Asian Journal of Drug Metabolism and Pharmacokinetics Paper ID 1608-2281-2004-0404-0261-24 Copyright by Hong Kong Medical Publisher Received June 19, 2004 ISSN 1608-2281 2004; 4(4):261-284 Accepted October 25, 2004

Information on research and application of Ginseng, the king of traditional and herbal medicines

Li-Qin Sun Liqin Sun Acupuncture and Herbs Clinic, 1720 S. San Gabril Blvd., Sulte 106, San Gabril, CA 91776, USA Abstract Ginseng, the root of Panax ginseng of the Araliaceae family, has been used in Oriental medicine since

ancient times as stimulant and tonic agents. In this review, The plant, chemistry, pharmacological effects, clinical pharmacology, adverse effects, drug iInteractions, and drug metabolism and pharmacokinetics and clinical application of Panax ginseng. The chemical constituents of ginseng root have been investigated since the beginning of the 20th century, and several classes of compounds have been isolated: triterpene saponins; essential oil-containing polyacetylenes and sesquiterpenes; polysaccharides; peptidoglycans; nitrogen-containing compounds; and various ubiquitous compounds such as fatty acids, carbohydrates, and phenolic compounds. 31 ginsenosides have been isolated from the roots of white and red ginseng. Polyacetylenes, mainly panaxytriol, panaxynol, and panaxydol, were isolated from ginseng. The chemical active compounds possess pharmacological activities such asstimulation of immunological function; effects on the cardiovascular system, for example, lowering blood pressure; effects on lipid metabolism shown by decreases in serum levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides and increases of serum level high-density lipoprotein cholesterol; effect on alcohol metabolism shown by the stimulation of alcohol dehydrogenase and the oxidation of alcohol in the liver; lowering of blood sugar levels; stimulation of the pituitary-adrenocortical system; and inhibition of tumor growth. Until recently, little was known about the absorption, distribution, excretion, and metabolism of ginseng saponins. Ginsenosides Rb1, Rb2, Rc, and Rd, were investigated for their inhibitory effects on hepatic CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Panax ginseng generally is well tolerated, and its adverse effects are mild and reversible. Panax ginseng may interact with caffeine to cause hypertension, and it may lower blood alcohol concentrations. It also may decrease the effectiveness of warfarin. Concomitant use of Panax ginseng and the monoamine oxidase inhibitor phenelzine may result in manic-like symptoms.

Key words ginseng; Panax ginseng; plant; chemistry; pharmacological effects; clinical pharmacology;

adverse effects; drug interactions; drug metabolism; pharmacokinetics; clinical application

Introduction

The genus name of ginseng "Panax" is derived

from the Greek pan (all) akos (cure), meaning "cure-all". This alone tells you a lot about this herb: no single herb can be considered a panacea but ginseng comes close to it. Ginseng is a tonic herb, or _____ Correspondence to Dr. Li-Qin Sun, Liqin Sun Acupuncture and

Herbs Clinic1720 S. San Gabril Blvd., Sulte 106, San Gabril, CA

91776, USA. E-mail: mfg3T@netzero. Net

an adaptogen that helps to improve overall health and restore the body to balance, and helps the body to heal by itself. Ginseng has been used for centuries to boost energy, sharpen the mind, reduce stress, treat impotence, and extend life. Other traditional uses include: to enhance the immune system, control blood pressure, regulate blood sugar levels, and stengthen the cardiovascular system. Ginseng is the most famous Asian herb, and has been in medicinal use for thousands of years. Materia Medica of Divine Plowman written in China about 2,000 years ago records ginseng as the highest quality herb. Ginseng

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has been used widely in Asia, Europe and America. The main active agents in Panax ginseng are

ginsenosides, which are triterpene saponins. The majority of published research on the medicinal activity of Panax ginseng has focused on ginsenosides. These are the compounds to which some ginseng products are now standardized. Research reviews 2,4 postulate that extracts of Panax ginseng affect the hypothalamus-pituitary-adrenal axis and the immune system, which could account for many of the documented effects. Animal models and in vitro studies mentioned in these reviews 2,4 indicate that Panax ginseng enhances phagocytosis, natural killer cell activity, and the production of interferon; improves physical and mental performance in mice and rats; causes vasodilation; increases resistance to exogenous stress factors; and affects hypoglycemic activity.

Ginseng, the root of Panax ginseng of the Araliaceae family, has been used in Oriental medicine since ancient times as a stimulant, tonic, diuretic, and digestive aid. In Europe, ginseng phytomedicines are sold over-the-counter and taken to increase physical and mental performance, to provide resistance to stress and disease, and to prevent exhaustion. In 1992, a review paper titled Recent advances in ginseng research in China was written by Professor Liu and Professor Xiao and published in Journal of Ethnopharemacology.[1] This paper summarized completely the advances of research and application of ginseng in China and appeared high cited frequency (more 100 cited times). In 2000, Modern Research and Application of Medicinal Plants edited by Professors Liu, Xiao and Li and published in Hong Kong Medical Publisher introduced systematically Ginseng.[2] In this review, the plant, chemistry, pharmacological effects, clinical pharmacology, adverse effects, drug interactions, and drug metabolism and pharmacokinetics and clinical application of Panax ginseng. Plant resources

Ginseng is a slow growing perennial herb (reaches about 2 feet tall) native to the mountainous area of north eastern China, Korea and far eastern regions of Russia. The older the root, the greater the concentration of ginsenosides, the active chemical compounds, thus the more potent the ginseng becomes. Ginseng roots can live longer than

hundreds of years. Ginseng has been cultivated extensively in China, Korea, and Japan, and Russia. Ginseng starts flowering in fourth year, and the roots take 4-6 years to reach maturity. The genus Panax includes many varieties of this small perennial herb. The common names of Panax ginseng include Oriental, Chinese, or Korean ginseng; Ginseng is a perennial aromatic herb with a short underground stem (rhizome) associated with a fleshy white root (Fig 1). Its root system consists of the primary root and its branches and of some adventitious roots developed from the rhizome

Fig 1. The ginseng plant (cited from reference 3)

Ginseng products are one of two kinds: white or red. The kind of product is determined by the process used to prepare it. White ginseng is the dried root, the skin of which is normally peeled off. Red ginseng is the steamed root, caramel-colored and resistant to the invasion of fungi and worms.

Panax quinquefolium is the strain that grows in North America. Herbal extracts of ginseng are prepared from the dried root and root hairs of the plant. Ginseng is a protected herb in China and Russia: exporting ginseng seeds is banned in China, and harvesting wild ginseng is illegal in Russia. Natural white ginseng is often steam- processed to produce "red ginseng" with different, higher medicinal potency. "Ginseng" refers to a wide spectrum of distinct species with different appearances and medicinal qualities and they grow or are cultivated in different geographical locations. 1. Panax ginseng (Asian ginseng): Often called Chinese or Korean ginseng, Panax ginseng represents the original, true ginseng with highest potency.

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Traditionally, Panax ginseng cultivated in Korea has been respected the most for its highest quality and potency, and was imported by China, Japan, and many other countries in Asia. 2. Panax quinquefolius (American ginseng): American ginseng is smaller than Asian ginseng, grows in North America and has been used by Native Americans to treat various ailments. Currently American ginseng is cultivated in Canada and US, the majority of which is exported to Asian countries. 3. Panax japonicus (Japanese ginseng): Often used by Japanese herbalists in place of Panax ginseng, Panax japonicus contains much less active ingredients (ginsenosides) than Panax ginseng, and is called a low-grade ginseng. 4. Eleutherococcus senticosus (Siberian ginseng): Although it belongs to the Araliaceae family, Siberian ginseng is not a true ginseng. Siberian ginseng is often sold as a cheaper, less potent alternative to Panax ginseng. 5. Panax notoginseng, or Panax pseudoginseng (Sanchi ginseng): Sanchi ginseng is quite different from Panax ginseng in potency, and has been used for different medicinal purposes such as hemostatic and pain relief, etc, by Chinese doctors. Panax pseudoginseng subspecies Himalaicus (Himalayan ginseng): Himalayans used this ginseng variant for people with low appetite and as a digestive aid. Medicinal potency is lower than Panax ginseng. 6. Panax trifolius (Dwarf ginseng): Panax trifolius is a rare variant of American ginseng, and grows in North America. Native Americans used Panax trifolius for headaches, cough, indigestion, and other ailments.

All of these species are in the Araliaceae plant family, but each has its own specific effects on the body. Ginseng products are popularly referred to as "tonics," a term that has been replaced by "adaptogens" in much of the alternative medicine literature. The term "adaptogen" connotes an agent that purportedly "increases resistance to physical, chemical, and biological stress and builds up general vitality, including the physical and mental capacity for work." Over-the-counter Panax ginseng products include Celestial Seasonings Ginseng, Centrum Herbals Ginseng, Korean Ginseng Extract from Nature's Way, Nature Made's Chinese Red Panax Ginseng, Pharmaton's Ginsana, and PhytoPharmica's Ginseng Phytosome.

Chemistry

The chemical constituents of ginseng root have been investigated since the beginning of the 20th century, and several classes of compounds have been isolated: triterpene saponins; essential oil-containing polyacetylenes and sesquiterpenes; polysaccharides; peptidoglycans; nitrogen-containing compounds; and various ubiquitous compounds such as fatty acids, carbohydrates, and phenolic compounds The biologically active constituents in Panax ginseng are the complex mixture of triterpene saponins known as ginsenosides, which are mainly triterpenoid dammarane derivatives. Ginsenosides Rx according to their mobility on thin-layer chromatography plates, with polarity decreasing from index "a" to "h" (Fig 2). The root contains 2-3% ginsenosides of which Rg1, Rc, Rd, Rb1, Rb2, and Rb0 are quantitatively the most important. At least 30 ginsenosides have been isolated and characterized. [2,3, 6]

Fig 2. Thin-layer chromatograms of the saponins of Panax

ginseng roots. The crude saponin fraction was analyzed on

a plate of silica gel 100F254 (Merck) with solvents as

indicated. (cited from Reference 4).

