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Probable Interaction Between an Oral Vitamin K Antagonist and Turmeric (Curcuma longa)
LETTER
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Thérapie 2014 Novembre-Décembre; 69 (6): 519–520 DOI: 10.2515/therapie/2014062
EDITOR
© 2014 Société Française de Pharmacologie et de Thérapeutique
Probable Interaction Between an Oral Vitamin K Antagonist and Turmeric (Curcuma longa) Amélie Daveluy1,2, Hélène Géniaux1,3, Lucile Thibaud4, Michel Mallaret5, Ghada MiremontSalamé1,2 and Françoise Haramburu1,2 1 CHU de Bordeaux, Département de pharmacologie, Centre régional de pharmacovigilance, Bordeaux, France 2 INSERM, U657, Bordeaux, France 3 Université de Bordeaux, U657, Bordeaux, France 4 Médecin généraliste, Basse Terre, Guadeloupe, France 5 CHU de Grenoble, Centre régional de pharmacovigilance, Grenoble, France Text received June 10th, 2014; accepted July 8th, 2014 This case has been notified to Regional Pharmacovigilance Center of Bordeaux on March 14th, 2013 Abstract – We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects. Keywords: curcuma; anticoagulants; herb-drug interactions; complementary therapies; international normalized ratio Résumé – Probable interaction entre antivitamine K et curcuma (Curcuma longa). Nous présentons un cas d’interaction entre le curcuma et un antivitamine K, la fluindione, ayant résulté en une augmentation de l’international normalized ratio (INR). Ce cas montre l’importance d’interroger le patient sur une éventuelle prise de produits de phytothérapie devant une interaction ou un effet indésirable sans cause évidente. Mots clés : curcuma ; anticoagulants ; interaction ; phytothérapie ; international normalized ratio Abbreviations: see end of article.
but is also used as a yellow coloring agent in foods. The main active ingredient of turmeric is curcumin, which is responsible for the yellow color and for numerous pharmacological activities, justifying the long history of use of turmeric and related Curcuma species in Chinese, Hindu, and, Ayurvedic medicines. Curcumin is traditionally used as a “treatment” for biliary and gastrointestinal disorders, as an anti-oxydant, and as an antiinflammatory agent.[1,2] Complementary or alternative medicines are extensively used[3] and when herbal products are combined with medications there is a real risk of interaction.[4,5] This is a major safety concern, in particular because herbal products are not often labeled regarding possible herb-drug interactions.[4] It may be particularly problematic with medications with a narrow therapeutic index, such as vitamin K antagonists (e.g. warfarin or fluindione, the latter being almost only used in France) with which there is a risk of thrombosis if underdosed and a risk of hemorrhage if overdosed. The risk associated with turmeric is recognized in certain recommendations[6,7] but these are based on the properties of the plant as it is reported that turmeric may increase the risk of bleeding or potentiate the effects of anticoagulants and antiplatelet agents.[8] However, there is a lack of clinical data on interactions between a vitamin K antagonist and turmeric. We report here what we believe to be the first case of such an interaction.
2. Observation A 56-year-old woman, living in Guadeloupe, French West Indies, was had been treated by fluindione for mitral valvulopathy since 1993. The international normalized ratio (INR) had always been steady and within the target range (INR 2-3). Even though there had been no recent change in fluindione dose, the patient’s INR rose suddenly from a therapeutic value to 6.5. There was no clinical sign of bleeding. The patient reported that she had been taking an infusion of turmeric (one tea spoon i.e. 2.5 g)[9] each evening for 5 days. No other explanation was found. This plant was recommended by her general practitioner for ankylosing spondylarthritis, after treatments with methotrexate, penicillamin, and leflunomide had failed. Fifteen days after withdrawal of turmeric, the INR was again within the target range. The role of turmeric was evaluated as “probable”, according to the drug interaction probability scale[10] and as “likely”, according to the French method of causality assessment.[11]
3. Discussion
1. Introduction Turmeric is the dried rhizome of Curcuma longa (Zingiberaceae). It is a constituent of curry powders and other food condiments,
This case report is of importance in light of known under-reporting of herb use by patients to their physicians[12] and the resulting under-recognition of herb-drug interactions. The mechanism of the interaction described herein may be explained by the pharmacological properties of turmeric. This plant is associated with a theoretical risk
Article publié par EDP Sciences
520
Daveluy et al.
