drug performance and toxicity: Food

• diet affecting drug performance and toxicity: Grapefruit Juice

• herb/food affecting drug performance and toxicity: Allium sativum (Garlic)

• nutrient constituent affecting drug performance: Bromelain (from fruit and stem of Ananas comosus)

• herb/food constituent affecting drug performance and toxicity: Papain as in Carica papaya (Papaya)
Note: see below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors.

• herb affecting drug performance and toxicity: Cinchona species (Quinine)

• herb affecting drug performance and toxicity: Ginkgo biloba (Ginkgo)

• nutrient affecting drug performance: Lentinas edodes (Shiitake)

• herb affecting drug performance and toxicity: Harpagophytum procumbens (Devil’s Claw)

• herb affecting drug performance and toxicity: Panax ginseng (Chinese Ginseng)

• herb affecting drug performance and toxicity: Salvia miltiorrhiza (Dan Shen)

• herbal constituent theoretically affecting drug performance and toxicity: Coumarin-containing Plants

Common herbs containing significant coumarin constituents:
Aesculus hippocastanum (Horse Chestnut seed)
Ammi visnaga (Visnaga)
Asperula odorata (Sweet Woodruff)
Galium odoratum (Bedstraw)
Melilotus spp. (Sweet Clover)
Trifolium pratense (Red Clover)

• herbal constituent affecting drug performance and toxicity: Platelet Aggregation Factor Interacting Plants (Platelet Interactors)

Plants with possible potentiation action due to Platelet Aggregation Inhibitors:
Allium cepa (Onion plant)
Allium sativum (Garlic)
Ananas comosus (Bromelain, from fruit and stem)
Capsicum annuum (Cayenne fruit)
Carica papaya (Papain, from leaves and unripe fruit)
Curcuma longa, Curcuma aromatica (Turmeric root)
Ganoderma lucidum (Reishi fruit bodies)
Ginkgo biloba (Ginkgo leaves)
Salvia miltiorrhiza (Dan Shen root)
Scutellaria baicalensis (Chinese Skullcap root)
Zingiber officinale (Ginger rhizome)

Note: See also Chinese Herbs topic: Blood-moving Herbs and Dan Shen



Interactions

nutrient affecting drug performance and toxicity: Coenzyme Q10

• mechanism: Warfarin exerts its therapeutic effect by interfering with vitamin K metabolism. Coenzyme Q10 or CoQ10, also known as Ubiquinone or Ubidecarenone, is chemically similar to K-vitamins.

• research: The research literature has contains some reports of Coenzyme Q10 interfering with the activity of warfarin. A decline in responsiveness to warfarin has been observed among patients using warfarin who have added CoQ10 to their supplement intake. When the individuals stopped taking the CoQ10 their previous responsiveness to warfarin resumed.
(Spigset O. Lancet 1994;344:1372-1373; Landbo C, Almdal TP. Ugeskr Laeger. 1998 May 25;160(22):3226-3227; Combs AB, et al. Res Commun Chem Pathol Pharmacol. 1976 Jan;13(1):109-114.)

• nutritional concerns: The clinical significance and frequency of occurrence of this interaction are uncertain even though the theoretical foundation for this interaction is sound and some case reports have come forth. Grounds for concern are amplified because of the high probability of overlap among the patient populations interested in benefits of coenzyme Q10 for cerebrovascular benefits and those being treated for the disorders for which warfarin is often prescribed. Individuals using warfarin should be aware of the possible risk of treatment failure when taking coenzyme Q10 and should consult their prescribing physician before beginning supplementation with CoQ10.

substance affecting drug performance: Aluminum

• mechanism: Aluminum-containing antacids reduce the bioavailability of warfarin.
(Roe DA. 1989: 84.)

nutrients affecting drug performance: Minerals such as Iron, Magnesium, and Zinc

• mechanism: Mineral such as iron, magnesium, and zinc may bind with warfarin, thereby reducing their absorption and activity.
(Holt GA. 1998, 284.)

• nutritional concerns: While the chemistry of common mineral nutrients binding warfarin is well founded the clinical significance and frequency of occurrence of this interaction are uncertain. Individuals using warfarin should be aware of the possible risk of reduced effectiveness of treatment when taking supplements containing iron, magnesium and/or zinc and should consult their prescribing physician before beginning such supplementation with minerals such as iron, magnesium, and zinc. Usually taking these minerals at least two hours apart from the warfarin provides adequate protection from unwanted interference.

nutrient affecting drug performance and toxicity: Vitamin C (Ascorbic Acid)

• nutrient affecting drug performance and toxicity: A variety of case reports have suggested a possible interaction between warfarin and vitamin C in which the drug's activity was increased. Numerous subsequent reviews and discussions have questioned these findings and no substantial research has ever been able to demonstrate such an interaction. Other research by Owen et al and Rosenthal et al have suggested that large doses of vitamin C may diminish the anticoagulant activity of warfarin.
(Owen CA Jr, et al. Mayo Clin Proc. 1970 Feb;45(2):140-140; Rosenthal G.JAMA. 1971 Mar 8;215(10):1671; Harris JE. J Am Dietet Assoc 1995;95:580-854; Feetam CL, et al. Toxicol Appl Pharmacol 1975 Mar;31(3):544-547; Weintraub M, et al. Toxicol Appl Pharmacol 1974 Apr;28(1):53-56; Hume R, et al. JAMA 1972 Mar 13;219(11):1479.)

• nutritional concerns: Individuals using warfarin should be aware of the possible risk of altered drug activity when taking vitamin C, and should consult their prescribing physician before beginning supplementation with vitamin C in doses greater than 500 mg per day.

nutrient affecting drug performance and toxicity: Vitamin D

• report: Concern has been raised about a possible dangerous interaction between vitamin D and anticoagulant medicines such as warfarin. The potential for increased activity of anticoagulants due to vitamin D has not been confirmed by any substantial research.
(Schrogie JJ. JAMA 1975;232:19.)

• nutritional concerns: Individuals using warfarin should be aware of the theoretical risk of enhanced drug activity when taking vitamin D. Even though the occurrence of this interaction would seem to be widespread if it represented a significant risk, concerned patients should consult their prescribing physician before beginning supplementation with vitamin D in doses greater than 400 IU per day.

nutrient affecting drug performance and toxicity: Vitamin E

• research: Concern for a possible interaction between vitamin E and warfarin was first raised in a case report of a single vitamin-K-deficient individual who experienced increased coagulation after concomitant use of vitamin E (up to 1200 IU per day) and warfarin. A subsequent double-blind clinical trial by Kim and White involving 21 subjects found no significant differences in warfarin activity in those given up to 1200 IU of vitamin E daily as compared with those given placebo.
(Corrigan J, Marcus FI. JAMA 1974 Dec 2;230(9):1300-1301; Kim JM, White RH. Am J Cardiol 1996;77:545-546; Corrigan JJ Jr. Am J Pediatr Hematol Oncol 1979 Summer;1(2):169-173; Corrigan JJ Jr. Ann N Y Acad Sci 1982;393:361-368.)