By applying various chemical and spectroscopic

methods, researchers have found that the genuine aglycones were protopanaxadiol and protopanaxatriol, which both have a dammarane skeleton. On acid treatment of protopanaxadiol and protopanaxatriol, a tertiary hydroxyl group attached to C-20 participates in ring closure with a double bond in the side chain (Fig 3). 31 ginsenosides have been isolated from the roots of white and red ginseng. They can be categorized in three groups depending on their aglycones: protopanaxadiol-type ginsenosides, protopanaxatriol-type ginsenosides, and oleanolic acid-type saponins. All dammarane ginsenosides

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isolated from ginseng root (white ginseng) are derivatives of the 20S protopanaxadiol (Table 1) and the 20S protopanaxatriol (Table 2), with the

exceptions of 20R ginsenoside Rg3 (9, 16), Rh4 (15), and koryoginsenoside R2.

Fig 3. The ginseng saponins have a protopanaxadiol and protopanaxatriol structure.

The panaxadiol and panaxatriol are artifacts of the hydrogenation of the actual structures.

Table 1 The ginseng saponins of protopanaxadiol

Saponin R1 R2

Rb1 Glc2-Glc Glc6-Glc

Rb2 Glc2-Glc Glc6-Ara(p)

Rc Glc2-Glc Glc6-Ara(f)

Rd Glc2-Glc -Glc

mRb1 Glc2-Glc6-Ma Glc6-Glc

mRb2 Glc2-Glc6-Ma Glc6-Ara(p)

mRc Glc2-Glc6-Ma Glc6-Ara(f)

Other diols include Ra1, Ra2, Ra3, Rb3, Rg3, Rh2, Rs1, Rs2, Q-R4, and mRd. All compounds are 20S， configuration except Rg3, which is a mixture of S and R. Rh2, Rs2, and NG-R4 are found only in， red ginseng, Glc, glucose; Ma, malonyl; Ara(p), arabinose in pyranose form, Ara(f), arabinose in furanose form.

Ginseng is specified in the German, Swiss, Austrian, and French pharmacopeias, among others. The Swiss pharmacopeia demands a total ginsenoside content, calculated as ginsenoside Rg1, of not less than 2.0%. According to the German pharmacopeia, the total ginsenoside content should be not less than 1.5%. Both pharmacopeias use a spectrophotometric method for quantification. However, a draft for the European pharmacopeia demands the content of

ginsenosides Rg1 and Rb1 to be not less than 0.3%, measured with an HPLC method. HPLC separations such as the one published by Samukawa and co-authors enable the separation of additional ginsenosides; 22 ginsenosides can be separated in a single run (Fig 4). Such methods are useful for the differentiation of white and red ginseng, for example, and for the detection of degradation products. However, they are not useful for a quantitative

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determination. As shown in the chromatograms in Fig5, malonyl ginsenosides occur only in white ginseng, whereas red ginseng shows additional peaks

for Rh1, 20R Rh1, 20R Rg2, Q-R1, Rs1, and 20S and 20R Rg3.

Table 2 The ginseng saponins of protopanaxatriol

Saponin R1 R2

Re -Glc2-Rha -Glc

Rf -Glc2-Glc -H

glc-Rc - Glc2-Glc -Glc

Rg1 -Glc -Glc

Rg2 -Glc2-Rha -H

Rh1 -Glc -H

NG-R1 -Glc2-Xyl -Glc All compounds have a 20S configuration except Rg2 and Rh1. The R forms of Rg2 and Rh1 may be produced during the production

process and are characteristic ginsenosides of red ginseng. Rha, rhamnose; Xyl, xylose.

Fig 4. An HPLC gradient elution chromatogram shows the differences

between red and white ginseng. (cited from Reference 5) The isolated polyacetylenes, mainly panaxytriol,

panaxynol, and panaxydol (Fig 5) show cytotoxic, antiplatelet, and anti-inflammatory effects, respectively. Experimental and clinical Pharmacology

The chemical constituents of ginseng that are believed to contribute to its pharmacological effects have been investigated extensively since 1955. The main activities for ginseng noted in the literature, in addition to use as a general tonic, werestimulation of immunological function; effects on the

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cardiovascular system, for example, lowering blood pressure; effects on lipid metabolism shown by decreases in serum levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides and increases of serum level high-density lipoprotein cholesterol; effect on alcohol metabolism shown by the stimulation of alcohol dehydrogenase and the oxidation of alcohol in the liver; lowering of blood

sugar levels; stimulation of the pituitary-adrenocortical system; and inhibition of tumor growth (Table 3). It has been claimed that Rg1 stimulates the central nervous system and enhances protein, DNA, and RNA synthesis, whereas Rb1 has tranquilizing effects on the central nervous system and improves memory.[6]

Fig 5. Polyacetylenes, Panaxytriol, panaxynol, and panaxydol, isolated from

ginseng have pharmacological effects (cited from reference 3)

Table 3. Effects claimed for ginseng

Activity Compounds responsible

Platelet inhibition Various ginsenosides (Ro, Rg1, and Rg2) and

polyacetylenes

Antioxidant Ginsenosides Rg1, Rb1

Tumor inhibition Polyacetylenes, polysaccharides, Rg3, Rh2

Cytoprotection Polysaccharides

Calcium channel inhibition Ginsenoside Rf

Immunomodulation Ginsenoside Rg1, polysaccharides

Neuroprotection Ginsenoside Rb1

The pharmacological actions of individual

ginsenosides may work in opposition. The main active components of Panax ginseng are ginsenosides, which are triterpene saponins. which have been shown to have a variety of beneficial effects, including anti-inflammatory, antioxidant, and anticancer effects. Results of clinical research studies demonstrate that Panax ginseng may improve psychologic function, immune function, and conditions associated with diabetes. Overall, Panax ginseng appears to be well tolerated, although caution is advised about concomitant use with some pharmaceuticals, such as warfarin, oral hypoglycemic

agents, insulin, and phenelzine. Panax ginseng does not appear to enhance physical performance. The two main ginsenosides Rb1 and Rg1 suppress and stimulate the central nervous system. These opposing actions may contribute to the adaptogenic properties of ginseng and its purported ability to balance bodily functions. Panax giseng contains a variety of other compounds as well as ginsenosides which are responsible for ginseng's complex pharmacological activities. Panacene is a peptidoglycan in ginseng with hypoglycemic activity; ginseng has a peptide with insulinomimetic properties; ginseng's salicylate and vanillic acids show anti-oxidant and anti-fatigue

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effects; ginseng possesses hormone-like and cholesterol-lowering capabilities; ginseng promotes vasodilation and act as an anxiolytic and anti-depressant; ginsaeng extracts and ginsenosides shows effectiveness in stimulating learning, memory, and physical capabilities, in supporting radioprotection, providing resistance to infection, enhancing energy metabolism, and reducing plasma total cholesterol and triglycerides while elevating HDL levels. Panax ginseng is used primarily to improve psychologic function, exercise performance, immune function, and conditions associated with diabetes. Traditional Chinese medicine and many current research studies often use products that combine ginseng with other herbal medicines or vitamins. Because of the use of combination products and the limitations of some studies on ginseng, e.g., poor methodologic quality, research focusing on healthy volunteers, small sample size, unstandardized ginseng preparations, varying doses, it is difficult to draw conclusions about some of the clinical effects of ginseng. Experimental and clinical pharmacological studies are very wide range and vast numbers. Here, we provide some recent information.

Effects on psychologic function

Trials investigating the effects of Panax ginseng on various psychologic parameters have shown positive effects, no effects, or both. In one study 9 of 112 healthy volunteers older than 40 years, the administration of 400 mg per day of the standardized ginseng product Gerimax for eight weeks resulted in better and faster simple reactions and abstract thinking, but no change in concentration, memory, or subjective experience. The results of two small studies, each including about 30 young, healthy volunteers who received 200 mg of G115 daily for eight weeks, showed improvement in certain psychomotor functions, such as better attention, processing, and auditory reaction time, social functioning, and mental health. However, some of the effects present at the fourth week disappeared by the eighth week.

A study of 384 postmenopausal women who were randomized to receive placebo or ginseng for 16 weeks showed improvements in three subsets of a Psychological General Well-Being index. In addition, a small study of 20 healthy young volunteers who

received a single 400-mg dose of ginseng found improvement in cognitive performance, secondary memory performance, speed of performing memory tasks, and accuracy of attentional tasks. However, another study showed no effect on positive affect, negative affect, or total mood disturbance in 83 young healthy volunteers who took 200 to 400 mg per day of G115 for eight weeks.

Effects on physical preformance

Most of the clinical studies investigating the value of Panax ginseng in enhancing physical performance have shown no clinical effect. One study

on the use of 200 mg per day of G115 in 19 healthy adult women showed no change in physical work performance, energy metabolic responses, or oxygen uptake. Similarly, a study of 31 healthy men who took 200 or 400 mg of G115 daily for eight weeks found no change in physiologic or psychologic responses to submaximal or maximal exercise.(Evidence level B, lower quality RCT). In another study, a different product standardized to 7 percent ginsenosides and administered at 200 mg per day was given to 28 healthy young adults for 21 days. No ergogenic effects were demonstrated, including no change in maximal oxygen consumption, exercise time, workload, plasma lactate level, hematocrit, or heart rate.

Effects on immune system

A study of 227 healthy volunteers demonstrated that daily administration of 100 mg of G115 for 12 weeks enhanced the efficacy of polyvalent influenza vaccine. The patients who received ginseng had a lower incidence of influenza and colds, higher antibody titers, and higher natural killer cell activity levels. Another study in 60 healthy volunteers showed enhanced chemotaxis, phagocytosis, increased total lymphocyte count, and increased numbers of T helper cells in those who received G115 in a dosage of 100 mg twice daily for eight weeks. In a study of 75 patients with acute exacerbation of chronic bronchitis who were treated with antibiotics or antibiotics plus ginseng, those in the ginseng group showed faster bacterial clearance.

