Pharmacology of Aardraka-Ginger (Zingiber officinale) Part 5



Pharmacology of Aardraka-Ginger
(Zingiber officinale) Part 5 

Some testimonials from modern research

Pharmacokinetics of Ginger 
             
A study was designed to investigate pharmacokinetics of Ginger (Zingiber officinale). After oral administration of 2.0 G of         Ginger (Zingiber officinale) extract to human volunteers, free 10-gingerol and 6-shogaol were detected in plasma with peak concentrations at 1 hour, but no free 6-gingerol and 8-gingerol were detected up to 24 hours. Very low concentrations (2-3 ng/mL) of 10-gingerol glucuronide and sulphate were found in colon tissues. Pharmacokinetic analysis showed that half lives of [6-8-10]-gingerol and 6-shogaol and their metabolites were 1-3 hours in human plasma. No accumulation of these phytochemicals and their metabolites was observed both in plasma and colon tissues after multiple daily dosing. [239]

In a study the solubility of phytochemicals from Ginger (Zingiber officinale) was found to be low to moderate in various pH buffers but on oral administration they were stable in gastric and intestinal juices. The metabolic products of these phytochemicals were unstable and showed high intrinsic clearance in mouse, rat, dog and human liver microsomes. Upon oral administration of 250mg/kg bodyweight of Ginger (Zingiber officinale) phenolics, sub-therapeutic concentration of the chemicals was observed. Trteament with β-glucuronidase increased the exposure of Ginger (Zingiber officinale) phenolics by 10 to 700 fold. [240]

Anti-Inflammatory activity of Ginger

For centuries, the rhizome of Ginger (Zingiber officinale) was used as an anti-inflammatory agent worldwide. The phytochemicals of the plant were shown to inhibit coclooxygenase-2. This explains anti-inflammatory activity of the plant. [241]

According to nine clinical studies, various phytochemicals in Ginger (Zingiber officinale) are strong anti-inflammatory agents. Of these, oleoresins are the strongest. Administered at 1-3 g per day over a period of two to three months, Ginger (Zingiber officinale) reduced the inflammatory marker C reactive protein (CRP) in the blood. The phytochemicals display anti-inflammatory activity by different mechanisms. The oleoresins show anti-inflammatory activity at cellular level. One of the pungent components blocked Nuclear Factor-κB (NF-κB) pathway that reduces the activity of inflammatory genes in immune cells. Some components inhibit the release of inflammatory cytokines such as Interleukin-1 β (IL- β). Some components block inflammation and pain causing cyclooxygenase (COX) enzymes, thereby reducing inflammation causing chemicals, leukotrienes and prostaglandins. [242]

Antioxidant activity of Ginger 

The rhizome of Ginger (Zingiber officinale) contains a very high level of antioxidants 3.85 mmol/100g. Reactive nitrogen species such as nitric oxide cause DNA damage. Ginger (Zingiber officinale) inhibits the production of nitric oxide. At a dose 100mg/kg bodyweight Ginger (Zingiber officinale) normalizes the nitric oxide levels. Ginger (Zingiber officinale) decreases age-related oxidative stress. [243]

Immunomodulatory activity of Ginger

In vitro and in vivo the volatile oil of Ginger (Zingiber officinale) significantly inhibited T-lymphocyte proliferation, decreased the number of the total T-lymphocytes and T-helper cells. In addition the volatile oil of Ginger (Zingiber officinale) inhibited interleukin-1α (IL-1 α) secretion by the peritoneal macrophages in the mice. [244]

Lipopolysaccharides induce production of nitric oxide. Phytochemicals of Ginger (Zingiber officinale) inhibit the production of nitric oxide, significantly reduce nitric oxide expression and modulate macrophage function. [245]   

Antibacterial activity of Ginger               

Ginger (Zingiber officinale) showed antibacterial activity against Enterobacter spp, Serratia marscense, Acinetobacter spp, Escherichia coli, Pseudomonas aeruginosa, Klebsiela spp, Salmonella spp, Staphylococcus spp, Streptococcus spp and Micrococcus spp. [246] 
Antiviral Activity of Ginger
Human respiratory syncytial virus when attaches to respiratory mucosa, causes inflammation of respiratory tract. Hot water extract of fresh Ginger (Zingiber officinale) but not of dry rhizome at a concentration of 300 μg/mL displays anti human respiratory syncytial virus (HRSV) activity. The extract prevents/blocks the attachment and internalization of the virus to respiratory mucosa. The effect is dependent on the dose employed. This activity was attributed sesquiterpenes contained in Ginger (Zingiber officinale) extracts.   

Another study showed that the inhibition of the human respiratory syncytial virus (HRSV) occurred more readily among the alveolar cells of the lung. Notably the dried Ginger (Zingiber officinale), shunthee, did not have the same effectiveness upon the virus. This indicates that some of the antiviral constituents of fresh ginger are lost during drying process. [247]

The human norovirus is surrogate of feline calivirus. This is a surrogate because calivirus is a type of Norwalk virus. Norovirus causes gastroenteritis in winter. Hence it is also known as winter vomiting bug. In humans it causes nausea, vomiting, diarrhea, stomach pain. In a study in 2016, researchers from the University of Minnesota showed that Ginger (Zingiber officinale) has anti-norovirus/ anti-Norwalk activity.   
Researchers from Japan found that Ginger (Zingiber officinale) extract stimulated the production of Tumor Necrosis Factor- α (TNF- α) expression by the human immune system. By this means Ginger (Zingiber officinale) inhibited the replication of Influenza A virus.  
  