• nutritional concerns: Research indicates that no significant interaction exists as a result of simultaneous use of warfarin and vitamin E. These findings are important since many individuals being treated by their physicians with warfarin might also consider using vitamin E for cardiovascular benefits. Individuals using warfarin should be aware that some physicians still believe that taking vitamin E and warfarin at the same time poses a risk.

nutrient affecting drug performance and toxicity: Vitamin K

• mechanism: The fundamental mechanism of action of warfarin involves its slowing the rate of blood clotting by interfering with the normal activity of vitamin K. Warfarin binds to the enzyme vitamin K 2,3-epoxide reductase in liver microsomes, interferes with the regeneration of vitamin K1 from its biologically inactive form, and reduces gamma-carboxylation of the precursors of vitamin D-dependent pro- and anticoagulant factors. The use of vitamin K in supplements would directly counter the therapeutic intent of the prescription.
(Harris JE. J Am Dietet Assoc 1995;95:580-584; Bell RG, Ren P. Biochem Pharmacol. 1981 Jul 15;30(14):1953-1958; Bell RG. Fed Proc. 1978 Oct;37(12):2599-2604; Bell RG, et al. Biochem Pharmacol. 1976 May 1;25(9):1067-1070; Lim JM, McKay M. Drug Information Bulletin, 15(2), 1995.)

• nutritional concerns: Individuals taking warfarin should avoid the use of supplements containing vitamin K unless acting under the direct supervision of their prescribing physician. In some cases such use of vitamin K is undertaken by physicians to rapidly correct excessive anticoagulation due to warfarin or other anticoagulant medications.
(Weibert RT, et al. Ann Intern Med 1997 Jun 15;126(12):959-962.)

plants/foods affecting drug performance: Edible Plants with High Levels of Vitamin K

• mechanism: Many plants, including many common vegetables are rich in vitamin K. The anticoagulant effects of warfarin and similar medications can be diminished whenever vitamin K levels are increased. Individuals using warfarin who consume large amounts of foods rich in vitamin K for an extended period of time could potentially experience decreased effectiveness of the drug. A single large serving of such vegetables is unlikely to significantly effect the anticoagulant effects of warfarin. However, consumption of large amounts of vitamin K-containing plants, mostly green leafy vegetables, on a daily basis for one week or more can often change the required therapeutic dosage for the medication. Likewise, sudden dietary changes in the amounts or frequency of these foods could potentially induce altered or inconsistent drug activity.
(Kempin SJ. N Engl J Med 1983 May 19;308(20):1229-1230; Tatro D, ed. Jul 1993; Harris JE. J Am Diet Assoc 1995;95:580-84; Brinker 1998; Holt GA. 1998.)

• nutritional concerns: Individuals using warfarin should consult their prescribing physician and/or a nutritionally oriented healthcare professional to review the relationship between their diet and the dosage of the medication in light of the possible risk of dietary influences on the effectiveness of their treatment.

• Plants with relatively high levels of Vitamin K capable of potential Warfarin antagonism:
Beta vulgaris (Beet root and greens)
Brassica oleracea v. acephala (Collard leaves)
Brassica oleracea v. capita (Cabbage leaves)
Brassica oleracea v. fruticosa (Kale leaves)
Brassica oleracea v. gemmifera (Brussels Sprouts buds)
Brassica oleracea v. italica (Broccoli flower buds)
Brassica campestris v. pekinensis (Chinese Cabbage leaves)
Brassica rapa (Turnip leaves)
Capsella bursa-pastoris (Shepherd’s Purse)
Lactuca sativa (Lettuce leaves)
Medicago sativa (Alfalfa plant)
Nasturtium officinale (Watercress)
Petroselinum crispum (Parsley leaves)
Plantago major (Plantain leaves)
Polygonum hydropiper, Polygonum punctatum (Smartweed plant)
Spinacea oleracea (Spinach leaves)
Urtica spp. (Stinging Nettles plant)
Zea mays (Corn silk stigmas)

substance affecting drug performance and toxicity: Alcohol

• mechanism: The consumption of alcohol, especially large amounts over an extended period, can decrease the therapeutic effectiveness of warfarin.
(Holt GA. 1998, 282.)

• nutritional concerns: Individuals using warfarin would reduce their risk of adverse outcomes by avoiding alcohol.

diet affecting drug performance and toxicity: Food

• research: As discussed above, many common foods can directly reduce the effectiveness of warfarin due to their rich vitamin K content. Charbroiled foods are also suspected of reducing warfarin activity. On the other hand, cooked onions and soy products may also increase warfarin activity.
(Hoult JR, Paya M. Gen Pharmacol 1996 Jun;27(4):713-722; Kempin SJ. N Engl J Med 1983 May 19;308(20):1229-1230; Tatro D, ed. Jul 1993; Harris JE J Am Diet Assoc 1995;95:580-584; Holt GA. 1998, 293, 284-285.)

• nutritional concerns: While the direct action of vitamin K-rich foods is known to be clinically significant given sustained and substantial intake, the significance of other potential food interactions has not been conclusively demonstrated.

diet affecting drug performance and toxicity: Grapefruit Juice

• mechanism: Grapefruit flavonoids inhibit the cytochrome P450 2A dependent metabolic pathways in the liver responsible for metabolizing warfarin and related anticoagulant drugs. The simultaneous consumption of grapefruit juice and warfarin can slow down the metabolism of the medication, increase its activity, and increase the risk of potential hemorrhage.

• research: It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways. Merkel et al found that if grapefruit juice was swallowed 30 min prior to the administration of coumarin, 7-hydroxycoumarin excretion was delayed by up to 6 hours. However, Sullivan et al concluded that the ingestion of grapefruit juice prepared from frozen concentrate did not change prothrombin times in patients treated with warfarin.
(Sullivan DM, et al. Am J Health Syst Pharm. 1998 Aug 1;55(15):1581-1583; Bailey DG, et al. Clin Pharmacokinet. 1994;26(2):91-98; Merkel U, et al. Eur J Clin Pharmacol. 1994;46(2):175-177.)