Effects on diabetes

The effects of Panax ginseng, given in a dosage

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of 100 or 200 mg per day for eight weeks, were studied in 36 patients with newly diagnosed non-insulin-dependent diabetes. The study showed improved fasting blood glucose levels, elevated mood, and improved psychophysical performance on a numbered diagram test. The 200-mg dose also resulted in improved hemoglobin A 1C values.

Among more than 30 ginsenosides as the active ingredients of ginseng, ginsenosides Rb1 and Rg1 are regarded as the main compounds responsible for many pharmaceutical actions of ginseng. In one study, primary cultures from embryonic mouse mesencephala were exposed to neurotoxic glutamate concentration and potential protective effects of these two ginsenosides on survival and neuritic growth of dopaminergic cells were tested. Treatment of primary mesencephalic culture with 500µmol glutamate for 15 min on the 10th day in vitro (DIV) increased the release of lactate dehydrogenase (LDH) into the culture medium, the propidium iodide (PI) uptake by cultured cells and the total number of nuclei with condensed and fragmented chromatin (apoptotic features) as evaluated with Hoechst 33342. Moreover, it extensively decreased the number of tyrosine hydroxylase immunopositive (TH+) cells and adversely affected the length and number of their neuronal processes. The toxic effect of glutamate was primarily mediated by over-activation of N-methyl-D-aspartate receptor (NMDA) as treatment of cultured cells with (+)-MK 801, an NMDA receptor antagonist, nearly abolished dopaminergic cells loss and LDH release induced by glutamate. When either ginsenoside was added alone for six consecutive days (at final concentrations 0.1, 1, 10, 20 µmol), ginsenoside Rb1 (at 10 µmol) significantly enhanced the survival of dopaminergic neurons compared to untreated controls. In these cultures, neurite lengths and numbers were not affected by both ginsenosides. Against glutamate exposure, ginsenosides Rb1 and Rg1 could not prevent cell death. However when pre-treating for 4 days or post-treating for 2 days following glutamate exposure, they significantly increased the numbers and lengths of neurites of surviving dopaminergic cells. Thus our study indicates that ginsenosides Rb1 and Rg1 have a partial neurotrophic and neuroprotective role in dopaminergic cell culture.[7]

The present study used in vivo rat heart to investigate (1) whether Shen-Fu (SF), a traditional Chinese formulation comprising Radix Ginseng (RG)

and Radix Aconitum Carmichaeli (AC), is protective against myocardium damage due to ischemia-reperfusion injury, and (2) whether the cardioprotective effect of SF is related to scavenging of hydroxyl radicals. The model of ischemia-reperfusion injury was established by ligation of left anterior descending coronary artery for 60 minutes followed by reperfusion for 240 minutes in anesthetized rats. The size of infarction and the pathologic changes of myocardium were observed. Lactate dehydrogenase (LDH) and creatine kinase (CK) in serum, the amounts of malondialdehyde (MDA) and superoxide dismutase (SOD) in myocardium were measured at the end of the reperfusion period. Pretreatment groups with SF (10 mg·kg-1), RG (9 mg·kg-1) and AC (1 mg·kg-1) inhibited the rise in MDA and LDH as well as CK, increased SOD activity, reduced the size of infarction, and improved the pathologic changes of myocardium during ischemia-reperfusion compared with the control group. The effect of SF is better than that of RG and AC. These results indicate that SF, RG and AC protect obviously myocardium against damage due to ischemia-reperfusion in rats. The cardioprotective effect of SF injection may be in part related to scavenging of hydroxyl radicals or inhibition of lipid peroxidation. SF is more effective than its separated herbal extracts prepared from RG and AC.[8]

Generally, the originating area of ginseng is known to be in Shangdang, China. The originating time, which has been estimated according to textual and archeological outcomes, is known to be the first century B.C., during the Han dynasty era. This can be referred to as the 'Chinese origin theory of ginseng'. According to such hypothesis, the Chinese only discovered ginseng 'suddenly' during this time when it should have been self-generating for thousands of years before. However, Shangdang has been one of the historic centers of China since the ancient period and specially took prominence in terms of the beginning and development of Chinese pharmaceutics. Moreover, there were six characters that expressed at the early stage and were used together with each other up to the days of Ming and Qing dynasty. Also, this theory did not explain clearly about the formation of ginseng character. Hence, it is fairly obvious that the 'Chinese origin theory of ginseng' do not answer appropriately to the fundamental questions of the origin of ginseng. In

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order to approach such mystery , perspectives need to be newly shifted to the 'outer origins' of Chinese ginseng. In this case. 'outer' only points to Manchuria and Korea, since these areas are the only candidates regarding the natural circumstances of ginseng growth. So, it can be inferred that ginseng has first been identified with the locals of Manchuria and Korea, and then underwent influx to China to have been used as a medicinal stuff. Following such theory, the reason why ginseng suddenly appeared in Han China was that around this period, specially during the Han commandery epoch, it had just been introduced to China as a part of Korean culture. Also the reason there are many characters can be said that the sound of indigenous Korean 'sim' was considered in respect to selecting similarly-articulated words. Reaching such conclusion, the formating principle of can be no other than borrowing -sound character. To summarize our discussion, it is still unknown when was the actual origin of ginseng but it was far earlier than two thousand years ago as was previously accepted as the origin of this medicine plant. The originating place was not Shangdang of Shanxi area of China as was commonly accepted, but Manchuria and Korea. Then, ginseng must have been known and utilized by the locals of these areas. This is Korean origin theory of ginseng' and simultaneously an indirect examination of the origin of Korean ginseng.[9]

Ginsenosides, the main effective components of the root of Panax ginseng, have been reported to modulate morphine action. In the present study, ginsenosides Rd, Rb2, Rgl and Re were divided into two groups according to their effects in mice on morphine-induced hyperactivity and conditioned place preference (CPP). Ginsenosides Rd, Rb2, Rgl had no effect on morphine-induced hyperactivity, but antagonized morphine-induced CPP. On the contrary, ginsenoside Re increased morphine-induced hyperactivity whereas it showed no effect on morphine-induced CPP. Furthermore, Re antagonized the inhibitory effect of the mixture involving Rd, Rb2 and Rgl on the morphine action. These results suggest that ginsenosides with different structures have antagonizing properties in the regulation of morphine-induced reinforcement.[10]

Ginseng root is used extensively in traditional Chinese medicine for its alleged tonic effect and possible curative and restorative properties. There are increasing evidences in the literature on the potential

role of ginseng in treating cardiovascular diseases. We herein examine the history of ginseng usage and review the current literature on a myriad pharmacological function of ginseng on the cardiovascular system. From the published studies involving cell cultures and animal models, ginseng is shown to have potential benefits on the cardiovascular system through diverse mechanisms, including antioxidant, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitters release, improving lipid profiles, and involving in glucose metabolism and glycemic control. In addition, the relevant clinical trials regarding the effects of ginseng on the cardiovascular disease are summarized, particularly in managing hypertension and improving cardiovascular function. Finally, the controversies in the literature and the possible adverse interactions between ginseng and other drugs are discussed. This review underscores the potential benefit effects of ginseng on cardiovascular diseases, highlights the gaps in our current research, and emphasizes the necessity for more rigorous systemic investigation.[11]

Previously Kurimoto et al reported that oral application of red ginseng significantly ameliorated learning deficits in aged rats and young rats with hippocampal lesions. In the present study, we investigated the effects of the nonsaponin fraction of red ginseng on learning deficits in aged rats in behavioral studies and those on long-term potentiation (LTP) in the hippocampal CA3 subfield in young rats in electrophysiological studies. In the behavioral studies, three groups of rats [aged rats with and without oral administration of the nonsaponin fraction of red ginseng and young rats] were tested with the three types of spatial-learning task [distance movement task (DMT), random-reward place search task (RRPST), and place-learning task (PLT)] in a circular open field. The results in the DMT and RRPST indicated that motivational and motor activity was not significantly different among the three groups of rats. However, performance of the aged rats without nonsaponin was significantly impaired in the PLT when compared with the young rats. Treatment with nonsaponin significantly ameliorated deficits in place-navigation learning in the aged rats in the PLT. In the electrophysiological studies, effects of nonsaponin on the LTP in the CA3 subfield of the hippocampal slices were investigated in vitro. Pretreatment with nonsaponin significantly

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augmented the increase in population spike amplitudes in the CA3 subfield after LTP induction. These results suggest that the nonsaponin fraction of red ginseng contains important substances to improve learning and memory in aged rats and that this amelioration by nonsaponin might be attributed partly to augmentation of LTP in the CA3 subfield.[12]

Forty randomised trials, involving 3448 people were included. All trials were conducted and published in China, and the methodological quality was assessed as generally low. No trial had diagnosis of viral myocarditis confirmed histologically, and few trials attempted to establish viral aetiology for the myocarditis. Twenty-five different herbal medicines were tested in the included trials, which compared herbs with supportive therapy (17 trials), other controls (three trials), or treatment of herbs plus supportive therapy with supportive therapy alone (20 trials). The trials reported electrocardiogram, myocardial enzymes, cardiac function, symptoms, and adverse effects. Shenmai and Shengmai injection (Ginseng preparation) showed significantly effects on reducing myocardial enzymes and improving cardiac function. No serious adverse effect was reported. Some herbal medicines may have anti-arrhythmia effect in suspected viral myocarditis. However, interpretation of these findings should be careful due to the low methodological quality, small sample size, and limited number of trials on individual herbs. In the light of the findings, some herbal medicines deserve further examination in rigorous trials.[13]

Oxidative stress plays an important role in the pathological processes of neurodegenerative diseases. Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants, some of which may be neurotoxic. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) induces apoptotic death in human neuronal SK-N-MC cells, as demonstrated by gel electrophoresis, which demonstrates the proteolytic cleavage of beta-catenin and poly(ADP-ribose) polymerase (PARP) and the characteristic ladder patterns of DNA fragmentation. In the present study, we investigated whether Panax ginseng extract protect human neuronal SK-N-MC cells from PCB 52-induced apoptosis. The addition of 500 microg/ml of ginseng extract to a culture medium significantly protected neuronal cell from the apoptosis mediated by PCB 52 and remarkably attenuated lipid peroxidation, the generation of reactive oxygen

species, and DNA fragmentation, and markedly reduced the PCB 52 induced proteolytic cleavage of beta-catenin and PARP. These results show that Panax ginseng extract protects human neuronal SK-N-MC cells from the apoptosis induced by PCB 52. It is suggested that Panax ginseng extracts may protect neuronal cells from oxidative injury.[14]

