МОНОГРАФИИ ВОЗ Т 4

Fructus Tribuli

Definition

Fructus Tribuli consists of the dried fruits of Tribulus terrestris L. (Zygophyllaceae) (1–4).

Synonyms

Tribulus lanuginosus L. (5).

Selected vernacular names

Abrojo, abrojos, akanti, alaf-e-kanguereh, baijili, bastitaj, be tha gokharu, bethu, bhakhra, bullhead, burnut, burra gookeron, calthrop, caltrap, caltrop, cat’s head, chotagokhru, cows hoof, croix de chevalier, croix de malte, dars el agûz, dava-tehokourtdi, demirdiken, deshi gokhru, devil’s thorn, ekanty, eskrundki, espáákh, espigón, gai ma duong, gatha, ghota, goathead, gokharu gokhru, gokhur, gokshura, goksuraka, gokhri, gokhurkata, gokhyura, gukhura, hamabishi, herbe terrestre, ikshugandha, jili, jilisi, kandaai, khar-e- khasak khurd, khárk-tehârouk khárk-tehârpar, khárkhassak, khôrbâr, khokkrasun, kouleh-tighak, krunda, land caltrops, malteserkors, meetha gokhru, Mexican sanbur, michirkand, mithagokharu, mithogokharu, naalkhar, naam din, nana gokharu, nature’s viagara, neggilamullu, neggilu, nerenchi, nerinjil, nerunjil, ookharu pakhda, outb, pakhda, pakhra, palleru, palleru kaya, palleruveru, pedda palgeru, punctur vine, qutiba, saligot terrestre, sannanaggilu, sannaneggilu, sarang, sarate, sekal-tali, sharwandi, sher sher, shitsurishi, small caltrop, svadamstraa, tahkandi, tat le, Teufelsdorm, Texas sandbur, traikantaka, tribolo commune, trikanta, tribule couché, tribule terrestre, tsi li, vejtidsel, zama (4–10).

Geographical distribution

Native to the Mediterranean regions, but also found throughout the world (6).

Description

A perennial, decumbent, pubescent herb, branches 0.5–1.8 m long, tips ascending; longer leaves up to 7 cm long, with 6–9 pairs of leaflets, shorter

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leaves up to 6 cm long with 3–5 pairs of leaflets, midrib ending in a mucro, 0.5–2 mm long; leaflets 6–22 mm by 2.5–9 mm, base obliquely rounded, apex subacute, both surfaces silky, subsessile, stipules falcate, 3–6 mm long, acuminate; pedicel 2–4 cm long, sepals narrowly lanceolate, 7–11 mm long, apex acute, appressed hairy, caducous, petals obovate-cuneate, 1–2 cm by 1–1.5 cm, apex broadly rounded-truncate, bright yellow, stamens subequal, anthers 1 mm long; cocci 4–5, spines stout, sharp, 2 lateral ones largest, pericarp rather thick, corky, seeds 1–3 in each mericarp (6).

Plant material of interest: dried fruits

General appearance

A pentagonal fruit 7–12 mm in diameter consists of 5 mericarps, radially arranged. Each mericarp often splitting into single hatchet-shaped, 3–6 mm long mericarp; dorsal surface yellowish-green, prominent, with longitudinal ribs and numerous spinelets, bearing symmetrically a pair of long spines and a pair of short spines; two lateral surfaces rough, with reticular striations, greyish-white. Texture hard. Each mericarp contains 1–3 seeds (1–3).

Organoleptic properties

Odourless; taste: bitter and pungent (1, 2).

Microscopic characteristics

Transverse section of fruit shows small epidermal cells of each coccus rectangular; unicellular trichomes in abundance; rilesocarp 6–10 layers of large parenchymatous cells, rosette of calcium oxalate crystals abundant; mesocarp followed by 3–4 compact layers of small cells containing prismatic crystals of calcium oxalate (4).

Powdered plant material

Yellow-green. The fibres are lignified, with upper and lower layers in a criss-cross arrangement, a few scattered singly, sometimes fibre bundles connected with stone cells. Stone cells elongated-elliptical or subrounded, occurring in groups. Testa cells polygonal or subsquare, about 30 μm in diameter, walls reticulately thickened, lignified. Prisms of calcium oxalate 8–20 μm in diameter (1).

General identity tests

Macroscopic and microscopic examinations (1, 2, 4), thin-layer chromatography (2) and microchemical test (3).

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Purity tests

Microbiological

Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues (11).

