RED GINGER (Zingiber officinale var. rubrum): ITS CHEMICAL CONSTITUENTS, PHARMACOLOGICAL ACTIVITIES AND SAFETY

Ginger (Zingiber officinale) which belongs to the Zingiberaceae family, was first cultivated in Asia (Indonesia and Malaysia). This plant is one of the most commonly used herbal supplements taken by many patients to treat various conditions. Z.officinale has three varieties based on its size, colors of rhizome and chemical constituents i.e. .Z. officinale var. officinale (big white ginger or giant ginger, badak or gajah), Z. officinale var. amarum (small white ginger, emprit), and Z. officinale var. rubrum (small red ginger, merah or beureum). These three varieties may partly be deferred from their essential oil contents and are used for different purposes. The essential oils contained in Z. officinale var. rubrum are higher than the other types of ginger, which makes stronger in its pungency smell and taste. There are many studies that confirm beneficial effects of red ginger against the symptoms of diseases, i.e. anti-inflammation, antioxidant, antiemetic, antibacterial and antidiabetics. Z.officinale var. rubrum is considered to be a safe herbal medicine with only few and insignificant adverse/side effects. Although the medicinal properties of red ginger have been known, further trials in humans are required to determine the efficacy of red ginger (or one or more of its constituents) and to establish what, if any, adverse effects are observed.


INTRODUCTION
Herbal medicines are currently in great demand in developed countries for primary health care because of its usefulness, safety and lower side effects (Bhargava et al., 2012). According to a report by the World Health Organization, 80 % of the population in developing countries depend on herbal medicine for their primary health care, and 85 % of herbal medicine are derived from plants (Ghasemzadeh et al., 2015).
The rhizome of Zingiber officinale has been used as a component in Indonesian jamu. This particular plant is classified into three varieties based on its size, colors of rhizome, and chemical constituents, i.e.
Z. officinale var. officinale Roscoe (big white ginger or giant ginger, badak or gajah), Z. officinale var. amarum (small white ginger, emprit), and Z. officinale var. rubrum (small red ginger, merah or beureum) (Figure 1). The essential oils of the big white ginger is the lowest compared to the other varieties. The big white ginger is commonly used for food and beverages, while the others are mostly used for medicinal purposes (Setyawan et al., 2014).
Z. officinale var. rubrum (Zingiberaceae) was first cultivated in Asia (Indonesia and Malaysia) but is now cultivated in the West and other tropical regions (Africa, India). Rhizome of red ginger has been used as seasoning ingredient, food flavor, as well as herbal medicine (Singletary, 2010;Bhattarai et al., 2001). There are many studies that confirmed benefical effects of red ginger as anti-inflammatory, antiemetic, antitumor, analgesic, anti-hemorrhagic, neuronal cell protective, anti-rheumatic, antifungal, and antibacterial agent (Mesomo et al., 2012;Kumar et al., 2011).

Botanical Description
Z. officinale var. rubrum is an annual plant that can grow up to 50-100 cm tall. The leaves are lancet-shaped with a length of 5-25 cm and width of 1.5-2 cm, the tip of the pointed leaves and clasping the stem by long sheaths. Stems grow perpendicular and rounded flat, not branched. Flowers are compounded and ovoid with stem length 10-25 cm oval shaped with a stalk length of 10-25 cm and crown of flowers purple measuring 2-2.5 cm. Small flower petals are tubular and jagged three. The fleshy rhizomes are thick and reddish-brown and red rhizome skin. The single root is getting bigger along with its age, to form the rhizomes and shoots that will grow into new plants. The roots grow from the bottom of the rhizome, while the buds will grow from the top of the rhizomes (Ross, 1999 andSupriadi et al., 2011).
Gingerol  The pungency of fresh ginger is due primarily to the gingerol, of which  (Wohlmuth, 2005). Degradation rates of gingerol to shogaol were also found to be pH dependent, with greatest stability at pH 4, whereas at 100 o C and pH 1, the reversible degradation was relatively rapid (Bhattarai et al., 2001).

Pharmacological Activities
The rhizome of Z. officinale, var. rubrum was reported for various medicinal properties including antiinflammatory activity, anti-oxidant activity, anti-nausea/antiemetic activity, anti-bacterial activity, cytotoxic activity and antidiabetic activity.

Anti-Inflammatory Activity
The effect of Z. officinale, var. rubrum extract (10-100 mg/kg) on acute inflammation was experimented on acetic acid induced abdominal inflammation model in mice 4 . In addition, intraperitoneal injection of [6]-gingerol (50mg/kg) relieved pain by 50%. As revealed in this experiment, this plant extract in low oral dose of 0.2-2mg/kg demonstrated effective analgesic and antiinflammatory effects suggesting the synergisms of various physiological compounds presents in the extract (Shan et al., 2010).