Cho et al studied the estrogenic activity of a component of Panax ginseng, ginsenoside-Rb1. The activity of ginsenoside-Rb1 was characterized in a transient transfection system, using estrogen receptor isoforms and estrogen-responsive luciferase plasmids, in COS monkey kidney cells. Ginsenoside-Rb1 activated both alpha and beta estrogen receptors in a dose-dependent manner with maximal activity observed at 100 microm, the highest concentration examined. Activation was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor. Treatment with 17beta-estradiol or ginsenoside-Rb1 increased expression of the progesterone receptor, pS2, and estrogen receptor in MCF-7 cells and of AP-1-driven luciferase genes in COS cells. Although these data suggest that it is functionally very similar to 17beta-estradiol, ginsenoside-Rb1 failed to displace specific binding of 3H-17beta-estradiol from estrogen receptors in MCF-7 whole-cell ligand binding assays. Our results indicate that the estrogen-like activity of ginsenoside-Rb1 is independent of direct estrogen receptor association.[15]

The aim was to explore the modulating and inhibiting effects of arsenic trioxide, ginseng saponin and beta-elemene on telomere length and telomerase activity in K562 cell line, and to study their anti-tumor mechanism and seek new method of therapy for acute leukemia. Human erythroleukemia cell line K562 was co-cultured with arsenic trioxide, ginseng saponin, beta-elemene separately, cells were collected after 24, 48 and 72 hours for further detecting. Telomere length and telomerase activity were detected by the methods of Southern-blot and PCR-ELISA respectively. The effects of these drugs on telomere length and telomerase activity were observed at different concentrations and length of time. The results showed that (1) telomerase activity of K562 cells decreased after co-cultured with arsenic trioxide, ginseng saponin and beta-elemene. The inhibiting effects depended on drug concentrations and length of time. When co-cultured at proper

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concentration and period of time, telomerase activity could be inhibited; (2) viability of K562 cells decreased after co-cultured with arsenic trioxide, ginseng saponin and beta-elemene, the inhibiting effect depends on drug concentrations and length of time; (3) after co-cultured with arsenic trioxide, ginseng saponin, and beta-elemene for 72 hours, telomere length of K562 cell line prolonged a little. It is concluded that (1) arsenic trioxide, ginseng saponin and beta-elemene can inhibit telomerase activity in K562 cell line, the suppression of telomerase activity may be one of the mechanisms of anti-tumor effect; (2) arsenic trioxide, ginseng saponin and beta-elemene can inhibit the growth of K562 cell line, the inhibiting effect depends on concentration and time; (3) when telomerase activity was suppressed, the telomere length prolonged a little, indicating that in K562 cell line may exist another mechanism to regulate telomere length, except telomerase activation.[16]

The root of Panax ginseng C.A. Meyer has been reported to have an anti-stress action. Therefore, the effects of ginseng components on functions of adrenal medulla, which is one of the most important organs responsive to stress, were investigated in vitro. First, the components of ginseng were mainly divided into two fractions, that is, the saponin-rich and non-saponin fractions. The saponin-rich fraction greatly reduced the secretion of catecholamines from bovine adrenal chromaffin cells stimulated by acetylcholine (ACh), whereas the non-saponin fraction did not affect it at all. The protopanaxatriol-type saponins inhibited the ACh-evoked secretion much more strongly than the protopanaxadiol-type. On the other hand, the oleanane-type saponin, ginsenoside-Ro, had no such effect. Recent reports have demonstrated that the saponins in ginseng are metabolized and absorbed in digestive tracts following oral administration of ginseng. All of the saponin metabolites greatly reduced the ACh-evoked secretion. M4 was the most effective inhibitor among the metabolites. M4 blocked ACh-induced Na(+) influx and ion inward current into the chromaffin cells and into the Xenopus oocytes expressing human α 3, β 4 nicotinic ACh receptors, respectively, suggesting that the saponin metabolites modulate nicotinic ACh receptors followed by the reduction of catecholamine secretion. It is highly possible that these effects of ginsenosides and their metabolites are associated with

the anti-stress action of ginseng.[17] An unspecific feeling of fatigue and asthenia

often pushes elderly patients to require any form of help even from non medically trained people. Traditional Chinese medicine suggest that Siberian ginseng could act as safe "adaptogenic" substance. The aim was thus to test the effect of a middle term Eleutherococcus senticosus Maxim. (Araliaceae) administration on elderly, health related quality of life. 20 elderly hypertensive and digitalized volunteers (age >/= 65 years) were randomized in a double -blind manner to E. senticosus dry extract 300 mg·d-1 or placebo for 8 weeks. The short form-36 health survey version 2 (SF-36v2), a validated general health status questionnaire, was used to access HRQOL at baseline and at 4 and 8 weeks. There were no significant differences in baseline demographics and SF-36v2 scores between the groups. At each visit, controls of digitalemia and blood pressure level were carried out. After 4 weeks of therapy, higher scores in social functioning (p = 0.02) scales were observed in patients randomized to E. senticosus; these differences did not persist to the 8-week time point. No adverse event has been observed in both groups of patients. No significant difference in both blood pressure control and digitalemia was observed in both treatment groups. Subjects give E. senticosus (70%) were more likely to state that they received active therapy than subjects given placebo (20%; p < 0.05). In conclusion, E. senticosus safely improves some aspects of mental health and social functioning after 4 weeks of therapy, although these differences attenuate with continued use.[18]

Immunomodulating effects Ginsan, a polysaccharide isolated from Panax

ginseng, has been shown to be a potent immunomodulator, producing a variety of cytokines such as TNF-α, IL-1, IL-2, IL-6, IL-12, IFN-gamma and GM-CSF, and stimulating lymphoid cells to proliferate. In the present study, we analyzed some immune functions 1st-5th days after ginsan i.p. injection, including the level of non-protein thiols as antioxidants, heme oxygenase (HO) activity as a marker of oxidative stress, zoxazolamine-induced paralysis time and level of hepatic cytochrome P-450 (CYP450) as indices of drug metabolism system, and activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and albumin level as indicators

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of hepatotoxicity. Ginsan in the dose of 100 mg/kg caused marked elevation (1.7 to approximately 2 fold) of HO activity, decrease of total CYP450 level (by 20-34%), and prolongation of zoxazolamine-induced paralysis time (by 65-70%), and showed some differences between male and female mice. Ginsan treatment did not seem to cause hepatic injury, since serum AST, ALT, and ALP activities and levels of total bilirubin and albumin were not changed.[19]

Effect on drug-metabolizing enzymes Interest in the use of herbal products has grown

dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. In one study, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs. It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.[20]

The current practice of ingesting phytochemicals to support the immune system or to fight infections is based on centuries-old tradition. One review reports on seven Chinese herbs, (Aloe vera Mill. (Aloaceae), Angelica species (Umbelliferae), Astragalus membranaceus Bunge. (Leguminosae), Ganoderma lucidum (Fr.) Karst. (Ganodermataceae), Panax ginseng C.A Mey. (Araliaceae), Scutellaria species (Lamiaceae) and Zingiber officinale Rosc. (Zingiberaceae) with emphasis to their immunomodulatory and antimicrobial activities. While some of these herbaceous plants have a direct

inhibitory effect on microbial organisms, we observe that each plant has at least one compound that selectively modulates cells of the immune system. The successful derivation of pure bioactive compounds from Ganoderma lucidum, ginseng and Zingiber officinale supports the traditional practice of using these plants to stimulate the immune system. As many modern drugs are often patterned after phytochemicals, studying the influence of each compound on immune cells as well as microbes can provide useful insights to the development of potentially useful new pharmacological agents.[21]

Anti-cancer effect Ginseng has an anti-cancer effect in several

cancer models. This study was to characterize active constituents of ginseng and their effects on proliferation of prostate cancer cell lines, LNCaP and PC3. Cell proliferation was measured by 3H-thymidine incorporation, the intracellular calcium concentration by a dual-wavelength spectrophotometer system, effects on mitogen-activated protein (MAP) kinases by Western blotting, and cell attachment and morphologic changes were observed under a microscope. Among 11 ginsenosides tested, ginsenosides Rg3 and Rh2 inhibited the proliferation of prostate cancer cells. EC50s of Rg3 and Rh2 on PC3 cells were 8.4 µmol and 5.5 µmol, respectively, and 14.1 µmol and 4.4 µmol on LNCaP cells, respectively. Both ginsenosides induced cell detachment and modulated three modules of MAP kinases activities differently in LNCaP and PC3 cells. These results suggest that ginsenosides Rg3 and Rh2-induced cell detachment and inhibition of the proliferation of prostate cancer cells may be associated with modulation of three modules of MAP kinases.[22]

This research team found in previous studies, that the ginseng saponin metabolite IH901 induces apoptosis in HepG2 cells via a mitochondrial-mediated pathway, which resulted in the activation of caspase-9 and subsequently of caspase-3 and -8. Based on these results, the involvement of the Fas/Fas ligand (FasL) death-receptor pathway, in IH901-induced apoptosis in HepG2 cells, was investigated. Levels of Fas and the Fas ligand (FasL) mRNA or protein were not increased by IH901, rather they were decreased significantly at 18 h post treatment. Soluble FasL (sFasL) was detectable by immunoprecipitation

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analysis in the medium of HepG2 cells treated with IH901. Increased levels of sFasL were inversely correlated with the levels of FasL. Preincubation of HepG2 cells with antagonistic anti-Fas antibody showed little protective effect, if any, on IH901-induced cell death. At a 30µmol (24 and 48 h) and 40 µmol (24 h) concentration of IH901, the cytotoxic effect of IH901 was less then 50%, anti-Fas antibody prevented IH901-induced cell death. However, at a 60 µmol (24 and 48 h) and 40 µmol (48 h) concentration of IH901, cell death rates were about 80% or more and most of the chemopreventive and chemotherapeutic effects of IH901 were manifested. Blocking the Fas receptor did not influence IH901-induced cell death. These results indicate that the Fas/FasL system is engaged, but not required for IH901-induced cell death, at pharmacologically significant concentrations.[23]