Indian researchers showed that the compound allicin found in Ginger (Zingiber officinale), by inhibiting the binding capacity of the virus, inhibited the H1N1 Influenza A virus. 

Researchers from Heidelberg University of Germany found that essential oils from Ginger (Zingiber officinale) inhibited the replication of Herpes Simplex Virus-2 (HSV-2) within RC-37 cells and halted the formation of plaque by 90 percent. Further study showed that by interacting with the viral envelope essential oils from Ginger (Zingiber officinale) inhibited the viral growth.

Researchers found that administration of 500 milligrams of Ginger (Zingiber officinale) twice a day significantly reduced nausea and vomiting in HIV-positive patients. Whether this was due to the antiviral activity of the herb or due to the beneficial gastrointestinal effects of the herb is not known. [248]

Antifungal Activity of Ginger        
Recently researchers isolated [6], [8], [10]-gingerols from Ginger (Zingiber officinale). These compounds displayed antifungal activity against Candida albicans. [249]

Anthelmintic activity of Ginger         
       
Administration of extracts of Shunthee, dry powder of Ginger (Zingiber officinale) to sheep at the dose of 1-3 gram/kg body weight eliminated gastrointestinal nematodes. The herb is also larvicidal against Anisakis simplex. [250], [251]

Actions of Ginger on Skin

Eczema is also known as dermatitis. It is an inflammatory disorder. In this disorder, inflamed, red, itchy, cracked, rough patches appear on the skin. The phytochemical 6-Shogaol of Ginger (Zingiber officinale) reduced eczema in mice. [252]

Topical application of [6]-gingerol or [6]-paradol for 30 minutes prior to 12-O-tetradecanoyl-phorbol-13-acetate attenuated the skin papillogenesis initiated by 7, 12- dimethylbenz[a]nthracene in female ICR mice. [253]

Actions on Musculoskeletal System

One of the features of inflammation is increased oxygenation of arachidonic acid. It is metabolized by two pathways- the cyclooxygenase (CO) and the 5-lipoxygenase (5-LO)-leading to the production of prostaglandins and leukotrienes respectively. They can induce inflammation in musculoskeletal system. In a study on 28 patients with rheumatoid arthritis, 18 with osteoarthritis and 10 with muscular discomfort, powdered Ginger (Zingiber officinale) was used for 3months to 2.5 years to treat these afflictions. Seventy five percent of the patients with arthritis experienced pain relief, and reduced joint pains. Those with muscular discomfort were relieved completely. None of the patients reported adverse effects during the period of consumption of Ginger (Zingiber officinale). The ameliorative effect could be due to inhibition of prostaglandin and leukotriene biosynthesis. [254]  

In another study administration of Ginger (Zingiber officinale) at a dose1g/day could reduce inflammatory markers in patients with osteoarthritis of the knee. This suggests that Ginger (Zingiber officinale) can be recommended as a suitable supplement for these patients. [255]

In one study of 261 patients with osteoarthritis, a standardized Ginger (Zingiber officinale) extract was administered for six weeks. The extract reduced the inflammation and symptoms of osteoarthritis. The extract was found to be safe and caused only mild stomach upset.

In another study of 75 patients with osteoarthritis Ginger (Zingiber officinale) extract was effective only for the short-term and the benefits were not sustained. The discrepancy could be due to the different Ginger (Zingiber officinale) extracts used. [256]

Researchers from various groups have confirmed that Ginger (Zingiber officinale) is modestly efficacious in the treatment of osteoarthritis of the knee.

Actions of Ginger on Hematopoetic system

12-O-tetradecanoylphorbol-13-acetate (TPA) by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system or xanthine oxidase system or both induces oxidative stress in human promyelocytic leukemia (HL)-60 cells and Chinese hamster ovary AS52 cells. Ginger (Zingiber officinale) compounds effectively inhibit superoxide production, suppress lipid peroxidation and prevent the lowering in glutathione levels. [257]

Chang and Whitakar reported that Ginger (Zingiber officinale) increased bleeding time after surgery or if taken in association with anticoagulant drugs such as warfarin. Someresearchers reported that Ginger (Zingiber officinale) has no effect on clotting status in healthy subjects. [258]

Actions of Ginger on Eye

A current study showed that Ginger (Zingiber officinale) extract containing 5% of 6-gingerol attenuated the retinal microvascular changes in rats with streptozotocin-induced diabetes. The gingerol showed ant-inflammatory and antiangiogenic activity in the experimental animals. This requires further investigation. [259]

