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PROFESSOR ALEJANDRO F. BARRERO Department of Organic Chemistry, University of Granada, Campus de Fuente Nueva, s/n, 18071, Granada, Spain
PROFESSOR ALESSANDRA BRACA Dipartimento di Chimica Bioorganicae Biofarmacia, Universita di Pisa, via Bonanno 33, 56126 Pisa, Italy
PROFESSOR DEAN GUO State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China [email protected]
PROFESSOR YOSHIHIRO MIMAKI School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo 192-0392, Japan
PROFESSOR STEPHEN G. PYNE Department of Chemistry
University of Wollongong
Wollongong, New South Wales, 2522, Australia
PROFESSOR MANFRED G. REINECKE Department of Chemistry, Texas Christian University, Forts Worth, TX 76129, USA
PROFESSOR WILLIAM N. SETZER Department of Chemistry
The University of Alabama in Huntsville
Huntsville, AL 35809, USA
PROFESSOR YASUHIRO TEZUKA Faculty of Pharmaceutical Sciences
Hokuriku University
Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan
PROFESSOR DAVID E. THURSTON Department of Pharmaceutical and Biological Chemistry,
The School of Pharmacy,
University of London, 29-39 Brunswick Square,
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HONORARY EDITOR
PROFESSOR GERALD BLUNDEN The School of Pharmacy & Biomedical Sciences,
University of Portsmouth, Portsmouth, PO1 2DT U.K.
Warfarin Interactions with Medicinal Herbs
Nataša Milića, Nataša Miloševića*, Svetlana Goločorbin Kona, Teodora Božićb, Ludovico Abenavolic and
Francesca Borrellid aDepartment of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
bDepartment of Surgery, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
cDepartment of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
dDepartment of Experimental Pharmacology, University of Naples Federico II, Naples, Italy [email protected]
Received: February 20th, 2014; Accepted: May 31st, 2014
Recognition of the adverse effects of medicinal herbs is not routine and the reports on such effects are even less frequent in clinical practice. Potential herb-drug interactions are of a major safety concern, especially for drugs with narrow therapeutic indices like warfarin, which can lead to severe adverse reactions that are sometimes life-threatening. The interactions between warfarin and medicinal herbs described in the literature have been summarized in this paper relying on Medline database (via PubMed) using the key words: warfarin, herbal supplements and interactions. The references on the analyzed literature have been investigated in order to collect the existing data. The case reports with severe adverse effects such as spontaneous postoperative bleeding, formation of hematomas, hematemesis, melena, thrombosis, subarachnoid hemorrhage and/or subdural hematomas after concomitant use of warfarin and the medicinal herbs: Panax ginseng, Hypericum perforatum, Salvia milthiorizza, Gingko biloba, Serenoa repens, Angelica sinensis, Vaccinium species, Allium sativum, Zingiber officinale, Tanacetum parthenium, Lucium barbarum, Matricaria chamomilla, Boswellia serrata and Camellia sinensis have been estimated. Some of the interactions between warfarin and medicinal herbs have been well assessed proving that they are closely-dependent.
The interactions between warfarin and medicinal herbs, not generally reported in previous reviews, are presented in our review. The health professionals who are involved in treating the patients are expected to be fully informed about the interactions between warfarin and medicinal herbs in order to minimize the health risks of the patients. Keywords: Warfarin, Herbal medicine, Adverse effect.
According to the WHO estimation, the global market of herbal products is worth about 60 billion U.S. $ annually and is constantly growing [1]. The recent WHO investigation reports with great concern that 70-80% of the world population, especially in developing countries, relies on traditional medicine, particularly herbal medicines in the treatment of a great number of diseases. The patients usually self-prescribe the herb products without being afraid of the adverse health effects since the herb products are "natural" and are considered as "safe" [2]. Due to the intense, self-prescribed use of herbal products, interactions between these and prescribed synthetic drugs occur very often. In particular, according to results of one survey conducted in January 2010, numerous medical professionals, primarily in the United Kingdom, do not have enough knowledge or interest in herbal medicine, so they should be adequately trained in this field because of the potential undesirable synthetic drugs/herbal medicines interactions [3]. Warfarin is the most commonly used anticoagulant. It is a coumarin derivative which possesses anticoagulant properties, used to treat or prevent blood clots in veins (deep vein thrombosis) and arteries, pulmonary embolism, chronic atrial fibrillation, and myocardial infarction. Racemic warfarin mixture consists of two optically active isomers, R and S, in approximately equal amounts. Warfarin is rapidly absorbed from the gastrointestinal tract, has high bioavailability and reaches maximum concentration in blood plasma after 90 minutes in healthy volunteers [4-6]. Racemic warfarin mixture circulates bound to plasma proteins (mainly albumins), accumulates in the liver, where the two isomers are metabolized via different metabolic pathways [7]. The main metabolic pathway for R-warfarin is CYP1A2, whereas for S-warfarin is CYP2C9. On the other hand, the secondary metabolic pathways of R and S-warfarin
are identical and are metabolized by CYP3A4, while a small amount of R-warfarin is metabolized through cytochrome CYP2C19 [8]. Half-life elimination of the racemic mixture is 36 to 42 h [7]. Vitamin K is a co-factor in the carboxylation of glutamate residues into -carboxyglutamates on the N-terminal regions of K- vitamin dependent proteins (coagulation factors II, VII, IX and X) [9]. Inhibition of the vitamin K conversion cycle by warfarin (Figure 1) induces hepatic production of partially decarboxylated proteins with decreased coagulation activity [10]. Carboxylation enables vitamin K-dependent coagulation factors to bind to phospholipids, thus accelerating the process of coagulation [11]. Warfarin has a narrow therapeutic index and many drug and food interactions make its safe use difficult for the clinicians. Warfarin therapy should be followed by constant monitoring to prevent potentially life-threatening outcomes due to over- and under-anticoagulation. However, even the standard warfarin therapy with the target international normalized ratio (INR) of 2.0-3.0, is associated with major hemorrhage of up to 7-8% annually [12,13]. Although warfarin interactions with numerous drugs are reported in the literature, few reviews on the interactions between warfarin and herbal drugs have been published so far, and accordingly warfarin-herbal product interactions are about to be recognized as one of the challenges in managing an oral anticoagulant therapy. Therefore, the aim of the authors is to provide an overview of the clinical data regarding the interaction between warfarin and medicinal herbs. Case reports, case series and clinical studies have primarily been reviewed and, in the absence of the clinical studies, the in vitro and in vivo studies have been considered. Also, the references on the analyzed literature have been investigated in order to collect the existing data.