Regulating intracellular Ca2+ levels in

neurons Jeong et al investigated the effect of the active

ingredients of Panax ginseng, ginsenosides, on store-operated Ca2+ entry (SOCE) using a two-electrode voltage clamp technique in Xenopus oocytes in which SOCE is monitored through Ca2+-activated Cl- currents. Under hyperpolarizing voltage clamp conditions, treatment with ginsenosides produced a biphasic Ca2+-activated Cl- current consisting of a rapid transient inward current and a slowly developing secondary sustained inward current. The transient inward current was inactivated rapidly, whereas the sustained inward current persisted for nearly 10 min. The effect of ginsenosides on the biphasic current was dose-dependent and reversible. The EC50 was 42.8+/-11.6 and 46.6+/-7.1 µg·mL-1 for the transient and sustained inward current, respectively. 3 In the absence of extracellular Ca2+ ginsenosides induced only a transient inward current but in the presence of extracellular Ca2+ ginsenosides induced the biphasic current. Magnitudes of the sustained currents were dependent on extracellular Ca2+ concentration. Sustained inward current induced by ginsenosides, but not transient inward current, and ginsenoside-induced store-operated Ca2+ (SOC) currents (ISOC) were blocked by La3+, a Ca2+ channel blocker, suggesting that the sustained inward current and ISOC was derived from an influx of extracellular Ca2+. 4 Treatment with 2-APB and

heparin, which are IP3 receptor antagonists, inhibited the ginsenoside-induced biphasic current. Treatment with the PLC inhibitor, U73122, also inhibited the ginsenoside-induced biphasic current. Intraoocyte injection of ATP-gammaS, but not adenylyl AMP-PCP, induced a persistent activation of ginsenoside-induced sustained current but did not affect the transient current. 5 In rat hippocampal neurons, ginsenosides inhibited both carbachol-stimulated intracellular Ca2+ release and intracellular Ca2+ depletion-activated SOCE. 6 These results indicate that ginsenoside might act as a differential regulator of intracellular Ca2+ levels in neurons and Xenopus oocytes.[24]

Protecting the heart against

ischemia-reperfusion Ginsenoside Re, a major ingredient of Panax

ginseng, protects the heart against ischemia-reperfusion injury by shortening action potential duration (APD) and thereby prohibiting influx of excessive Ca2+. Ginsenoside Re enhances the slowly activating component of the delayed rectifier K+ current (IKs) and suppresses the L-type Ca2+ current (I(Ca,L)), which may account for APD shortening. Researchers used perforated configuration of patch-clamp technique to define the mechanism of enhancement of IKs and suppression of I(Ca,L) by ginsenoside Re in guinea-pig ventricular myocytes. S-Methylisothiourea (SMT, 1 µmol ), an inhibitor of nitric oxide (NO) synthase (NOS), and N-acetyl-L-cystein (LNAC, 1 µmol), an NO scavenger, inhibited IKs enhancement. Application of an NO donor, sodium nitroprusside (SNP, 1 µmol), enhanced IKs with a magnitude similar to that by a maximum dose (20 µmol) of ginseonside Re, and subsequent application of ginsenoside Re failed to enhance IKs. Conversely, after IKs had been enhanced by ginsenoside Re (20 µmol), subsequently applied SNP failed to further enhance IKs. An inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ, 10µmol), barely suppressed IKs enhancement, while a thiol-alkylating reagent, N-ethylmaleimide (NEM, 0.5 mm), clearly suppressed it. A reducing reagent, di-thiothreitol (DTT, 5 mm), reversed both ginsenoside Re- and SNP-induced IKs enhancement. I(Ca,L) suppression by ginsenoside Re (3 microm) was abolished by SMT (1 µmol) or LNAC (1 mm). NEM (0.5 µmol) did not suppress I (Ca,L) inhibition

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and DTT (5 µmol) did not reverse I(Ca, L) inhibition, whereas in the presence of ODQ (10 µmol), ginsenoside Re (3µmol) failed to suppress I(Ca,L). These results indicate that ginsenoside Re-induced IKs enhancement and I(Ca,L) suppression involve NO actions. Direct S-nitrosylation of channel protein appears to be the main mechanism for IKs enhancement, while a cGMP-dependent pathway is responsible for I(Ca,L) inhibition.[25]

Platelet activating molecule expression In order to explore the relationship between the

active components and the functional links of Chinese herbs, the effect of Xuesaitong capsule, a preparation made of multi-component Panax notoginseng saponins (PNS) on platelet activating molecule expression and aggregation in patients with blood hyperviscosity syndrome (BHS) was observed, with aspirin (ASP) as a control: One hundred and twenty patients with BHS were divided, adopting randomized, double-blinded and double simulated principle into 2 groups, the PNS group and the ASP group, 60 in each group. Changes of the TCM clinical syndrome, platelet adhesion and aggregation, endothelin (ET), prostacyclin, thromboxane, CD62P and CD41 before treatment and after 28 days treatment were observed. Comparison between the therapeutic effects of the two groups on TCM clinical syndrome showed that the total effective rate in the PNS group was 86.67% and that in the ASP group 56.67%, showing significant difference. Compared with before treatment, after treatment, levels of platelet adhesion and aggregation, endothelin, prostacyclin and thromboxane were significantly different in both groups; levels of CD62P and CD41 in the PNS group were also significantly different, but the difference was insignificant in the ASP group; no significant difference was shown in both groups in levels of triglyceride, total cholesterol and very low density lipoprotein-cholesterol. It was showed that PNS may inhibit activation of platelet through multiple components and multiple pathways, which is different from that of ASP, only through inhibition on arachidonic acid metabolism to suppress platelet aggregation. PNS has effects of decreasing platelet superficial activation, inhibiting platelet adhesion and aggregation, preventing thrombosis and improving microcirculation, and its therapeutic effect on clinical syndrome is better than that of ASP.[26]

To assess the effects of chronic supplementation

with two different dosages of Panax ginseng C.A. Meyer on physiologic and psychological responses during graded maximal aerobic exercise. Thirty-six healthy men consuming an otherwise supplement-free diet who maintained their usual activity level. A standardized Panax ginseng C.A. Meyer concentrate (G115) was added to the normal diet of study participants at a dosage level of either 200 or 400 mg/day, where 100 mg of the preparation is equivalent to 500-mg P. ginseng root. Submaximal and maximal aerobic exercise responses before and after an 8-week trial intervention. Thirty-one subjects completed the study. Supplementation with ginseng had no effect on the following physiologic and psychological parameters: oxygen consumption (mL·kg-1 per minute), respiratory exchange ratio, minute ventilation (L·min-1), blood lactic acid concentration (µmol·L -1), heart rate (beats/min), and perceived exertion. The study data in healthy men do not offer support for claims that P. ginseng C.A. Meyer is an ergogenic aid to improve submaximal and maximal aerobic exercise performance.[27]

Panax ginseng is used in traditional Chinese medicine to enhance stamina and capacity to cope with fatigue and physical stress. Major active components are the ginsenosides, which are mainly triterpenoid dammarane derivatives. The mechanisms of ginseng actions remain unclear, although there is an extensive literature that deals with effects on the central nervous system (CNS-memory, learning, and behavior), neuroendocrine function, carbohydrate and lipid metabolism, immune function, and the cardiovascular system. Reports are often contradictory, perhaps because the ginsenoside content of ginseng root or root extracts can differ, depending on the method of extraction, subsequent treatment, or even the season of its collection. Therefore, use of standardized, authentic ginseng root, both in research and by the public, is to be advocated. Several recent studies have suggested that the antioxidant and organ-protective actions of ginseng are linked to enhanced nitric oxide (NO) synthesis in endothelium of lung, heart, and kidney and in the corpus cavernosum. Enhanced NO synthesis thus could contribute to ginseng-associated vasodilatation and perhaps also to an aphrodisiac action of the root. As public use of ginseng continues to grow, it is important for this industry and Federal regulatory authorities to encourage efforts to study the efficacy of ginseng in humans by means of appropriately

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designed, double-blind, clinical studies.[28] There has been continuing interest in the

development of synthetic and natural compounds which modify the immune response, particularly for the treatment of AIDS and cancer. Panax ginseng, employed for its putative medicinal properties in South Asia, was examined for its immunomodulatory properties in mice. A systematic evaluation of multiple immune system components revealed that Panax ginseng stimulated basal natural killer (NK) cell activity following subchronic exposure and helped stimulate recovery of NK function in cyclophosphamide-immunosuppressed mice but did not further stimulate NK activity in poly I:C treated mice. Other immunological parameters examined, including T- and B-cell responses, were not affected. Panax ginseng provided a degree of protection against infection with L. monocytes but did not inhibit the growth of transplanted syngeneic tumor cells. Increased resistance to L. monocytogenes was not detected in challenged mice previously given immunosuppressive doses of cyclophosphamide. Taken together, these data suggest that Panax ginseng has some immunomodulatory properties, primarily associated with NK cell activity.[29]