Actions of Ginger on Nervous System

Eight trials were published on analgesic activity of Ginger (Zingiber officinale). The study included 481 patients. Researchers reported satisfactory analgesic activity in osteoarthritis, dysmenorrhea, muscular aches and pains. This is due to the anti-inflammatory property of the constituents of the rhizome of the plant. [260]
Various extracts of the dried rhizome of Ginger (Zingiber officinale), Shunthee; display Muscarinic, Ca++ antagonist and specific butyrylcholinesterase inhibitory activity. This explains its use in dementia. [261]

Studies on 60 middle aged women revealed that daily intake of 400 to 800 mg of Ginger (Zingiber officinale) extract for 2 months enhanced cognition. This was due to the antioxidant property of the herb. [262] 

Alzheimer’s disease (AD) is a chronic, progressive, irreversible neurodegenerative disorder among aging people. The anti-inflammatory and antioxidant properties of   phenolics from Ginger (Zingiber officinale) prevent the aggregation of amyloid-β (Aβ) in the brain. Additionally the herb displays serotonin 5 hydroxytryptamine 1A (5HT-1A) receptor agonist activity. This also helps prevent and treat Alzheimer’s disease (AD).  [263], [264]       

Actions of Ginger on Respiratory System

Components of Ginger (Zingiber officinale) suppress allergic reactions. This property is useful for the prevention and treatment of bronchial asthma. Ghayur et al reported that in mouse model Ginger (Zingiber officinale) extract via calcium channel mediated pulmonary inflammation, inhibited airway contraction. Intraperitoneal injections of Ginger (Zingiber officinale) extract markedly decreased eosinophil accumulation in the lungs. The researchers feel that gingerols contained in the herb are instrumental for these effects. [265]    

Actions of Ginger on Cardiovascular System    

At least one group of researchers found that administration or consumption of Ginger (Zingiber officinale) extract decreased atherosclerotic lesions in aorta, plasma cholesterol and triglycerides. The study showed that the extract exerted anti-hyperlipidemic effects. Furthermore administration of 3 grams of Ginger (Zingiber officinale) powder every day to volunteers significantly lowered the lipid levels. Administration of 0.1 g/kg body weight of dried Ginger (Zingiber officinale) powder, Shunthee, for 75 days to rats lowered the development of atheroma in the aorta and coronary arteries by 50 percent. This suggests that consumption of Ginger (Zingiber officinale) improves lipid metabolism. 

Administration of Ginger (Zingiber officinale) extract or Ginger (Zingiber officinale) compounds showed antiplatele aggregation activity. This prevents coronary artery disease without the side effects of aspirin. A study showed that consumption of 5 g of Ginger (Zingiber officinale) inhibited platelet aggregation. 

Ginger (Zingiber officinale) showed a very mild blood pressure lowering activity. However Ginger (Zingiber officinale) and nifedipine were reported to have synergistic effect in hypertensive patients. Ginger (Zingiber officinale) and ginger compounds have been reported to directly stimulate myocardial sarcoplasmic reticulum calcium uptake but its therapeutic use in treating heart failure has not been advocated. [266]

In an experimental study, atherosclerosis was induced in rabbits by feeding cholesterol (0.3 g/kg body weight per animal) for 75 days. The atheroma developed in aorta and coronary arteries. Administration of Ginger (Zingiber officinale) / Shunthee at the dose of 0.1 g/kg body weight per animal for 75 days significantly inhibited the development of atheroma by 50%. Treatment with Shunthee significantly decreased lipid peroxidation and enhanced fibrinolytic activity in the animals. However Ginger (Zingiber officinale) / Shunthee did not lower blood lipids to a significant extent. Prevention of the development atherosclerosis by Ginger (Zingiber officinale) / Shunthee was probably due to free radical scavenging, prostaglandin inhibitory and fibrinolytic properties. [267]

Researchers found that activity of Angiotensin Converting Enzyme (ACE) was high in rats fed on high cholesterol diet. However when the animals were fed on red ginger 2% and white ginger 4% the levels of Angiotensin Converting Enzyme (ACE) were lowered. Furthermore the plasma levels of total cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol and triglyceride decreased. The level of high density lipoprotein cholesterol increased. [268]  

Actions of Ginger on Gastro-Intestinal System

Ginger (Zingiber officinale) extract and ginger compounds are very potent antiemetic agents. They are also useful for the treatment of flatulent dyspepsia, indigestion and acid peptic disease. (For details see above)
El-Abhar et al reported that Ginger (Zingiber officinale) extract alleviated the symptoms of acetic acid-induced ulcerative colitis. [269]

The anti-inflammatory and antioxidant activities play an important role in prevention and treatment of gastrointestinal cancers. [270]

Actions of Ginger on the Liver 

Administration of two capsules of 500mg each one hour after breakfast and after dinner for 12 weeks to participants suffering from Nonalcoholic Fatty Liver Disease (NAFLD) showed significant reduction in inflammatory cytokines,   alanine aminitransferase, γ-glutamyl transferase, hepatic steatosis grade as well as insulin resistance index. Researchers did not find much reduction in aspartate aminotransferase and hepatic fibrosis. [271]

