Giordana Ferraris e Deborah De Maio
INTRODUCTION
The English word ginseng derives from the Chinese term rénshēn. Rén means "Person" and shēn means "plant root"; this refers to the root's characteristic forked shape, which resembles the legs of a person. The English pronunciation derives from a southern Chinese reading, similar to Cantonese yun sum and the Hokkien pronunciation "jîn-sim".
Ginseng is any one of the 11 species of slow-growing perennial plants with fleshy roots, belonging to the genus Panax of the family Araliaceae.
Ginseng is found in North America and in eastern Asia (mostly Korea, northeast China, Bhutan, eastern Siberia), typically in cooler climates. Panax vietnamensis, discovered in Vietnam, is the southernmost ginseng known. Ginseng is characterized by the presence of ginsenosides and gintonin.
In 2010, nearly all of the world's 80,000 tons of ginseng in international commerce was produced in four countries: South Korea, China, Canada, and the United States. Sales exceeded $2.1 billion, half of which came from South Korea. Historically, Korea has been the largest provider, and China the largest consumer. Control over the ginseng fields was an issue in the 16th century.
In this article we will speak about the interaction between this energy drink and Warfarin.
Warfarin is a vitamin K antagonist, which is the most widely used oral anticoagulant drug. Because of its narrow therapeutic index, predisposition to drug and food interactions, and propensity to cause hemorrhage, warfarin requires continuous patient monitoring and education.
CHEMICAL COMPOSITION OF GINSENOSIDES AND GINTONIC
Ginsenosides or panaxosides are a class of natural product steroid glycosides and triterpene saponins. Compounds in this family are found almost exclusively in the plant genus Panax (ginseng), which has a long history of use in traditional medicine that has led to the study of pharmacological effects of ginseng compounds. As a class, ginsenosides exhibit a large variety of subtle and difficult-to-characterize biological effects when studied in isolation.
Ginsenosides can be isolated from various parts of the plant, though typically from the roots, and can be purified by column chromatography. The chemical profiles of Panax species are distinct; although Asian ginseng, Panax ginseng, has been most widely studied due to its use in traditional Chinese medicine, there are ginsenosides unique to American ginseng (Panax quinquefolius) and Japanese ginseng (Panax japonicus). Ginsenoside content also varies significantly due to environmental effects.
Ginsenosides can be broadly divided into two groups based on the carbon skeletons of their aglycones: the four-ring dammarane family, which contains the majority of known ginsenosides, and the oleanane family. The dammaranes can be further subdivided into two main groups, the protopanaxadiols and protopanaxatriols, with other smaller groups such as the ocotillol-type pseudoginsenoside F11 and its derivatives.
Oleanane family
Four-ring dammarane family
The biosynthetic pathway of ginsenosides is not entirely characterized, though as steroids they derive from pathways that lead to the synthesis of isoprene units. A proposed pathway converts squalene to 2,3-oxidosqualene via the action of squalene epoxidase, at which point dammaranes can be synthesized through dammarenediol synthase, oleananes through beta-amyrin synthase, and another class of molecules, the phytosterols, through cycloartenol synthase. Ginsenosides likely serve as mechanisms for plant defense.
Gintonin is a glycolipoprotein fraction isolated from ginseng. The non-saponin ingredient was designated as gintonin, where “gin” was derived from ginseng, “ton” from the tonic effects of ginseng, and “in” from protein. The main component of gintonin is a complex of lysophosphatidic acids (LPA) and proteins.
Gintonin molecular
Lysophospholipid receptors are the high affinity and selective target receptor of gintonin. Gintonin induces [Ca2+] transient in animal cells. Gintonin also shows in vivo antimetastatic effect by inhibition of autotaxin activity.
Ginseng is generally consumed orally as a dietary supplement, and thus its component ginsenosides may be metabolized by gut flora. This process is known to vary significantly between individuals. In some cases the metabolites of ginsenosides may be the biologically active compounds.
