Khella

Scientific Name(s): Ammi majus L. and Ammi visnaga Lam. Family: Apiaceae (carrots)

Common Name(s): Ammi , visnaga , khella , khellin

Uses

Khella has been used for the treatment of urologic, dermatologic, and respiratory symptoms. It is used in the management of bronchial asthma and angina pectoris. The plant also possesses antimicrobial activity and inhibits certain mutagens. However, research reveals no clinical data regarding the use of khella for any of these conditions. Current research focuses on the use of khellin in the treatment of vitiligo.

Dosing

The pure compound khellin has been applied topically as a 2% preparation for vitiligo. In a study of cholesterol regulation, khellin 200 mg/day was administered orally.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

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

Interactions

None well documented.

Adverse Reactions

Nausea, vomiting, and ophthalmic changes (eg, decreased visual acuity) have occurred.

Toxicology

The use of oral khellin is limited by toxicity (eg, elevated liver enzymes, phototoxicity, dermatitis).

Botany

This annual plant grows to approximately 120 cm in height, primarily in Egypt, other regions of the Middle East, and the Mediterranean. A. visnaga has been naturalized to parts of the southeastern US. It has a slightly aromatic odor and a very bitter taste. The products of ammi consist of the dried ripe fruits, typically of A. visnaga .

History

The plant has been cultivated for hundreds of years and was known by the Assyrians. A. majus was cultivated for the cut-flower trade. Both species have been used medicinally. These plants have been used in traditional medicine for millennia, particularly for the management of angina and respiratory diseases. Portions of the plant are made into toothpicks. 1 The fruits have been used in Egyptian folk medicine as diuretics and for the treatment of kidney and bladder stones. 2 Khella also has been used for the traditional management of diabetes in Israel. 3

Chemistry

A. visnaga contains coumarins and furocoumarins (psoralens), the most important of which are khellin and visnagin. Khellin is present in fruits in a concentration of approximately 1% and visnagin in a concentration of approximately 0.3%. 4 Biosynthesis of khellin, visnagin, furocoumarin, and visnadin have been investigated. 5 Xanthotoxin (methoxsalen) and ammidin (imperatorin), 2 furocoumarins from khella fruits, have been discovered. 6 Solubility and dissolution studies of khellin also have been described. 7

Numerous reports regarding khella constituents are available evaluating their concentrations at various stages of maturity, 2 , 8 their presence in certain plant parts, 9 and interactions with different plant extracts. 10

Various methods for determination of khella components have been performed including the following: Micro method (khellin and visnagin), 11 thin-layer chromatography separation (khellin and visnagin), 12 spectrometric determination (khellin and bergapten), 13 high-performance liquid chromatography (khellin and visnagin), 4 , 14 and a polarographic method (khellinum in fruits). 15 Improved methods to determine ammi components also have been reported. 16 , 17

Dihydroseselins have been determined from khella fruits and extracts. 18 Genetically transformed khella cultures have been evaluated. 19 In addition, marmesin, ammoidin, and ammidin have been characterized. 20 The fruit contains a small amount (less than 0.03%) of a volatile oil.

Uses and Pharmacology

Animal data

Acting at multiple sites, visnagin inhibited induced contractile responses in rat vascular smooth muscle. 21 Similarly, visnadin demonstrated peripheral and coronary vasodilatory activities in isolated rat vascular smooth muscle. 22

Clinical data

In the 1940s and 1950s, khellin was considered a safe vasodilator for the treatment of angina pectoris in doses up to 300 mg daily. 23 Khellin is commercially available in several multi-ingredient European proprietary preparations for oral and parenteral administration as a vasodilator. It is used in the management of bronchial asthma and angina pectoris. 6 The structure of cromolyn sodium, used in the management of allergic respiratory illness, was based on components derived from A. visnaga . 24 Lipophilic extracts from the plant, including the active components visnadin, khellin, and visnagin, exhibited calcium channel-blocking actions, with visnadin being the most active. 25

Antimicrobial

Khella extract showed marked antimicrobial activity against gram-positive bacteria and Candida species. 26 Constituent khellin from ammi fruit parts inhibited the mutagenicity of certain promutagens in Salmonella typhimurium . 27

Animal data

Research reveals no animal data regarding the use of khella as an antimicrobial.

Clinical data

Research reveals no clinical data regarding the use of khella as an antimicrobial.

Vitiligo

Interest in khellin as an adjunct to ultraviolet (UV) light therapy in the treatment of vitiligo is based on the structural similarity between khellin and the psoralens. 28 Success has been reported using oral and topical khellin in clinical studies, 23 , 29 , 30 and a mechanism of action has been studied in cultured human cells. 31

Clinical data

Studies using oral (100 mg 23 ) or topical khellin (0.005% encapsulated in liposomes 30 and 5% khellin in water/oil emulsion 29 ) plus UVA therapy achieved success rates comparable to those seen with standard psoralen plus UVA (PUVA) therapy.