To evaluate the protective effect of Ginger (Zingiber officinale) against fatty liver, by injecting intraperitoneally 120 mg/kg body weight of oxytetracycline for three consecutive days, hepatotoxicity and fatty liver was induced in albino rats. The animals were treated with water extract of Ginger (Zingiber officinale) at the dose of 125 mg/kg body weight for 30 days. The results showed that after treatment with Ginger (Zingiber officinale) extract the levels of liver enzymes, cholesterol, proteins, sugar returned to normal. The histological changes of fatty liver returned to normal. Researchers recommend Ginger (Zingiber officinale) as diet additive for patients with fatty liver. [272]   
 
Studies have shown that feeding rats with a diet containing 1% Ginger (Zingiber officinale) extract for four consecutive weeks was effective in ameliorating the hepatotoxicity induced by ethanol.[273]

Subsequent studies have also shown that administration of 500 mg/kg body weight of aqueous extract of Ginger (Zingiber officinale) for two consecutive weeks was effective in ameliorating alcohol induced hepatotoxicity. [274]

Additionally, studies have also shown that oral administration of 200 mg/kg body weight of alcoholic extract of Ginger (Zingiber officinale) was effective in reducing elevated serum levels of Aspartate Aminotransferase (AST) aka Serum Glutamic-Oxaloacetic Transaminase (SGOT), Alanine Aminotransferase (ALT) aka Serum Glutamic-Pyruvic Transaminase (SGPT), Alkaline Phosphatase (ALP) and Gamma-Glutamyl Transferase (GGT). [275]

Acetaminophen or paracetamol is one of the most commonly used analgesic and antipyretic agent. However its injudicious use can cause hepatotoxicity (liver damage). Studies have shown that administration of a single dose of 200 and 400 mg/kg body weight of aqueous extract of Ginger (Zingiber officinale) to rats before administration of paracetamol was effective in preventing paracetamol-induced hepstotoxicity. Other studies have shown that administration of graded doses of 100, 200 and 400 mg/kg body weight extract of Ginger (Zingiber officinale) to rats at 12 hour interval for 48 hours prior to administration of a single dose of 640 mg/kg body weight of paracetamol displayed hepatoprotective effect. [276]    
  
Oral administration of ethanolic extract of Ginge (Zingiber officinale) to rats ameliorated carbon tetrachloride-induced hepatotoxicity. Additionally histopathological study also showed that the extract normalized the structure of the liver.  [277]

Lindane is used to treat lice and scabies. It works by killing lice and mites. It is also known as gammaxene, Gammallin and gamma-hexachlorocyclohexane (γ-HCH). Sometimes it is ironically called as benzene hexachloride (BCH). It is organochlorine, an isomer of hexachlorocyclohexane. [278]

Lindane is a potent toxin that damages the nervous system, liver and kidneys. Studies have shown that dietary supplement of Ginger (Zingiber officinale) 1%w/w was effective in reducing Lindane-induced lipid peroxidation and hepatotoxicity. This is due to antioxidant property of Ginger (Zingiber officinale). [279]

Ethylene-bis-dithiocarbamate (Mancozeb) is a potent fungicide. It is widely used in agriculture to protect field crops, fruits and nuts. Mancozeb is a cholinesterase inhibitor and affects the nervous system. Mancozeb is hepatotoxic. Studies on albino rats have shown that Ginger (Zingiber officinale) at the concentration of 24mg/ml (dose not mentioned) three times a week for six weeks was effective in protecting the liver against mancozeb-induced liver toxicity. [280]

Bromobenzene is used in industry as a solvent. It is used as an additive to motor oils. Exposure to bromobenzene causes neurotoxicity and hepatotoxicity. Studies have shown that administration of ethanolic extract of Ginger (Zingiber officinale) at 100, 200 and 300 mg/kg body weight for two weeks, one week prior to exposure to bromobenzene prevents hepatotoxicity or alleviates previously existing hepatotoxicity.  [281]

Parabens are an important class of preservatives. They are widely used in pharmaceutical industries, for preparing shampoos, commercial moisturizers, shaving creams, tropical lubricants, tooth pastes, tanning solutions etc. Methylparaben, ethylparaben, propylparaben, butylparaben are most commonly used parabens. They are shown to induce allergic reactions hepatotoxicity. Studies on mice have shown that co administration of 3 mg/kg bodyweight of aqueous extract of Ginger (Zingiber officinale) per animal for 30 days along with parabens ameliorated paraben toxicity. [282]     

Heavy metals like lead, arsenic, zinc, cadmium, mercury etc are hepatotoxic. They are environmental pollutants. Studies by Vitalis et al showed that feeding Ginger (Zingiber officinale) containing diet to male Wistar rats was effective in ameliorating hepatotoxicity. [283]

Ferrous sulphate is the commonest oral iron supplement used to treat iron deficiency anemia in humans. Iron overload induces toxic effects in the body. In an experimental study, ferrous sulphate was administered to rats at 30 mg/kg body weight/ day for 14 days. To evaluate the protective role of hydroalcoholic extract of Ginger (Zingiber officinale) against ferrous sulphate induced hepato-renal dysfunction and structural damages, the rats were treated with Ginger extract at 400mg/kg body weight for 14 days. The results suggest that Ginger (Zingiber officinale) ameliorates ferrous sulphate induced toxicity.[284]

