Fructus Ammi Visnagae , Herbal Medicine

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Fructus Ammi Visnagae

Defi nition

Fructus Ammi Visnagae consists of the dried ripe fruits of Ammi visnaga

(L.) Lam. (Apiaceae) (1–3).

Synonyms

Daucus visnaga L., Selinum visnaga E.H.L. Krause, Sium visnaga Stokes,

Visnaga daucoides Gaertn. (2, 4). Apiaceae are also known as Umbelliferae.

Selected vernacular names

Ammi, besnika, bisagna, bishop’s weed, herbe aux cure-dents, herbe aux

gencives, kella, kella balady, khelal dandane, khella, nunha, owoc keli,

Spanish carrot, viznaga, Zahnstocherkraut (2, 5–8).

Geographical distribution

Indigenous to the Mediterranean region. Cultivated in North America

and in Argentina, Chile, Egypt, India, Islamic Republic of Iran, Mexico,

Tunisia and Russian Federation (2, 5–7).

Description

An annual or biennial herb, up to 1.0 m high. Leaves dentate, in strips.

Stems erect, highly branched. Infl orescence umbellate; rays, highly swollen

at the base, become woody and are used as toothpicks. Fruits as described

below (2, 6).

Plant material of interest: dried ripe fruits

General appearance

Cremocarp usually separated into its mericarps; rarely, occurs entire with a

part of the pedicel attached. Mericarp small, ovoid, about 2 mm long, 1 m

wide, brownish to greenish-brown, with a violet tinge. Externally glabrous,

marked with fi ve distinct, pale brownish, broad primary ridges, four inconspicuous,

dark secondary ridges, and a disc-like stylopod at the apex. Internally

comprises a pericarp with six vittae, four in the dorsal and two in the

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commissural side, a large oily orthospermous endosperm and a small apical

embryo. Carpophore single, passing into the raphe of each mericarp (1, 2).

Organoleptic properties

Odour: slightly aromatic; taste: aromatic, bitter, slightly pungent (1, 2).

Microscopic characteristics

Epidermis of the pericarp consists of polygonal cells, elongated on the ridges,

with occasional crystals of calcium oxalate and fi nely striated cuticle, but

no hairs. Mesocarp consists of parenchyma, traversed longitudinally by

large, schizogenous vittae, each surrounded by large, slightly-radiating cells,

and in the ridges by vascular bundles, each forming a crescent around a comparatively

large lacuna and accompanied by fi bres and reticulate, lignifi ed

cells. Innermost layer consists of large, polygonal, brown-walled cells, with

thick, porous inner walls. Endocarp composed of narrow tangentially elongated

cells, some of which are in regular arrangements in variously oriented

groups, adhering to the brown seed coat, which is formed of similar but

wider, shorter cells. Endosperm consists of polygonal, thick-walled, cellulosic

parenchyma containing fi xed oil and numerous small, oval aleurone

grains, each enclosing a minute, rounded globoid and a microrosette crystal

of calcium oxalate. Carpophore, passing at the apex into the raphe of each

mericarp, traversed by a vascular bundle of fi bres and spiral vessels (1, 2).

Powdered plant material

Brown and characterized by fragments of pericarp with some brownish

pieces of vittae, reticulate cells, vessels and fi bres. Also present are fragments

with inner porous mesocarp cells crossed by and intimately mixed with

variously oriented groups of endocarpal cells; and numerous fragments of

endosperm. Other fragments show cells of the brown seed coat and aleurone

grains 4–10 μm in diameter, containing microrosette crystals of calcium oxalate

2–5 μm in diameter. Hairs and starch grains absent (1, 2).

General identity tests

Macroscopic and microscopic examinations, microchemical tests (1–3), and

thin-layer chromatography for the presence of khellin and visnagin (3, 6, 9).

Purity tests

Microbiological

Tests for specifi c microorganisms and microbial contamination limits are

as described in the WHO guidelines on quality control methods for medicinal

plants (10)

25Foreign organic matter

Not more than 2% (3).

Total ash

Not more than 8% (2).

Acid-insoluble ash

Not more than 3.5% (1).

Loss on drying

Not more than 10% (3).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than

0.05 mg/kg (11). For other pesticides, see the European pharmacopoeia

(11), and the WHO guidelines on quality control methods for medicinal

plants (10) and pesticide residues (12).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO

guidelines on quality control methods for medicinal plants (10).

Radioactive residues

Where applicable, consult the WHO guidelines on quality control methods

for medicinal plants (10) for the analysis of radioactive isotopes.

Other purity tests

Chemical, sulfated ash, water-soluble extractive and alcohol-soluble extractive

tests to be established in accordance with national requirements.

Chemical assays

Contains not less than 1% γ-pyrones (furanochromone derivatives) calculated

as khellin, determined by spectrophotometry (1–3). A number of

high-performance liquid chromatography methods are also available for

quantitative analysis (13–17).

