Perioperative Herbal Supplement Use in Cancer Patients: Potential Implications and Recommendations for Presurgical Screening

Nagi B. Kumar, PhD, RD, FADA; Kathy Allen, MA, RD; Heather Bell, MS, RD

Disclosures

Cancer Control. 2005;12(3):149-157. 

In This Article

Herbal Supplements That Modulate Coagulation in Cancer Patients

Garlic, ginger, ginkgo, and ginseng, known as the "4 Gs," are the most popular herbal supplements used by cancer patients that modulate coagulation. Other herbal supplements that have been demonstrated to interact with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are bromelain, cayenne, chamomile, feverfew, dong quai, eleuthero/Siberian, licorice, bilberry, turmeric, meadowsweet, and willow. Those containing coumarin (chamomile, motherwort, horse chestnut, fenugreek, and red clover) and tamarind enhance the risk of bleeding.

Garlic is the most extensively researched herbal remedy in the United States and elsewhere, although there is considerable variation in the nature of the research. The major putative active constituents of garlic contain sulfur. Intact cloves contain alliin, which is stable.When a clove is cut, the enzyme alliinase (a C-S lyase)[1] reacts with alliin to form various strong-odored compounds associated with garlic, including the thiosulfinate allicin. Thiosulfinates are highly reactive, consisting of two linked sulfur atoms with an oxygen molecule attached to one. They transform relatively quickly to other substances. Alliin is short-lived and can launch many derivatives, including a large number of related thiosulfinates. Three of the more widely studied stable metabolites are diallyl sulfide, diallyl disulfide, and S-allyl cysteine. Other stable metabolites include ajoene, methyl ajoene, vinyldithiins, diallyl trisulfide, and S-allyl mercaptocysteine. Additional sulfides include methyl allyl trisulfide, allyl propyl disulfide, and allyl mercaptan. In addition, garlic contains fructosans and saponins as potentially active substances.[15]

Garlic has been reported to have antithrombotic properties.[16,17] It contains inhibitors of adenosine deaminase and cyclic AMP phosphodiesterase, which could account for antithrombotic and vasodilatory actions. Ajoene, an antithrombotic substance, is present in small quantities in some forms of macerated garlic.[18] Ajoene [(E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide) is a potent antiplatelet compound isolated from alcoholic extracts of garlic (Allium sativum). Ajoene reversibly inhibits in vitro platelet aggregation as well as release reaction induced by all known agonists, suggesting that ajoene may be useful for the acute prevention of thrombus formation induced by vascular damage.[19] Garlic has antiplatelet aggregation properties in a dose-dependent manner. Aqueous extract of garlic inhibited aggregation induced by adenosine diphosphate, collagen, arachidonate, epinephrine, and calcium ionophore A23187 in a dose-dependent manner. Garlic appears to contain components that might exert their effects at various stages involved in the process of platelet aggregation.[20] In addition, serious hematologic side effects have been reported when garlic has been taken in conjunction with blood-thinning prescription drugs such as warfarin.[21] Garlic changes pharmacokinetic variables of paracetamol, decreases blood concentrations of warfarin, and produces hypoglycemia when taken with chlorpropamide.[21]

Although there have been no randomized, controlled clinical trials on the use of garlic supplements in the preoperative period to examine their effect on bleeding risk, the properties of the constituents and metabolites of garlic to potentially inhibit platelet aggregation and antithrombotic action warrant discontinuation of this herbal supplement prior to surgery. Since the half-life of elimination of garlic is 10 to 30 hours, the patient should discontinue supplementation for a minimum of 2 to 3 days prior to surgery to avoid bleeding and poor surgical wound healing in this potentially nutritionally compromised patient population.

Ginger is the rhizome part of the plant whose botanical name is Zingiber officinale. Its Chinese name is sheng jiang or shen jing. The plant is also known as Jamaica ginger, ingwer, gengibre, palu, shokyo, shoga, and other names in various cultures. Powdered ginger is the dried rhizome that contains 1% to 4% essential oil, but its composition varies considerably depending on the region where it is grown. Sesquiterpene hydrocarbons cause the characteristic ginger aroma. These compounds include (-)-zingiberene, (+)-ar-curcumene, (-)ß-sesquiphellan-drene, and ß-bisabolene. The active constituents in ginger are thought to be chemicals known as gingerols [1-(3′-methoxy-4′-hydroxyphenyl)-5-hydroxyalkan-3-ones] and shogaols, their dehydration products, which are responsible for the sharp taste of ginger.[22]