• nutritional concerns: Given the inconsistent findings from research sources no conclusive advice can be offered regarding the significance of potential risks from combining warfarin and grapefruit juice. Pending further study, individuals using warfarin should consult with their prescribing physician and/or a nutritionally oriented healthcare professional to determine whether the consumption of grapefruit juice should be avoided.

herb/food affecting drug performance and toxicity: Allium sativum (Garlic)

• mechanism: Garlic has gained much notoriety for its potential value in reducing cardiovascular risk, especially due to atherosclerosis, by inhibiting the ability of platelets to adhere to one another. One consequence of this process is that it can also enhance the tendency for bleeding due to decreased clotting.
Note: See below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors.

• research: Reports of medicinal garlic contributing to excessive bleeding are rare but have been heard. Likewise, case reports have been published of incidents where an interaction between garlic and warfarin has resulted in increased anticoagulant activity.
(Gadkari JV, Joshi VD. J Postgrad Med 1991 Jul;37(3):128-131; Sunter WH. Pharm J 1991;246:722; Burnham BE. Plast Reconst Surg 1995;95:213; Jain RC. Am J Clin Nutr 1977 Sep;30(9):1380-1381; Chutani SK, Bordia A. Atherosclerosis 1981 Feb-Mar;38(3-4):417-421.)

• herbal/nutritional concerns: The clinical significance and frequency of occurrence of this interaction are uncertain even though the theoretical foundation for this interaction is sound and some case reports have come forth. These findings are important since many individuals being treated by their physicians with warfarin might also consider using garlic for cardiovascular benefits. Individuals using warfarin should be aware of the possible risk of adverse interactions when taking both garlic and warfarin and should consult their prescribing physician before beginning supplementation with medicinal dosages of garlic. Pending further research, caution would be appropriate and physician supervision advised when using standardized extracts of garlic. Likewise, daily doses of more than one clove of garlic should be avoided if warfarin is being taken.
Note: See below: Plants with Possible Potentiation Action due to Platelet Aggregation Inhibitors.

nutrient constituent affecting drug performance: Bromelain (from fruit and stem of Ananas comosus)

• mechanism: Bromelain has many actions similar to prescription anticoagulants such as warfarin, and could, in theory, potentiate the anticoagulant activity of such drugs when taken in combination.
Note: See below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors.
(Innerfield I, Rowley GR. Life Sci [II] 1970 Dec 8;9(23):1359-1367; Harris JE. J Am Dietet Assoc 1995;95:580-584.)

• reports: A single case report involving a woman in Mexico using an enzyme preparation containing a variety of substances seems to have generated a number of warnings against potential interactions of the part of the individual constituents of that formulation. The substance in question is a multi-enzyme formulation marketed under the brand name non-steroidal anti-inflammatory drug, sold in Mexico under the name of Wobenzym (R), and containing pancreatin, bromelain, papain, lipase, amylase, trypsin, alpha chymotrypsin and rutin. Some writers have mistakenly referred to this compound as a "non-steroidal anti-inflammatory drug." Apparently, in conjunction with warfarin, the patient in question demonstrated many symptoms of coumadin overdose, such as prolonged prothrombin time, prolonged activated thromboplastin time, and low functional and antigenic levels of prothrombin. However, her platelet count, and the thrombin, reptilase and bleeding times were all normal, and all laboratory and clinical abnormalities returned to normal after administration of fresh frozen plasma and parenteral vitamin K.
(Perez-Jauregui J, et al. Rev Invest Clin 1995 Jul-Aug;47(4):311-313; Shaw D, et al. Drug Safety 1997;17(5):342-356.)

• nutritional/herbal concerns: The theoretical concerns regarding potential interaction between warfarin and bromelain have not yet been confirmed by conclusive research. Although Ananas comosus is not commonly prescribed as an herbal medicine per se, bromelain is commonly used as an anti-inflammatory for musculoskeletal conditions and has been suggested by some practitioners as a viable alternative to pharmaceutical anticoagulants. Individuals using warfarin should consult with their prescribing physician and/or a nutritionally trained healthcare professional before using bromelain.

herb/food constituent affecting drug performance and toxicity: Papain as in Carica papaya (Papaya)
Note: See below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors.

• report: A single case report involving a woman in Mexico using an enzyme preparation containing a variety of substances seems to have generated a number of warnings against potential interactions of the part of the individual constituents of that formulation. The substance in question is a multi-enyme formulation marketed under the brand name non-steroidal anti-inflammatory drug, sold in Mexico under the name of Wobenzym®, and containing pancreatin, bromelain, papain, lipase, amylase, trypsin, alpha chymotrypsin and rutin. Some writers have mistakenly referred to this compound as a "non-steroidal anti-inflammatory drug." Apparently, in conjunction with warfarin, the patient in question demonstrated many symptoms of coumadin overdose, such as prolonged prothrombin time, prolonged activated thromboplastin time, and low functional and antigenic levels of prothrombin. However, her platelet count, and the thrombin, reptilase and bleeding times were all normal, and all laboratory and clinical abnormalities returned to normal after administration of fresh frozen plasma and parenteral vitamin K.
(Perez-Jauregui J, et al. Rev Invest Clin 1995 Jul-Aug;47(4):311-313; Shaw D, et al. Drug Safety 1997;17(5):342-356; Innerfield I, Rowley GR. Life Sci [II] 1970 Dec 8;9(23):1359-1367.)

• herbal concerns: Individuals taking warfarin should avoid the consumption of papaya-derived substances such as papain and be watchful for its presence in enzyme formulas or other digestive aids. Although Carica papaya is not commonly prescribed as an herbal medicine per se, papain is commonly used as a digestive enzyme and in anti-inflammatory formulations. Individuals using warfarin should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before using Papaya derivatives as a medicinal agents.

herb affecting drug performance and toxicity: Cinchona species (Quinine)

• mechanism: The bark of the Cinchona tree is the traditional source of quinine. Some reports have indicated the possibility that quinine, as a drug, may increase warfarin activity.
(Tatro D, ed. Jul 1993.)

• herbal concerns: Individuals taking warfarin should avoid the consumption of quinine and be watchful for its presence on labels. Although Cinchona is not commonly prescribed as an herbal medicine, individuals using warfarin should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before taking Cinchona or introducing other medicinal herbs into their therapeutic regime. The use of Cinchona, also known as China, as a homeopathic remedy poses no significant risk due to its presence in microdilution.

herb affecting drug performance and toxicity: Ginkgo biloba (Ginkgo)

• mechanism: Extracts of Ginkgo exhibit PAF inhibitory activity. The terpene fraction, particularly ginkgolide B is thought to be the principal PAF inhibitory component. While PAF antagonists do not operate directly on the clotting cascade, at least two reports of Ginkgo use associated with hemorrhagic episodes (see below) have noted increased PT/PTT times which normalized on cessation of Gingko consumption. This suggests the possibility of an additive effect on coagualibility through an unknown synergistic mechanism, since PAF antagonism alone should not affect coagulation times.

