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
24
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
Fructus Ammi Visnagae
26
WHO monographs on selected medicinal plants
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
Fructus Ammi Visnagae
28
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
29
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].
6. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC
Press, 1994.
7. Physician’s desk reference for herbal medicine. Montvale, NJ, Medical
Economics Co., 1998.
8. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of
Illinois at Chicago, 9 February 2001 production (an online database available
directly through the University of Illinois at Chicago or through the Scientifi
c and Technical Network (STN) of Chemical Abstracts Services).
9. Wagner H, Bladt S. Plant drug analysis – a thin-layer chromatography atlas,
2nd ed. Berlin, Springer, 1996.
31
10. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
11. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
12. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed.
Geneva, World Health Organization, 1997 (WHO/FSF/FOS/97.7; available
from Food Safety, World Health Organization, 1211 Geneva 27, Switzerland).
13. Martelli P et al. Rapid separation and quantitative determination of khellin
and visnagin in Ammi visnaga (L.) Lam. fruits by high-performance liquid
chromatography. Journal of Chromatography, 1984, 301:297–302.
14. Franchi GG et al. High-performance liquid chromatography analysis of the
furanochromones khellin and visnagin in various organs of Ammi visnaga
(L.) Lam. at different developmental stages. Journal of Ethnopharmacology,
1985, 14:203–212.
15. El-Domiaty MM. Improved high-performance liquid chromatographic
determination of khellin and visnagin in Ammi visnaga fruits and pharmaceutical
formulations. Journal of Pharmaceutical Sciences, 1992, 81:475–478.
16. Ganzera M, Sturm S, Stuppner H. HPLC-MS and MECC analysis of
coumarins. Chromatographia, 1997, 46:197–203.
17. Zgorka G et al. Determination of furanochromones and pyranocoumarins in
drugs and Ammi visnaga fruits by combined solid-phase extraction-highperformance
liquid chromatography and thin-layer chromatography-highperformance
liquid chromatography. Journal of Chromato graphy A, 1998,
797:305–309.
18. Abou-Mustafa EA et al. A further contribution to the γ-pyrone constituents
of Ammi visnaga fruits. Planta Medica, 1990, 56:134.
19. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier,
1995.
20. Kubas J. Investigations on known or potential antitumoural plants by means
of microbiological tests. Part III. Biological activity of some cultivated plant
species in Neurospora crassa test. Acta Biologica Cracoviensia, Series Botanica,
1972, 15:87–100.
21. Grange JM, Davey RW. Detection of antituberculous activity in plant
extracts. Journal of Applied Bacteriology, 1990, 68:587–591.
22. Mahmoud A-LE. Inhibition of growth and afl atoxin biosynthesis of
Aspergillus fl avus by extracts of some Egyptian plants. Letters in Applied
Microbiology, 1999, 29:334–336.
23. Rauwald HW, Brehm H, Odenthal KP. Screening of nine vasoactive medicinal
plants for their possible calcium antagonist activity. Strategy of selection
and isolation for the active principles of Olea europaea and Peucedanaum
ostruthium. Phytotherapy Research, 1994, 8:135–140.
24. Rauwald HW, Brehm H, Odenthal KP. The involvement of Ca2+ channel
blocking mode of action in the pharmacology of Ammi visnaga fruits. Planta
Medica, 1994, 60:101–105.
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WHO monographs on selected medicinal plants
25. Erbring H, Uebel H, Vogel G. Zur Chemie, Pharmakologie und Toxicologie
von Visnadin. [Chemistry, pharmacology, and toxicology of visnadine.] Arzneimittelforschung,
1967, 17:283–287.
26. Duarte J et al. Vasodilator effects of visnagin in isolated rat vascular smooth
muscle. European Journal of Pharmacology, 1995, 286:115–122.
27. Duarte J et al. Effects of visnadine on rat isolated vascular smooth muscles.
Planta Medica, 1997, 63:233–236.
28. Galal EE, Kandil A, Latif MA. Evaluation of cardiac inotropism of Ammi
visnaga principles by the intra-ventricular technique. Journal of Drug Research
of Egypt, 1975, 7:45–57.
29. Kandil A, Galal EE. Short-term chronic toxicity of Ammi visnaga principles.
Journal of Drug Research, 1975, 7:109–122.
30. Galal EE, Kandil A, Latif MA. Acute toxicity of Ammi visnaga principles.
Journal of Drug Research of Egypt, 1975, 7:1–7.
31. Egyed MN, Shlosberg A, Eilat A. The susceptibility of young chickens,
ducks and turkeys to the photosensitizing effect of Ammi visnaga seeds.
Avian Diseases, 1975, 19:830–833.
32. Shlosberg A, Egyed MN, Eilat A. Comparative photosensitizing properties
of Ammi majus and Ammi visnaga in goslings. Avian Diseases, 1974, 18:544–
550.
33. Saeed MA, Khan FZ, Sattar A. Studies on the contact dermatitic properties of
indigenous Pakistani medicinal plants. Part III. Irritant principles of Ammi
visnaga L. seeds. Journal of the Faculty of Pharmacy, Gazi University, 1993,
10:15–23.
34. Harvengt C, Desager JP. HDL-cholesterol increase in normolipaemic subjects
on khellin: a pilot study. International Journal of Clinical Pharmacology
Research, 1983, 3:363–366.
35. Blumenthal M et al., eds. The complete German Commission E monographs.
Austin, TX, American Botanical Council, 1998.
36. Schimmer O, Rauch P. Inhibition of metabolic activation of the promutagens,
benzo[α]pyrene, 2-aminofl uorene and 2-aminoanthracene by furanochromones
in Salmonella typhimurium. Mutagenesis, 1998, 13:385–389.
37. Mahmoud I, Alkofahi A, Abdelaziz A. Mutagenic and toxic activities of several
spices and some Jordanian medicinal plants. International Journal of
Pharmacognosy, 1992, 30:81–85.

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