of bleeding in recommendations,[6,7] as turmeric has been reported to have both in vitro and in vivo anticoagulant activities.[8] Kim et al. have shown that curcumin and an other polyphenolic analogue, bisdemethoxycurcumin, could prolong prothrombin and activated partial thromboplastin times, and could inhibit activated factor X and thrombin synthesis.[13] Furthermore, animal studies have described an anti-platelet effect of curcumin, as well as a prolonged bleeding time.[2,14,15] In addition to this potential pharmacodynamic interaction, a pharmacokinetic interaction can also been implied as turmeric is an inhibitor of the 2C9 and 3A4 isoenzymes of cytochrome P450.[16,17] Curcumin is also an inhibitor of the P-glycoprotein (Pgp).[16] Therefore, an interaction may be expected for both vitamin K antagonists and new oral anticoagulants.[18] These data are only partially supported by another study that showed that administration of curcumin to rats had no effect on pharmacodynamic parameters of warfarin, such as anticoagulation rate and antiplatelet aggregation, although it confirmed the effect on pharmacokinetics.[19] As the authors noted, despite a potential lack of pharmacodynamic interaction, the pharmacokinetic interaction alone is sufficient to be of potential clinical importance.[19] There is currently an absence of clinical data and thus the dose for which such an interaction can occur is not known. In the present case, the daily intake was slightly below the doses traditionally used for inflammatory conditions (3-10 g daily),[6] but far greater than the quantities and possibly frequency ingested through diet (curry for example). Regulations with regards to safety and pharmacokinetics in human are highly required for herbal products. Taken together, this case provides clinical data for a previously hypothesized interaction with vitamin K antagonists and turmeric and underlines the importance of considering potential exposure to herbal medications when evaluating adverse effects. Conflicts of interests. None. Abbreviations. INR: international normalized ratio; P-gp: P-glycoprotein.
3.
4. 5.
6.
7.
8.
9. 10. 11.
12.
13. 14.
15.
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17.
18.
References 1.
Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009; 14: 141-53
2.
Taylor RA, Leonard MC. Curcumin for inflammatory bowel disease: a review of human studies. Altern Med Rev 2011; 16: 152-6
© Société Française de Pharmacologie et de Thérapeutique
19.
Harris PE, Cooper KL, Relton C, et al. Prevalence of complementary and alternative medicine (CAM) use by the general population: a systematic review and update. Int J Clin Pract 2012; 66: 924-39 Williamson EM. Interactions between herbal and conventional medicines. Expert Opin Drug Saf 2005; 4: 355-78 Elmer GW, Lafferty WE, Tyree PT, et al. Potential interactions between complementary/alternative products and conventional medicines in a Medicare population. Ann Pharmacother 2007; 41: 1617-24 Commitee on herbal medicinal products (HMPC). Assessment report on Curcuma longa L. Rhizoma, 2009 http://www.ema.europa.eu/docs/en_GB/document_library/ Herbal_-_HMPC_assessment_report/2010/02/WC500070700.pdf Accessed July 9th, 2014 (26 pages) Health Canada. Monograph: Curcumin, 2010 http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=74&lang=eng Accessed July 9th, 2014 Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000; 57: 1221-7; quiz 1228-30 Wichtl M, Bisset NG. Herbal drugs and Pharmaceuticals. Stuttgart: Medpharm GmbH Scientific Publishers, 1994 Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007; 41: 674-80 Begaud B, Evreux JC, Jouglard J, et al. Imputabilité des effets inattendus ou toxiques des médicaments. Actualisation de la méthode utilisée en France. Therapie 1985; 40: 111-8 Cheung CK, Wyman JF, Halcon LL. Use of complementary and alternative therapies in community-dwelling older adults. J Altern Complement Med 2007; 13: 997-1006 Kim DC, Ku SK, Bae JS. Anticoagulant activities of curcumin and its derivative. BMB Rep 2012; 45: 221-6 Prakash P, Misra A, Surin WR, et al. Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis. Thromb Res 2011; 127: 111-8 Shah BH, Nawaz Z, Pertani SA, et al. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acidmediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol 1999; 58: 1167-72 Lee CK, Ki SH, Choi JS. Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin. Biopharm Drug Dispos 2011; 32: 245-51 Appiah-Opong R, de Esch I, Commandeur JN, et al. Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues. Eur J Med Chem 2008; 43: 1621-31 Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 2013; 52: 69-82 Liu AC, Zhao LX, Lou HX. Curcumin alters the pharmacokinetics of warfarin and clopidogrel in Wistar rats but has no effect on anticoagulation or antiplatelet aggregation. Planta Med 2013; 79: 971-7