• reports: Reports of problematic interactions between Ginkgo and coumadin are rare but remain more than a theoretical concern. Ginkgo inhibits platelet adhesion and can increase any tendency toward bleeding. Case reports of Ginkgo associated with neurovascular bleeding include one of hyphema, one of subdural hemorrhage and one of subarachnoid hemorrhage. In these reports Gingko use was self prescribed and not disclosed to the physician until after the hemorrhagic episode. Aspirin was a concurrent medication in one report. The only report of hemorrhage involving a warfarin stabilized patient was that of Matthews, who did not reveal the dose or nature of Gingko preparation involved. Vigilant monitoring of PT/INR values with warfarin using patients who consume Ginkgo extracts is essential.
(Kleijnen J, Knipschild P. Lancet 1992;340:1136-1139; Mathews MK. Neurology 1998 Jun;50(6):1933-1934; Rosenblatt M, Mindel J. New Engl J Med 1997 Apr 10;336(15):1108; Rowin J, Lewis SL. Neurology 1996 Jun;46(6):1775-1776; Skogh M. Lancet. 1998 Oct 3;352(9134):1145-1146.)

nutrient affecting drug performance: Lentinas edodes (Shiitake)

• reports and research: According to Hobbes a watery extract of the whole shiitake has been reported to hinder blood coagulation. However, Otsuka et al found that a mixture consisting of dried Shiitake mushrooms treated with wet-heating and fructo-oligosaccharides produced an anti-thrombotic action in rats were evaluated.
(Hobbs C. 1995, 125-128; Otsuka M, et al. Yakugaku Zasshi. 1996 Feb;116(2):169-173.)

• nutritional/herbal concern: Individuals taking warfarin or other anticoagulant medicines should refrain from consuming Shiitake beyond occasional use in foods until they have consulted with their prescribing physician and/or a healthcare professional trained in herbal prescribing.

herb affecting drug performance and toxicity: Harpagophytum procumbens (Devil’s Claw)

• reports: Devil’s Claw was associated with purpura (bleeding under the skin) in a patient treated with warfarin.
(Shaw D, et al. Drug Safety 1997;17(5):342-356.)

• herbal concerns: Individuals using warfarin should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before taking Devil’s Claw or introducing other medicinal herbs into their therapeutic regime.

herb affecting drug performance and toxicity: Panax ginseng (Chinese Ginseng)

• reports: Several case reports involving potential interactions between warfarin and Panax ginseng have been published. In two cases vaginal bleeding was associated with the use of substances reported to contain ginseng. Hopkins et al attributed the one instance of postmenopausal bleeding to ginseng's estrogen-like effect on genital tissues. a case report by Janetzky and Morreale described a possible interaction between warfarin and ginseng as evidenced by a reduction of the international normalized ratio (INR), indicating a decrease in warfarin activity, in a patient on warfarin.
(Hopkins MP, et al. Am J Obstet Gynecol 1988;159(5):1121-1122; Greenspan EM. JAMA 1983;249(15):2018; Janetzky K, Morreale AP. Am J Health-Syst Pharm 1997;54:692-693.)

• herbal concerns: Individuals using warfarin should consult with their prescribing physician and a healthcare professional trained in botanical prescribing before taking ginseng or introducing other medicinal herbs into their therapeutic regime. While the actual identity and dosage of the herbs involved in the cases found in the literature remains uncertain, they most likely involved the use of Panax ginseng, also known as Chinese or Korean Ginseng. Even so, the cautions might be extended to also cover Siberian ginseng (Eleutherococcus senticosus) even though it is a distinctly different plant and a member of a different genus.

herb affecting drug performance and toxicity: Salvia miltiorrhiza (Dan Shen)
Note: see below: Plants with possible potentiation action due to Platelet Aggregation Inhibitors

• reports: Several cases have appeared in the medical literature discussing the dangerous interaction which can result from the simultaneous use of warfarin and the Chinese herb known as Dan shen, Salvia miltiorrhiza, either alone or in formulations. This reaction would be expected from the understanding of Dan shen and its clinical uses within the prescribing traditions of Chinese herbal medicine.
(Cheng TO. Ann Thorac Surg. 1999 Mar;67(3):894; 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.)

Note: While Dan shen is a member of the Salvia genus, it is quite distinct from the common Western herb Sage (Salvia officinalis), which has not been associated with interactions involving warfarin.

• herbal concerns: Individuals using warfarin should consult with their prescribing physician and a healthcare professional trained and experienced in Chinese herbal medicine before taking dan shen or introducing other medicinal herbs into their therapeutic regime.

herbal constituent theoretically affecting drug performance and toxicity: Coumarin-containing Plants

• Common herbs containing significant coumarin constituents:
Aesculus hippocastanum (Horse Chestnut seed)
Ammi visnaga (Visnaga)
Asperula odorata (Sweet Woodruff)
Galium odoratum (Bedstraw)
Melilotus spp. (Sweet Clover)
Trifolium pratense (Red Clover)

• mechanism: Some authorities have suggested that coumarin-containing plants can theoretically exert an additive effect with pharmaceutical anticoagulants such as warfarin. However, coumarins in plants have not been shown to be blood thinning and there is no evidence they are fermented into bioactive dicoumarol.

• herbal concern: Excessive bleeding would not be likely to appear unless relatively large doses of these herbs or their combinations were consumed for an extended period of time. The combination of these plants with anticoagulant drugs such as warfarin theoretically increases the risk of excessive bleeding or other adverse side effects. In contrast, the effect of Platelet Aggregation Factor interactor herbs on coagulation is much more probable and problematic.

herbal constituent affecting drug performance and toxicity: Platelet Aggregation Inhibitor-containing Plants (Platelet Interactors)

• Plants with possible potentiation action due to Platelet Aggregation Inhibitors:
Allium cepa (Onion plant)
Allium sativum(Garlic)
Ananas comosus (Bromelain, from fruit and stem)
Capsicum annuum(Cayenne fruit)
Carica papaya (Papain, from leaves and unripe fruit)
Curcuma longa, Curcuma aromatica (Turmeric root)
Ganoderma lucidum (Reishi fruit bodies)
Ginkgo biloba (Ginkgo leaves)
Salvia miltiorrhiza (Dan Shen root)
Scutellaria baicalensis (Chinese Skullcap root)
Zingiber officinale(Ginger rhizome)

• mechanism: Some herbs that inhibit platelet aggregation could conceivably potentiate the anticoagulant activity of warfarin or similar drugs. Generally, adverse effects would not be likely to appear unless relatively large doses of these herbs or their combinations were consumed for an extended period of time. The combination of these plants with anticoagulant drugs such as warfarin inherently increases the risk of excessive bleeding or other adverse side effects. In order for several of these plants, some being common foods, to produce a significant risk or interaction the consumption of sizable amounts over an extended period would most likely be required.

