ARTICLE ON THE HERB GINGER

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Herbal Pharmacy: Ginger

Spice or medicine? This popular culinary herb has many medicinal uses. Wendell

L. Combest, Ph.D.

Associate Professor of Pharmacology Department of Pharmaceutical Sciences

University School of Pharmacy, Buies Creek, NC <<Ginger (Zingiber

officinale Roscoe), which belongs to the family Zingiberaceae, is a slender

perennial that reaches a height of 2–3 feet and has greenish-yellow flowers

resembling orchids. The underground rhizomes are the medicinally and culinary

useful part of the plant; they are irregular in shape and size with thick

multiple lobes that are pale yellow and aromatic. Ginger is thought to have

originated in the tropical jungles of Asia and was among the first vegetatively

cultivated plants. It has been grown in India and China for thousands of years

and today is widely cultivated in many tropical countries around the world. The

ginger plant thrives in hot and moist climates with abundant shade and in rich,

well-drained loamy soil. Ginger is typically consumed as a fresh root, a dried

powder, slices preserved in syrup, a candy (crystallized ginger) or a tea. In

many countries, especially India, fresh ginger is popularly used to prepare

vegetable and meat dishes. Ginger is widely used as a flavoring agent in

beverages and many food preparations.

The medicinal history of ginger is extensive. Ginger has played an important

role in Chinese, Indian and Japanese medicine. It has developed a reputation in

the treatment of many gastrointestinal disorders and is often promoted as an

effective herbal antiemetic. It has long been believed to possess

anti-inflammatory, cholesterol-lowering and anti-thrombotic properties. Today,

ginger is perhaps most popular in the U.S. in treating nausea and vomiting

associated with motion sickness.

Chemical Composition and Active Constituents The oleoresin fraction of ginger

rhizomes contains both volatile oils and nonvolatile pungent compounds which can

be extracted with solvents such as acetone or alcohol.

Volatile Oils: The volatile oil components in ginger consist mainly of

sesquiterpene hydrocarbons, predominantly zingeberene (35%), curcumene (18%) and

farnesene (10%), with lesser amounts of bisabolene and b-sesquiphellandrene. A

smaller percentage of at least 40 different monoterpene hydrocarbons is present

with 1,8-cineole, linalool, borneol, neral, and geraniol being the most

abundant.1 A sesquiterpene alcohol known as zingiberol has also been isolated.

Many of these volatile oil constituents contribute to the distinctive aroma and

taste of ginger, but most are not unique to ginger.

Nonvolatile Pungent Compounds: Several nonvolatile constituents give ginger its

characteristic pungent flavor as well as being responsible for many of its

pharmacological actions. The principle component of this fraction are the

gingerols with [6]-gingerol being the most common.1 n[6]-, [8]- and [10]-Shogaol

forms are dehydroxylated derivatives of gingerols whose concentrations increase

in dired ginger after prolonged storage. Paradol is similar to gingerol and is

formed from hydrogenation of shogoal.

Other Constituents: In addition to the extractable oleoresins, ginger contains

many fats, waxes, carbohydrates, vitamins and minerals. Ginger rhizomes also

contain a potent proteolytic enzyme called zingibain. Medicinal Uses and

Pharmacology

Antiemetic Effects: One of the most popular uses of ginger is to relieve the

symptoms of nausea and vomiting associated with motion sickness, surgery and

pregnancy. Results of most clinical trials support the efficacy of ginger as an

antiemetic agent, although some studies were unable to verify these findings.

An often cited example of the effectiveness of ginger in alleviating motion

sickness was carried out by Mowrey and Clayson in 1982.2 Thirty-six subjects

highly susceptible to motion sickness were tested while blindfolded in a tilted

rotating chair. Powdered ginger (940 mg) was found to be more effective than 100

mg of dimenhydrinate in reducing the symptoms of motion sickness. In contrast, a

more recent U.S. study tested 28 subjects for motion sickness in a similar

rotating chair.3 The effects of ginger were compared to scopolamine and placebo.

Results indicated that neither powdered ginger (1 g) nor fresh ginger root (1 g)

protected against motion sickness. Holtmann et al. conducted a

placebo-controlled double-blind study to determine if powdered ginger could

prevent motion sickness triggered by optokinetic or vestibular stimuli.4 Results

of their study indicated that dimenhydrinate had an influence on the vestibular

and oculomotor components of motion sickness, but that ginger did not. They

concluded that any reduction of motion sickness symptoms with ginger use was

likely due to its direct effects on the gastrointestinal system rather than any

action via the CNS.