The liver cancer is caused by chronic consumption of hepatotoxins, viruses such as hepatitis B and C. Feeding of oleoresins from Ginger (Zingiber officinale) at 100 mg/kg body weight to rats for eight weeks reduced the number of liver nodules. [285]

 

Mechanisms of Action

By various mechanisms Ginger (Zingiber officinale) exerts its pharmacological actions. They can be summarized as……

1. It is a potent anti-inflammatory agent

2. It has a potent antioxidant and free radical scavenging property.

3. It inhibits/breaks the chain of lipid peroxidation.

4. It enhances enzymatic and non-enzymatic antioxidant systems in vitro and in vivo  

5. It modulates detoxifying enzymes.


Actions on Pancreas

To evaluate the action of aqueous extract of Ginger (Zingiber officinale) on function and structure of pancreas, alloxan was used to induce diabetes in rats. Diabetic rats were then treated with 500mg/kg body weight per day and 1000mg/kg body weight per day of aqueous extract of Ginger (Zingiber officinale). The result showed with either dose the extract was effective in lowering serum glucose to normal levels. The microscopic study showed that the extract also restored the pancreatic structure to normal. [286] 

A group of researchers studied the effect of ethanol extract of Ginger (Zingiber officinale) on human pancreatic cancer cell lines including Panc-1 cells. The extract enhanced the vacuolization of the cytoplasm in Panc-1 cells. Researchers also found that cancer cell death was due to autosis (autophagy) and not due to apoptosis. Focal cell membrane rupture, nuclear shrinkage, focal swelling of the perinuclear space and electron dense mitochondria, the unique features of autosis were observed. The extract enhanced the generation of reactive oxygen species. Additionally the antioxidant N-acetylcystein attenuated cell death. The extract did not show adverse side effects on normal cells. [287]

Actions on Metabolism

To evaluate the efficacy of lipid lowering activity of aqueous infusion of Ginger (Zingiber officinale) the infusion was administered orally (100, 200, and 400mg/kg body weight) to hypercholesterolaemic rats. The infusion was administered for 2-4 weeks. The results revealed that the infusion significantly lowered all parameters in lipid profile in hypercholesteraemic rats. The effect was comparable to that of atorvastatin.  [288]

Subclinical hypothyroidism is associated with dyslipidaemia. Due to reduction in the number of cell surface receptors for low density lipoprotein (LDL), the catabolism of LDL results. Hence there is accumulation of LDL resulting in high levels of low density lipoprotein (LDL). In subclinical hypothyroidism/ hypothyroidism, diminished secretion of cholesterol into the bile has been demonstrated. In hypothyroidism, though the rate of synthesis of triglycerides is normal, reduced lipoprotein lipases activity results into hypertriglyceridaemia.

The relationship between lipid levels and hypothyroidism remains controversial. Various observers have obtained variable and inconsistent results. But elevated levels of lipids and triglycerides are observed in majority of cases. [289]  

In an experimental study, by using propylthiouracil, hypothyroidism was induced in rats. Subsequently lipid profile was studied. To evaluate the effects of Ginger (Zingiber officinale) on dyslipidemia of hypothyroid rats, 300 mg/kg body weight of Ginger (Zingiber officinale) extract was administered to rats for 30 days. The results showed that the extract corrected the dyslipidaemia. [290]

Peroxisome proliferator-activited receptor β and δ are nuclear hormone receptors that govern a variety of biological processes. They may be involved in the development of several chronic diseases such as obesity, diabetes, atherosclerosis and cancer. This protein has been shown to be involved in lipid accumulation. Administration of Ginger (Zingiber officinale) to mice fed on high fat diet enhanced fat burning. Some animals showed weight loss. In some animals the exercise endurance improved. This activity is mediated via PPAR δ pathway [291]

Actions of Ginger against Diabetes

Administration of raw Ginger (Zingiber officinale) intraperitoneally (IP) at 500 mg/kg bodyweight daily to streptozotocin-induced diabetic rats, lowered serum glucose, cholesterol and triglyceride levels. It decreased thirst and excessive water intake, stabilized urine output, decreased urine protein levels, prevented weight loss associated diabetes. This suggests that Ginger (Zingiber officinale) may be valuable in managing effects of diabetes mellitus in humans. [292]   

Actions of Ginger on Urinary System
A study showed that treatment with ethanol extract of Ginger (Zingiber officinale) ameliorated carbon tetrachloride-induced nephropathy. [293]
Gentamycin (GM) is the commonest aminoglycoside used for the treatment of urinary tract infections. However it is nephrotoxic. In a study on Wistar rats, to one group, 200 mg/kg body weight of Ginger (Zingiber officinale) was administered orally to each animal for 3 days. Then Gentamycin (GM) 80 mg/kg body weight was administered for 7 days. To another group Ginger (Zingiber officinale) was administered orally to each animal for 3 days then ginger plus gentamycin for 7 days. To third group gentamycin (GM) for 7 days followed by Ginger (Zingiber officinale) orally 200 mg/kg body weight for 10 days. The results showed that in all the groups Ginger (Zingiber officinale) protected the rats from gentamycin induced nephrotoxicity.[294]
Lead poisoning is associated with structural and functional abnormalities of multiple organs. A study was arranged to evaluate the effects of Ginger (Zingiber officinale) on nephrotoxicity induced by lead poisoning. The rats with lead-nephropathy were treated with 150 mg/kg body weight of Ginger (Zingiber officinale) extract for3 weeks. The results revealed that the Ginger (Zingiber officinale) extract ameliorated the toxic effects lead. [295]  