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No. 8
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1212 Natural Product Communications Vol. 9 (8) 2014 Milić et al.
Figure 1: Vitamin K cycle and wafarin mechanism of anticoagulant activity.
The interactions between warfarin and certain herbs have been proved directly in either randomized double-blind studies, or, what is more usual, by communicating the individual case reports, and in animal studies. Warfarin activity, examined in the clinical studies or in the case reports, reviewed on the basis of the available literature, is usually obtained by direct estimation of the warfarin concentration in plasma, prothrombin time or by INR. The interactions between warfarin and the medicinal herbs are summarized in Table 1. Panax ginseng: Ginsenosides (primarily, panaxadiol and panaxytriol [14]) inhibit platelet aggregation in vitro and in vivo, prolonged the coagulation time and activated thromboplastin [15-17]. An open randomized study with 12 healthy volunteers, who were treated with warfarin and ginseng (each capsule contained the extract equivalent of 0.5 g of Panax ginseng root and 8.93 mg ginsenosides as ginsenoside Rg1) concomitantly for seven days, and had previously been treated with ginseng for seven days, indicated that there was not any interaction between ginseng and warfarin. Platelet aggregation, INR, plasma protein binding and the concentration of S-warfarin metabolites were not significantly changed [18]. However, in the randomized, open, double-blind study with 20 healthy volunteers, prothrombin time was decreased and the anticoagulation effect of warfarin was reduced. The subjects were treated only with ginseng (1 g daily, twice as much compared with the previous study) during the first week, and during the second week they were treated either with warfarin (5 mg daily) or placebo. The authors suggested that the ginsenosides, which had stimulated the hepatic enzymes, were responsible for the reduction of prothrombin time and thus increased the metabolism of warfarin [19]. Another double blind randomized study was conducted with 31 volunteers who had undergone heart valve replacement, and who were either receiving concomitantly warfarin and Korean red ginseng (1 g daily) for six weeks or warfarin and placebo for three weeks. The first group presented lower values of prothrombin time compared with the placebo group. Ginsenosides could induce the liver microsomal enzymes and accelerate the metabolism of warfarin [20, 21]. It could be assumed that high doses of P. ginseng (over 1 g daily) seriously changed the pharmacological effect of warfarin and undesirable clinical outcomes could be expected. In a double-blind study, 25 ischemic stroke patients were randomized into 2 groups: the ginseng group (n = 12), given both 0.5 g dry
P. ginseng extract and warfarin, and the control group (n = 13), given only warfarin, both groups for 2 weeks. The co-administration of P. ginseng and warfarin did not influence the pharmacological action of warfarin [22]. However, in two case reports (the patient with aortic valve replacement and the patient with atrial fibrillation) a sudden rise in INR due to the combination of warfarin and Panax ginseng were described. In the cases where active bleeding could not be determined, the use of the drug had been terminated and the dosage of warfarin was re-evaluated before discharging the patients [23]. Furthermore, a 58-year old patient with mechanical bileaflet aortic valve prosthesis was admitted with thrombosis caused by inadequate anticoagulant levels that occurred after a period of self-medication with a ginseng product [24]. Contradictory results were reported about the probable interactions between warfarin and P. ginseng, probably due to a different dosage of P. ginseng. Regardless of the fact that there are different presumed mechanisms of the interaction between warfarin and ginseng with consequently different outcomes, the concomitant use of ginseng extracts and warfarin are not recommended. Hypericum perforatum: Warfarin interaction with Hypericum
perforatum (St. John's wort) reduced the prothrombin time in 22 cases in the period 1998-2002 [25, 26]. An open randomized clinical trial of a possible interaction between warfarin and H.
perforatum was conducted with 12 healthy male volunteers divided into two groups. The first group was treated with 1 g of H.
perforatum flowers (hypericin 0.825 mg and 12.5 mg hyperforin) twice a day, while the control was not. Both groups received warfarin within seven days. St. John's wort affected the pharmacokinetics of the warfarin racemic mixture, which led to a significant reduction in the area under the curve (AUC-Area under the Curve) and half-time elimination of both warfarin forms, while the clearance of warfarin was significantly increased. On the other hand, St. John's wort did not affect either the maximum concentration or the time required to reach the maximum plasma concentration of warfarin or binding of warfarin to the plasma proteins. However, St. John's wort significantly decreased the pharmacological effect of warfarin since the prothrombin time was reduced. It was proved that St. John's wort induced not only CYP1A2 and/or CYP3A4, because it undoubtedly affected the pharmacokinetics of R-warfarin, but it also induced CYP2C9, as it could be observed on the basis of the altered pharmacokinetics of the S–enantomer [18], which is consistent with the previous in vitro reports [27, 28]. The study of an upper gastrointestinal bleeding in an 85-year-old male patient with a history of hypertension, old anterior wall myocardial infarction and atrial fibrillation caused by the concomitant use of warfarin and St. John’s wort was reported in 2011. Unexpectedly, the patient’s INR was increased and a severe bleeding diathesis had been developed, which manifested itself with hematemesis and melena [29]. Since St John’s wort contains a number of active ingredients, hyperforin, flavonols, flavonol glycosides, biflavones, naphthodianthrones, acylphloroglucinols, and phenylpropanes [30, 31], one or more combinations of these active ingredients might affect the drug metabolism of warfarin in sensitive individuals by potentiating its effect on the clotting cascade. The published results indicate that the possible interactions of warfarin with St. John’s wort are not exempt, and therefore, this combination should be avoided.
Salvia miltiorrhizza: Salvia miltiorrhiza (Danshen) proved to be an inhibitor of warfarin hydroxylation due to the inhibition of the microsomal enzymes: CYP1A1, CYP2C6 and CYP2C11 in in vitro and in vivo trials on rats. The active biomolecules, tanshinone I, tanshinone II and cryptotanshinone, extracted from danshen inhibited the formation of 4’- 6- and 7-hydroxywarfarin both
Warfarin interactions with medicinal herbs Natural Product Communications Vol. 9 (8) 2014 1213
statistically and significantly in the in vivo studies. Namely, the plasma concentration of warfarin in the experimental rats was elevated by 23% after the concomitant application with danshen ethyl acetate extract [32]. In addition, three cases of the possible interaction between danshen and warfarin were reported [33-36]. Based on a few case reports, it can be concluded that danshen could intensify the warfarin effect (elevated INR and prothrombin time), and if the co-medication is necessary, the patient should be under constant supervision.