Major chemical constituents

The major constituents are γ-pyrones (furanochromone derivatives; up to

4%), the principal compounds being khellin (0.3–1.2%) and visnagin

(0.05–0.30%). Other γ-pyrones of signifi cance are khellinol, ammiol,

khellol and its glucoside khellinin (0.3–1.0%). A second group of major

constituents are the coumarins (0.2–0.5%), the main one being the

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pyranocoumarin visnadin (0.3%). Essential oil contains camphor,

α-terpineol and linalool, among others, and also fi xed oil (up to 18%)

(6, 8, 13–15, 18, 19). Representative structures are presented below.

Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and well established documents

As an antispasmodic, muscle relaxant and vasodilator (1).

Uses described in traditional medicine

Treatment of mild anginal symptoms. Supportive treatment of mild obstruction

of the respiratory tract in asthma, bronchial asthma or spastic

bronchitis, and postoperative treatment of conditions associated with the

presence of urinary calculi. Treatment of gastrointestinal cramps and

painful menstruation (6). Internally as an emmenagogue to regulate menstruation,

as a diuretic, and for treatment of vertigo, diabetes and kidney

stones (8).

Pharmacology

Experimental pharmacology

Antimicrobial activities

A 50% acetone, 50% aqueous or 95% ethanol extract of Fructus Ammi

Visnagae inhibited the growth of the fungus Neurospora crassa in vitro

Mycobacterium

tuberculosis H37RVTMC 102 at a dilution of 1:40 in vitro (21).

An aqueous extract of the fruits, 2–10 mg/ml inhibited growth and afl atoxin

production by Aspergillus fl avus; the effects were dose-dependent

(22).

Antispasmodic effects

A methanol extract of the fruits, 1.0 mg/ml, inhibited potassium chlorideinduced

contractions in rabbit aorta in vitro (23). A chloroform extract of

the fruits (concentration not specifi ed) inhibited potassium chlorideinduced

contractions in guinea-pig aorta in vitro (24). Visnadin inhibited

carbaminoylcholine- and atropine-induced contractions in isolated

guinea-pig ileum at concentrations of 8.8 μmol/l and 0.02 μmol/l, respectively

(25). Visnagin, 1.0 μmol/l, inhibited the contractile responses in rat

aortic rings induced by potassium chloride, norepinephrine and phorbol

12-myristate 13-acetate, and spontaneous myogenic contractions of rat

portal veins. Visnagin appears to inhibit only contractions mediated by

calcium entry through pathways with low sensitivity to classical calcium

channel blockers (26, 27).

Cardiovascular effects

Visnadin, 60.0 μg/ml or 120.0 μg/ml, increased coronary blood fl ow in

isolated guinea-pig hearts by 46% and 57% and blood fl ow in a Laewan-

Trendelenburg frog vascular preparation by 78% and 147%, respectively

(25). Interarterial administration of 10.0 mg/kg body weight (bw) of visnadin

to anaesthetized dogs increased blood fl ow by 30–100%, the effect

lasting for 20 minutes after administration (25). Six compounds isolated

from the fruits were tested for their ability to dilate coronary blood vessels

in rabbits. Coronary vasospasm and myocardial ischaemia were induced

by daily intramuscular injections of vasopressin tannate. All compounds

were administered at 4.7 mg/kg bw per day by intramuscular

injection for 7 days. Visnadin, dihydrosamidin, khellin and samidin effectively

normalized the electrocardiogram, while visnagin and khellol

glucoside were inactive (28). Positive inotropic effects were observed in

dogs treated with intramuscular injections of samidin and khellol glucoside.

No effects were observed for visnadin, dihydrosamidin, khellin and

visnagin at varying doses (28).

Toxicology

In mice, the oral and subcutaneous median lethal doses (LD50) of the fruits

were 2.24 g/kg bw and > 370.0 mg/kg bw, respectively (25). In rats, the

oral LD50 was > 4.0 g/kg bw, and in rabbits, the intravenous LD50 was

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WHO monographs on selected medicinal plants

50.0 mg/kg bw. In dogs, the oral and intravenous LD50 values were

20.0 mg/kg bw and 200.0 mg/kg bw, respectively.

Subchronic oral administration of visnadin to mice, rats and rabbits at

doses of up to 2.2 g/kg bw, up to 600.0 mg/kg bw and 6.0 mg/kg bw,

respectively, produced no pronounced toxicity (25). In dogs, daily intramuscular

injections of isolated chemical constituents of the fruits at ten

times the therapeutic concentration for 90 days produced toxic effects

characterized by increases in the serum glutamic-pyruvic and glutamicoxaloacetic

transaminases, increases in plasma urea, haematological

changes and, in some cases, death. Of the six compounds tested, samidin

was the most toxic, dihydrosamidin was the least toxic and khellin, visnagin,

visnadin and khellol glucoside were of intermediate toxicity (29). The

acute toxicities of khellin, visnagin, visnadin and samidin were assessed in

mice and rats after intramuscular injection of doses of 0.316–3.16 mg/kg

bw. The LD50 values were: khellin, 83.0 mg/kg bw in mice and 309.0 mg/

kg bw in rats; visnagin, 123.0 mg/kg bw and 831.0 mg/kg bw; visnadin,

831.8 mg/kg bw and 1.213 g/kg bw; and samidin, 467.7 mg/kg bw and

1.469 g/kg bw (30).