Note: See also Chinese Herbs topic: Blood-moving Herbs and Dan Shen

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Do not rely solely on the information in this article.

References

Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice and drugs - How significant is the interaction? Clin Pharmacokinet. 1994;26(2):91-98.

Bell RG, Caldwell PT, Holm EE. Coumarins and the vitamin K-K epoxide cycle. Lack of resistance to coumatetralyl in warfarin-resistant rats. Biochem Pharmacol. 1976 May 1;25(9):1067-1070.

Bell RG, Ren P. Inhibition by warfarin enantiomers of prothrombin synthesis, protein carboxylation, and the regeneration of vitamin K from vitamin K epoxide. Biochem Pharmacol. 1981 Jul 15;30(14):1953-1958.

Bell RG. Metabolism of vitamin K and prothrombin synthesis: anticoagulants and the vitamin K--epoxide cycle. Fed Proc. 1978 Oct;37(12):2599-2604. (Review)
Abstract: Vitamin K is primarily located in hepatic microsomes, where the vitamin K-dependent carboxylation in prothrombin synthesis occurs. Recent evidence supports the idea that the carboxylation is linked to the metabolism of the vitamin--specifically the cyclic interconversion of vitamin K and vitamin K epoxide. The primary site of action of coumarin and indandione anticoagulants appears to be an inhibition of the epoxide-to-vitamin K conversion in this cycle. There is a correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K from the epoxide by anticoagulants. In hamsters and warfarin-resistant rats prothrombin synthesis and the epoxide-K conversion are less sensitive to warfarin than in the normal rat. The epoxide-K conversion is impaired in resistant rats, which may explain their high vitamin K requirement. There is also a correlation between vitamin K epoxidation and vitamin K-dependent carboxylation, but the apparent link may be because vitamin K hydroquinone is an intermediate in the formation of the epoxide and also the active form in carboxylation. The vitamin K-epoxide cycle is found in extrahepatic tissues such as kidney, spleen, and lung and is inhibited by warfarin.

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Brochet B, Guinot P, Orgogozo JM, Confavreux C, Rumbach L, Lavergne V, and the ginkgolide study group in multiple sclerosis. Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. J Neurol Neurosurg Psychiatry 1995;58:360-362.

Burnham BE. Garlic as a possible risk for postoperative bleeding. Plast Reconstr Surg 1995 Jan;95(1):213. (Letter)

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 1998 Jul;36(7):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.

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

Chung KF, Dent G, McCusker M, Guinot P, Page CP, Barnes PJ. Effect of a ginkgolide mixture (BN 52063) in antagonising skin and platelet responses to platelet activating factor in man. Lancet 1987;1:248-251.
Abstract: Antagonism of the effects of platelet activating factor (PAF) by the ginkgolide mixture BN 52063 was assessed in a double-blind, placebo-controlled, crossover study in 6 normal subjects. Weal and flare responses to 400 ng PAF, examined 2 h after ingestion of BN 52063 (80 mg, 120 mg) were inhibited in a dose-related manner. After 120 mg the flare area was reduced by a mean 62.4% (p less than 0.005) and the weal volume by a mean 60% (p less than 0.05). Both doses of BN 52063 significantly inhibited PAF-induced platelet aggregation in platelet-rich plasma (p less than 0.001). In vitro, BN 52063 inhibited PAF-induced but not ADP-induced platelet aggregation. Thus BN 52063 seems to be an antagonist of PAF in man.

Chutani SK, Bordia A. The effect of fried versus raw garlic on fibrinolytic activity in man. Atherosclerosis 1981 Feb-Mar;38(3-4):417-421.
Abstract: The effect of fried and raw garlic on blood fibrinolytic activity has been compared in 20 patients with ischaemic heart disease. Three blood samples were collected on the first day of the study and similarly on the 2nd and 7th days after garlic administration, either in raw or fried form. Fibrinolytic activity increased by 72% and 63% within 6 h of administration of raw or fried garlic, respectively. The elevated levels were maintained up to 12 h. In the second part of the study, raw or fried garlic was administered for 4 weeks to patients with ischaemic heart disease and fibrinolytic activity was measured at weekly intervals. It showed a sustained increase, rising to 84.8% at the end of 28th day when raw garlic was administered. Similarly, with fried garlic the rise was 72%. The study shows that: (i) both raw and fried garlic significantly enhance fibrinolytic activity (FA); (ii) garlic enhances FA within hours of administration; (iii) FA continues to rise with continued administration of garlic; (iv) frying removes the strong acrid smell of garlic, but preserves its useful effect on FA.

Combs AB, Porter TH, Folkers K. Anticoagulant activity of a naphthoquinone analog of vitamin K and an inhibitor of coenzyme Q10-enzyme systems. Res Commun Chem Pathol Pharmacol. 1976 Jan;13(1):109-114.
Abstract: Synthetic 2-hydroxy-3-h-dodecylmercapto-1,4-naphthoquinone is an analog of both vitamin K1 and coenzyme Q10. This naphthoquinone analog is an effective inhibitor of coenzyme Q10-enzymes of mammalian mitochondria, which are components of electron transfer mechanisms of respiration and coupled oxidative phosphorylation. This analog increased the prothrombin time in rats when it was administered orally or parenterally. Vitamin K1 reversed the prothrombin time increase, but that form of coenzyme Q, hexahydrocoenzyme Q4, which has the same phytyl side chain as vitamin K1, did not reverse the increase, constituting the biological differentiation between vitamin K and coenzyem Q. Two benzoquinone analogs of coenzyme Q10, 5-n-octadecylmercapto-2,3-dimethoxy-1,4-benzoquinone and 5-beta-naphthylmercapto-2,3-dimethoxy-1,4-benzoquinone, the latter being a strong inhibitor of coenzyme Q10-enzymes, did not increase the prothrombin time under comparable conditions.

Corrigan JJ Jr. Coagulation problems relating to vitamin E. Am J Pediatr Hematol Oncol 1979 Summer;1(2):169-173.
Abstract: In the studies outlined in this report, normal dogs receiving megadoses of vitamin E displayed no abnormalities in their coagulation mechanisms. However, when made mildly vitamin-K-deficient by using warfarin, the introduction of vitamin E produced a profound coagulopathy. This coagulopathy was characterized by a further reduction in the vitamin-K-dependent coagulation factors and did not influence the levels of the non-vitamin K coagulation factors. Only one human case has been described to date, and this particular patients was vitamin-K-deficient at the time he was receiving vitamin E. Further studies are necessary to ascertain the usefulness of this vitamin in trombotic disease and to define the possible hematological toxicity in those patients with concomitant vitamin K deficiency.