Ginkgo biloba: At least 15 cases are documented with postoperative and spontaneous intracranial bleeding after self-medication with Ginkgo biloba (ginkgo). Subarachnoid hemorrhage and subdural hematomas after self-medication with ginkgo were also described in the literature [37-40]. Ginkgolide B, the active principle of ginkgo, which could interact with warfarin, was demonstrated to be a platelet aggregation inhibitor [41, 42]. However, the increased coagulation time, after the concomitant use of ginkgo leaf extract and warfarin, was proved in recent in vivo studies in mice to be the consequence of the bilobalides activity. Namely, bilobalides inhibited the microsomal enzymes CYP1A1 and CYP2C2 and warfarin metabolism [43]. According to the existing study results and the case reports, bleeding can be expected if ginkgo is administered together with warfarin.
Vaccinium: The interaction of cranberry juice with warfarin was reported in at least 12 cases to the Committee on Safety of Medicines of Great Britain by October 2004. The elevation of INR with or without bleeding was recorded in eight cases. The INR value was unstable in three cases, while in one case the INR level was decreased. The Committee recommended the patients, who were stabilized on warfarin, not to take cranberry juice. If cranberry juice had to be used for medical reasons, the patients should be under constant supervision [44]. Subsequently, the interaction between cranberry juice and warfarin was also reported in several cases by 2006 [45, 46]. Several more cases of the interaction after co-administration were reported from 2007 to 2011 [47-49]. The patients stabilized on warfarin experienced significant elevation of INR after the administration of cranberry juice in all cases. However, none of the randomized clinical studies confirmed the influence of cranberry juice on the pharmacological effect of warfarin. Namely, in two randomized placebo-controlled studies, involving 30 patients stabilized on warfarin, the patients consumed cranberry (genus Vaccinium) juice for two weeks. Neither statistically significant change of the INR value, nor warfarin concentration were registered in the control group compared with the placebo group [50, 51]. The reports of three more randomized placebo-controlled studies confirmed that cranberry did not affect either the pharmacokinetics or pharmacodynamics of warfarin. The INR value remained unchanged in the control group in comparison with the placebo when cranberry juice was administered in the dosage of 240 mL twice a day [52], 250 mL once a day [53] or cranberry extract tablets of 100 mg three times a day [54] in both groups, the patients stabilized on warfarin [52, 53] and the healthy volunteers [54]. Furthermore, there was no change in the plasma concentration of warfarin, the degree of binding to the plasma proteins, the platelet aggregation or the activity of coagulation factors II, VII and X; only a mild increment of the INR area under the curve at 90% significance level, which is rarely used, was recorded [53]. Although the existing clinical studies did not detect interactions between cranberry juice and warfarin, the patients stabilized on warfarin should not be treated with cranberry due to a number of the reported possible interactions after their concomitant use.
Allium sativum: In a double-blind placebo-controlled study of 60 volunteers with cerebrovascular risk factors and constantly increased platelet aggregation, it was demonstrated that the daily ingestion of 800 mg of powdered Allium sativum (garlic) in the form of coated tablets over 4 weeks led to a significant inhibition of the pathologically increased ratio of the circulating platelet aggregates and of spontaneous platelet aggregation. The normalized platelet aggregation was reached after a 4-week wash-out [55]. Additionally, two case reports indicated that an increased intake of garlic extract could cause spontaneous postoperative bleeding and the formation of hematomas [56, 57], which confirmed the findings of the in vitro conducted studies where garlic oil and its bioactive ingredient ajoene inhibited platelet aggregation induced by different aggregation agents [58, 59]. However, a possible interaction between garlic and warfarin was not reported in an open-label, randomized crossover clinical trial undertaken with 12 healthy male subjects who were pre-treated with enteric-coated garlic tablets, labelled to contain 2000 mg of fresh garlic bulb equivalent to 3.71 mg of allicin per tablet and then treated with a single dose of 25 mg warfarin [54]. The interaction, after the concomitant use of garlic and warfarin, was not detected in this study probably due to the treatment of the healthy male subjects with a single dose, while most of the patients had previously been stabilized on warfarin for a long-time period. Garlic should be avoided before surgery due to the probable inhibition of platelet aggregation.
Zingiber officinale: In a randomized, double-blind study, 1 g of Zingiber officinale (ginger), administered an hour before surgery, reduced postoperative nausea for 50%. In the same study, ginger had no effect on the prothrombin time after surgery [60]. In another study, 12 healthy male volunteers were pre-treated with ginger (capsules containing 0.4 g of pulverized ginger rhizome) for a week and then warfarin was administrated with either ginger capsules or placebo for seven days. The study indicated that a small recommended amount of ginger neither affected the pharmacodynamics nor the pharmacokinetics of warfarin. Namely, the percentage of warfarin bound to the plasma proteins, the highest plasma concentration, the maximum concentration time and the drug clearance remained unchanged after the concomitant use of the drug and ginger. The bleeding time was not significantly changed after ginger had been introduced in the therapy [61]. However, the study conducted with 20 healthy volunteers (5 g of ginger per day) reported a significant reduction of platelet aggregation in all volunteers [62]. Long and abundant use of ginger could affect platelet aggregation and might increase the bleeding time. Ginger (its active component gingerol) is a strong inhibitor of thromboxane synthetase. It is believed that ginger inhibits the synthesis of thromboxane A2 and stimulates the synthesis of prostacylins which negatively affect platelet aggregation [63]. Small doses of ginger do not affect warfarin activity, but a long and contemporaneous use of ginger in large amounts combined with warfarin should be avoided.
Angelica sinensis: Only one case report of the possible interaction of Angelica sinensis (dong quai or “female ginseng”) with warfarin was described in the literature [64]. Dong quai is rich in coumarins (psoralen, bergapten, osthole, phellopterin, scopoletin, angelols A-H) which are vitamin K antagonists. In addition, ferulic acid, which is a bioactive molecule, inhibits the platelet aggregation process and enhances the warfarin anticoagulant activity. These findings are consistent with the in vitro studies conducted on rabbits which indicated that dong quai did not affect the pharmacokinetics of warfarin, but significantly lowered the prothrombin time values 3 days after the co-treatment with a single dose of warfarin [65]. The possible interactions of dong quai and warfarin should be either accepted or rejected in further studies [66]. The constant monitoring
1214 Natural Product Communications Vol. 9 (8) 2014 Milić et al.
Table 1: Signs and symptoms of interactions between warfarin and medicinal herbs.