Correspondence and offprints: Amélie Daveluy, Centre régional de pharmacovigilance Hôpital Pellegrin, CHU, 33076 Bordeaux Cedex, France. E-mail: [email protected]
Thérapie 2014 Novembre-Décembre; 69 (6)
TO
Thérapie 2014 Novembre-Décembre; 69 (6): 519–520 DOI: 10.2515/therapie/2014062
EDITOR
© 2014 Société Française de Pharmacologie et de Thérapeutique
Probable Interaction Between an Oral Vitamin K Antagonist and Turmeric (Curcuma longa) Amélie Daveluy1,2, Hélène Géniaux1,3, Lucile Thibaud4, Michel Mallaret5, Ghada MiremontSalamé1,2 and Françoise Haramburu1,2 1 CHU de Bordeaux, Département de pharmacologie, Centre régional de pharmacovigilance, Bordeaux, France 2 INSERM, U657, Bordeaux, France 3 Université de Bordeaux, U657, Bordeaux, France 4 Médecin généraliste, Basse Terre, Guadeloupe, France 5 CHU de Grenoble, Centre régional de pharmacovigilance, Grenoble, France Text received June 10th, 2014; accepted July 8th, 2014 This case has been notified to Regional Pharmacovigilance Center of Bordeaux on March 14th, 2013 Abstract – We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects. Keywords: curcuma; anticoagulants; herb-drug interactions; complementary therapies; international normalized ratio Résumé – Probable interaction entre antivitamine K et curcuma (Curcuma longa). Nous présentons un cas d’interaction entre le curcuma et un antivitamine K, la fluindione, ayant résulté en une augmentation de l’international normalized ratio (INR). Ce cas montre l’importance d’interroger le patient sur une éventuelle prise de produits de phytothérapie devant une interaction ou un effet indésirable sans cause évidente. Mots clés : curcuma ; anticoagulants ; interaction ; phytothérapie ; international normalized ratio Abbreviations: see end of article.
but is also used as a yellow coloring agent in foods. The main active ingredient of turmeric is curcumin, which is responsible for the yellow color and for numerous pharmacological activities, justifying the long history of use of turmeric and related Curcuma species in Chinese, Hindu, and, Ayurvedic medicines. Curcumin is traditionally used as a “treatment” for biliary and gastrointestinal disorders, as an anti-oxydant, and as an antiinflammatory agent.[1,2] Complementary or alternative medicines are extensively used[3] and when herbal products are combined with medications there is a real risk of interaction.[4,5] This is a major safety concern, in particular because herbal products are not often labeled regarding possible herb-drug interactions.[4] It may be particularly problematic with medications with a narrow therapeutic index, such as vitamin K antagonists (e.g. warfarin or fluindione, the latter being almost only used in France) with which there is a risk of thrombosis if underdosed and a risk of hemorrhage if overdosed. The risk associated with turmeric is recognized in certain recommendations[6,7] but these are based on the properties of the plant as it is reported that turmeric may increase the risk of bleeding or potentiate the effects of anticoagulants and antiplatelet agents.[8] However, there is a lack of clinical data on interactions between a vitamin K antagonist and turmeric. We report here what we believe to be the first case of such an interaction.
2. Observation A 56-year-old woman, living in Guadeloupe, French West Indies, was had been treated by fluindione for mitral valvulopathy since 1993. The international normalized ratio (INR) had always been steady and within the target range (INR 2-3). Even though there had been no recent change in fluindione dose, the patient’s INR rose suddenly from a therapeutic value to 6.5. There was no clinical sign of bleeding. The patient reported that she had been taking an infusion of turmeric (one tea spoon i.e. 2.5 g)[9] each evening for 5 days. No other explanation was found. This plant was recommended by her general practitioner for ankylosing spondylarthritis, after treatments with methotrexate, penicillamin, and leflunomide had failed. Fifteen days after withdrawal of turmeric, the INR was again within the target range. The role of turmeric was evaluated as “probable”, according to the drug interaction probability scale[10] and as “likely”, according to the French method of causality assessment.[11]
3. Discussion
1. Introduction Turmeric is the dried rhizome of Curcuma longa (Zingiberaceae). It is a constituent of curry powders and other food condiments,
This case report is of importance in light of known under-reporting of herb use by patients to their physicians[12] and the resulting under-recognition of herb-drug interactions. The mechanism of the interaction described herein may be explained by the pharmacological properties of turmeric. This plant is associated with a theoretical risk
Article publié par EDP Sciences
520
Daveluy et al.