Corrigan J, Marcus FI. Coagulopathy associated with vitamin E ingestion. JAMA 1974 Dec 2;230(9):1300-1301.

Corrigan JJ Jr. The effect of vitamin E on warfarin-induced vitamin K deficiency. Ann N Y Acad Sci 1982;393:361-368.
Abstract: Vitamin K-deficient animals and humans developed a more severe coagulopathy when treated with vitamin E, which was due to further reduction in the vitamin K-dependent coagulation factors (II, VII, IX, and X). This phenomenon was not seen in normal vitamin K-sufficient animals or human subjects. The mechanism by which vitamin E causes this effect is not known. These coagulation factors are produced by the liver in precursor forms and are converted to functional proteins by a vitamin K-dependent reaction. Analysis of one of these coagulation factors, prothrombin (factor II), in plasma of vitamin K-deficient animals and humans treated with vitamin E was done in this study. The precursor of factor II is antigenically similar to biologically active factor II and can be activated to form thrombin by Echis carinatus venom. The data showed that functional factor II coagulant activity was reduced below base in warfarin-treated humans and animals given vitamin E. Factor II antigen as determined by electroimmunoassay in humans and factor II coagulant activity as measured using Echis venom in animals were unchanged and no different from untreated controls. The data suggest that vitamin E acts at the vitamin K-carboxylase step of carboxylation of precursor prothrombin and not in the synthesis of the precursor protein.

Eilat S, Vered Z, Mirelman D. [Influence of garlic on blood lipids and blood coagulation]. Harefuah 1993 Apr 1;124(7):418-421. (Review) [Article in Hebrew]

Feetam CL, Leach RH, Meynell MJ. Lack of a clinically important interaction between warfarin and ascorbic acid. Toxicol Appl Pharmacol 1975 Mar;31(3):544-547.

Gadkari JV, Joshi VD. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med 1991 Jul;37(3):128-131.
Abstract: The effect of raw garlic on serum cholesterol, fibrinolytic activity and clotting time was studied in 50 medical students of the age group of 17 to 22 years before and after feeding raw garlic. All pre-experimental values ranged within normal limits. The volunteers were then divided into experimental and control groups. The subjects of the experimental group were given 10 gm of raw garlic daily after breakfast for two months. Fasting blood samples of all the subjects were investigated after two months. In the control group, there was no significant change in any of the above parameters. In the experimental group, there was a significant decrease in serum cholesterol and an increase in clotting time and fibrinolytic activity. Hence, garlic may be an useful agent in prevention of thromboembolic phenomenon.

Greenspan EM. Ginseng and vaginal bleeding. JAMA 1983 Apr 15;249(15):2018. (Letter)

Harris JE. Interaction of dietary factors with oral anticoagulants: Review and application. J Am Diet Assoc 1995 May;95(5):580-584. (Review)

Hobbs C. Medicinal Mushrooms. Santa Cruz, CA: Botanica Press, 1995, 125-128.

Hogan RP 3d. Hemorrhagic diathesis caused by drinking an herbal tea. JAMA. 1983 May 20;249(19):2679-2680.

Holt GA. Food and Drug Interactions. Chicago, Precept Press, 1998, 282-285.

Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol 1988 Nov;159(5):1121-1122.
Abstract: A case of postmenopausal bleeding attributed to the use of topical ginseng is reported. Ginseng appears to have an estrogen-like effect on genital tissues.

Hoult JR, Paya M. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen Pharmacol 1996 Jun;27(4):713-722. (Review)
Abstract: 1. More than 300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. More complex related compounds based on the coumarin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxins and the psoralens (photosensitizing agents). 2. Coumarin itself (1,2-benzopyrone) has long-established efficacy in slow-onset long-term reduction of lymphoedema in man, as confirmed in recent double-blind trials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage-induced proteolysis of oedema protein. However, coumarin has low absolute bioavailability in man (< 5%), due to extensive first-pass hepatic conversion to 7-hydroxycoumarin followed by glucuronidation. It may, therefore, be a prodrug. 3. Scoparone (6,7-dimethoxycoumarin) has been purified from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear cells, to relax smooth muscle, to reduce total cholesterol and triglycerides and to retard the characteristic pathomorphological changes in hypercholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to scavenge reactive oxygen species, inhibition of tyrosine kinases and potentiation of prostaglandin generation. 4. Osthole (7-methoxy-8-[3-methylpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese medicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic antiplatelet actions, inhibits PMN neutrophil function and causes vasodilatation. Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions. These coumarins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromolar concentrations. Another related coumarin, 5,7-dihydroxy-4-methylcoumarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simple coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hypochlorous acid, and is a potent inhibitor of cyclo-oxygenase, but is not pro-oxidant. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin both reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen-derived free radicals are implicated), showing that these antioxidant coumarins possess beneficial properties in this pathophysiological model. 8. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

Hume R, Johnstone JM, Weyers E. Interaction of ascorbic acid and warfarin. JAMA 1972 Mar 13;219(11):1479.

Innerfield I, Rowley GR. Low dosage proteases, clotting factors, capillary permeability and cellular viability. Life Sci [II] 1970 Dec 8;9(23):1359-1367.

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.

Jain RC. Effect of garlic on serum lipids, coagulability and fibrinolytic activity of blood. Am J Clin Nutr 1977 Sep;30(9):1380-1381. (Letter)

Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health-Syst Pharm 1997 Mar 15;54(6):692-693.

Kempin SJ. Warfarin resistance caused by broccoli. N Engl J Med 1983 May 19;308(20):1229-1230. (Letter)

Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol 1996 Mar 1;77(7):545-546.
Abstract: To clarify whether vitamin E enhances the pharmacologic effect of warfarin, we completed a double-blind clinical trial in which 21 subjects taking chronic warfarin therapy were randomized to receive either vitamin E or placebo. None of the subjects who received vitamin E had a significant change in the international normalized ratio, and thus it appears that vitamin E can safely be given to patients who require chronic warfarin therapy.

Kim YS, Pyo MK, Park KM, Park PH, Hahn BS, Wu SJ, Yun-Choi HS. Antiplatelet and antithrombotic effects of a combination of ticlopidine and ginkgo biloba ext (EGb 761).Thromb Res. 1998 Jul 1;91(1):33-38.
Abstract: The antiplatelet and antithrombotic effects of the oral combination treatment of ticlopidine and Ginkgo biloba extract (EGb 761) were studied in normal and thrombosis-induced rats. The ex vivo inhibitory effect on ADP-induced platelet aggregation of a small dose of ticlopidine (50 mg/kg/day) in combination with EGb 761 (40 mg/kg/day) was comparable to a larger dose of only ticlopidine (200 mg/kg/day). Bleeding time was also prolonged by 150%. Thrombus weight was also consistently decreased by a combination of ticlopidine and EGb 761 in an arterio-venous shunt model at two doses of ticlopidine (50 mg/kg) plus EGb 761 (20 mg/kg) and ticlopidine (50 mg/kg) plus EGb 761 (40 mg/kg). A combinatory treatment in acute thrombosis model in mice also showed a higher recovery than a single treatment.

Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992 Nov 7;340(8828):1136-1139. (Review)

Landbo C, Almdal TP. [Interaction between warfarin and coenzyme Q10]. Ugeskr Laeger. 1998 May 25;160(22):3226-3227. [Article in Danish]
Abstract: Coenzyme Q10 (Ubidecarenone) is marketed as a dietary supplement. Drug interaction between coenzyme Q10 and warfarin has previously been reported. In the present case, a 72-year-old female treated with warfarin showed less responsiveness to warfarin than previously. It appeared she had taken coenzyme Q10, and when this was stopped, her responsiveness to warfarin was the same as before. Coenzyme Q10 is chemically similar to K-vitamins, which may explain the interaction with warfarin. Patients in treatment with warfarin should be aware of the possible risk of treatment failure when taking coenzyme Q10. The need for questioning patients concerning not only medications but also use of dietary supplements and alternative medications is emphasised.

Lim JM, McKay M. Food-drug interactions. Drug Information Bulletin. Los Angeles: UCLA Dept. of Pharmaceutical Services, 15(2), 1995.

Lo AC, Chan K, Yeung JH, Woo KS. Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits. Eur J Drug Metab Pharmacokinet 1995 Jan-Mar;20(1):55-60.
Abstract: Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self-medicate with Danggui or other TCM products while on chronic treatment with warfarin.

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.

Matthews MK Jr. Association of Ginkgo biloba with intracerebral hemorrhage. Neurology 1998 Jun;50(6):1933-1934. (Comment, Letter)

Merkel U, Sigusch H, Hoffman A. Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers. Eur J Clin Pharmacol. 1994;46(2):175-177.
Abstract: The effect of grapefruit juice on the urinary excretion of 7-hydroxycoumarin after oral administration of 10 mg coumarin, as an index of cytochrome P450 dependent coumarin metabolism, has been investigated in an open, randomised cross over study in 13 healthy volunteers (7 female, 6 male). The percentage of 7-hydroxycoumarin found in urine was significantly decreased up to 8 h after simultaneous intake of 300 ml grapefruit juice. If the same volume of juice was swallowed 30 min prior to the administration of coumarin, 7-hydroxycoumarin excretion was delayed by up to 6 h. MRTexcr. of coumarin was 70% extended by coadministration of grapefruit juice. It appears that grapefruit flavonoids inhibit cytochrome P450 2A dependent metabolic pathways. The mechanism of cytochrome P450 inhibition by these flavonoids is still poorly understood.

Otsuka M, Shinozuka K, Hirata G, Kunitomo M. [Influences of a shiitake (Lentinus edodes)-fructo-oligosaccharide mixture (SK-204) on experimental pulmonary thrombosis in rats]. Yakugaku Zasshi. 1996 Feb;116(2):169-173. [Article in Japanese]
Abstract: Effects of the mixture (SK-204) consisting of dried shiitake mushroom (Lentinus edodes) treated with wet-heating and fructo-oligosaccharides (7:3) on the experimental models of pulmonary thrombosis induced by lactic acidosis in rats were evaluated. Chronic oral administration (10 weeks) of SK-204 significantly prevented the thrombus formation on this thrombosis model. However, decreases in the numbers of platelet and fibrinogen level by lactate were not changed by SK-204. These results suggest that SK-204 have an anti-thrombotic action, which is due to neither the inhibition of platelet aggregation nor coagulation, but probably due to the promotion of fibrinolysis and thrombolysis.

Owen CA Jr, Tyce GM, Flock EV, McCall JT. Heparin-ascorbic acid antagonism. Mayo Clin Proc. 1970 Feb;45(2):140-145.

Palareti G, Legnani C. Warfarin withdrawal. Pharmacokinetic-pharmacodynamic considerations. Clin Pharmacokinet 1996 Apr;30(4):300-313.

Perez-Jauregui J, Escate-Cavero A, Vega-Galina J, Ruiz-Arguelles GJ, Macip-Nieto G. [Probable coumarin poisoning upon ingestion of an anti-inflammatory agent]. Rev Invest Clin 1995 Jul-Aug;47(4):311-313. [Article in Spanish]
Abstract: Warfarin overdose leads to hypoprothrombinemia and bleeding diathesis. We report here the case of a 47 year old woman who ingested an overdose of a non-steroidal anti-inflammatory drug, sold in Mexico under the name of Wobenzym (R), and containing, according to the manufacturer: pancreatin, bromelin, papain, lipase, amylase, trypsin, alpha chymotrypsin and rutin. She developed skin, urinary and gastrointestinal bleeding and was found to be apparently under the effect of a coumadin overdose, i.e. prolonged prothrombin time, prolonged activated thromboplastin time, and low functional and antigenic levels of prothrombin. A platelet count, and the thrombin, reptilase and bleeding times were normal. All laboratory and clinical abnormalities reverted to normal by using fresh frozen plasma and parenteral vitamin K. In addition, we were able to show that the commercial preparation could prolong the prothrombin time in rabbits and, by high-performance liquid chromatography, a pike consonant with purified coumadin was found in the drug. It is concluded that this drug is probably contaminated by coumadin, and that physicians must be aware of its potential side effects.

Rose KD, Croissant PD, Parliment CF, Levin MB. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: A case report. Neurosurg 1990;26:880-882.

Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. New Engl J Med 1997 Apr 10;336(15):1108. (Letter)

Rosenthal G.Interaction of ascorbic acid and warfarin. JAMA. 1971 Mar 8;215(10):1671.

Rowin J, Lewis SL. Spontaneous bilateral subdural hematoma with chronic Gingko biloba ingestion. Neurology 1996 Jun;46(6):1775-1776.

Schrogie JJ. Coagulopathy and fat soluble drugs. JAMA 1975 Apr 7;232(1):19. (Letter)

Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements: a 5-year toxicological study (1991-1995). Drug Safety 1997;17(5):342-356.

Skogh M. Extracts of Ginkgo biloba and bleeding or haemorrhage. Lancet. 1998 Oct 3;352(9134):1145-1146.

Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994 Nov 12;344(8933):1372-1373. (Letter)

Stockley IH. Drug Interactions, 4th ed., Pharmaceutical Press, London, 1996.