Herbal supplement Signs and symptoms Source
Alium sativum Inhibition of platelet aggregation Inhibition of platelet aggregation No effect on platelet aggregation Spontaneous postoperative bleeding
In vitro study [58,59] Clinical study [55]
Clinical study [54]
Case report [56,57] Angelica sinensis Increased INR and prothrombin time Case report [64]; In vitro studies [65]Boswellia serrata Increased INR and inhibition of metabolic pathway (CYP2C19, CYP3A4, CYP 2C9) Case reports [70] Camelia sinensis Decreased INR Case report [68] Gingko biloba Inhibition of platelet aggregation
Intracranial and postoperative bleeding, ecchimosis
In vitro studies [43]
Clinical study [41,42]
Case report [37-40] Hypericum perforatum Inhibition of metabolic pathway (CYP2D6, CYP3A4, CYP 2C9)
Decreased prothrombin time Decreased prothrombin time and inhibition of metabolic pathway (CYP1A2 and/or CYP3A4, CYP 2C9) Increased prothrombin time
In vitro study [27,28] Case reports [25, 26] Clinical study [18]
Case report [29] Lucium barbarum Increased INR Case reports [72-74] Matricaria chamomilla Increased INR and prothrombin time, ecchimosis Case report [71] Panax ginseng Inhibited platelet aggregation and prolonged coagulation time
No effect on warfarin activity Decreased INR and prothrombin time Decreased prothrombin time Increased prothrombin time, thrombosis
In vitro and in vivo studies [15-17] Clinical study [18, 22] Clinical study [19]
Clinical study [20, 21]
Case reports [23, 24] Salvia milthiorizza Inhibition of metabolic pathway
Increased INR and bleeding time In vitro and in vivo studies [32] Case reports [33-36]
Serenoa repens Increased bleeding time Case report [67] Tanacetum parthenium Inhibition of platelet aggregation
Stimulated platelet aggregation No effect on platelet aggregation
In vitro studies [75,76] In vitro studies [77,78] Clinical study [79]
Vaccinium No effect on warfarin concentration prothrombin time and INR Increased INR and prothrombin time, hempothysis, hemoathemesis
Clinical studies [50-54] Case report [43-49]
Zingiber officinale No effect on warfarin activity Decrement of platelets aggregation
Clinical studies [60, 61] Clinical study [62]
of the prothrombin time and the INR value are mandatory if warfarin and dong quai are co-medicated. Serenoa repens: A case of uncontrolled bleeding during surgery when the patient lost approximately two liters of blood was reported. The patient did not mention to his physician the continuous use of Serenoa repens (saw palmetto) for benign prostatic hyperplasia considering it to be natural and hence a safe product [67]. The use of saw palmetto in patients stabilized on warfarin is not recommended without clear medical indications. Camellia sinensis: A 44-year-old Caucasian male was stabilized on warfarin with an INR value of around 3.0, after mitral valve replacement. Twenty-two days after surgery, his INR decreased from a stable 3.0 to 1.37. The patient was drinking half a gallon of green tea (Camellia sinensis) per day [68]. The authors of this case report believed that the high content of vitamin K [69] in green tea, which is an antagonist of warfarin, reduced its anticoagulant effect. The long-term co-medication of warfarin and green tea should be carefully monitored. Boswellia serrata: Two cases of the interaction between Boswellia
serrata (boswellia) and warfarin were reported. In both patients the INR values were elevated. Boswellic acid might cause the interaction between boswellia and warfarin since it inhibits lipoxygenase and interferes with COX-1. Furthermore, boswellia could inhibit CYP2C19, CYP3A4 and CYP2C9, the isoenzymes responsible for warfarin metabolism, which emphasizes its anticoagulant activity [70]. Based on current findings, introduction of boswellia in patients stabilized on warfarin is not recommended. Matricaria chamomilla: Only one case of the interaction between Matricaria chamomilla (chamomile) and warfarin was reported. Chamomile contains coumarin derivatives, umbelliferone and herniarin, which have a synergistic activity with warfarin and cause an increment in prothrombin time [71]. The simultaneous usage of chamomile and warfarin should be avoided.
Lycium barbarum: The possible interaction between Lycium
barbarum (wolfberry, also called goji berry) and warfarin is postulated in three case reports [72-74]. The INR ratio was elevated in all three cases, and in one case [72] serious clinical symptoms of epistaxis, bruising and rectal bleeding were described. The authors of these studies assumed that the enhanced effect of warfarin was caused by metabolic interaction and the inhibition of CYP2C9 (S-warfarin pathway) which led to the slow degradation of the S-enantiomer. The co-application of warfarin and wolfberry is not recommended until further investigations confirm or deny possible interactions.
Tanacetum parthenium: Tanacetum parthenium (feverfew) neutralizes sulfhydryl groups and inhibits platelet activity [75, 76]. After feverfew extract was applied in the range of 5-50 µg/mL, the inhibition of eicosanoids was found to be irreversible and dose-effective. Feverfew contains sesquiterpene lactones which inhibit the arachidonic acid conversion into prostaglandins and leukotrienes thromboxane A2 (TXA2), a product of a cascade degradation of arachidonic acid which stimulates the activation of new platelets and increases platelet aggregation [77, 78]. However, in another study on humans, continuous and discontinuous application of a feverfew extract in a period of six months did not change the platelet aggregation [79]. Contradictory results were reported on possible interaction between feverfew and warfarin due to various active components of feverfew which possesses (anti)coagulant activity. Therefore, until the interaction between feverfew extract and warfarin is scientifically proved, the concomitant use should be prevented. The scientific evidence for the interactions of warfarin with medicinal herbs comes predominantly from in vitro studies, animal studies and individual case reports, while the clinical studies are rare and the meta-studies are not documented in the literature. The obtained results from the in vitro and in vivo studies cannot be extrapolated on humans and hence they cannot be used for a simple prediction of warfarin interaction with herbal supplements in humans. On other hand, the case reports show the side effects of
Warfarin interactions with medicinal herbs Natural Product Communications Vol. 9 (8) 2014 1215
drug-herb interactions, but cannot predict the prevalence of the interaction risks. Besides, specific factors, such as polypharmacy, co-morbidity or even patient’s lifestyle, can affect the findings described in the case reports. Additionally, unlike conventional drugs, herbal supplements before the registration for the market are not subjected to the same safety, efficacy, quality, impurity and residue controls. Nevertheless, allergens, pollens, spore or even the series of cultivated herbs can also cause adverse effects. New interactions between warfarin and medicinal herbs can be expected because of the widespread use of herbal supplement therapy and a small therapeutic index of warfarin. Each case report must be well documented, carefully evaluated and revised because such practice
can lead to further studies of possible interactions between warfarin and some bioactive molecules of medicinal herbs. Patients stabilized on warfarin are not recommended to be treated with herbal supplements. Co-administration of herbal supplements, when patients are stabilized on warfarin, should be carefully monitored. Acknowledgments - This work has been done within the project TR31029 "Functional products based on cereals for persons with metabolic disorders", funded by the Ministry of Education and Science of the Republic of Serbia.