Foreign organic matter

Not more than 4.0% fruit stalks and not more than 1% other foreign matter (2, 3).

Total ash

Not more than 12% (1).

Acid-insoluble ash

Not more than 1.5% (2).

Water-soluble extractive

Not less than 10% (4).

Alcohol-soluble extractive

Not less than 8.5% (2).

Water

Not more than 9% (1).

Loss on drying

Not less than 11% (2).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (12). For other pesticides, see the European pharmacopoeia (12) and the WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues (11) and pesticide residues (13).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues (11).

Radioactive residues

Where applicable, consult the WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues (11).

Chemical assays

To be established in accordance with national requirements.

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Major chemical constituents

The major constituents of the fruit are steroidal saponins including gitonin, protodioscin (0.245%, tribulosaponins A and B, tribulosin and terrestrosins A–K, among others. Other constituents include alkaloids, tribulusamides A and B, and trace amounts of harman and norharman; and flavonols such as kaempferol, quercetin and rutin (5, 14, 15). The structures of the major chemical constituents are presented below.

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Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and well established documents

Orally for the treatment of cough, headache and mastitis (1).

Although clinical trials have assessed the use of the crude drug for the symptomatic treatment of angina pectoris and male infertility (16–22), randomized controlled clinical trials are needed before the use of the crude drug can be recommended for the treatment of these conditions.

Uses described in traditional medicine

Orally for the treatment of abdominal distension, diarrhoea, kidney stones, nosebleeds and vitiligo (5, 23). Also used as an aphrodisiac, diuretic, galactagogue, general tonic and uterine tonic (5).

Pharmacology

Experimental pharmacology

Angiotensin-converting enzyme inhibitory effects

The renin-angiotensin-aldosterone system, including angiotensinconverting enzyme plays an important role in the control of blood pressure and fluid volume (24, 25). An aqueous extract of the fruit (1 g fruit in 10 ml water) inhibited the activity of angiotensin-converting enzyme in vitro at a concentration of 0.33 mg/ml (24). The mechanism of action of the aqueous extract (500 mg fruit in water 2:1 w/v) was investigated in 2K1C hypertensive rats by measurement of circulatory and local angiotensin converting enzyme activity in aorta, heart, kidney and lung. Hypertension was induced using a silver clip on the renal artery inserted by surgery. The animals were treated with a single oral daily dose of 10 mg/ kg body weight (bw) of a lyophilized aqueous extract of the fruit for 4 weeks. The systolic blood pressure was increased in 2K1C rats as compared with control rats. The systolic blood pressure of rats treated with the crude drug extract was significantly decreased compared to hypertensive rats (p < 0.05). The angiotensin-converting enzyme activity in all tissues of 2K1C rats including aorta, heart, kidney and lung as well as in the serum was significantly increased compared to that of normal rats. The angiotensin-converting enzyme activity in all tissues of hypertensive rats treated with the fruit extract was significantly lower than that of control hypertensive rats (26).

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Anti-inflammatory activity

A methanol extract of the fruit inhibited cyclooxygenase 2 activity in lipopolysaccharide-induced mouse macrophages RAW264.7 by > 80% at a concentration of 10.0 μg/ml in vitro (27).

Diuretic activity

An aqueous extract of the fruit was dissolved in physiological saline and administered by gavage to rats to determine its diuretic effects. When administered at an intragastric dose of 5.0 g/kg bw, the extract induced diuresis, and was slightly more effective than furosemide. The sodium, potassium and chloride ion concentrations in the urine of animals treated with the extract were also increased. Addition of the extract to the bath medium for strips of isolated guinea-pig ileum induced contractile activity of guinea-pig ileum (28).

A dried ether extract of the fruit induced diuresis and increased creatinine clearance in anaesthetized dogs; however no further details of this study were available (6).

Hepatoprotective activity

Addition of the tribulusamides A and B, lignanamides isolated from a 70% ethanol extract of the fruit, to a medium containing primary cultured mouse hepatocytes at a concentration of 20 μM significantly (p < 0.05) prevented D-galactosamine/tumour necrosis factor alphainduced cytotoxicity (14).

Stimulation of melanocyte proliferation

An aqueous fruit extract was tested in an assay using sulforhodamine B protein stain for cell number to determine if the extract was capable of stimulating melanocyte proliferation, and could be useful for the treatment of vitiligo. Significant stimulation (p < 0.05) of melanocyte proliferation was observed, in the absence of tetradecanoyl phorbol acetate, using aqueous extracts of the fruit at concentrations of 0.01–1 mg/ml (29).