Administration of Ammi visnaga seeds at 1.25–3% in the diet for

14 days had no toxic effects on turkeys or ducks. However, in chickens,

the 3% dose produced mild signs of photosensitization within 6–8 days

(31). Administration of 2.0 g/day for 4–8 days to goslings at age 3–5 weeks

induced photosensitivity in the form of erythema, haematomas and blisters

on the upper side of the beak (32).

The chemical constituents responsible for the induction of contact

dermatitis in the mouse-ear assay were khellol, visnagin and khellinol,

median irritant doses 0.125 μg/5 μl, 1.02 μg/5 μl and 0.772 μg/5 μl, respectively

(33).

Clinical pharmacology

A placebo-controlled study assessed the effects of oral administration of

50 mg of khellin four times per day for 4 weeks on the plasma lipids of 20

non-obese, normolipaemic male subjects. Plasma lipids were measured

every week during treatment and 1 week after cessation. Plasma total

cholesterol and triglyceride concentrations remained unchanged, while

high-density-lipoprotein cholesterol concentrations were signifi cantly elevated,

the effect lasting until 1 week after cessation of treatment (34).

Adverse reactions

Pseudoallergic reactions and reversible cholestatic jaundice have been reported

(35). High oral doses of khellin (100.0 mg/day) reversibly elevated

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the activities of liver transaminases and γ-glutamyltransferase (35). Prolonged

use or overdose may cause nausea, vertigo, constipation, lack of

appetite, headache and sleeplessness (6).

Contraindications

Fructus Ammi Visnagae is used in traditional systems of medicine as an

emmenagogue (8), and its safety during pregnancy has not been established.

Therefore, in accordance with standard medical practice, the

fruits should not be used during pregnancy.

Warnings

No information available.

Precautions

General

Exposure to sun or other sources of ultraviolet light should be avoided

during treatment because khellin causes photosensitivity (35).

Drug interactions

No drug interactions have been reported. However, khellin is reported to

inhibit microsomal cytochrome P450 subenzymes, and may therefore decrease

the serum concentrations of drugs metabolized via this pathway,

such as ciclosporin, warfarin, estrogens and protease inhibitors (36).

Carcinogenesis, mutagenesis, impairment of fertility

A 95% ethanol extract of Fructus Ammi Visnagae, 10.0 mg/plate, was not

mutagenic in the Salmonella/microsome assay using S. typhimurium

strains TA98 and TA102. Furthermore, an infusion of the fruits had antimutagenic

effects against ethyl methanesulfonate- or 2-amino-anthraceneinduced

mutagenicity in S. typhimurium strains TA98 and TA100 (37).

Khellin also inhibited the mutagenicity of promutagens such as benzopyrene,

2-aminofl uorene and 2-aminoanthracene in S. typhimurium TA98.

However, there was no effect on direct-acting mutagens, such as 2-nitrofl

uorene, 4-nitro-o-phenylenediamine, in S. typhimurium TA100 (36).

Pregnancy: teratogenic effects

Intragastric administration of up to 600.0 mg/kg bw of visnadin to rats on

days 8–12 of pregnancy produced no toxic effects (25).

Pregnancy: non-teratogenic effects

See Contraindications.

Fructus Ammi Visnagae

30

Nursing mothers

Owing to the lack of safety data, Fructus Ammi Visnagae should be taken

internally only under the supervision of a health-care provider.

Paediatric use

Owing to the lack of safety data, Fructus Ammi Visnagae should be taken

internally only under the supervision of a health-care provider.

Other precautions

No information available on precautions concerning drug and laboratory

test interactions.

Dosage forms

Dried fruits, infusions, extracts and other galenical preparations (35).

Store fully dried fruits in well closed containers in a cool and dry place

protected from light (1).

Posology

(Unless otherwise indicated)

Average daily dose: Fructus Ammi Visnaga 0.05–0.15 g (1).

References

1. Egyptian pharmacopoeia. Vol. 2, 3rd ed. Cairo, General Organization for

Government Printing, 1972.

2. African pharmacopoeia. Vol. 1. Lagos, Organization of African Unity, Scientifi

c, Technical and Research Commission, 1985.

3. Homöopathisches Arzneibuch 2000. [Homoeopathic pharmacopoeia 2000.]

Stuttgart, Deutscher Apotheker Verlag, 2000.

4. Flora reipublicae popularis sinicae, Tomus 55. China, Science Press, 1985.

5. Zargari A. [Medical plants, Vol. 2.], 4th ed. Tehran, Tehran University, 1989

(Tehran University Publications, No. 181012) [in Farsi].

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