References
[1] WHO Country Cooperation Strategy 2006-2011 - Supplement on Traditional Medicine. (2006) New Delhi, India, p. 1 [2] WHO Traditional Medicine Strategy 2002-2005. (2002) Document WHO/EDM/TRM/2002.1, WHO: Geneva, p. 11 [3] Drug and Therapeutics Bulletin (DTB) Survey on herbal medicines. (2010) Drug and Therapeutics Bulletin, 48, 6–47 [4] Breckenridge A. (1978) Oral anticoagulant drugs: pharmacokinetic aspects. Seminars in Hematology, 15, 19–26. [5] O’Reilly RA. (1976) Vitamin K and other oral anticoagulant drugs. Annual Review of Medicine, 27, 245–261. [6] Kelly JG, O’Malley K. (1979) Clinical pharmacokinetics of oral anticoagulants. Clinical Pharmacokinetics, 4, 1–15. [7] O’Reilly RA. (1986) Warfarin metabolism and drug-drug interactions. In: The New Dimensions of Warfarin Prophylaxis: Advances in
Experimental Medicine and Biology. Wessler S, Becker CG, Nemerson Y. (Eds). Plenum, New York. 205–212. [8] Wittkowsky AK. (2001) Drug interactions update: Drugs, herbs, and oral anticoagulation. Journal of Thrombosis and Thrombolysis, 12, 67–71. [9] Choonara IA, Malia RG, Haynes BP, Hay CR, Cholerton S, Breckenridge AM, Preston FE, Park BK. (1988) The relationship between inhibition of
vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin. British Journal of Clinical Pharmacology, 25, 1–7. [10] Malhotra OP, Nesheim ME, Mann KG. (1985) The kinetics of activation of normal and gamma carboxy glutamic acid deficient prothrombins. The
Journal of Biological Chemistry, 260, 279–287. [11] Borowski M, Furie BC, Bauminger S, Furie B. (1986) Prothrombin requires two sequential metal-dependent conformational transitions to bind
phospholipids: conformation-specific antibodies directed against the phospholipid-binding site on prothrombin. The Journal of Biological
Chemistry, 261, 14969–14975. [12] Ryan F, Byrne S, O’Shea S. (2008) Managing oral anticoagulant therapy: improving clinical outcomes. A review. Journal of Clinical Pharmacy
and Therapeutics, 33, 581-590. [13] Lane Ma, Devine ST, McDonald JR. (2012) High-risk antimicrobial prescriptions among ambulatory patients on warfarin. Journal of Clinical
Pharmacy and Therapeutics, 37, 157-160. [14] Xiang YZ, Shang HC, Gao XM, Zhang BL. (2008) A comparison of the ancient use of ginseng in traditional Chinese medicine with modern
pharmacological experiments and clinical trials. Phytotherapy Research, 22, 851–858. [15] Ang-Lee MK, Moss J, Yuan CS. (2001) Herbal medicines and perioperative care. Journal of the American Medical Association, 286, 208–216. [16] Park HJ, Lee JH, Song YB, Park KH. (1996) Effects of dietary supplementation of lipophilic fraction from Panax ginseng on cGMP and cAMP in
rat platelets and on blood coagulation. Biological & Pharmaceutical Bulletin, 19, 1434–1439. [17] Kimura Y, Okuda H, Arichi S. (1998) Effects of various ginseng saponins on 5-hydroxytryptamine release and aggregation in human platelets. The
Journal of Pharmacy and Pharmacology, 40, 838–843. [18] Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. (2004) Effect of St John’s wort and ginseng on
the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. British Journal of Clinical Pharmacology, 57, 592-599. [19] Yuan CS, Wei G, Dey L, Karrison T, Nahlik L, Maleckar S, Kasza K, Ang-Lee M, Moss J. (2004) Brief communication: American ginseng reduces
warfarin’s effect in healthy patients. A randomized controlled trial. Annals of Internal Medicine, 141, 23–27. [20] Lee YH, Lee BK, Choi YJ, Yoon IK, Chang BC, Gwak HS. (2010) Interaction between warfarin and Korean red ginseng in patients with cardiac
valve replacement. International Journal of Cardiology, 145, 275-276. [21] Wee JJ, Kim YS, Kyung JS, Song YB, Do JH, Kim DC, Sung DL. (2010) Identification of anticoagulant components in Korean red ginseng.
Journal of Ginseng Research, 34, 355-362. [22] Lee SH, Ahn YM, Ahn SY, Doo HK, Lee BC. (2008) Interaction between warfarin and Panax ginseng in ischemic stroke patients. The Journal of
Alternative and Complementary Medicine: Research on Paradigm, Practice, and Policy, 14, 715-721. [23] Turfan M, Tasal A, Ergun F, Ergelen M. (2012) A sudden rise in INR due to combination of Tribulus terrestris, Avena sativa, and Panax ginseng
(Clavis Panax). Archives of the Turkish Society of Cardiology, 40, 259-261. [24] Rosado MF. (2003) Thrombosis of a prosthetic aortic valve disclosing a hazardous interaction between warfarin and a commercial ginseng product.
Cardiology, 99, 111. [25] Ernst E. (1999) Second thoughts about safety of SJW. Lancet, 354, 2014–2016. [26] Yue QY, Bergquist C, Gerden B. (2000) Safety of St John's wort. Lancet, 355, 576–577. [27] Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. (2000) An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected
commercial herbal extracts and tinctures. Phytomedicine, 7, 273–282. [28] Obach RS. (2000) Inhibition of human cytochrome P450 enzymes by constituents of St. John’s Wort, an herbal preparation used in the treatment of
depression. The Journal of Pharmacology and Experimental Therapeutics, 294, 88–95. [29] Uygur Bayramıçlı O, Kalkay MN, Oskay Bozkaya E, Doğan Köse E, Iyıgün O, Görük M, Sezqin G. (2011) St. John’s wort (Hypericum
perforatum) and warfarin: Dangerous liaisons! The Turkish Journal of Gastroenterology, 22, 115. [30] Kent T. (1999) The saintly root of the problem. The Chemist and Druggist, 249, 22–26. [31] Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. (2002) St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes.