In a double-blind, randomized placebo-controlled trial, 80 naval cadets prone to

seasickness were given 1 g of powdered ginger or placebo for four consecutive

hours during sailing. Ginger reduced vomiting and cold sweating significantly.5

Although it appeared that ginger was effective in treating the symptoms of

certain forms of motion sickness, more studies are needed to confirm these

findings. Several studies have investigated the effectiveness of ginger in the

prevention of postoperative nausea and vomiting. In a double-blind, randomized

study, the effectiveness of ginger (0.5 g powdered root) as an antiemetic agent

was compared with placebo and metoclopramide in 60 women who had major

gynecological surgery.6 Compared to the placebo group, ginger was as effective

as metoclopramide in reducing nausea. et al. found similar results in a

randomized, double-blind trial in which 120 women underwent elective

laparoscopic surgery on a day stay basis.7 The incidence of nausea and vomiting

in patients given metoclopramide was similar to that in patients given ginger,

and was significantly less than in those who received placebo. However, in

another controlled clinical trial consisting of 108 patients also undergoing

laparoscopic surgery under general anesthesia,8 ginger (0.5–1 g powdered root)

did not reduce the incidence of nausea and vomiting. The reason for the

discrepancy between this study and the others is unclear but could be due to

differences in the anesthesia used or in how the ginger was administered.

Ginger has also been shown to be effective in the treatment of nausea and

vomiting associated with pregnancy. In one study, 19 of 27 women taking powdered

ginger in daily doses of 1 g experienced significantly less symptoms when

compared to placebo.9 However, because ginger is a potent thromboxane synthetase

inhibitor, it may affect testosterone receptor binding in the fetus.10 Whether

or not ginger in the quantities typically consumed might adversely affect fetal

development is unknown but should be investigated.

Gastrointestinal and Antiulcer Effects: Ginger is often prescribed in Chinese

and Japanese medicine for a variety of gastrointestinal disorders. In the U.S.

ginger is often promoted as a digestive aid and treatment for abdominal pain,

indigestion and ulcers. Although human clinical trials have not been conducted,

several animal studies support some of these claims. One study found that orally

administered acetone extracts of ginger, [6]-shogaol, and [6], [8]-, and

[10]-gingerols all enhanced gastrointestinal motility in mice to a similar

extent as did metoclopramide and donperidone.11 Previous studies by this same

Japanese group demonstrated that a diterpenoid, galanolactone, isolated from

ginger inhibited contractions induced by serotonin (5-HT3) in guinea pig ileum

likely acting as a 5-HT3 receptor antagonist.12 Studies show that various

compounds in ginger are able to inhibit prostaglandin and thromboxane synthesis.

Yamahara et al. first demonstrated that crude acetone extracts of ginger,

isolated zingiberene, as well as [6]-gingerol significantly inhibited gastric

lesions induced by HCl and ethanol in rats.13 Similar studies, also in rats,

showed that extracts of ginger were cytoprotective against damage by ethanol,

HCl, NaOH, high NaCl, as well as gastric lesions produced by non-steroidal

anti-inflammatory drugs and stress.14 Similarly, Chinese investigators utilized

various experimental gastric ulcer models with orally administered dry and

roasted ginger decoctions and found them to be protective against stomach

damage.15 Most recently Yoshikawa et al. in Japan identified a new compound

[6]-gingesulfonic acid in ginger extracts. This compound was effective in

preventing ulcers in an experimental rat model.16 These protective effects on

the gastric mucosa seem to involve an increased mucosal resistance or

potentiation of some defensive factor or mechanism against noxious chemicals.

Alterations in prostaglandins with associated changes in blood flow to the

mucosa could also contribute to the protective effects. Clearly more work is

necessary to further substantiate these animal studies and to clarify which

ginger constituents are active and by what mechanisms.