Kim et al previously reported that an acidic polysaccharide from Panax ginseng named ginsan inhibits the incidence of benzo[a]pyrene-induced autochthonous lung tumors in mice. To elucidate the mechanism of antineoplastic activity, ginsan was tested for its ability to generate LAK cells and to produce cytokines. Spleen cells became cytotoxic to a wide range of tumor cells after 5 days of culture with ginsan in a nonmajor histocompatibility restricted manner, and the activity of ginsan was 12 times higher than that of lentinan. The generation of killer cells by rIL-2 was neutralized only in the presence of anti-IL-2, whereas by ginsan it was neutralized in the presence of anti-IL-2 as well as anti-IFN gamma, or anti-IL-1 alpha. It was confirmed that ginsan induces the expression of mRNA for IL-2, IFNγ, IL-1 α, and GM-CSF. Depletion of AsGM1+ cells from spleen cells reduced the generation of LAK by rIL-2. In contrast, depletion of AsGM1+ as well as Thy1+ cells, CD4+ cells, or DC8+ cells reduced the generation of LAK cells by ginsan. The serologic phenotype of rIL-2 induced LAK cells was CD8- cells, whereas the ginsan induced LAK cells, were CD8+ cells. Ginsan synergized with rIL-2 to generate LAK cells (2.0-15 fold) and the most dramatic synergy was seen at

rIL-2 concentrations below 3 U·mL-1. Ginsan alone inhibited pulmonary metastasis of B16-F10 melanoma cells and enhanced the inhibition of lung colonies by rIL-2. These findings demonstrate that ginsan generates LAK cells from both NK and T cells through endogeneously produced multiple cytokines. This property may contribute to its effectiveness in the immunoprevention and immunotherapy of cancer.[30]

There was no significant difference in mortality, weight gain, liquid consumed, or pathogenesis between mice ingesting four different ginseng infusions for up to 96 days and control mice drinking distilled water. These results suggest no toxicity or tea selectivity of mice subjected to such regimens. Mice that drank concentrated Siberian ginseng wuchaseng extract with sugar showed significantly more aggressive behavior than those drinking other infusions or distilled water. However, there was no significant difference in stamina or longevity between mice drinking infusions of two preparations of Siberian ginseng, Oriental ginseng, or American ginseng, and control mice when subjected to swimming trials in cold water 38, 46, and 96 days after treatment began. Consequently, ingestion of adaptogenic glycosides did not significantly affect the survival of mice under major environmental stress.[31]

The subjects of this double-blind, randomized, crossover study were 50 healthy, male sports teachers aged 21-47 years. Every day for six weeks each subject received two capsules of a preparation containing ginseng extract, dimethylaminoethanol bitartrate, vitamins, minerals, and trace elements, or two capsules of placebo. The subjects then performed an exercise test on a treadmill at increasing workloads. The total workload and maximal oxygen consumption during exercise were significantly greater after the ginseng preparation than after placebo. At the same workload, oxygen consumption, plasma lactate levels, ventilation, carbon dioxide production, and heart rate during exercise were significantly lower after the ginseng preparation than after placebo. The effects of ginseng were more pronounced in the subjects with maximal oxygen consumption below 60 mL·kg-1·min-1 during exercise than in the subjects with levels of 60 mL·kg-1·min-1 or above. The results indicate that the ginseng preparation increased the subjects' work capacity by improving muscular oxygen utilization.[31]

The aim of the study was to determine the

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properties of a standardized extract of ginseng root in inducing a higher immune response in vaccination against influenza. Attention was also paid to the common cold in this multicentre, two-arm, randomized, placebo-controlled, double-blind investigation. A total of 227 volunteers who visited 3 private practices in Milan received daily oral capsule doses of either placebo (113) or 100 mg of standardized ginseng extract Ginsana G 115 (114) for a period of 12 weeks within which they received an anti-influenza polyvalent vaccination at week 4. As a result, while the frequency of influenza or common cold between weeks 4 and 12 was 42 cases in the placebo group, it was only 15 cases in the G115 group, the difference being statistically highly significant. Whereas antibody titres by week 8 rose to an average of 171 units in the placebo group, the antibody titres rose to an average of 272 units in the G115 group. Natural killer (NK) activity levels at weeks 8 and 12 were nearly twice as high in the G115 group as compared to the placebo group. In all the volunteers, laboratory values of 24 safety parameters showed no significant differences between the end and the beginning of the 12-week study in either of the groups. There were only 9 adverse events in the study, the principal one being insomnia.[32]

Extracts of Echinacea purpurea and Panax ginseng were evaluated for their capacity to stimulate cellular immune function by peripheral blood mononuclear cells (PBMC) from normal individuals and patients with either the chronic fatigue syndrome or the acquired immunodeficiency syndrome. PBMC isolated on a Ficoll-hypaque density gradient were tested in the presence or absence of varying concentrations of each extract for natural killer (NK) cell activity versus K562 cells and antibody-dependent cellular cytotoxicity (ADCC) against human herpesvirus 6 infected H9 cells. Both echinacea and ginseng, at concentrations greater than or equal to 0.1 or 10 micrograms/kg, respectively, significantly enhanced NK-function of all groups. Similarly, the addition of either herb significantly increased ADCC of PBMC from all subject groups. Thus, extracts of E. purpurea and P. ginseng enhance cellular immune function of PBMC both from normal individuals and patients with depressed cellular immunity.[33]

In a double-blind, controlled, clinical trial. The treatment group received two capsules of Gericomplex (ginseng, vitamins, minerals, and trace

elements) daily for 8 weeks, while the control group had identical-looking placebo capsules. Participants consisted of 60 geriatric patients, mean age 77.9 years. The principal study variables were length of stay in hospital, and activities of daily living according to the Barthel ADL Index. Cognitive function was assessed at baseline and after 8 weeks, using the Mini-Mental State Examination, the Kendrick Object Learning test, and the Trail Making test. Somatic symptoms, and symptoms of depression and anxiety were scored on a 23-question version of the Hopkins Symptom Checklist. Length of stay in hospital did not differ in the two groups, which also improved to the same degree on the various functional outcome measures, except for the Kendrick Object Learning test, where the placebo group improved more markedly. In conclusion, no identifiable effect of ginseng as an adjuvant to treatment and rehabilitation of geriatric patients was observed.[34]

Short-term (4 days), but not acute, treatment with ginseng saponin (GS, 10 and 20 mg·kg-1·d-1) significantly prolonged the aerobic endurance of nontrained rats exercising at approximately 70% VO2max. Compared to the saline controls, GS treatment significantly increased the plasma-free fatty acid (FFA) level and maintained plasma glucose level during exercise. Both the liver and skeletal muscle glycogen levels of the GS-treated rats were slightly higher than those of saline-treated controls after exhaustive exercise. These results indicate that GS enhances exercise endurance by altering fuel homeostasis during prolonged exercise, presumably by increasing FFA utilization in preference over glucose for cellular energy demands. To further search for the active components responsible for the ergogenic effect of GS, it was found that a GS preparation devoid of Rg1 and Rb1 failed, whereas injection of either Rg1 or Rb1 enhanced aerobic exercise performance. These results indicate that both Rg1 and Rb1 are key ingredients in GS-mediated enhancement in aerobic endurance.[35]

The immunopotentiating effects of the traditional Chinese drugs Ginsenoside (GS) and Glycyrrhiza polysaccharide (GPS) are reported. It was demonstrated that GS promotes the phagocytic activity of plaque-forming cells (PFC) and enhances the mitogenesis of T and B lymphocytes primed by mitogens. The mechanism of these effects is related to the ratio of cGMP to cAMP. Ginsenoside also

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plays a role in the NKC-IFN-IL-2 regulatory system, inhibits the growth of tumor cells, and antagonizes the suppression of ADCC and NK cytotoxicities in mice with surgical stress. Ginsenoside exhibits bidirectional effects on immunological functions. Glycyrrhiza polysaccharide increases the phagocytosis of macrophages, induces macrophages to secret IL-1, enhances both NK and ADCC activities, behaves as a mitogen of B lymphocytes, inhibits the multiplication of several viruses, and induces the release of IFN from spleen cells.[36]

This study presents the risk of various cancers in relation to ginseng intake based on the data from a case-control study conducted in the Korea Cancer Center Hospital. Ginseng intakers had a decreased risk (odds ratio = 0.50, 95% confidence interval, CI = 0.44-0.58, for cancer compared with nonintakers. On the type of ginseng, the odds ratios for cancer were 0.37 for fresh ginseng extract intakers, 0.57 for white ginseng extract intakers, 0.30 for white ginseng powder intakers, and 0.20 for red ginseng intakers. Intakers of fresh ginseng slice, fresh ginseng juice, and white ginseng tea, however, showed no decreasing risk. There was a decrease in risk with the rising frequency and duration of ginseng intake, showing a dose-response relationship. On the site of cancer, the odds ratios were 0.47 for cancer of the lip, oral cavity, and pharynx; 0.20 for esophageal cancer; 0.36 for stomach cancer; 0.42 for colorectal cancer; 0.48 for liver cancer; 0.22 for pancreatic cancer; 0.18 for laryngeal cancer; 0.55 for lung cancer; and 0.15 for ovarian cancer. In cancers of the female breast, uterine cervix, urinary bladder, and thyroid gland, however, there was no association with ginseng intake. In cancers of the lung, lip, oral cavity and pharynx, and liver, smokers with ginseng intake showed decreased odds ratios compared with smokers without ginseng intake. These findings support the view that ginseng intakers had a decreased risk for most cancers compared with nonintakers.[37]

A number of studies have reported that increased consumption of natural products reduced the risk of cancer. Our previous case-control studies have shown a significant reduction in the risk of cancer development among those who regularly consumed ginseng. Yun et al conducted a prospective cohort study to evaluate the preventive effect of ginseng against cancer on a population residing in a ginseng cultivation area on the basis of the result of

case-control studies. They studied 4634 people over 40 years old who completed a questionnaire on ginseng intake. In an attempt to obtain detailed information about ginseng intake, we asked them to specify their age at initial intake, their frequency and duration of ginseng intake, the kind of ginseng, and so on. Multiple logistic regression was used to estimate relative risks (RR) when controlling simultaneously for covariates.Ginseng consumers had a decreased risk (RR = 0.40) compared with non-consumers. On the type of ginseng, the RR was 0.31 for fresh ginseng extract consumers and 0.34 for consumers of multiple combinations. There was no cancer death among 24 red ginseng consumers. There was a decreased risk with a rise in the frequency of ginseng intake, showing a dose-response relationship. The RR of ginseng consumers was 0.33 in gastric cancer and 0.30 in lung cancer. Among ginseng preparations, fresh ginseng extract consumers were significantly associated with a decreased risk of gastric cancer (RR = 0.33). These results strongly suggest that Panax ginseng C.A. Meyer has nonorgan-specific preventive effect against cancer, providing support for the previous case-control studies.[38]