British Journal of Clinical Pharmacology, 54, 349–356. [32] Wu WP, Yeung JK. (2010) lnhibition of warfarin hydroxylation by major tanshinones of Danshen (Salvia miltiorrhiza) in the rat in vitro and in
vivo. Phytomedicine, 17, 219-226. [33] Yu CM, Chan JC, Sanderson JE. (1997) Chinese herbs and warfarin potentiation by danshen. Journal of Internal Medicine, 241, 337-339. [34] Izzat M. (1998) A taste of Chinese medicine. The Annals of Thoracic Surgery, 66, 941-942.
1216 Natural Product Communications Vol. 9 (8) 2014 Milić et al.
[35] Tam L ,Chan T, Leung W. (1995) Coumadin interactions with Chinese traditional medicines: danshen and methyl salicylate medicated oil. [Letter]. Australian and New Zealand Journal of Medicine, 25, 258.
[36] Chan TY. (2001) Interaction between warfarin and danshen (Salvia miltiorrhiza). The Annals of Pharmacotherapy, 35, 501-504. [37] Rowin J, Lewis SL. (1998) Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology, 46, 1775–1776. [38] Vale S. (1998) Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet, 352, 36. [39] Bent S, Goldberg H, Padula A, Avins A. (2005) Spontaneous bleeding associated with Ginkgo biloba a case report and systematic review of the
literature. Journal of General Internal Medicine, 20, 657-661. [40] Matthews MK Jr. (1998) Association of Ginkgo biloba with intracerebral hemorrhage. Neurology, 50, 1933–1934. [41] Chung KF, Dent G, McCusker M, Guinot P, Page CP, Barnes PJ. (1987) Effect of a ginkgolide mixture (BN 52063) in antagonising skin and
platelet responses to platelet activating factor in man. Lancet, 1, 248–251. [42] Lamant V, Mauco G, Braquet P, Chap H, Douste-Blazy L. (1987) Inhibition of the metabolism of platelet activating factor (PAF-acether) by three
specific antagonists from Ginkgo biloba. Biochemical Pharmacology, 36, 2749–2752. [43] Taki Y, Yokotani K, Yamada S, Shinozuka K, Kubota Y, Watanabe Y, Umegaki K. (2012) Ginkgo biloba extract attenuates warfarin-mediated
anticoagulation through induction of hepatic cytochrome P450 enzymes by bilobalide in mice. Phytomedicine, 2, 177-182. [44] Aston JL, Lodolce AE, Shapiro NL. (2006) Interaction between warfarin and cranberry juice: literature review. Pharmacotherapy, 26, 1314-1319. [45] Grant P. (2004) Warfarin and cranberry juice: an interaction? The Journal of Heart Valve Disease, 13, 25-26. [46] Rindone JP, Murphy TW. (2006) Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding. American Journal
of Therapeutics, 13, 283-284. [47] Paeng CH, Sprague M, Jackevicius CA. (2007) Interactions between warfarin and cranberry juice. Clinical Therapeutics, 29, 1730-1735. [48] Haber SL, Cauthon KA, Raney EC. (2012) Cranberry and warfarin interaction: a case report and review of the literature. The Consultant
Pharmacist: the Journal of the American Society of Consultant Pharmacists, 27, 58-65. [49] Hamann GL, Campbell JD, George CM. (2011) Warfarin-cranberry juice interaction. The Annals of Pharmacotherapy, 45, e17. [50] Ansell J, McDonoug M, Harmatz JS, Greenblatt DJ. (2008) A randomized double-blind trial of the interaction between cranberry juice and
warfarin. Journal of Thrombosis and Thrombolysis, 25, 112. [51] Ansell J, McDonough M, Zhao Y, Harmatz JS, Greenblatt DJ. (2009) The absence of an interaction between warfarin and cranberry juice: a
randomized, double-blind trial. Journal of Clinical Pharmacology, 49, 824-830. [52] Mellen CK, Ford M, Rindone J. (2010) Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients. British Journal of
Clinical Pharmacology, 7, 139-142. [53] Li Z, Seeram NP, Carpenter CL, Thames G, Minutti C, Bowerman S. (2006) Cranberry does not affect prothrombin time in male subjects on
warfarin. Journal of the American Dietetic Association, 106, 2057-2061. [54] Mohammed Abdul MI, Jiang X, Williams KM, Day RO, Roufogalis BD, Liauw W, Xu H, McLachlan AJ. (2008) Pharmacodynamic interaction of
warfarin with cranberry but not with garlic in healthy subjects. British Journal of Pharmacology, 154, 1691-1700. [55] Kiesewetter H, Jung F, Jung EM, Mrowietz C, Koscienly J. (1993) Effect of garlic on platelet aggregation in patients with increased risk of juvenile
ischaemic attack. European Journal of Clinical Pharmacology, 45, 333-336. [56] Burnham BE. (1995) Garlic as a possible risk for postoperative bleeding. Plastic and Reconstructive Surgery, 95, 213. [57] Rose KD, Croissant PD, Parliament CF, Levin MB. (1990) Spontaneous spinal epidural hematoma with associated platelet dysfunction from
excessive garlic ingestion: a case report. Neurosurgery, 26, 880-882. [58] Apitz-Castro R, Ledezma E, Escalante J, Jain MK. (1986) The molecular basis of the antiplatelet action of ajoene: direct interaction with the
fibrinogen receptor. Biochemical and Biophysical Research Communications, 141, 145–150. [59] Bordia A. (1978) Effect of garlic on human platelet aggregation in vitro. Atherosclerosis, 30, 355–360. [60] Phillips S, Ruggier R, Hutchinson SE. (1993) Zingiber officinale (ginger)-an antiemetic for day case surgery. Anaesthesia, 48, 715-717. [61] Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. (2005) Effect of ginkgo and ginger on the
pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. British Journal of Clinical Pharmacology, 59, 425-432. [62] Verma SK, Sinhg J, Khamesra R, Bordia A. (1993) Effect of ginger on platelet aggregation in man. The Indian Journal of Medical Research, 98,
240-242. [63] Backon J. (1986) Ginger: inhibition of thromboxane synthetase and stimulation of prostacyclin: relevance for medicine and psychiatry. Medical
Hypotheses, 20, 271-278. [64] Page RL, Lawrence JD. (1999) Potentiation of warfarin by dong quai. Pharmacotherapy, 19, 870-876. [65] Lo AC, Chan K, Yeung JH, Woo KS. (1995) Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin
in rabbits. European Journal of Drug Metabolism and Pharmacokinetics, 20, 55-60. [66] Cheng B, Hung CT, Chiu W. (2002) Herbal medicines and anaesthesia. Hong Kong Medical Journal, 8, 123-130. [67] Cheema P, El-Mefty O, Jazeih AR. (2001) Intraoperative haemorrhage associated with the use of extract of Saw Palmetto herb: a case report and
review of literature. Journal of Internal Medicine, 250, 167-169. [68] Taylor JR, Wilt VM. (1999) Probable antagonism of warfarin by green tea. The Annals of Pharmacotherapy, 33, 426-428. [69] Schneider C, Segre T. (2009) Green tea: potential health benefits. American Family Physician, 78, 591-594. [70] Paoletti A, Gallo E, Benemei S, Vietri M, Lapi F, Volpi R, Menniti-Ippolito F, Gori L, Muggelli A, Firenzuoli F. (2011) Interactions between
natural health products and oral anticoagulants: spontaneous reports in the Italian surveillance system of natural health products. Evidence-
based Complementary and Alternative Medicine 2011:ID612150. [71] Segal R, Pilote L. (2006) Warfarin interactions with Matricaria chamomilla. CMAJ: Canadian Medical Association Journal, 174, 1281-1282. [72] Lam AY, Elmer GW, Mohutsky MA. (2001) Possible interaction between warfarin and Lycium barbarum L. The Annals of Pharmacotherapy, 35,
1199-1201. [73] Leung H, Hung A, Hui ACF, Chan TYK. (2008) Warfarin overdose due to possible effects of Lycium barbarum L. Food and Chemical Toxicology,
46, 1860-1862. [74] Rivera CA, Ferro CL, Bursua AJ, Gerber BS. (2012) Probable interaction between Lycium barbarum (Goji) and warfarin. Pharmacotherapy, doi:
10.1002/PHAR.1018. [Epub ahead of print] [75] Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. (1987) Extracts of feverfew may inhibit platelet behavior via neutralization of
sulphydryl groups. The Journal of Pharmacy and Pharmacology, 39, 459-465. [76] Makheja AN, Bailey J. (1981) The active principle in feverfew [letter]. Lancet, 2, 1054. [77] Sumner H, Salan U, Knight DW, Hoult JR. (1992) Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew: involvement of
sesquiterpene lactones and other components. Biochemical Pharmacology, 43, 2313-2320. [78] Gorenewegen WA, Heptininstall S. (1990) A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on
platelet activity in vitro. The Journal of Pharmacy and Pharmacology, 42, 553-557. [79] Biggs MJ, Johnson EW, Persaud NP, Ratcliffe DM. (1982) Platelet aggregation in patients using feverfew for migraine [letter]. Lancet, 2, 776.
Natural Product Communications Vol. 9 (8) 2014 Published online (www.naturalproduct.us)
Evaluation of Anti-melanoma Activities of (1S,2E,4R,6E,8R,11S,12R)-8,12-epoxy-2,6-cembradiene-4,11-diol,
(1S,2E,4R,6E,8S,11R,12S)-8,11-epoxy-4,12-epoxy-2,6-cembradiene and (1S,4R,13S)-cembra-2E,7E,11E-trien-4,13-diol from
the Red Sea soft coral Sarcophyton glaucum
Pawel T. Szymanski, Safwat A. Ahmed, Mohamed M. Radwan, Sherief I. Khalifa and Hesham Fahmy 1143
Spiculisporic Acid E, a New Spiculisporic Acid Derivative and Ergosterol Derivatives from the Marine-Sponge Associated
Fungus Talaromyces trachyspermus (KUFA 0021) Decha Kumla, Tida Dethoup, Suradet Buttachon, Narong Singburaudom, Artur M.S. Silva and Anake Kijjoa 1147
Chemical Composition of Bioactive Alkaloid Extracts from Some Narcissus Species and Varieties and their Biological Activity Jana Havlasová, Marcela Šafratová, Tomáš Siatka, Šárka Štěpánková, Zdeněk Novák, Miroslav Ločárek, Lubomír Opletal, Martina Hrabinová, Daniel Jun, Nina Benešová, Jiří Kuneš and Lucie Cahlíková 1151
Quantititative Determination of Lycorine and Galanthamine in Galanthus trojanus and G. cilicicus by HPLC-DAD Gulen Irem Kaya, Derya Cicek Polat, Buket Sarikaya, Mustafa Ali Onur and Nehir Unver Somer 1157
Anthranilic Acid Derivatives and Other Components from Ononis pusilla Lyes Khouni, Christophe Long, Hamada Haba, Nicolas Molinier and Mohammed Benkhaled 1159
Trigonelline Accumulation in Leaves of Panicum virgatum Seedlings Lauren M. Schwartz, Andrew J. Wood and David J. Gibson 1163
New Phenylpropanoid-Substituted Flavan-3-ols from Pu-er Ripe Tea Mu-Ke Tao, Min Xu, Hong-Tao Zhu, Rong-Rong Cheng, Dong Wang, Chong-Ren Yang and Ying-Jun Zhang 1167
Parvisides A and B, New Glucosides from Galinsoga parviflora
Nighat Afza, Abdul Malik, Shazia Yasmeen, Muhammad Irfan Ali, Sadia Ferheen and Rasool Bakhsh Tareen 1171
Structure Activity Relationships of Flavonoids as Potent -Amylase Inhibitors Erdong Yuan, Benguo Liu, Qingyi Wei, Jiguo Yang, Lei Chen and Qiong Li 1173
Two New Anxiolytic Phenanthrenes Found in the Medullae of Juncus effusus Yang Wang, Gui-Yun Li, Qian Fu, Tai-Sen Hao, Jian-Mei Huang and Hai-Feng Zhai 1177