Actions on Ginger on Male Reproductive System

A study on rats showed that oral administration of 100mg/kg bodyweight per day of Ginger (Zingiber officinale) increased total serum testosterone. Besides Ginger (Zingiber officinale) increased the sperm count, the percentage of viable sperms and the motility of the sperms. This suggests that Ginger (Zingiber officinale) may be used to improve fertility in subfertile males. [296]  

More than twenty years ago, scientists have discovered the link between Ginger (Zingiber officinale) and testosterone. Recent studies showed that of 75 infertile/ subfertile males treated with Ginger (Zingiber officinale) for three months, 17% showed increase in testosterone levels. The treatment also increased the sperm count and motility of the sperms. [297]

Studies reveal that administration of 500 mg daily for three months of Ginger (Zingiber officinale) powder to infertile men protected sperm DNA against oxidative damge. After treatment their sperm DNA quality greatly improved. Essential oil of Ginger (Zingiber officinale) also reduced DNA damage from aflatoxin B1 in cells. [298]  

Cisplatin is an anticancer chemotherapeutic agent. It is cytotoxic to many normal tissues also. Its toxic effects on reproductive organs are ominous. To evaluate the beneficial effects of Ginger (Zingiber officinale) against cisplatin toxicity, ethanol extract of Ginger (Zingiber officinale) at the dose of 1g/kg body weight/ day was administered orally to albino rats 21 days prior to a single intraperitoneal (IP) injection of 10 mg/kg body weight of cisplatin. Oral administration of Ginger (Zingiber officinale) was continued to a total of 26 day-course (21 days prior and 5 days after cisplatin). The extract protected the animals from cisplatin toxicity. There was no testicular damage and sperm motility was restored to normal. [299]   

The term “gavage” refers to supplying nutrition or medicines by means of a nasogastric or orogastric tube. This route of administration is preferred for studies on experimental animals. Sodium arsenite is toxic to male reproductive system. In a study male rats were exposed to sodium arsenite at the dose, 10mg/kg body weight/day by gavage via oral cannula. Weight of the reproductive organs, sperm count, motility of the sperms; weight of the epididymis, weight of the prostate and seminal vesicles confirmed the toxicity of male reproductive system. The animals were then treated with aqueous extract of Ginger (Zingiber officinale) at the dose 500mg/kg body weight for 30 days. The extract was found to protect the reproductive system from the toxicity of sodium arsenite. [300]


Actions on Female Reproductive System              
A group of researchers studied the effect of steam distilled extract of Ginger (Zingiber officinale) on endometrial cancer cell (ECC) lines (ECC-1) and Ishikawa cells. At the concentration of 1.25μg/mL the steam distilled Ginger extract (SDGE) inhibited the proliferation of ECC-1 and Ishikawa cells. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin, decreased proliferation of ECC-1 and Ishikawa cells and induced apoptosis. Of various phenolic compounds contained in Ginger (Zingiber officinale), 6-gingerol was weaker than 6-shogaol in this regard. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and 20 to 40% decrease in the mitochondrial membrane potential. The researchers concluded that terpenoids from steam distilled ginger extract (SDGE) mediated apoptosis by activating p53. This activity should therefore be investigated as agents for the treatment of endometrial cancer.  [301]
In an experimental study, cultured ovarian cancer cells were treated with Ginger (Zingiber officinale). The treatment resulted in inhibition of nuclear factor-κ-B (NF-κ-B) activation, diminution of secretion of Vascular Endothelial Growth Factor (VEGF) and diminution of secretion of Interleukin-8 (IL-8). Thus treatment with Ginger (Zingiber officinale) resulted in inhibition of growth of ovarian cancer cells. [302]   

Six clinical trials revealed that 750 mg to 2000 mg of powder form of Ginger (Zingiber officinale) i.e. Shunthee per day during first three days of menstruation relieved symptoms of premenstrual syndrome (PMS), especially pain due to dysmenorrhea better than mefenamic acid or ibuprofen, commonly used non steroidal anti-inflammatory drugs (NSAIDs)  [303]

Antitumor Activity of Ginger

A number of preclinical investigations have shown that phytochemicals of Ginger (Zingiber officinale) possess chemopreventive and antineoplastic effect. A number of mechanisms have been observed to be involved. Researchers feel that the cancer preventive activity of Ginger (Zingiber officinale) is due to free radical scavenging, antioxidant pathways, alteration of gene expressions and induction of apoptosis. They contribute towards decrease in tumor initiation, promotion and propagation. [304]