The water extract of Panax ginseng was fractionated by its solubility in ethanol and then the ethanol-insoluble fraction was tested for immunomodulatory activity. The ethanol-insoluble fraction of ginseng (Fr. 3) proliferated splenocytes and generated activated killer cells in vitro. These activated killer cells killed both NK cell sensitive and insensitive tumor target cells without MHC-restriction. Activation of splenocytes by ginseng was mediated through the endogenously produced IL-2. To investigate the effects of Fr.3 on the autochthonous neoplasm, a single subcutaneous injection of 0.5 mg of benzo[a]pyrene (BP) was given within 24 hours after birth of male N: GP(S) mice, and Fr.3 was administered in drinking water at a concentration of 2 mg·mL-1, 1 mg·mL-1, or 0.5 mg·mL-1 for 6 weeks after weaning. The treatment with Fr. 3 significantly inhibited lung tumor incidence compared with the BP alone group at a concentration of 2 mg·mL-1 or 1 mg·mL-1 in drinking water at the ninth week after BP treatment. These results suggest that the ethanol-insoluble fraction of ginseng shows antitumor effects as an immunomodulator.[39]

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Pharmacokinetics and metabolism of ginsenosides

Until recently, little was known about the

absorption, distribution, excretion, and metabolism of ginseng saponins. In the past decade, various investigations dealing with the pharmacokinetics and metabolism of ginsenosides have been published. From these studies, it can be concluded that the decomposition modes are different for protopanaxadiol and protopanaxatriol saponins. Ginsenoside Rg1 (protopanaxatriol-type) showed an extremely short half-life of 27 min after intravenous administration into minipigs. In contrast, the protopanaxadiol-type ginsenoside Rb1 showed a half-life in the ß-phase of 16 h. These results correlated with the pharmacokinetic results in rats and in rabbits. The high persistence of Rb1 in serum and tissues was attributed to a high degree of plasma protein binding. Rg1 was rapidly absorbed by mice after oral administration (~30% after 1 h). The concentration of Rg1 and metabolites was high in the blood, liver, bile, subcutis, conjunctiva, and epithelia of the oral cavity, esophagus, and nasal cavity; the concentration was low in muscle and endocrine organs and very low in the brain. Rg1 also was metabolized rapidly. Intact Rg1 was excreted in mouse urine and feces in very small amounts, but the metabolite concentration was high. Five metabolites could be detected; two of them were ginsenoside Rh1 and 25-OH-Rh1. Intact cells were used to study the metabolism of ginsenoside Rh2. In a medium containing 2% fetal calf serum and B16 melanoma cells, uptake reached a maximum after 3-6 h. Rh2 was deglycosylated to protopanaxadiol. Ginsenoside Rh2 and protopanaxadiol inhibited the growth of B16 melanoma cells.[7,9]

Ginseng and cytochrome P450

Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology. In this article, a literature overview is provided of known or suspected

interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer. Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes, cytochrome p450 isozymes (CYP) and/or the drug transporter, ginseng (Panax ginseng). Ginseng participates in potential pharmacokinetic interactions with anticancer drugs. It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.[45]

Herbal medicines are widely consumed by patients in different clinical settings in the United States and all over the world. In this study, ginseng components, ginsenosides Rb1, Rb2, Rc, and Rd, were investigated for their inhibitory effects on hepatic CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Tolbutamide 4-methylhydroxylation and testosterone 6ß-hydroxylation were used as index reactions of CYP2C9 or CYP3A4 catalytic activities, respectively. The metabolites of both reactions were measured by high-performance liquid chromatography and used as indicators of whether enzymes were inhibited or unaffected by these agents. The compounds investigated were capable of inhibiting CYP2C9 and CYP3A4 catalytic activities, but the potencies differed. Ginsenoside Rd also had significant inhibitory potency on both CYP2C9- and CYP3A4-mediated index reactions with IC(50) values of 105 and 62 µmol·L-1, respectively. Ginsenosides Rb1, Rb2, and Rc had limited inhibitory activities on both enzyme reaction systems. It is concluded that the components of ginseng are capable of inhibiting CYP2C9- and CYP3A4-mediated metabolic reactions. These findings suggest that ginsenoside Rd have the potential to interact with conventional medicines that are metabolized by CYP2C9 and CYP3A4 in vivo.[49]

To determine if soy extract or Panax ginseng increases the urinary excretion of the 6-beta- hydroxycortisol/cortisol ratio as a marker of CYP 3A enzyme induction, subjects received a soy extract containing 50 mg isoflavones twice daily or Panax ginseng 100 mg standardized to 4% ginsenosides twice daily for 14 days. Neither Panax ginseng nor soy extract significantly altered the urinary

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6-beta-OH-cortisol/cortisol ratio. Studies in vitro using human liver microsomes were performed to determine the effect of soy extract on probe substrates of CYP and UDP glucuronosyltransferase (UGT). Unhydrolyzed soy extract produced very little inhibition of CYP1A2, CYP2A6, and CYP2D6 and a trend of activation of CYP3A4. Hydrolyzed soy extract showed inhibition of all of the CYPs tested, particularly CYP2C9 and CYP3A4. UGT2B15 was the only UGT significantly inhibited. Even though both soy extract and ginseng have been shown to activate CYP3A4 in vitro, there is a lack of an in vitro correlation with the in vivo effects.[50]

Siberian ginseng ([SG]; Eleutherococcus senticosus) is a commonly used herbal preparation. In normal volunteers, the influence of a standardized SG extract on the activity of cytochrome P450 CYP2D6 and 3A4. Probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at baseline and again following treatment with SG (1╳485 mg twice daily) for 14 days. Urinary concentrations of dextromethorphan and dextorphan were quantified, and dextromethorphan metabolic ratios (DMRs) were determined at baseline and after SG treatment. Likewise, plasma samples were collected (0-60 h) for alprazolam pharmacokinetics at baseline and after SG treatment to assess effects on CYP3A4 activity. Validated high performance liquid chromatography methods were used to quantify all compounds and relevant metabolites. There were no statistically significant differences between pre- and post-SG treatment DMRs indicating a lack of effect on CYP2D6 (P > 0.05). For alprazolam there also were no significant differences in the pharmacokinetic parameters determined by noncompartmental modeling (Cmax, Tmax, area under the curve, half-life of elimination) indicating that SG does not significantly induce or inhibit CYP3A4 (P > 0.05). Our results indicate that standardized extracts of SG at generally recommended doses for over-the-counter use are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination.[51]

The effects of the subchronic administration of Panax ginseng extracts were examined on the hepatic cytochrome P450-dependent monooxygenase system of guinea pigs pre-exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Panax

ginseng extracts were intraperitoneally administered to guinea pigs at 100 mg·kg -1 d -1 for 14 days from 1 week after a single intraperitoneal injection of 1 microg of TCDD·kg -1 of body weight. TCDD treatment increased the total cytochrome P450 content 2.86-fold, and this was remarkably inhibited by the administration of Panax ginseng extracts. Treatment with ginseng extract alone also decreased the contents of cytochrome P450 by 33%, but both TCDD and ginseng extracts had no effect on cytochrome b(5) content. The administration of TCDD resulted in a 1.73-fold increase in microsomal NADPH-cytochrome P450 reductase activity in the guinea pig liver, and this was significantly inhibited by ginseng extracts, but treatment with ginseng extracts alone had no effect on its activity, and no statistical changes in the activity of NADPH-cytochrome b(5) reductase were observed in guinea pig liver due to TCDD and/or ginseng extract administration. Compared to the control, ECOD activity remarkably (1.76-fold) increased after TCDD administration, but this increase was completely inhibited by treatment with ginseng extract. Treatment with ginseng extract alone resulted in a 50% reduction of ECOD activity. TCDD administration remarkably induced benzphetamine demethylation (BPDM) activity, while ginseng extract also slightly increased the enzyme's activity, but the induction attributed to ginseng extracts was not statistically significant. Even though administration of ginseng extracts slightly inhibited TCDD-induced BPDM activity, the inhibition was not statistically significant. These results indicate that ginseng extract exerts different effect on the induction of P450 isozymes. From these results, it suggests that Panax ginseng extracts may act as an inhibitor of CYP1A rather than that of CYP2B.[52]

Park et al studied the effects of ginsenoside Rb1 (GRb1) on the change in lipid contents in rat liver. When GRb1 was administered intraperitoneally to rats, liver microsomal cytochrome P-450 content and NADPH-cytochrome P-450 reductase activity were lower than those in control rats. The contents of triglyceride (TG) and cholesterol were decreased, but those of total phospholipid, phosphatidylcholine, and phosphatidylethanolamine were increased in the GRb1-treated group compared with controls. These results indicate that GRb1 might be involved in lipid metabolism by regulating the activity of microsomal cytochrome P-450 monooxygenase. Although liver

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TG levels were reduced by GRb1, the levels of TG and beta-lipoprotein in serum from the GRb1-treated group did not change as compared with those in controls. Thus we suggest that the decrease in liver TG levels with GRb1-treatment is not associated with the secretion of TG-rich very low-density lipoprotein. Furthermore, the level of cAMP was also significantly increased in the GRb1-treated group as compared with that in controls. Additionally, the cAMP level was more markedly increased as compared with that in the GRb1-treated group or control group when GRb, was exogenously added to the reaction system for measuring cAMP production in homogenates from control group liver. Accordingly, these results demonstrate that GRb1 might lower TG levels via cAMP-production in the liver, and GRb1 might be an interesting candidate to for a modulator of cAMP-mediated effects, especially within the liver steatosis system.[53]