Most studies of the biological effects of ginsenosides have been in cell culture or animal models and thus their relevance to human biology is unknown. Effects on the cardiovascular system, the central nervous system and the immune system have been reported, primarily in rodents. Antiproliferative effects have also been described. Two broad mechanisms of action have been suggested for ginsenoside activity, based on their similarity to steroid hormones. They are amphiphilic and may interact with and change the properties of cell membranes. Some ginsenosides have also been shown to be partial agonists of steroid hormone receptors. It is not known how these mechanisms yield the reported biological effects of ginsenosides. The molecules as a class have low bioavailability due to both metabolism and poor intestinal absorption.
CHEMICAL COMPOSITION OF WARFARIN
The succinct synthesis of warfarin starts with condensation of ortho-hydroxyacetophenone (1–2) with ethyl carbonate to give the b-ketoester as the intermediate shown in the enol form. Attack of the phenoxide on the ester grouping leads to cyclization and formation of the coumarin. Conjugate addition of the anion from that product to methyl styryl ketone gives the corresponding Michael adduct and thus warfarin.
Synthesis of warfarin
The mechanism of action of warfarin is due to its ability to antagonize the functions of vitamin K. Various coagulation factors (prothrombin and factors VII, IX and X) in order to become active have to undergo post-translational modifications which consist in carboxylation of certain glutamic acid residues, in order to generate the acid γ-carboxyglutamic. During decarboxylation process of vitamin K, which fixes and then transfers the CO2 molecule, is converted in epoxide vitamin K which is then converted back to the previous form by epoxide vitamin K reductase. This enzyme is the target of the action of warfarin, which determines the inhibition.
In order to obtain the anticoagulant effects of the drug, it is necessary that the pool of vitamin K is largely converted into epoxide. Only then, in fact, the factors of coagulation products will not be made active and will not be able to exert its action. Also some coagulation factors have a half-life of a few days: you will have to wait to be consumed naturally or degraded to achieve a pharmacological complete. It is for these reasons that the effects of the drug begin to appear after 8-12 hours after ingestion and reach their maximum effect after 48-72 hours.
Warfarin is presented as two enantiomers (S and R), the first of which presents a greater anticoagulant activity than the second. The two enantiomers are metabolized by two different cytochromes: CYP2C9 is in charge of S-warfarin, the CYP3A4 is responsible for the R. These isoenzymes determine the production of inactive metabolites that are conjugated with glucuronic acid in the liver and eliminated in faeces and urine.
INTERACTION
Ginseng is an energy drink very used in people. So it’s important to know the interaction between this drink and drugs that people take. There are some studies about this issue.
The first one is a case report conducted by Katherine Janetzky and Anthony P. Morreale in 1997.
In this study the authors examine a 47-year-old man with a St. Jude-type mechanical heart valve in the aortic position, who had received anticoagulation therapy with warfarin since 1990 to prevent embolic events. He had a history of hypertension, angina, and osteoarthritis. Other medications included diltiazem hydrochloride 30 mg three times daily, nitroglycerin as needed for chest pain, and salsalate 500 mg three times daily as needed. He had taken diltiazem since July 1988, nitroglycerin as needed since 1990, and salsalate as needed since 1992. The dosage of warfarin sodium had remained 5 mg/day (7.5 mg each Tuesday). The International Normalized Ratio (INR) had ranged from 3.0 to 4.0 (goal, 2.5–3.5) for the past nine months; INR was measured every two to seven weeks. In February 1995 the patient started taking ginseng capsules (Ginsana) three times daily in an effort to boost his “energy level”. His INR was 3.1 four weeks before he started taking ginseng. Two weeks after the patient started taking ginseng, his INR declined to 1.5. Ginseng was discontinued, and the INR returned to 3.3 in two weeks. The patient denied changing his drug regimen during this period and said his dietary vitamin K content had been consistent and his compliance with all of his medications good.