A New Depside from Usnea aciculifera Growing in Vietnam Tuong L. Truong, Vo T. Nga, Duong T. Huy, Huynh B. L. Chi and Nguyen K. P. Phung 1179
Chemical Analysis of Volatile Oils from West Himalayan Pindrow Fir Abies pindrow Rajendra C. Padalia, Ram S. Verma, Amit Chauhan, Prakash Goswami and Chandan S. Chanotiya 1181
Characterization of Volatiles of Necrotic Stenocereus thurberi and Opuntia littoralis and Toxicity and Olfactory
Preference of Drosophila melanogster, D. mojavensis wrigleyi, and D. mojavensis sonorensis to Necrotic Cactus Volatiles Cynthia R. Wright and William N. Setzer 1185
Accounts/Reviews
Cytotoxicity Studies of Lycorine Alkaloids of the Amaryllidaceae Jerald J. Nair and Johannes van Staden 1193
Warfarin Interactions with Medicinal Herbs Nataša Milić, Nataša Milošević, Svetlana Goločorbin Kon, Teodora Božić, Ludovico Abenavoli and Francesca Borrelli 1211
Acemannan, an Extracted Polysaccharide from Aloe vera: A Literature Review Gerardo Daniel Sierra-García, Rocío Castro-Ríos, Azucena González-Horta, Jorge Lara-Arias and Abelardo Chávez-Montes 1217
Natural Product Communications
2014 Volume 9, Number 8
Contents
Articles dedicated to Prof. Josep Coll Toledano on the Occasion of his 70th
Birthday
Original Paper Page
Sesquiterpene Hydrocarbons from the Liverwort Treubia isignensis var. isignensis with Chemotaxonomic Significance Paul Coulerie, Mohammed Nour, Louis Thouvenot and Yoshinori Asakawa 1059
Microbial Transformation of the Diterpene 7-epi-Foliol by Fusarium fujikuroi
Braulio M. Fraga, Carlo Bressa, Pedro González and Ricardo Guillermo 1061
1H and 13C NMR Analysis of the neo-Clerodane Diterpenoid Scutecyprin Plamen N. Penchev, Stefka R. Nachkova, Tonka A. Vasileva and Petko I. Bozov 1065
Ecdysteroid Profiles of Two Ajuga species, A. iva and A. remota
Ahmed Bakrim, Johnpeter Ngunjiri, Sophie Crouzet, Louis Guibout, Christine Balducci, Jean-Pierre Girault and René Lafont 1069
Antiparasitic Indole Alkaloids from Aspidosperma desmanthum and A. spruceanum from the Peruvian Amazonia Matías Reina, Lastenia Ruiz-Mesia, Wilfredo Ruiz-Mesia, Frida Enriqueta Sosa-Amay, Leonor Arevalo-Encinas, Azucena González-Coloma and Rafael Martínez-Díaz 1075
Analysis of Bioactive Amaryllidaceae Alkaloid Profiles in Lycoris Species by GC-MS Ying Guo, Natalia B. Pigni, Yuhong Zheng, Jean Paulo de Andrade, Laura Torras-Claveria, Warley de Souza Borges, Francesc Viladomat, Carles Codina and Jaume Bastida 1081
Mechanistic Studies on the Intramolecular Cyclization of O-Tosyl Phytosphingosines to Jaspines Ramón Crehuet, David Mormeneo, Josep M. Anglada and Antonio Delgado 1087
Chemistry and Biological Activity of Coumarins at Molecular Level Hugo A. Garro, Celina García, Víctor S. Martín, Carlos E. Tonn and Carlos R. Pungitore 1091
Chemoenzymatic Solvent-free Synthesis of 1-Monopalmitin Using a Microwave Reactor Rubén Torregrosa, Mercé Balcells, Mercé Torres and Ramon Canela-Garayoa 1095
EAG Responses Increase of Spodoptera littoralis Antennae after a Single Pheromone Pulse Carmen Quero, Berta Vidal and Angel Guerrero 1099
Cuticular and Internal Chemical Composition of Biting Midges Culicoides spp. (Diptera: Ceratopogonidae),
Potential Vectors of Viral Diseases Mikel González, Sergio López, Gloria Rosell, Arturo Goldarazena and Angel Guerrero 1103
Valorization of Essential Oils from Moroccan Aromatic Plants Omar Santana, María Fe Andrés, Jesús Sanz, Naima Errahmani, Lamiri Abdeslam and Azucena González-Coloma 1109
A List of and Some Comments about the Trail Pheromones of Ants Xim Cerdá, Louise van Oudenhove, Carlos Bernstei and Raphaël R. Boulay 1115
----------------
New Pseudoguaiane Derivatives from Inula aschersoniana Janka var. aschersoniana Antoaneta Trendafilova, Milka Todorova, Viktoriya Genova, Pavletta Shestakova, Dimitar Dimitrov, Milka Jadranin and Slobodan Milosavljevic 1123
A New Sesquiterpene Glucoside from Lysionotus pauciflorus
Yaya Wen, Hongjian Du, Yanbei Tu, Wei Luo, Qin Li, Yanfang Li and Bing Liang 1125
Two New Labdane-type Diterpenes from the Wood of Cunninghamia konishii Chi-I Chang, Yen-Cheng Li, Che-Yi Chao, Sheng-Yang Wang, Hsun-Shuo Chang, Louis Kuoping Chao, Chang Syun Yang and Yueh-Hsiung Kuo 1127
Antibacterial activity of Taxodium ascendens Diterpenes against Methicillin-resistant Staphylococcus aureus Courtney M. Starks, Vanessa L. Norman, Russell B. Williams, Matt G. Goering, Stephanie M. Rice, Mark O’Neil-Johnson and Gary R. Eldridge 1129
Use of Circular Dichroism to Determine the Absolute Configuration of a Pimarane Diterpenoid from the Southern
African Sclerocroton integerrimus (Euphorbiaceae) Vuyelwa J. Tembu, Moses K. Langat, Neil R. Crouch and Dulcie A. Mulholland 1131
Isolation and Structure Elucidation of Rebaudioside D2 from Bioconversion Reaction of Rebaudioside A to Rebaudioside D Indra Prakash, Cynthia Bunders, Krishna P. Devkota, Romila D. Charan, Catherine Ramirez, Maunik Parikh and Avetik Markosyan 1135
2-Acetoxyverecynarmin C, a New Briarane COX Inhibitory Diterpenoid from Pennatula aculeata
Anu Bahl, Sanjay M. Jachak, Kishneth Palaniveloo, Tulasiramanan Ramachandram, Charles S. Vairappan and Harish K. Chopra 1139
Continued inside backcover