Ginger has been shown to act as a potent inhibitor of thromboxane synthetase, raising levels of prostacyclin without a concomitant rise in prostaglandin E2 or prostaglandin F2 alpha having implications in bleeding times.[23] Patients who are taking anticoagulant drugs or those who have blood coagulation disorders may be at risk if they are also taking ginger supplementation. On the other hand, ginger has been known for its antiemetic properties and has been demonstrated to be as effective as the drug droperidol in the prevention of postoperative nausea and vomiting after outpatient gynecologic surgery.[24] The effect of ginger on postoperative nausea and vomiting was reported to be equal to or better than that of metoclopramide,[25] with significantly fewer cases of postoperative nausea and vomiting in 60 patients taking ginger compared with those taking placebo.[26] However, a double-blind, randomized study[27] found that ginger did not prevent postsurgical nausea and vomiting. In examining the mechanism of action, it is likely that gin-ger's antinausea and antimotion sickness effects derive from its influence on gastric activity and do not involve the central nervous system.[22]

Since no pharmacokinetics (PK) trials on ginger supplementation have been completed yet, the elimination half-life of ginger is unavailable to make a recommendation for its discontinuation a specific number of days prior to surgery based on empirical evidence. However, with the known implications of ginger on coagulation, it would be prudent to discontinue supplements a minimum of 5 to 7 days prior to surgery.

Ginkgo biloba has been used for thousands of years in China and is widely used in Europe for the treatment of blood circulation disorders. It was the third best-selling herbal product in the US health food market in 1997.[28] The extract is obtained from the leaves of the Ginkgo biloba tree, also known as the maidenhair or kew tree, the oldest known living tree species. The active ingredients in Ginkgo biloba are believed to be two compounds -- flavone glycosides and terpene lactones -- found in the extracts of the whole leaf. Flavone glycosides include three separate bioflavonoids: quercetin (also present in certain vegetables such as red and yellow onion), kaempferol, and isorhamnetin. Terpene lactones are unique to ginkgo and have not been found in any other plant. The flavones act as antioxidants, and the terpene lactones (ginkgolides) inhibit blood clotting.[29]

Ginkgo contains compounds that act as anticoagulants, inhibiting platelet aggregation.[30,31] Long-term use has been associated with increased bleeding time and spontaneous hemorrhage and thus is contraindicated in patients taking prescription anticoagulants such as warfarin. The use of aspirin and NSAIDs combined with Ginkgo biloba extracts has been reported to cause bleeding into the brain and eyes.[32,33] Although the bleeding resolves after discontinuing the ginkgo usage, the combination of ginkgo with aspirin or any drug with anticoagulant action should be avoided during the perioperative period. Other ginkgo interactions include raised blood pressure when combined with a thiazide diuretic and coma when combined with trazodone.[21] Since no trials on the elimination half-life of ginkgo have been conducted, a recommendation to discontinue ginger supplementation prior to surgery lacks empirical evidence. However, with the known implications of ginkgo on coagulation, it would be prudent to discontinue supplements a minimum of 5 to 7 days prior to surgery.

Ginseng has been used for centuries in traditional Chinese medicine for diabetes and many conditions associated with aging, including reduced stamina and cognitive decline. The most commonly available and most popular varieties in the United States are the Chinese/Korean variety (Panax ginseng) and the American variety (Panax quinquefolium). The chief constituents responsible for the activity of ginseng are the ginsenosides or panaxocides. Chemical analysis indicates that there are at least four active compounds -- saponin glycoside, panaxin, panacene, and panaxic acid.[34,35]

Ginsenosides have been shown to inhibit platelet aggregation in vitro.[36,37] Animal studies have demonstrated that ginsenocides prolong coagulation times of thrombin and activated partial thromboplastin.[38] A few case reports suggest that ginseng increases bleeding time in subjects taking warfarin, but subsequent animal studies show no significant impact of ginseng on the pharmaco-kinetics/pharmacodynamics of warfarin when the two are concomitantly administered.[39] Yuan et al[40] recently reported that American ginseng administered to 20 patients for a 4-week period reduced the anticoagulant effects of warfarin. Ginseng has also been shown to raise blood pressure, and its use is contraindicated with estrogens or corticosteroids due to possible additive effects.[41] Ginseng has also been reported to cause headache, tremulousness, and manic episodes in patients treated with phenelzine sulfate.[21,41] Pharmacokinetics studies are currently limited to animal models, with elimination half-lives in rabbits ranging between 0.8 and 7.4 hours.[42] Therefore, recommendations to discontinue supplement use 24 hours prior to surgery are warranted.

In summary, the effect of herbal supplements taken perioperatively in wound healing has not been established in clinical trials. However, there is sufficient data that poor platelet aggregation can affect wound healing, as demonstrated in prospective studies in patients using anticoagulant therapies.[43,44] Currently, there are no studies examining the adverse effect of specific herbal supplements on wound healing. With the current knowledge of the pharmacokinetic properties of herbal supplements -- specifically, adverse effects such as inhibition of platelet aggregation -- these herbal supplements may modulate surgical wound healing. To avoid endangering this patient population, this issue would be better addressed in retrospective observations rather than prospective randomized trials.

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