Anti-inflammatory Effects and Arthritis Treatment: Srivastava and Mustafa first

reported in 1989 the results of treating six rheumatoid arthritis patients with

ginger.17 All the patients ingested either 5 g of fresh or 0.5–1 g powdered

ginger daily for three months and reported pain relief, better joint movement

and decreased swelling and morning stiffness. These results were confirmed and

expanded in a later study in which 56 patients suffering from either rheumatoid

arthritis, osteoarthritis, or muscular discomfort received 0.5–2 g of powdered

ginger for 3 months to 2.5 years.18 Three-fourths of the patients experienced

relief in pain and swelling to varying degrees. The results of two animal

studies support these clinical findings. Suekawa found that [6]-shogaol isolated

from ginger extracts inhibited experimentally-induced swelling of the hind paw

in rats.19 This correlated with the ability of [6]-shogaol to inhibit

cyclooxygenase in a concentration dependent manner. In the other study,

arthritis was experimentally induced in the right knee and paw of rats.20 Ginger

oil (33 mg/kg) was given orally one day prior to the experiment and continued

for six days. The ginger treatment markedly inhibited both paw and joint

swelling.

Mechanical, chemical and immunological tissue damage stimulates production and

the oxygenation of arachidonic acid in inflamed tissues. Enhanced cyclooxygenase

and 5-lipoxygenase activities produce prostaglandins and leukotrienes,

respectively, which are important mediators of inflammation. They also intensify

pain responses by sensitizing nociceptic nerve endings to various inflammatory

mediators such as bradykinin and 5-HT.

Several studies indicate that various compounds in ginger are capable of

inhibiting both prostaglandin and thromboxane synthesis as well as leukotriene

biosynthesis. These inhibitory effects could explain the demonstrated

effectiveness of ginger in reducing pain and swelling in inflamed tissues.

Kiuchi and coworkers showed that ginger extracts contained potent inhibitors of

both prostaglandin and leukotriene biosynthesis.21 Various gingerols and

shogaols and several gingerdiones were found to be potent inhibitors in vitro.

Aqueous extracts of ginger were shown to reduce platelet thromboxane formation

from exogenous arachidonate.22 In a human study, thromboxane B2 levels in venous

blood decreased after subjects consumed 5 g of fresh ginger dailyfor a week.23

Cardiovascular Effects: Shoji et al. first demonstrated the potent positive

inotropic effect of methanol extracts of ginger rhizomes on guinea pig isolated

left atria.24 Further investigations confirmed this observation and identified

the effect as being due to gingerols. [8]-Gingerol produced a

concentration-dependent positive inotropic effect in isolated guinea pig

atria.25 The mechanism of action was postulated to be via stimulation of Ca2+

uptake by the sarcoplasmic reticulum since gingerol was shown to activate a

Ca2+-ATPase in cardiac sarcoplasmic reticulum. Several studies in Japan have

demonstrated an effect of gingerol and shogaol on blood vessel smooth muscle

contraction. Administration of [6]-shogaol to rats caused a peripheral pressor

response believed to be due to the release of an unknown pressor substance from

non-adrenergic and non-cholinergic nerves.26 Additional studies utilizing

isolated mouse mesenteric veins and arteries and aorta preparations demonstrated

that [6]-, and [8]-gingerols potentiated the contraction induced by several

prostaglandins (PGF2a, PGE2 and PGI2) but inhibited the contraction stimulated

by thromboxane A2 and leukotrienes.27 In a followup study this group found that

both [6]-gingerol and [6]-shogaol inhibited contractile responses to

norepinephrine but potentiated the contraction produced by PGF2a.28 These

studies indicate a complex modulation by ginger of various eicosanoid and

neurotransmitter-induced vascular smooth muscle responses.

Two animal studies indicate the presence of compounds in ginger which affect

cholesterol metabolism. The activity of hepatic cholesterol-7-alpha-hydroxylase,

the rate-limiting enzyme in bile acid biosynthesis, was significantly elevated

in ginger fed rats.29 This conversion of cholesterol to bile acids is an

important method of eliminating cholesterol from the body. Tanabe et al. have

recently isolated a new compound from ginger rhizomes, [E]-8b,

17-epoxylabd-12-ene-15, 16-dial (ZT), that lowered plasma cholesterol levels in

experimentally-induced hypercholesterolemia in mice.30 In a human

placebo-controlled study of patients with coronary artery disease administration

of 4 g of powdered ginger daily for three months did not affect blood

cholesterol levels.31 These negative results could be due to an insufficient

dose of ginger. Alternatively, the levels of cholesterol lowering components in

ginger may be too low in whole ginger preparations and require isolation and

concentration to produce effects on cholesterol blood levels.