Topical therapy with the khellin-UVA combination required longer duration to achieve treatment goals but also demonstrated fewer side effects. 29 Follow-up (mean, 40 months) of patients who received oral khellin showed no long-term side effects. 23

Other uses

An ethnobotanical survey including 130 respondents reported khella to be 1 of 16 species of Israeli medicinal plants used for diabetes. 3 However, no clinical trials support this hypoglycemic action.

Extracts of A. majus seeds fed to rats with experimentally induced kidney stones showed no beneficial effect in terms of stone passage or size reduction. 32

A combination product containing khella demonstrated spasmolytic activity on guinea pig ileum in 1 report. 33

When given orally, khellin 50 mg 4 times daily increased HDL-cholesterol levels without affecting total cholesterol or triglyceride concentrations. 7

Dosage

Pure compound khellin has been applied topically as a 2% preparation for vitiligo, 29 and 100 mg was administered orally to vitiligo patients in a study assessing the effectiveness and safety of khellin. 23 In a study of cholesterol regulation, khellin 200 mg/day was administered orally. 34

Pregnancy/Lactation

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

Interactions

None well documented.

Adverse Reactions

A. majus has been associated with the development of severe ophthalmologic changes, particularly pigmentary retinopathy in photosensitized fowl. 35 , 36 In a study of 28 patients, 1 patient (4%) reported a temporary reduction in visual acuity that resolved upon discontinuation of treatment. 23 Patients receiving khella or its extracts should be monitored for ophthalmologic changes.

The furocoumarins (psoralens) may cause photosensitization and dermatitis. 37 One study reports 4 irritant compounds from ammi seeds and evaluates potential for contact dermatitis. 38 In patients who received oral khellin to reduce blood lipids and in a study to treat vitiligo, nausea and vomiting were observed frequently (29% of patients in the vitiligo study). Elevated AST and ALT also were reported during therapy (7% to 14%). 23 , 34

Toxicology

The use of oral khellin is limited by toxicity (eg, elevated liver enzymes, phototoxicity, dermatitis). 23 , 34 , 37 , 38

