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Terminalia

Scientific Name(s): Terminalia arjuna Wight and Arn., Terminalia bellirica (Gaertn.) Roxb., Terminalia chebula Retz.
Common Name(s): Argun kahua, Arjuna, Axjun, Bahera (Bahira), Bala harade (T. chebula), Balera (T. bellirica), Behada, Hara, Harada, Haritaki (T. chebula), Hirala, Kumbuk (T. arjuna), Myrobalan

Clinical Overview

Use

Terminalia has been evaluated to a limited extent for its cardiovascular properties and for its role in cancer therapy. Hepatoprotective, cardiovascular, antidiabetes, cholesterol-reducing, antimicrobial, and antioxidant effects have been described.

Dosing

Clinical studies have been conducted in cardiovascular disorders using T. arjuna bark extract at doses of 500 mg every 8 hours for up to 3 months. Dosages for other Terminalia species have not been clinically defined.

Contraindications

Contraindications have not been determined.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Avoid use.

Interactions

None well documented.

Adverse Reactions

Extracts of T. arjuna are well tolerated. Adverse reactions similar to those seen with placebo (constipation, headache, abdominal discomfort, body ache) have been described. T. arjuna has also been found to exert antiplatelet and anticoagulant activity. In rats, T. arjuna extract was found to decrease thyroid hormone levels.

Toxicology

Information is limited.

Botany

Terminalia species are evergreen trees. T. arjuna reaches approximately 30 m in height, has light-yellow flowers, and cone-shaped leaves. T. bellirica has clustered oval leaves and greenish, foul-smelling flowers with brown, hairy fruit about the size of a walnut. T. chebula grows approximately 21 m in height with white flowers and small, ribbed fruits. T. arjuna is used primarily for its bark; in other Terminalia species, the fruit is used.1, 2, 3, 4, 5

History

Arjuna bark has been used in the traditonal Ayurvedic medical system for at least 3,000 years as a remedy for heart ailments, and T. chebula has been used as a digestive aid. This species, referred to as "king of medicine" by Tibetans, is often depicted in the extended palm of Buddha. A traditional Ayurvedic herbal combination dating back 5,000 years is a mixture of 3 herbs, 2 of which are Terminalia species: T. bellirica (for health-harmonizing qualities), T. chebula (to normalize body balance), and Emblica officinalis (for vitamin C content; see separate Emblica monograph).3, 4 The fruit of T. arjuna has been used as a tonic, with the leaf paste applied externally on sores and ulcers. Additionally, the stem bark has been used for its antidysenteric, antipyretic, astringent, cardiotonic, and lithotriptic effects. The bark powder has diuretic effects and is used to treat hepatic cirrhosis and hypertension. The extract of the bark has been used to treat sores, ulcers, and scorpion stings, and to lower blood glucose.6

Chemistry

Tannins, flavonoids, and sterols have been identified in Terminalia species. Other constituents include amino acids, fructose, resin, and fixed oils.

In varying compositions, anthraquinones, gallic acid, chebulinic and chebulagic acid, ellagic and ethaedioic acids, and terpinenes and terpinenols have been described from T. chebula.4, 5, 7, 8

T. arjuna roots contain the oleanane triterpenoids arjunic acid, arjungenin, glycosides, and cardenolide.9, 10 Anthraquinones and gallic acid have been isolated from T. bellirica.4, 11

Uses and Pharmacology

Antimicrobial

In vitro/Animal data

Activity has been demonstrated against various gram-positive and gram-negative bacteria including Staphylococcus aureus,12, 13, 14, 15, 16 Salmonella typhi,15, 17 Clostridium perfringens, Escherichia coli,8 certain dermatophytes,18 Bacillus subtilis,15 Staphylococcus epidermidis,15 Pseudomonas aeruginosa,15 and Candida species.18, 19, 20 Aqueous, methanol, butanol, and other fractions have all been evaluated and have somewhat different properties.