Antioxidant Activity
Ginger extracts inhibited lipid peroxidation by 72% in human erythrocyte membranes, whereas in human chondrocytes, ginger's volatile oil effectively prevented the production of hydrogen peroxide usually induced by fulvic acid. Animal study using high fat diet rat model revealed that supplementation with ginger provided significant antioxidant effects, raising tissue concentrations of superoxide dismutase and catalase and reducing glutathione (Kemper, 1999). In addition, the antioxidant effect of Z. officinale was reported by DPPH radical scavenging activity. The total phenolic content in the alcoholic extract of the dried rhizome of Z. officinale was 870.1 mg/g of dry extract. The extract exhibited 90.1% of DPPH radical scavenging activity with the IC50 concentration of 0.64 µg/ml (Kumar et al., 2011).

Antinausea/Antiemetic
Some of the disparities in study outcomes may be due to differences in dosages used. Typically 1 g/d of ginger powder was administered, although in some studies doses as low as 0.3 g/d and as high as 2.0 g/d were evaluated. Differences in timing of outcome measurements also could have contributed to disparities. In those studies demonstrating efficacy, there were generally no adverse effects (Chaiyakunapruk et al., 2006). Ginger also may act on the 5-HT3 receptor ionchannel complex in the gastrointestinal tract. In humans, ginger intake (1-2 g) may block production of gastric prostaglandins and decrease plasma vasopressin release induced by circular vection (Riyazi et al., 2007).

Antibacterial
In vitro studies of ginger extracts and ginger chemical constituents have been reported and indicated a growth suppression of various common infectious bacteria including Staphylococcus aureus and Listeria monocytogenes (Norajid et al., 2007). The inhibitory activity of of gingerols and phenolic metabolites towards the growth of Helicobacter pylori suggested a new potential use of ginger in combating H. pylori related gastrointestinal diseases (Siddaraju dan Dharmesh, 2007).

Cytotoxic Activity
Red ginger extract revealed anticancer activity through inhibition of NF-κB activation, furthermore this plant showed anti-inflammatory activity through inhibition of TNF-α . Single-dose toxicity test using 2000mg/kg of red ginger extract (maximum dosage without burden on animals) resulted no fatal event and no abnormal changes in the weight of mice (compared to control). Similarly, no abnormal changes detected in organs of mice upon partial inspection conducted after the test. The LD50 (oral) of red ginger extract on male/female mice is deduced to be >2,000mg/kg (Kitagata et al., 2011).

Antidiabetic Activity
Hypoglycaemic activity of ginger was reported in streptozotocin-induced diabetic rats. Treatment with aqueous extract (500 mg/kg body weight, i.p.) of ginger for a period of 7 weeks significantly decreased the serum glucose, cholesterol and triacylglycerol levels in the diabetic-induced rats compared with the control group (Alamin et al., 2006). Treatment with ginger juice in streptozotocin-induced type I diabetic rats resulted a significant increase in insulin levels and a decrease in fasting glucose levels. Ginger treatment also caused a decrease in serum cholesterol, serum triglyceride and blood pressure in diabetic rats (Akhani et al., 2004).

Safety and Dosage
The Food and Drug Administration has given ginger GRAS (generally recognized as safe) status for use as a food supplement. Food allergy to spices is infrequent Aside from mild stomach upset in persons unaccustomed to spicy foods, ginger has no known acute toxicity at the usual doses consumed for dietary or medicinal purposes. Very large doses of 6 grams or more of ginger may lead to gastric irritation and loss of protective gastric mucosa. At normal doses (up to 2 grams daily), ginger does not interfere with blood clotting or any individual coagulation parameter. A dose of 0.5 -1.0 g of ginger powder ingested 2-3 times for periods ranging from 3 months to 2.5 years did not cause any adverse effects. The British Herbal Compendium documents no adverse effects of ginger. The acute oral LD 50 in rats of roasted ginger is 170 g/kg body weight. Dry ginger is more than 250 g/kg body weight. In addition other research, the acute LD50 of ginger in rats is greater than 5 grams of ginger oil per kilogram of body weight (Singletary, 2010;Kumar, 2011).
Red ginger can be consumed as a fresh or dried root and is often prepared in teas, soft drinks (including ales), and breads. No specific dosing studies have been performed; however, most clinical research has used between 250 mg and 1 g of the powdered root in capsular form, taken one to four times daily. Recommended daily dose for (1) red ginger extract: 15-20 mg 4 , (2) dried powder: 250-1000 mg four times daily by mouth. Chinese herbalists may use up to 10 times this amount (Kemfer, 1999 andWhite, 2007).

CONCLUSION
Z officinale var. rubrum is considered to be a safe herbal medicine with only few and insignificant adverse/side effects. Although the medicinal properties of red ginger have Fitofarmaka Jurnal Ilmiah Farmasi been known for thousands of years, a significant number of in vitro, in vivo, and epidemiological studies further provide substantial evidence that ginger and its active compounds are effective against wide variety of human diseases. Further trials in humans are required to determine the efficacy of red ginger (or one or more of its constituents) and to establish what, if any, adverse effects are observed.