Bibliography

1. Mabberley D. The Plant-Book . Cambridge: Cambridge University Press; 1987.
2. Franchi GG, Bovalini L, Martelli P, Ferri S, Sbardellati E. High performance liquid chromatography analysis of the furanochromones khellin and visnagin in various organs of Ammi visnaga (L.) Lam. at different developmental stages. J Ethnopharmacol . 1985;14:203-212.
3. Yaniv Z, Dafni A, Friedman J, Palevitch D. Plants used for the treatment of diabetes in Israel. J Ethnopharmacol . 1987;19:145-151.
4. Martelli P, Bovalini L, Ferri S, Franchi GG. Rapid separation and quantitative determination of khellin and visnagin in Ammi visnaga (L.) Lam. fruits by high-performance liquid chromatography. J Chromatogr . 1984;301:297-302.
5. Chen M, Stohs SJ, Staba EJ. The biosynthesis of radioactive khellin and visnagin from C14 - acetate by Ammi visnaga plants. Planta Med . 1969;17:319-327.
6. Le Quesne P, et al. Furocoumarins from the fruit of Ammi visnaga . J Nat Prod . 1985;48:496.
7. Fromming K, et al. Influence of biopharmaceutical properties of drugs by natural occurring compounds as exemplified with khellin in an Ammi visnaga dry extract. Pharm Ind . 1989;51:439-443.
8. Balbaa S, et al. Study of the active constituent of Ammi visnaga fruits collected at different stages of maturity. J Pharm Sci UAR . 1968;9:15-26.
9. Franchi G, et al. Ammi visnaga (L.) Lam.: occurrence of khellin and visnagin in primary rib channels and endosperm, and emptiness of vittae, revealed by U.V. microscopy. Int J Crude Drug Res . 1987;25:137-144.
10. Gharbo S, et al. Modified chromatographic method of assay of Ammi visnaga L. fruits and its galenicals. J Pharm Sci . 1968;9:7-14.
11. Karawya M, et al. Micro method for the estimation of khellin and visnagin in Ammi visnaga fruits and in formulations. J Pharm Sci . 1969;10:189-196.
12. Karawya MS, el-Kiey MA, Sina A, Nour G. Simultaneous TLC separation of khellin and visnagin and their assay in Ammi visnaga fruits, extracts, and formulations. J Pharm Sci . 1970;59:1025-1027.
13. Ibrahim S, et al. Use of acid-dye technique in the analysis of natural products. Part 3. Spectrophotometric microdetermination of khellin and bergapten. Lloydia . 1979;42:366-373.
14. Mesbah M. Determinatioin of khellin and visnagin in Ammi visnaga fruits and in renal teas by high-performance liquid chromatography. Egypt J Pharm Sci . 1992;33:897-904.
15. Orlov Y, et al. Polarographic determination of khellinum in Ammi visnaga fruits. Farmatsiia . 1989;38:47-50.
16. el-Domiaty MM. Improved high-performance liquid chromatographic determination of khellin and visnagin in Ammi visnaga fruits and pharmaceutical formulations. J Pharm Sci . 1992;81:475-478.
17. Zgorka G, Dragan T, Glowniak K, Basiura E. Determination of furanochromones and pyranocoumarins in drugs and Ammi visnaga fruits by combined solid-phase extraction-high-performance liquid chromatography and thin-layer chromatography-high-performance liquid chromatography. J Chromatogr A . 1998;797:305-309.
18. Karawya MS, Sina A, Nour G. Determination of dihydroseselins in fruits and extracts of Ammi visnaga L. J Pharm Sci . 1969;58:1545-1547.
19. Kursinszki L, et al. Biologically active compounds of genetically transformed Ammi visnaga cultures. Gyogyszereszet . 1997;41:84-87.
20. Abu-Mustafa E, et al. Isolation of Marmesin from the Fruits of Ammi majus Linn. Nature . 1958;182:54.
21. Duarte J, Perez-Vizcaino F, Torres AI, Zarzuelo A, Jimenez J, Tamargo J. Vasodilator effects of visnagin in isolated rat vascular smooth muscle. Eur J Pharmacol . 1995;286:115-122.
22. Durate J, Vallejo I, Perez-Vizcaino F, Jimenez R, Zarzuelo A, Tamargo J. Effects of visnadine on rat isolated vascular smooth muscles. Planta Med . 1997;63:233-236.
23. Hofer A, Kerl H, Wolf P. Long-term results in the treatment of vitiligo with oral khellin plus UVA. Eur J Dermatol . 2001;11:225-229.
24. Evans W. Pharmacognosy . 13th ed. London: Bailliere Tindall; 1989.
25. Rauwald HW, Brehm O, Odenthal KP. The involvement of a Ca2+ channel blocking mode of action in the pharmacology of Ammi visnaga fruits. Planta Med . 1994;60:101-105.
26. Jawad A, et al. Antimicrobial activity of sesquiterpene lactone and alkaloid fractions from Iraqi plants. Int J Crude Drug Res . 1988;26:185-188.
27. Schimmer O, Rauch P. Inhibition of metabolic activation of the promutagens, benzo[a]pyrene, 2-aminofluorene and 2-aminoanthracene by furanochromones in Salmonella typhimurium. Mutagenesis . 1998;13:385-389.
28. Morliere P, Honigsmann H, Averbeck D, et al. Phototherapeutic, photobiologic, and photosensitizing properties of khellin. J Invest Dermatol . 1988;90:720-724.
29. Valkova S, Trashlieva M, Christova P. Treatment of vitiligo with local khellin and UVA: comparison with systemic PUVA. Clin Exp Dermatol . 2004;29:180-184.
30. de Leeuw J, van der Beek N, Maierhofer G, Neugebauer WD. A case study to evaluate the treatment of vitiligo with khellin encapsulated in L-phenylalanin stabilized phosphatidylcholine liposomes in combination with ultraviolet light therapy. Eur J Dermatol . 2003;13:474-477.
31. Carlie G, Ntusi NB, Hulley PA, Kidson SH. KUVA (khellin plus ultraviolet A) stimulates proliferation and melanogenesis in normal human melanocytes and melanoma cells in vitro. Bri J Dermatol . 2003;149:707-717.
32. Ahsan SK, Tariq M, Ageel AM, al-Yahya MA, Shah AH. Effect of Trigonella foenum-graecum and Ammi majus on calcium oxalate urolithiasis in rats. J Ethnopharmacol . 1989;26:249-254.
33. Westendorf J, Vahlensieck W. Spasmolytic and contractile effects of a combination product from plants on the smooth muscle of the guinea pigs [in German]. Arzneimittelforschung . 1981;31:40-43.
34. Harvengt C, Desager JP. HDL-cholesterol increase in normolipaemic subjects on khellin: a pilot study. Int J Clin Pharmacol Res . 1983;3:363-366.
35. Shlosberg A, Egyed MN, Eilat A. The comparative photosensitizing properties of Ammi majus and Ammi visnaga in goslings. Avian Dis . 1974;18:544-550.
36. Shlosberg A, Egyed MN. Examples of poisonous plants in Israel of importance to animals and man. Arch Toxicol Suppl . 1983;6:194-196.
37. Kavli G, Volden G. Phytophotodermatitis. Photodermatol . 1984;1:65-75.
38. Saeed M, et al. Studies on the contact dermatitic properties of indigenous Pakistani medicinal plants. Part 3. Irritant principles of Ammi visnaga L. seeds. Gazi Univ Eczacilik Farultesi Derg . 1993;10:15-23.

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