T. bellirica has demonstrated antimicrobial activity in vitro, including activity against methicillin-resistant S. aureus.13, 21, 22

The organic extracts of T. arjuna leaves inhibited the growth of human isolates of S. aureus, Proteus mirabilis, Acinetobacter, and P. aeruginosa. Bark extracts of T. arjuna showed inhibitory activity against these bacteria, except for P. aeruginosa.16

Experimentation in Helicobacter pylori-infected gastric epithelial cells with 24 medicinal plants indigenous to Pakistan was conducted to evaluate their effect on secretion of interleukin (IL)-8 and generation of reactive oxygen species (ROS) in order to assess anti-inflammatory and cytoprotective effects. Although no significant direct cytotoxic effects on the gastric cells or bactericidal effects on H. pylori were found, T. chebula fruit extract was observed to have strong inhibitory activity on IL-8 at 50 and 100 mcg/mL in H. pylori-infected gastric cells.76

Certain Terminalia species demonstrate in vitro antiviral activity.23, 24, 25, 26, 27

Clinical data

No clinical data exist regarding the use of Terminalia for its antimicrobial effects.

Cancer

In vitro/Animal data

T. chebula (dried fruit)28 and T. arjuna (bark)29, 30 have been investigated for activity against human cancer cell lines. Growth inhibition and cytotoxic effects are apparent, with both concentration-dependent apoptosis and cell necrosis as the proposed cytotoxic mechanisms. In Swiss mice with Ehrlich ascites carcinoma (EAC), a methanolic extract of T. arjuna leaf decreased tumor volume, weight, and viable cell count as well as extending survival.6 Additionally, aqueous extracts of T. arjuna demonstrated antioxidant activity in aldo-keto reductase (AKR) mice with Dalton’s lymphoma. Specifically, oral administration of T. arjuna increased the activity of catalase, superoxide dismutase, and glutathione transferase.31

Arjunic acid isolated from the bark of T. arjuna was cytotoxic against human oral (KB), ovarian (PA 1), and liver (HepG2 and WRL-68) cancer cell lines.32

An aqueous extract of T. arjuna bark reduced buccal pouch carcinomas in hamsters, decreased lipid peroxidation, and increased antioxidant levels.33

T. bellerica inhibited the growth of HepG2 human hepatocellular carcinoma and A549 lung carcinoma cells. Additionally, T. bellerica combined with cisplatin in low to medium doses in A549 cells showed synergistic and additive effects. A low-dose combination of T. bellerica and doxorubicin showed synergistic effects in HepG2 cells. All other combinations demonstrated antagonistic effects.34

Administration of triphala, an Ayurvedic herbal combination consisting of T. chebula, Phyllanthus emblica, and T. bellerica, 1 g/kg given orally to mice for 7 days prior to whole body gamma-irradiation reduced mortality by 60%.35

Taxol at a level of 211.1 mcg/L was produced by endophytic fungus Pestalotiopsis terminaliae isolated from healthy, mature T. arjuna leaves.36

Clinical data

No clinical data exist regarding the use of Terminalia for cancer.

Cardiovascular

Animal data

Experiments in rats with T. arjuna and extracted arjunolic acid have demonstrated an antiplatelet and anticoagulant action similar to that of acetylsalicylic acid.37, 38

In dogs, T. arjuna bark extract caused dose-dependent hypotension, suggesting adrenergic beta-2 receptor agonist activity.39

Therapeutic and prophylactic doses of T. arjuna bark significantly improved left ventricular function as measured by myocardial contractility index and left ventricular pressures in rats with isoproterenol-induced heart failure. Additionally, T. arjuna restored alterations in serum CK-MB levels and improved lipid levels.40

Clinical data

Clinical studies have been conducted in coronary heart disease using T. arjuna bark extract at doses of 500 mg every 8 hours.