Reproductive effects

The effect of an extract of the fruit on the isolated corpus cavernosal tissue of New Zealand white rabbits was studied. Twenty-four rabbits were randomly assigned to one of four experimental groups of six animals each. Group 1 served as control. Groups 2, 3 and 4 were treated with an oral dose of the extract at doses of 2.5 mg/kg bw, 5.0 mg/kg bw and 10.0 mg/ kg bw, respectively, for 8 weeks. After killing the rabbits, the penile tissue was isolated and evaluated by the response to both contracting and relaxing pharmacological agents and electrical field stimulation. The relaxant responses to electrical field stimulation, acetylcholine and nitroglycerin in

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noradrenaline-precontracted corpus cavernosal strips from treated groups showed an increase in relaxation of a concentration-dependent nature when compared to that of the tissues from the control group. However, the contractile, anti-erectile response of corpus cavernosal tissue to noradrenaline and histamine did not differ significantly between the treatment and the control groups. The relaxant responses to acetylcholine, nitroglycerin and electrical field stimulation by more than 10%, 24% and 10%, at the doses of 2.5 mg/kg bw, 5.0 mg/kg bw and 10.0 mg/kg bw, respectively, compared to their control values and the lack of such effect on the contractile response to noradrenaline and histamine indicate that the extract has a pro-erectile activity (30).

An extract of the fruit containing protodioscin was investigated in both normal and castrated rats to determine aphrodisiac effects. Rats were divided into five groups of eight animals each. The treatments were distilled water (normal and castrated animals), testosterone (normal and castrated animals, 10.0 mg/kg bw, subcutaneously, bi-weekly) and extract (castrated animals, 5.0 mg/kg bw, orally once daily for 8 weeks). Decreases in body weight and prostate weight were observed among the castrated groups of rats as compared to the normal rats. There was an overall reduction in the sexual behaviour parameters in the castrated rats as reflected by a decrease in mount and intromission frequencies and an increase in mount, intromission and ejaculation latencies as well as post-ejaculatory interval. Compared to the castrated control animals, treatment of castrated rats with either testosterone or the extract led to a mild to moderate improvement of the sexual behaviour parameters as demonstrated by an increase in mount frequency and intromission frequency and a decrease in mount latency, intromission latency and post-ejaculatory interval (29).

Formation of uroliths (urinary calculi)

An ethanol extract of the fruit exhibited a dose-dependent protection against uroliths induced by glass bead implantation in albino rats. The extract provided significant protection against deposition of calculogenic material around the glass bead. It also protected against leukocytosis and elevation of serum urea levels (32).

Toxicity

The plant, when used as fodder, has been reported to cause photosensitivity in livestock and is responsible for the diseases geeldikkop (in South Africa) and “bighead” (in Australia and the USA) in sheep. The condition is characterized by oedema of the head, fever and jaundice, leading to death (6). Two beta-carboline indoleamines (harman and norharman), present in trace amounts in the seeds of Tribulus terrestris have been im-

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plicated in causing central nervous system effects in sheep that have grazed on Tribulus over a period of months. Harman and norharman appear to accumulate in tryptamine-associated neurons of the central nervous system and gradually interact irreversibly with a specific sequence of neuronal gene DNA. The extractable alkaloid content was 44.0 mg/kg dry matter. Synthetic harman and norharman administered subcutaneously to sheep at a dose of 54 mg/kg, caused nervous system effects similar to those caused by the fresh plant (33).

Behavioural, haematological, biochemical, functional and morphological studies on the acute, subchronic and chronic toxicities of protodioscin, one of the chemical constituents of the crude drug, showed no toxic manifestations under experimental conditions. No data were available from which conclusions could be drawn concerning carcinogenic and teratogenic effect (33).

Clinical pharmacology

Saponin-containing extracts of the fruit have been used to treat coronary heart disease (22). In a clinical observation study involving 406 patients and a cross-test (67 cases) the results showed that the extract was significantly more effective than the control for the treatment of angina pectoris, with a remission rate of 82.3% and 67.2% (p < 0.05), in the treatment and control groups, respectively. Electrocardiogram improvement was 52.7% in the treated group and 35.8% in the control group. The extract dilates the coronary artery and improves coronary circulation, and thus is more effective than the control treatment in improving the electrocardiogram of myocardial ischaemia. No adverse reactions were observed on haematological parameters or hepatic and renal functions (22).