The anticancer properties are attributed to pungent vanillyl compounds viz. [6]-gingerol and [6]-shogaol and other constituents zingerone etc. These compounds are anti-inflammatory, antioxidant agents. [305]

Toxicity/ Safety Assessment

Administration for 13 weeks of ginger oil at doses of 100, 200, 500 mg/kg body weight per day to rats of either sex did not show signs of toxicity. These doses did not reveal changes in hematological parameters, hepatic-renal functions, no changes in serum electrolytes. [306]

In another study, administration of 500, 1000, 2000 mg/kg body weight for 35 days of Ginger (Zingiber officinale) to rats was not associated with any mortalities, any abnormalities in general conditions, behavior, growth and food and water consumption. However in male rats, dose-related decrease in serum lactate dehydrogenase activity was observed. Very high dose of 2000 mg/kg body weight of Ginger (Zingiber officinale) led to slightly reduced weight of testes. [307]   

Side Effects

While Ginger (Zingiber officinale) is safe for use as medicine, some people can have moderate side effects such as heart burn, gastric discomfort and diarrhea. Some women have reported extra menstrual bleeding while taking Ginger (Zingiber officinale).

Ginger (Zingiber officinale) is possibly safe when applied to the skin appropriately, short term. However its long term use may cause skin irritation for some people. [308]    

Special Precautions

Children: Ginger (Zingiber officinale) is safe for use in children up to 4 days and for teenage girls around the beginning of their period.                    

Pregnancy: Pregnancy is a special event in the life of a woman. While Ginger (Zingiber officinale) is useful for the treatment of morning sickness its use in later part of pregnancy is controversial. There is some concern that Ginger (Zingiber officinale) might increase the risk of bleeding during delivery. However if Ginger (Zingiber officinale) is necessary to be used, risk against benefit must be assessed before its use. 

Lactation and breast feeding: There is not enough reliable data regarding the use of Ginger (Zingiber officinale) during lactation and breast feeding. It is safer to avoid its use during lactation.

Bleeding disorders: Taking Ginger (Zingiber officinale) certainly increases the risk of bleeding. It must be avoided in such conditions.

Diabetes: Ginger (Zingiber officinale) might increase the insulin levels and lower blood sugar levels. Those who take anti-diabetic drugs should take precautions before using Ginger (Zingiber officinale).

Heart ailments: Ginger (Zingiber officinale) might worsen some heart ailments. [309]

Contraindications

There are no specific contraindications for the use of Ginger (Zingiber officinale). With proper precautions it can safely be used. 

Traditional and Ayurvedic uses

Gastro-Intestinal Troubles (GIT): According to Ayurveda and proverbial grandmothers, Ginger (Zingiber officinale) is a remedy par excellence for nausea, vomiting, dyspepsia and indigestion. It was indeed the drug of choice used by pregnant women for morning sickness. In this condition its action is slow and the dose to be used may be a little larger. Traditionally a combination of Ginger (Zingiber officinale) and lemon juice is used to treat Gastro-Intestinal troubles (GIT).

Jaundice:  Ginger (Zingiber officinale) was an important drug used for jaundice. Here it was used in combination with lemon juice or with   jaggery to make it more palatable or agreeable.

Dizziness, Fainting, Vertigo etc: This group of symptoms has a wide range of etiology. Whatever the cause be Ginger (Zingiber officinale) does relieve these symptoms.

Respiratory disorders: While episodic cough is troublesome to the patient, the incessant cough disturbs others around him. Ginger (Zingiber officinale) powder or aqueous extract does relieve cough.

Whether Ginger (Zingiber officinale) relieves bronchial asthma is a subject for debate.

Arthritis: Joint pain of any kind is annoying, troublesome. Be it due to traumatic arthritis, rheumatoid arthritis or osteoarthritis the sufferer becomes restless, for he/she cannot endure the pain and does not find certain cure for the malady. The analgesic property of Ginger (Zingiber officinale) can alleviate the joint pain to some extent.

Dysmenorrhea: Painful menstruation is the worst insult inflicted on womanhood, especially at menarche and few years of young age. Taking Ginger (Zingiber officinale) powder 500 to 2000 mg during the first 3-4 days of menstrual cycle can offer relief from dysmenorrheal. 

Additional information:

Ginger (Zingiber officinale) can possibly be used in following conditions though there is insufficient evidence. In some conditions its efficacy is also debated.

1. Nausea, vomiting following chemotherapy for cancer. Taking Ginger (Zingiber officinale) with chemotherapy does not seem to prevent nausea and vomiting, but taking Ginger (Zingiber officinale) two days prior to chemotherapy alleviate this adverse effect. This effect of Ginger (Zingiber officinale) in alleviating nausea and vomiting are conflicting. It possible that Ginger (Zingiber officinale) helps to reduce nausea and vomiting caused by certain drugs and not caused by others.

2. Loss of appetite, stomach upset is a common complaint. In many patients no satisfactory cause can be found. Taking a single dose of 1.2 grams of Shunthee i. e. dry Ginger (Zingiber officinale) powder one hour before food intake improves this condition.