Statistically significant reduction in angina and improved diastolic function were shown in patients with ischemic mitral regurgitation at 1 and 3 months with T. arjuna.41 Effects similar to those of isosorbide mononitrate 40 mg daily treatment were demonstrated in patients with chronic stable angina given T. arjuna bark extract. Reduction in the frequency of angina and improved treadmill exercise test parameters were found.42

Brachial artery endothelial dysfunction was improved after 2 weeks of T. arjuna bark extract versus placebo in young male smokers.43

In a small study of 12 patients with New York Heart Association (NYHA) class IV refractory heart failure, patients were randomized to receive T. arjuna bark 500 mg 3 times daily or placebo for 2 weeks followed by a crossover with a wash-out period for 2 weeks. Following this phase (phase 1), patients who showed improvement with T. arjuna were continued in an open-label phase study (phase 2) where they continued to take T. arjuna for 20 to 28 months (average, 24 months). In phase 1, patients treated with T. arjuna demonstrated improvement in walking and effort tolerance, weight loss, and reduction in heart size. Following phase 2, patients receiving T. arjuna showed continual benefit related to ejection fraction and quality of life.44, 45

In a case-control study, the ethanolic bark extract of T. arjuna was found to significantly inhibit platelet aggregation in controls and in patients with coronary artery disease. Additionally, it was found to attenuate calcium release and P-selectin expression.46

A case report described a 50-year-old man with beta-thalassemia minor and hyperlipoproteinemia(a), hypertension, and with an elevated Lp(a) level of 51.8 mg/dL. After 6 months of taking bark stem powder T. arjuna 500 mg 3 times daily, his Lp(a) level dropped to 39 mg/dL.47, 48

Cholesterol

In vitro/Animal data

In combination with E. officinalis and T. chebula, T. bellirica reduced cholesterol-induced atherosclerosis in rabbits.49 In another report, T. bellirica reduced lipid levels in hypercholesterolemic animals.50 Fractions of T. arjuna at 175 and 350 mg/kg body weight were found to exert significant effects on lipid levels to varying extents in mice with PX-407 induced hyperlipidemia.51 Triphala, consisting of T. chebula, T. belerica, and Emblica officinalis, was given 1 g/kg for 48 days to hypercholesterolemic mice and was found to significantly reduce low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), triglyceride (TG), and total cholesterol levels.52 In rabbits, T. arjuna was found to reduce total cholesterol, LDL and TG levels, increase high-density lipoprotein (HDL) levels, and reduce atherosclerotic lesions in the aorta.53

In obese TSOD mice with type 2 diabetes mellitus, administration of a hot water extract of T. bellirica fruit caused significant suppression in the rise of glucose levels following a glucose load, and decreased TG levels, and was associated with reduced TG content in the liver. T. bellirica was found to exert inhibitory activity against pancreatic lipase. Findings from the study suggest a potential role of T. bellirica for components of metabolic syndrome.54

Clinical data

A reduction in total cholesterol and LDL cholesterol in humans has also been reported with T. arjuna bark extract at a dosage of 500 mg daily.55

Diabetes mellitus

In vitro/Animal data

Chebulagic acid, isolated from T. chebula, was found to exert noncompetitive and reversible inhibition of maltase, suggesting a potential role in the management of diabetes via alpha-glucosidase inhibition.56 In another study, T. chebula fruit extract demonstrated inhibition against alpha-glucosidase, with the ethyl acetate extract exerting the strongest inhibition, likely because of the high content of chebulagic and chebulinic acids.57 Additionally, chebulagic acid 100 mg/kg orally was found to significantly decrease postprandial blood glucose levels in Sprague-Dawley rats receiving maltose (127 ± 6 mg/dL) compared with controls (165 ± 8 m/dL). However, this effect was not noted in rats receiving sucrose or glucose loads.58

In streptozotocin-induced diabetic mice, daily oral administration of an aqueous extract of T. chebula for 2 months was found to decrease the blood glucose level by 43% (P < 0.01) and significantly reduce the hemoglobin A1c level.59

A 50% methanolic extract of T. arjuna was found to inhibit amylase activity.60

Clinical data

No clinical data exist regarding the use of Terminalia for diabetes mellitus.