Ginseng extract has been reported to decrease the incidence of 7,12-dimethylbenz[a]anthracene (DMBA)-initiated tumorigenesis in mice. A potential mechanism for this effect by ginseng is inhibition of DMBA-bioactivating P450 enzymes. In the present in vitro study, we examined the effect of a standardized Panax ginseng (or Asian ginseng) extract (G115), a standardized Panax quinquefolius (or North American ginseng) extract (NAGE), and individual ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1) on CYP1 catalytic activities, as assessed by 7-ethoxyresorufin O-dealkylation. G115 and NAGE decreased human recombinant CYP1A1, CYP1A2, and CYP1B1 activities in a concentration-dependent manner. Except for the competitive inhibition of CYP1A1 by G115, the mode of inhibition was the mixed-type in the other cases. A striking finding was that NAGE was 45-fold more potent than G115 in inhibiting CYP1A2. Compared with G115, NAGE also preferentially inhibited 7-ethoxyresorufin O-dealkylation activity in human liver microsomes. Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1, either individually or as a mixture and at the levels reflecting those found in an inhibitory concentration (100 µg·mL-1) of NAGE or G115, did not influence CYP1 activities. However, at a higher ginsenoside concentration (50 µg·mL-1), Rb1, Rb2, Rc, Rd, and Rf inhibited these activities. Overall, in vitro findings indicate that standardized NAGE and G115 extracts, which were not treated with calf serum or subjected to acid hydrolysis, inhibited CYP1 catalytic

activity in an enzyme-selective and extract-specific manner, but the effects were not due to Rb1, Rb2, Rc, Rd, Re, Rf, or Rg1.[54]

In vitro experiments shown that ginseng preparations at high concentrations (> 2000 micrograms/ml) are able to inhibit CYP2E1 enzymatic activity in mouse and human microsomes. However, any modification of CYP2E1 gene expression (enzymatic activity, protein and mRNA levels) was not observed in mice treated with either crude extract or total saponins. Taken together, these data demonstrated that Panax vietnamensis could be used as a hepatoprotectant. However, the mechanism of action is not associated with CYP2E1 expression, as previously suggested in vitro in rat for total saponins from Panax ginseng.[55]

Because little is known about the interactions between herbal products and standard medications, the effects of seven ginsenosides and two eleutherosides on the catalytic activity of c-DNA expressed cytochrome P450 isoforms were studied in in vitro experiments. Increasing concentrations of ginsenosides Rb1, Rb2, Rc, Rd, Re, Rf, and Rg1 and eleutherosides B and E were incubated with a panel of recombinant human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their effects on the conversion of specific surrogate substrates measured fluorometrically in a 96-well plate format. For each test substance, the IC50 was estimated and this value compared with that obtained for positive control inhibitory drugs furafylline, sulfaphenazole, tryanylcypromine, quinidine, and ketoconizole. Of the components tested, three ginsenosides (Rd, Rc, and Rf) modified the activity of the recombinant enzymes. Ginsenoside Rd produced weak inhibitory activity against the surrogate substrates for CYP3A4 and CYP2D6 and even weaker inhibitory activity against the surrogate substrates for CYP2C19 and CYP2C9. The IC50 values of 58 and 74 µmol for the two substrates for CYP3A4 are orders of magnitude higher than that for the potent inhibitor ketoconazole used as a positive control. Ginsenoside Rc produced an increase in the activity of CYP2C9 (70% at 200 µmol) and ginsenoside Rf produced an increase in the activity of CYP3A4 (54% at 200 µmol). The biological significance of this is unclear at this time. Enzyme "activation", the process by which direct addition of one compound to an enzyme enhances the rate of reaction of the substrate, has been observed in a

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number of cases with P450 enzymes; however, a matrix effect caused by the test compound fluorescing at the same wavelength as the metabolite of the marker substrate cannot be ruled out. These studies suggest that the ginsenosides and eleutherosides tested are not likely to inhibit the metabolism of coadministered medications in which the primary route of elimination is via cytochrome P450; the potential of ginsenosides to enhance the catalysis of certain substrates requires further investigation.[56]

A possible role of P450 inhibition by red ginseng saponins in carbon tetrachloride (CCl4)-induced lipid peroxidation was investigated in liver microsomes prepared from male Sprague Dawley rats. The total saponin of red ginseng standardized on ginsenosides-Rb1, -Rb2, -Rc, -Rd, -Re, and -Rg1 whose composition was studied in our previous report was used in the present study. The standardized saponin of red ginseng showed inhibitory effects on P450-associated monooxygenase activities in a dose-dependent manner, particularly p-nitrophenol hydroxylase activity which has been known to represent CCl4-activating P450 2E1 enzyme. Meanwhile, silymarin enhanced the activity of P450 2E1 enzyme in liver microsomes. When the lipid peroxidation was induced by incubating rat liver microsomes with CCl4 in the presence of NADPH, the standardized saponin significantly blocked the formation of thiobarbituric acid-reactive substances at the same concentrations showing P450 inhibition in liver microsomes. Silymarin revealed more potent protection against CCl4-induced lipid peroxidation. When the lipid peroxidation was induced by FeCl3, in which metabolic activation may not be required, only silymarin could protect the lipid peroxidation in liver microsomes. The obtained results indicated that the inhibitory effects of red ginseng saponin on P450 enzymes may have a critical role in CCl4-induced lipid peroxidation in rat liver microsomes and that the mechanism of hepatoprotection by red ginseng saponin may be distinct from that of silymarin.[57] Clinical application

Ginseng and Aging

Ginseng has been studied in its relationship to the process of aging among humans. It is stated that aging is a declining process associated with

dysfunction of neuro-endocrino-immuno-system network. The atrophy of the thymus places a role in decreased lymphocyte function.[40] Scientists at the Beijing Institute of Geriatrics conducted a study on the direct effects of Rg1, extracted from Panax ginseng, on lymphocytes of aged people. The study concluded that the Rg1 saponin used could stimulate and enhance the function of lymphocytes, restoring it to normal.[41] Furthermore, this study provided insight on the immunostimulatory mechanisms of saponin and other herbs. Ginseng contains ten saponins, or polysaccharides with specific characteristics, including Rc, Rc2, Rd, and Rg1. Some of the researchers found that ginseng can promote synthesis of protein, RNA, and DNA in tissues and organs such as the kidney, liver, bone marrow, and plasma of rats. In 1994, a group of scientists conducted a study on the life span, motor activity and antibody production in senescence accelerated mice (SAM). A ginseng containing compound, DX-9386 (ginseng, acorus, polygala, and hoelen) was given to SAM for 13 consecutive months starting from two months of age. The results concluded that DX-9386 significantly prolonged the life span of SAM, prevented body weight decrease with aging, and tended to improve the senile syndrome. Antibody production was however markedly decreased and DX-9386 showed no effect of raising that.[46] .

Effects on Stress

Electric shock and other physical stress manipulations are known to cause antinociception, or an increase in the threshold of pain, in experimental animals. The mechanisms of stress-induced antinociception are controlled by emotional factors such as anxiety and fear. Panax ginseng has been demonstrated to suppress the development of adaptation to psychological stress in mice. Other scientists studied the effects Vietnamese ginseng saponins, especially R2, had on psychological stress and foot shock stress-induced antinociception in mice. It was found that acute administration of VG crude saponin significantly suppressed the antinociceptive response caused by the psychological stress. Repeated administration of the saponin had no effect on the development of adaptation to either psychological or foot-shock stress exposure.[42]

Quality of Life/ Physical Stamina

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Among the varied promises of Ginseng are those of an increased physical stamina and a higher quality of life. Many advertisers promise a feeling of an increased overall well being. They offer testimonies of people who claim that after taking the extract they "feel better." Scientists in Sweden conducted a double-blind, randomized study with a 12 week duration to determine the effect of ginseng extract G115 on the quality of life. Healthy, employed volunteers, 25 years old or older were included in the study measuring two standards. Self-administered questionnaires were given concerning the Psychological General Well-Being Index and the Sleep Dysfunction scale. 185 subjects taking a placebo and 205 subjects taking the active substances completed the study.[46] The results of the study showed an improvement in the quality of life of both groups, showing an improved alertness, relaxation, appetite, as well as an improved overall score, although a more pronounced improvement was seen in those taking the extract. It was concluded that treatment with the combination of active substances had significant advantages over placebo therapy. A group of 43 triatheletes of good standing, aged 24-36, was studied during the sport season using cross-over design for two consecutive periods of ten weeks. No significant conclusions were made after the first period. However, the second period of ten weeks showed a prevention by the drug in the loss of physical performance characteristic of end of the season tiredness. The experimenter concluded that G115 could be a non-doping "adaptagen".[44]

Memory

Ginseng was studied to determine its effects on learning and memory performance in the step-down and lever-press tests in normal mice. The prescription of S-113m (Panax ginseng and Schisandra chinensis) had no effect on memory registration, consolidation and retrieval processes or on motor activity.[43]

Adverse Effects, Drug Interactions, and Contraindications

Interpretation of documented adverse effects and drug interactions can be difficult because of the variety of available ginseng formulations, and because the exact amount of ginseng in these products may not be identified. Panax ginseng

generally is well tolerated, and its adverse effects are mild and reversible. Associated adverse effects include nausea, diarrhea, euphoria, insomnia, headaches, hypertension, hypotension, mastalgia, and vaginal bleeding. Panax ginseng may interact with caffeine to cause hypertension, and it may lower blood alcohol concentrations. It also may decrease the effectiveness of warfarin. Concomitant use of Panax ginseng and the monoamine oxidase inhibitor phenelzine may result in manic-like symptoms.

Contraindications to the use of Panax ginseng include high blood pressure, acute asthma, acute infections, and nose bleeds or excessive menstruation. These effects appear to occur primarily with high dosages or prolonged use. Ginseng also causes hypoglycemic activity, and caution should be exercised in using ginseng products in patients with diabetes because of possible interactions with oral hypoglycemic agents and insulin. One source 2

recommends avoiding the use of ginseng products in children and in women who are pregnant or lactating, until more rigorous studies prove safety in these groups. Ginseng may have possible estrogen-like effects, including postmenopausal bleeding. Early reports that high doses or prolonged use of ginseng could cause sleeplessness, nervousness, diarrhea, and elevated blood pressure are now discredited. Many sources still mention other side effects based on a report by Siegel. Several studies have since rejected the conclusions of this report because of flawed research methods.

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