A clinical study was conducted to assess the effectiveness of a specific dosage and period of administration of protodioscin on sperm quality and quantity in men with moderate idiopathic oligozoospermia. This study also evaluated the effect of protodioscin on libido, erection, ejaculation and orgasm. The results demonstrated that oral treatment with the dose of 3 × 2 tablets per day for 60 days increased sperm quantity and quality in men diagnosed with moderate idiopathic oligozoospermia and restored libido, erection, ejaculation and orgasm of sexual intercourse. These results were observed in more than 80% of the treated patients (18).

A double-blind study was done on 45 men with infertility due to oligoasthenoteratozoospermia. Thirty-six men were treated with 500.0 mg purified extract of the fruit containing protodioscin, orally 3 times daily for 3 months. The nine men in the control group were given a placebo for the same period of time. Spouses of eight of the men in the treated group became pregnant after treatment of their husbands, whereas no pregnan-

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cies occurred in the spouses of the men in the control group. An improvement in the sperm morphology, acrosome morphology and reaction seemed to account for the increased fertility after treatment. In addition, the extract was shown to increase the level of dehydroepiandrosterone and might also have contributed to the activation of cell membrane receptors and the production of weak androgens (16).

An interesting correlation of dehydroepiandrosterone sulfate level with the incidence of low sex drive and higher occurrence of impotence was discovered in studies of patients diagnosed with diabetes mellitus. A clinical trial involving 30 men with erectile dysfunction, but not diabetes, 30 with neither erectile dysfunction nor diabetes and 15 men with both diabetes and erectile dysfunction was performed to assess the relationship between dehydroepiandrosterone sulfate and erectile dysfunction. The men were given an extract of the fruit at a dose of 3 × 250 mg per day for 3 weeks. The dehydroepiandrosterone sulfate levels, as well as other blood and liver parameters were evaluated. The results of the study showed a significant increase of dehydroepiandrosterone sulfate levels in subjects with and without diabetes after treatment, and a significant increase in the frequency of successful intercourse of 60% in subjects with or without diabetes and with or without erectile dysfunction (17).

Adverse reactions

No information was found.

Contraindications

Fructus Tribuli is contraindicated in cases of hypersensitivity or allergy to the plant.

Warnings

Due to the possibility of phototoxic reactions, patients using Fructus Tribuli should avoid excessive exposure to sunlight and use a sunscreen with a high sun protection factor (> 30) while taking the crude drug.

Precautions

Carcinogenesis, mutagenesis, impairment of fertility

No information was found.

Pregnancy: teratogenic effects

Due to the lack of safety data, use of the crude drug during pregnancy is not recommended.

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Pregnancy: non-teratogenic effects

Due to the lack of safety data, use of the crude drug during pregnancy is not recommended.

Nursing mothers

Due to the lack of safety data, use of the crude drug during breastfeeding is not recommended.

Paediatric use

Due to the lack of safety data, use of the crude drug in children under the age of 12 years is not recommended.

Other precautions

No information was found.

Dosage forms

Crude drug and extracts.

Posology

(Unless otherwise indicated)

Oral daily dosage: 3–6 g of the powdered crude drug as a decoction (4); 6–9 g in divided doses daily as a decoction (1).

References

1.Pharmacopoeia of the People’s Republic of China. Beijing, Chemical Industry Press, 2005.

2.The Japanese pharmacopoeia XIV, Supplement 2. Tokyo, Ministry of Health and Welfare, 2003.

3.The Korean herbal pharmacopoeia, IV (English ed.), 2002. Seoul, Korea Food and Drug Administration, 2003.

4.The Ayurvedic Pharmacopoeia of India, Part I. Vol. I, 1st ed. New Delhi, Government of India Ministry of Health and Family Welfare, Department of Indian Systems of Medicine and Homeopathy, 1990 (reprinted 2001).

5.Farnsworth NR, ed. NAPRALERT database. Chicago, University of Illinois at Chicago, IL (an online database available directly through the University of Illinois at Chicago or through the Scientific and Technical Network [STN] of Chemical Abstracts Services), 30 June 2005.

6.Van Valkenburg JLCH, Bunyapraphatsara N, eds. Medicinal and poisonous plants – 2. Leiden, Backhuys, 2001 (PROSEA. Plant resources of South-east Asia, No. 12(2)).

7.Al-Yahya MA et al. Saudi plants: a phytochemical and biological approach. Riyadh, King Abdulaziz City for Science and Technology, King Saud University Press, 1990.

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