Other uses

Anti-inflammatory

Chebulagic acid extracted from T. chebula suppressed the onset and progression of collagen-induced arthritis in mice.61

Antioxidant

Experiments in mice51, 62, 63 and human tissue8, 64 as well as one clinical trial55 have demonstrated antioxidant action of T. arjuna and T. chebula species.

Hepatoprotection

In clinical trials and animal experiments, T. bellirica11 and T. arjuna, individually62 and in combination,65 exhibited hepatoprotective effects. In Swiss albino mice exposed to carbon tetrachloride, aqueous T. arjuna extract was found to protect against alterations in glutathione S-transferase, superoxide dismutase, and catalase levels, suggesting antioxidant defense activities.66

Anticaries

A 10% concentrated mouth rinse made from the fruit of T. chebula was found to increase salivary pH and buffering capacity and decrease microbial count (Streptococcus mutans and lactobacilli). However, the peak effect on pH and buffering capacity were noted at 30 minutes after rinse and declined by 90 minutes after rinse.67

Dermatological effects

A water-in-oil emulsion of T. chebula applied topically increased moisture content following application. The effect was not significant with respect to time, but was with regard to base (vehicle) and formulation. Erythema was also reduced. However, effects on skin melanin and sebum were not important.68 In addition, Triphala, a formulation consisting of T. chebula, T. bellirica, and Phyllanthus emblica, prepared as a 10% w/w ointment, was found to significantly improve wound closure in rats from day 4 and onward. Complete wound healing was noted at day 16 in rats treated with Triphala, compared with 25 days in the untreated group. The bacterial count was also less on day 4 in those treated with Triphala compared with controls.69

GI effects

In a study of rats, rats treated with morphine and given 125 and 250 mg/kg of T. chebula seeds produced similar numbers of fecal pellets compared with those rats given saline.70

T. arjuna at doses of 400 and 500 mg/kg exerted gastroprotective effects against diclofenac sodium induced ulceration in a murine model. Specifically, rats receiving T. arjuna showed a significant reduction in the lesion index compared with controls.71 In a similar study, T. arjuna was gastroprotective (ie, antiulcer and ulcer-healing activity) against 80% ethanol, diclofenac sodium, and dexamethasone-induced ulceration in doses of 100, 400 and 200 mg/kg, respectively.72

Protective effects against urolithiasis

T. chebula prevented injury against calcium oxalate–induced damage in both NRK-52E and MDCK renal epithelial cells in a dose-dependent manner, suggesting a potential role against urolithiasis.73

Antidepressant effects

Aqueous and ethanolic extracts of T. bellirica showed antidepressant effects in mice. Specifically, a dose-dependent reduction in immobility time in the forced swim test and tail suspension test occurred in mice receiving the aqueous extract as well as with the 100 mg/kg ethanolic extract. In addition, the dose of aqueous extract 200 mg/kg and dose of ethanolic extract 100 mg/kg were found to be equivalent to imipramine 15 mg/kg and fluoxetine 20 mg/kg when given for 10 successive days.74

Dosing

Clinical studies have been conducted in cardiovascular disorders using T. arjuna bark extract 500 mg every 8 hours.41, 42, 43 Dosages for other Terminalia species have not been clinically defined.

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking; avoid use. One source cautions against taking T. bellirica and T. chebula during pregnancy.4

Interactions

None well documented. Potentiation of the anticoagulant effect of warfarin and other anticoagulants might be expected because T. arjuna bark extract exhibits antiplatelet and anticoagulant action similar to that of aspirin.37

Adverse Reactions

Evidence suggests extracts of T. arjuna are well tolerated. Adverse reactions similar to those seen with placebo (constipation, headache, abdominal discomfort, body ache) were described in one clinical trial42 while mild gastritis was noted in another.41 T. arjuna also exhibits antiplatelet and anticoagulant activity.37 In a study of rats, T. arjuna extract decreased thyroid hormone levels.75

Information on other species is limited.

Toxicology

There were no toxicities when T. arjuna was given at a dose of 2,000 mg/kg to mice.51

References

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