The study conducted by Yeon Hong Lee, Byung Koo Lee, Yoon Jung Choi, In Kyung Yoon, Byung Chul Chang, Hye Sun Gwak in 2009 reports different results.
Many patients, who undertook cardiac valve replacement with anticoagulation therapy, desire to take Korean red ginseng. Although many studies have examined interactions between warfarin and ginseng or other herbal supplements, there is no information about the interaction between warfarin and Korean red ginseng. The objective of this study was, therefore, to determine whether an interaction exists between warfarin and Korean red ginseng. The correlation between INR and warfarin concentrations or weekly doses was also ass assessed. One group initially received warfarin with 1 g of Korean red ginseng extract for 6 weeks and then after a 3-week washout period, received warfarin and placebo (Treatment A). Alternative group received treatment in the opposite order (Treatment B). Blood samples were collected to measure INR and plasma warfarin levels.
The primary outcome was the change of INR at 3 and 6 weeks. The secondary outcome was the correlation between INR and warfarin concentrations or weekly doses. Warfarin concentration was analyzed by a validated HPLC method. The changes in INR and warfarin concentration after administration of placebo and Korean red ginseng were evaluated by using Wilcoxon signed ranks test. Correlation between INR and warfarin concentrations or weekly doses was assessed using Pearson correlation coefficient.
There was a statistically significant correlation between warfarin dose and racemic warfarin concentration on the 3rd (r= 0.56, P= 0.0001) and 6th weeks (r= 0.68, Pb0.0001) of study period. However, significant correlation was not found between warfarin dose and concentration of each enantiomer. INR was not correlated with either warfarin dose or warfarin (racemic, S- and R-warfarin) concentration.
There are some reports that Korean red ginseng strongly inhibits the synthesis of thromboxane A2 in the aggregation of human platelets induced by thrombin in vitro, and has potent antithrombotic effect in vivo. Moreover, Korean red ginseng is known to have a significant protective effect on artery thrombosis in vivo and blood circulation in humans. These results indicate that Korean red ginseng has potential to prevent thrombotic and cardiovascular disease, which may be due to antiplatelet rather than anticoagulation activity. In this study, Korean red ginseng did not enhance the anticoagulation effect. Even though it was not statistically significant, mean INR was rather reduced by co-administration with Korean red ginseng. Further study is needed to analyze vitamin K content in Korean red ginseng. This study is the first study which investigated practical interactions between Korean red ginseng and warfarin. Based on the results, it was concluded that Korean red ginseng could be used with close monitoring and under appropriate education in patients who take warfarin. Considering that patients could take higher amount of Korean red ginseng with warfarin concomitantly, the effects of Korean red ginseng intake amount on the warfarin response have to be studied further.
This two studies demonstrate that there isn’t an accord in scientific literature about the interaction between ginseng and warfarin. More studies have to be conducted.
MEDICAL USES
The root is most often available in dried form, either whole or sliced. Ginseng leaf, although not as highly prized, is sometimes used too. Folk medicine attributes various benefits to oral use of American ginseng and Asian ginseng (P. ginseng) roots, including roles as an aphrodisiac, stimulant, type II diabetes treatment, or cure for sexual dysfunction in men.
Ginseng may be included in small doses in energy drinks or herbal teas, such as ginseng coffee. It may be found in hair tonics and cosmetic preparations, as well, but those uses have not been shown to be clinically effective.
Ginsenosides, unique compounds of the Panax species, are under basic and clinical research to investigate their potential for use in medicine. Research has also been conducted into the effectiveness of ginseng when taken as a dietary supplement. There are not enough studies to reach definitive conclusions about its effectiveness for diabetes. There are not enough studies to draw definitive conclusions about whether ginseng affects erectile dysfunction.
CONCLUSIONS
Natural is a term of abuse, and it is not always synonymous with healthy. Infact, a common side effect of P. ginseng may be insomnia, but this effect is disputed. Other side effects can include nausea, diarrhea, headaches, nose bleeds, high blood pressure, low blood pressure, and breast pains.