An aqueous ginger extract was shown to inhibit platelet aggregation induced by

arachidonic acid, epinephrine, ADP and collagen.32 In isolated platelets the

ginger extract was also shown to reduce the formation of thromboxane and

prostaglandins. In a study of 20 males who had enhanced platelet aggregation

following dietary supplementation of 100 g of butter, 5 g of dried ginger twice

daily significantly inhibited platelet aggregation induced by ADP and

epinephrine.33 This study supports the benefits of the common practice in India

of adding ginger to a diet rich in fat. A randomized double-blind study in 8

healthy males tested the effects of daily doses of 2 g of dried ginger on

platelet function.34 There were no differences in bleeding time or platelet

aggregation between the ginger and placebo groups. In a similar study of 60

patients with coronary artery disease, a daily dose of 4 g of powdered ginger

for three months also did not affect ADP and epinephrine-induced platelet

aggregation.31 However, a single dose of 10 g of powdered ginger after 4 h

produced a significant reduction in platelet aggregation induced by the two

agonists. These two studies indicate that relatively large doses of ginger are

necessary to inhibit platelet function in humans.

Antitumor Activity: The National Cancer Institute is focusing on finding cancer

preventative agents in foods. Several compounds in ginger rhizomes have been

shown to possess antitumor or antimutagenic activities. Recently, ethanol

extracts of ginger were shown to have antitumor promoting effects in a mouse

skin tumorigenesis model.35 The animals pretreated with ginger extracts showed

substantially lower tumor body burdens compared with non ginger treated

controls. Aqueous extracts of ginger were found to be cytotoxic to lymphoma

ascites tumor cells in culture.36 Ginger extracts, gingerol and shogaol were

found to be mutagenic when tested in a Salmonella/microsome assay in the

presence of a rat liver metabolic activation system.37 In contrast, zingerone

was found not to be mutagenic. Interestingly, zingerone suppressed the mutagenic

activity of gingerol and shogaol in a dose-dependent manner. Antioxidant

Effects: Many cellular lipids, and especially polyunsaturated fatty acids, are

vulnerable to attack by reactive oxygen species resulting in the formation of

lipid peroxides. The peroxidized lipids can cause cellular damage such as

cross-linking of proteins and DNA damage. Also, oxidized low density

lipoproteins can contribute to the formation of atherosclerotic plaques. Water

and alcoholic extracts of ginger have been shown to possess potent antioxidant

activity on fats and oils and prevent lipid peroxidation.38 Zingerone was found

to inhibit liver microsomal lipid peroxidation at concentrations greater than

150 mM.39 In addition zingerone functions as an effective scavenger of

superoxide anions as measured by nitrobluetetrazolium reduction in a

xanthine-xanthine oxidase system.40

Antimicrobial and Antiparasitic Effects: Several sesquiterpenes, especially

b-sesquiphellandrene, were isolated from ginger extracts and found to possess

significant antirhinoviral activity.41 Some antibacterial properties are present

in ginger extracts but only towards a few strains of bacteria, and effects are

seen only at high concentrations. Several studies support the long-practiced use

of ginger to treat parasitic infections. Alcoholic extracts of ginger injected

subcutaneously (100 mg/kg) in dogs infected with Dirofilaria immitis reduced

microfilarial concentrations in the blood by 98%.42 The ginger compounds

[6]-gingerol and [6]-shogaol were demonstrated to result in a dose-dependent

lethal effect on Anisakis larvae in vitro.43 Anisakiasis is a common parasitic

infection in Japan largely from widespread consumption of raw seafood.

Side Effects and Toxicity

There have been no reports of significant side effects or severe toxic reactions

following the consumption of ginger in usual therapeutic doses. This fact and

the use of ginger for thousands of years by many different cultures attest to

its safety. Ginger has been approved by the German Commission E and is on the

FDA's GRAS list. However, recent studies have demonstrated the presence of

potent bioactive compounds in ginger that could cause adverse effects. For

example, high doses of ginger could result in significant inhibition of blood

platelet aggregation and cause increased bleeding due to inhibition of

prostaglandin, leukotriene and thromboxane biosynthesis. Accordingly, its use as

a postoperative treatment of nausea and vomiting should be cautioned. Also the

presence of potent cardiotonic and pressor compounds could potentially

complicate certain cardiovascular conditions such as hypertension.

The mutagenic potential of certain ginger constituents, notably gingerols

detected in the Salmonella/microsome assay, should be investigated. Finally, the

unknown effects of certain ginger components on fetal development caution

against its use during pregnancy.>>

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FROM SUNNY CALIFORNIA,

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