3. Taking Ginger (Zingiber officinale) alone does not seem to improve symptoms of Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD). But some polyherbal formulations containing Ginger (Zingiber officinale) seem to alleviate the symptoms of the patients suffering from these conditions. Probably the synergy of the ingredients is beneficial.                                                           

4.  Many drugs especially antitubercular drugs are hepatotoxic and cause hepatic dysfunction. Taking Ginger (Zingiber officinale) along with these drugs might help prevent hepatic damage in some people.

5. Taking Ginger (Zingiber officinale) before consumption of alcohol decreases the symptoms of alcohol hangover including alcohol-induced nausea, vomiting and diarrhea.  

6.  Taking two capsules of specific combination product AKL1, AKL containing Ginger (Zingiber officinale) twice daily for eight weeks does not improve respiratory symptoms in patients with Chronic Obstructive Pulmonary Disease (COPD)  

7. Administration of 120 mg of Ginger (Zingiber officinale) extract daily for up to 21 days, improves the respiratory comfort in patients with respiratory failure. They may not require respiratory support on ventilator. However Ginger (Zingiber officinale) extract does not affect the death rates in people with this condition. 

8. Drinking black tea with small quantity of Ginger (Zingiber officinale) might be useful in reducing blood pressure in some people with hypertension. This activity is through blockade of voltage dependent calcium channel.      

9. Taking at least 3 grams of Ginger (Zingiber officinale) per day lowers increased blood sugar. However it might take 2-3 months before benefits are seen. Lower dose is not effective in lowering blood sugar.

10. Taking 1 gram of Ginger (Zingiber officinale) three times daily for 45 days lowers cholesterol in persons with high cholesterol levels. This dose also lowers triglycerides.

11. Taking Ginger (Zingiber officinale) alone helps obese people lose weight a little bit. But there may not be much discernible effect. There is no added advantage of taking polyherbal formulations with Ginger (Zingiber officinale) as one of the ingredients.

12. Ginger (Zingiber officinale) is said to reduce the intensity of pain in migraine. It might also reduce the length of migraine pain. [310]

Interactions

Ginger (Zingiber officinale) might slow blood clotting. Hence it can interact with anticoagulants, antiplatelet agents like heparin, warfarin, aspirin, clopidogrel, phenprocoumon (a long acting anticoagulant available outside the US). Ginger (Zingiber officinale) can interact with nonsteroidal anti-inflammatory agents (NSAIDs) like ibuprofen, diclofenac, naproxen etc.     

Ginger (Zingiber officinale) might lower blood sugar. As hypoglycemic agents lower blood sugar, Ginger (Zingiber officinale) can exert summation effect with them or might even potentiate the actions of hypoglycemic agents.

Ginger (Zingiber officinale) might lower blood pressure. This action is similar to calcium channel blockers. Hence Ginger (Zingiber officinale) should be used with caution if a patient is taking calcium channel blockers.  

Ginger (Zingiber officinale) is known to lower cholesterol and triglycerides. Hence the dose of lipid lowering agents should be adjusted carefully. [311]

Preparations and doses    

Usually fresh ginger or ginger powder (Shunthee) is used in the doses from 500 mg to 3 grams as a single dose or in aliquots; three or four times a day.
The following doses and routes of administration have been documented by researchers.
  
Oral Route:

For nausea and vomiting: 1 gram of fresh ginger or powder (Shunthee) daily in two divided doses 30 minutes before each meal for 14 days.

For Dysmenorrhea, PCOD: 250 to 500 mg of ginger extract three to four times a day for first three days from the start of the menstrual period.
Also 500 mg ginger powder three times a day, for three days starting from two days before menstruation and continuing for three days of the menstrual cycle. 

For morning sickness: 500 mg of fresh ginger two to three times a day up to three weeks as required.

For Osteoarthritis: 250 mg of extract or 250 mg of ginger powder two to three a day. 

Some special formulations-----

Eurovita Extract 33, EV ext-33: 170 mg three times a day. 

Eurovita Extract 77, EV ext-77 which combines ginger with alpinia: 225 mg twice daily.

Zintona EC (ginger extract): 250 mg four times a day.

Eurovita Extract 35, EV ext-35 (Ginger extract): 340 mg daily in combination with 1000 mg of glucosamine daily for four weeks.

For nausea and vomiting after surgery: 1 to2 grams of ginger powder after surgery.

For Vertigo: 1 gram of ginger powder as a single dose one hour before expected or suspected attack.                                         

Inhaled as Aroma therapy:

A solution of ginger essential oil has been used. In aroma therapy ginger alone or in combination with spearmint, peppermint and cardamom is used. It is inhaled through nose and exhaled through mouth.

Application to skin:

For osteoarthritis, a specific gel containing ginger and plai, (Plygersic gel recommended by Thailand Institute of Scientific and Technological Research) 1 gram four times a day for six weeks [312]




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[310] https://www.webmed.com/vitamins/ai/ingredientmono-961/ginger

[311] https://www.webmed.com/vitamins/ai/ingredientmono-961/ginger















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