Sullivan DM, Ford MA, Boyden TW. Grapefruit juice and the response to warfarin. Am J Health Syst Pharm. 1998 Aug 1;55(15):1581-1583.
Abstract: The effect if any of prepared frozen grapefruit juice on prothrombin times (PTs) in patients undergoing stabilized warfarin therapy was studied. Patients receiving low-intensity warfarin therapy (targeted International Normalized Ratio [INR], 2-3) who had two consecutive baseline PTs within 10% of each other were recruited. Patients who regularly consumed grapefruit juice or alcohol or who were taking drugs known to interact with grapefruit juice were excluded. A one-week supply of freshly prepared frozen grapefruit juice in individual 8-oz containers was given to all the subjects, who were told to drink the entire contents of on container three times a day for one week. PTs were measured and INRs calculated on the day before grapefruit juice ingestion began (day 0) and a days 2, 6, and 8. Ten men (mean age, 66 years) were enrolled; one withdrew because of diarrhea. Compliance in consuming the juice was reported to range from 85.7% to 100% among patients. There was no significant difference among PT or INR values over the course of the study in any of the nine subjects. Ingestion of grapefruit juice prepared from frozen concentrate did not change PTs in patients treated with warfarin.

Sunter WH. Warfarin and garlic. Pharm J 1991;246:722. (Letter)

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.

Tatro D, ed. Anticoagulants-quinine derivatives. In Drug Interaction Facts. St. Louis, MO: Facts and Comparisons, Jul 1993.

Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet. 1998 Jul 4;352(9121):36. (Letter)
Abstract: A 61-year-old man presented in September, 1997, with a 5-day history of headache, back pain, nausea, and sleepiness. He had been previously in excellent health and enjoyed outdoor exercise. On examination no physical abnormalities were found, including his neurological status. Blood pressure was 135/85 mm Hg. He had a normal blood count and mildly increased bleeding time (6 min, normal 1-3). Serum urea, nitrogen, creatinine, bilirubin, and hepatic enzymes were normal, as were prothrombin and partial thromboplastin times. A computed tomographic cranial scan obtained without the administration of contrast material was also normal. A lumbar puncture yielded 6 mL of slightly xanthochromic fluid without gross blood. Microscopical examination revealed 6 cells per µL of which five were red cells and one was white. Glucose was 3·7 mmol/L protein 240 mg/L. A subarachnoid haemorrhage was diagnosed. Detailed questioning revealed that
he had been taking Ginkgo biloba 40 mg tablets, three or four times a day, for more than 6 months before the beginning of his symptoms. The patient recovered uneventfully. He was advised to stop the extract and in January, 1998, he was doing well. His bleeding time is now 3 min and he has refused further medical investigations.

Weibert RT, Le DT, Kayser SR, et al. Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 1997 Jun 15;126(12):959-962.
Abstract: BACKGROUND: Despite earlier acceptance of oral vitamin K1 (phytonadione) for the treatment of excessive anticoagulation, some recent guidelines do not recommend its use. OBJECTIVE: To reevaluate the efficacy of oral vitamin K1 in correcting excessive anticoagulation. DESIGN: Case series. SETTING: Anticoagulation clinics at two university medical centers. PATIENTS: 81 outpatients who had an international normalized ratio (INR) greater than 5.0 but did not have significant bleeding. INTERVENTIONS: Withholding 1 or 2 doses of warfarin, administering 2.5 mg of oral vitamin K1, measuring the INR after 24 to 48 hours, and adjusting the warfarin dose. MEASUREMENTS: INRs were obtained from a portable capillary fingerstick monitor or from an automated photooptical coagulometer. RESULTS: In 68 of 71 patients (96%), oral vitamin K1 lowered the INR from between 5.0 and 10.0 to less than 5.0 without inducing resistance to further anticoagulation. CONCLUSIONS: Withholding 1 or 2 doses of warfarin and administering 2.5 mg of oral vitamin K1 is a reliable, safe, and inexpensive way to rapidly correct excessive anticoagulation (INR > 5.0) in patients who do not have serious bleeding episodes and have an INR of less than 10.0.

Weintraub M, Griner PF. Warfarin and ascorbic acid: lack of evidence for a drug interaction. Toxicol Appl Pharmacol 1974 Apr;28(1):53-56.

Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994 Nov 1;121(9):676-683. (Review)
Abstract: PURPOSE: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance. DATA SOURCES: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only. STUDY SELECTION: All articles reporting original data on drug and food interactions with warfarin. DATA EXTRACTION: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred. Inter-rater agreement was assessed using a weighted kappa statistic. RESULTS: Of 793 retrieved citations, 120 contained original reports on 186 interactions. The weighted kappa statistic was 0.67, representing substantial agreement. Of 86 different drugs and foods appraised, 43 had level 1 evidence. Of these, 26 drugs and foods did interact with warfarin. Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole. Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado. CONCLUSIONS: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications. Many of these drug interactions increase warfarin's anticoagulant effect.

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.

Zhu M, Chan KW, Ng LS, Chang Q, Chang S, Li RC. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats. J Pharm Pharmacol 1999 Feb;51(2):175-180.
Abstract: We evaluated the significance of a reported clinical case of drug-drug interaction between ginseng and warfarin using a robust pharmacokinetic/pharmacodynamic approach in a rat model. The influence of ginseng on the pharmacokinetics and pharmacodynamics of oral warfarin after a single dose (2 mg kg(-1)) and at steady state (0.2 mg kg(-1) daily x 6 days) was studied in male Sprague-Dawley rats. Prothrombin time was employed as a pharmacodynamic index. Warfarin plasma concentration and vitamin K content in the ginseng extract were assessed by validated HPLC assays. The pharmacokinetics of warfarin after a single dose were not altered in the presence of ginseng; peak plasma concentration (control 7.8+/-0.5; ginseng 7.3+/-2.5 microg mL(-1)), time to peak (control 2.6+/-1.0; ginseng 3.1+/-1.1 h), elimination half-life (control 14.3+/-5.8; ginseng 10.6+/-3.1 h), and oral clearance (control 17.5+/-3.3; ginseng 20.2+/-5.5 mL h(-1)) were not significantly different (P>0.05). Similarly, alterations in the pharmacokinetics of warfarin were not detected under the multiple dosing paradigm. Under both dosing conditions, ginseng also showed no significant impact on the pharmacodynamics of warfarin as assessed by the area under the prothrombin time vs time curve (multiple dosing; control 3776+/-619, ginseng 3830+/-362 sh) and maximum prothrombin time (control 57.2+/-11.8, ginseng 63.3+/-9.1 s). Furthermore, the content of vitamin K was undetectable in the ginseng decoction. In conclusion, current data obtained in the rat showed no significant impact of ginseng on the pharmacokinetics/pharmacodynamics of warfarin when they are concomitantly administered.