of bleeding in recommendations,[6,7] as turmeric has been reported to have both in vitro and in vivo anticoagulant activities.[8] Kim et al. have shown that curcumin and an other polyphenolic analogue, bisdemethoxycurcumin, could prolong prothrombin and activated partial thromboplastin times, and could inhibit activated factor X and thrombin synthesis.[13] Furthermore, animal studies have described an anti-platelet effect of curcumin, as well as a prolonged bleeding time.[2,14,15] In addition to this potential pharmacodynamic interaction, a pharmacokinetic interaction can also been implied as turmeric is an inhibitor of the 2C9 and 3A4 isoenzymes of cytochrome P450.[16,17] Curcumin is also an inhibitor of the P-glycoprotein (Pgp).[16] Therefore, an interaction may be expected for both vitamin K antagonists and new oral anticoagulants.[18] These data are only partially supported by another study that showed that administration of curcumin to rats had no effect on pharmacodynamic parameters of warfarin, such as anticoagulation rate and antiplatelet aggregation, although it confirmed the effect on pharmacokinetics.[19] As the authors noted, despite a potential lack of pharmacodynamic interaction, the pharmacokinetic interaction alone is sufficient to be of potential clinical importance.[19] There is currently an absence of clinical data and thus the dose for which such an interaction can occur is not known. In the present case, the daily intake was slightly below the doses traditionally used for inflammatory conditions (3-10 g daily),[6] but far greater than the quantities and possibly frequency ingested through diet (curry for example). Regulations with regards to safety and pharmacokinetics in human are highly required for herbal products. Taken together, this case provides clinical data for a previously hypothesized interaction with vitamin K antagonists and turmeric and underlines the importance of considering potential exposure to herbal medications when evaluating adverse effects. Conflicts of interests. None. Abbreviations. INR: international normalized ratio; P-gp: P-glycoprotein.
3.
4. 5.
6.
7.
8.
9. 10. 11.
12.
13. 14.
15.
16.
17.
18.
References 1.
Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009; 14: 141-53
2.
Taylor RA, Leonard MC. Curcumin for inflammatory bowel disease: a review of human studies. Altern Med Rev 2011; 16: 152-6
© Société Française de Pharmacologie et de Thérapeutique
19.
Harris PE, Cooper KL, Relton C, et al. Prevalence of complementary and alternative medicine (CAM) use by the general population: a systematic review and update. Int J Clin Pract 2012; 66: 924-39 Williamson EM. Interactions between herbal and conventional medicines. Expert Opin Drug Saf 2005; 4: 355-78 Elmer GW, Lafferty WE, Tyree PT, et al. Potential interactions between complementary/alternative products and conventional medicines in a Medicare population. Ann Pharmacother 2007; 41: 1617-24 Commitee on herbal medicinal products (HMPC). Assessment report on Curcuma longa L. Rhizoma, 2009 http://www.ema.europa.eu/docs/en_GB/document_library/ Herbal_-_HMPC_assessment_report/2010/02/WC500070700.pdf Accessed July 9th, 2014 (26 pages) Health Canada. Monograph: Curcumin, 2010 http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=74&lang=eng Accessed July 9th, 2014 Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000; 57: 1221-7; quiz 1228-30 Wichtl M, Bisset NG. Herbal drugs and Pharmaceuticals. Stuttgart: Medpharm GmbH Scientific Publishers, 1994 Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007; 41: 674-80 Begaud B, Evreux JC, Jouglard J, et al. Imputabilité des effets inattendus ou toxiques des médicaments. Actualisation de la méthode utilisée en France. Therapie 1985; 40: 111-8 Cheung CK, Wyman JF, Halcon LL. Use of complementary and alternative therapies in community-dwelling older adults. J Altern Complement Med 2007; 13: 997-1006 Kim DC, Ku SK, Bae JS. Anticoagulant activities of curcumin and its derivative. BMB Rep 2012; 45: 221-6 Prakash P, Misra A, Surin WR, et al. Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis. Thromb Res 2011; 127: 111-8 Shah BH, Nawaz Z, Pertani SA, et al. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acidmediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol 1999; 58: 1167-72 Lee CK, Ki SH, Choi JS. Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin. Biopharm Drug Dispos 2011; 32: 245-51 Appiah-Opong R, de Esch I, Commandeur JN, et al. Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues. Eur J Med Chem 2008; 43: 1621-31 Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 2013; 52: 69-82 Liu AC, Zhao LX, Lou HX. Curcumin alters the pharmacokinetics of warfarin and clopidogrel in Wistar rats but has no effect on anticoagulation or antiplatelet aggregation. Planta Med 2013; 79: 971-7
Correspondence and offprints: Amélie Daveluy, Centre régional de pharmacovigilance Hôpital Pellegrin, CHU, 33076 Bordeaux Cedex, France. E-mail: [email protected]
Thérapie 2014 Novembre-Décembre; 69 (6)