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Khella

Scientific Name(s): Ammi majus L., Ammi visnaga Lam.
Common Name(s): Ammi, Bisnaga, Khella, Khellin, Toothpickweed, Visnaga

Medically reviewed by Drugs.com. Last updated on Oct 1, 2019.

Clinical Overview

Use

Khella has traditionally been used for the management of vitiligo, psoriasis, kidney and urinary stones, diabetes, asthma, and urinary tract infections. It is also a potent coronary vasodilator with antispasmodic effects, making it useful in treating angina.

Dosing

A typical dose of khella is an amount that provides 20 mg of the khellin constituent per day. In safety and efficacy studies of khellin use in combination with ultraviolet (UV) light therapy for treatment of vitiligo, pure compound khellin was applied topically as a 5% preparation, and as 100 mg administered orally. In a study evaluating effects of khellin on cholesterol regulation, khellin 200 mg/day orally was administered for 4 weeks.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Khellin should not be used in women who are pregnant or breastfeeding. It possesses uterine stimulant activity. Insufficient information is available regarding use in breastfeeding.

Interactions

None well documented.

Adverse Reactions

Nausea and vomiting have been frequently observed. Elevated AST and ALT have also been reported. Other potential adverse reactions include dizziness, constipation, headache, itching, insomnia, lack of appetite, allergic reactions, and ophthalmologic changes.

Toxicology

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

Scientific Family

  • Apiaceae (carrot)

Botany

Khella is an annual plant found primarily in Egypt, other regions of the Middle East, and the Mediterranean. A. visnaga has been naturalized to parts of the southeastern United States. The plant can grow to approximately 1 m in height. It has a slightly aromatic odor and a very bitter taste. Products of ammi consist of the dried ripe fruits, typically of A. visnaga.Franchi 1985

History

The khella 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 in traditional medicine for millennia, particularly for the management of angina and respiratory diseases. Portions of the plant are made into toothpicks.Mabberley 1987 The fruit has been used in Egyptian folk medicine as a diuretic and for the treatment of kidney and bladder stones.Franchi 1985 Khella has also traditionally been used for the management of diabetes in Israel,Yaniv 1987 and to treat urinary tract infections in Palestine.Jaradat 2017

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 is present in a concentration of approximately 0.3%.Martelli 1984 Biosynthesis of khellin, visnagin, furocoumarin, and visnadin have been investigated.Chen 1969 Xanthotoxin (methoxsalen) and ammidin (imperatorin), 2 furocoumarins from khella fruits, have been discovered.Le Quesne 1985 Two furoquinoline alkaloids with varying cytotoxic activity have been isolated from A. majus.Mohammed 2017 Solubility and dissolution studies of khellin also have been described.Fromming 1989

Numerous reports regarding khella constituents (ie, their concentrations at various stages of maturity,Franchi 1985, Balbaa 1968 presence in certain plant parts,Franchi 1987 and interactions with different plant extracts) are available.Gharbo 1968

Various methods identifying khella components have been performed, including micro method (khellin and visnagin),Karawya 1969 thin-layer chromatography separation (khellin and visnagin),Karawya 1970 spectrometric determination (khellin and bergapten),Ibrahim 1979 high-performance liquid chromatography (khellin and visnagin),Martelli 1984, Mesbah 1992 and a polarographic method (khellinum in fruits).Orlov 1989 Improved methods to determine ammi components have also been reported.el-Domiaty 1992, Zgórka 1998

Dihydroseselins have been determined from khella fruits and extracts.Karawya 1969 Genetically transformed khella cultures have been evaluated.Kursinszki 1997 In addition, marmesin, ammoidin, and ammidin have been characterized.Abu-Mustafa 1958 The fruit contains a small amount (less than 0.03%) of a volatile oil.

Uses and Pharmacology

Anti-Inflammatory effects

Animal and in vitro data

Using the carrageenan-induced rat paw edema method, anti-inflammatory activity comparable to that with indomethacin was noted with compounds extracted from A. majusSelim 2012 These findings were also noted in a similar model 30 and 60 minutes following administration of A. majus 50 mg/kg and 100 mg/kg.Koriem 2012

Antimicrobial effects

In vitro data

In vitro, khella extract showed marked antimicrobial activity against gram-positive bacteria and Candida spp.Jawad 1988 The constituent khellin from A. visnaga fruit parts inhibited the mutagenicity of certain promutagens in Salmonella typhimurium.Schimmer 1998 Compounds derived from A. majus exerted antiviral activity against vesicular stomatitis virus in a concentration-dependent manner. However, there was no effect against herpes simplex virus.Selim 2012 Another in vitro study demonstrated that A. majus was effective against Staphylococcus aureus, Escherichia coli, and Proteus vulgaris.Al Akeel 2014

Antipyretic effects

Animal data

In a study of albino rats and mice, 100 mg/kg of an ethanolic extract of A. majus exhibited antipyretic effects.Koriem 2012

Antispasmodic/Antianginal effects

Khellin has been noted to be a potent coronary vasodilator with antispasmodic effects, making it useful in treating angina. In the 1940s and 1950s, khellin was considered a safe vasodilator for the treatment of angina pectoris in doses up to 300 mg daily.Abu-Hashem 2015

Animal and in vitro data

Acting at multiple sites, visnagin inhibited induced contractile responses in rat vascular smooth muscle.Duarte 1995 Similarly, visnadine demonstrated peripheral and coronary vasodilatory activities in isolated rat vascular smooth muscle.Durate 1997 In one report, a combination product containing khella demonstrated spasmolytic activity on guinea pig ileum.Westendorf 1981

Asthma

In vitro data

Khellin is a chromone, characterized by the presence of 5:6 benz-1:4-pyrone in its chemical structure; specifically, chromones block the release of inflammatory mediators from mast cells.Edwards 2014 Ethanolic and aqueous extracts of A. visnaga were found to exert antioxidant activity in 2, 2-diphenyl-1-picryhydrazyl free radical scavenging assays.Hilmi 2014

Cholesterol effects

Animal data

In a study of albino rats and mice, 50 mg/kg and 100 mg/kg doses of an ethanolic extract of A. majus seed lowered total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol, and increased high-density lipoprotein (HDL) cholesterol.Koriem 2012

Clinical data

When given orally to male patients with normal lipid levels, khellin 50 mg 4 times daily increased HDL cholesterol levels without affecting total cholesterol or triglyceride concentrations.Fromming 1989 In a case report, 10 days of A. visnaga seed administration improved HDL cholesterol (from 32 to 56 mg/dL), with no impact on other cholesterol parameters.Bhagavathula 2015

Gastric secretion

Animal data

In a study of fasting rabbits, administration of A. visnaga in combination with carbachol reduced the volume and free and total acidity of gastric secretion.Jan 2014

Hypoglycemic effects

An ethnobotanical survey including 130 respondents reported khella to be 1 of 16 species of Israeli medicinal plants used for diabetes.Yaniv 1987

Animal data

In a study of normal and streptozotocin-induced diabetic rats, an aqueous extract of A. visnaga dosed orally at 20 mg/kg produced a significant reduction in blood glucose 6 hours after administration (P<0.005) as well as 9 days after continued daily administration (P<0.05).Jouad 2002

Larvicidal activity

In vitro data

In one study, A. visnaga, particularly khellin and visnagin, demonstrated larvicidal activity against Culex quinquefasciatus.Pavela 2016

Psoriasis

Clinical data

In a 4-month controlled study, oral khellin 100 mg daily plus sunlight exposure was found to improve psoriasis in 8 of 10 treated patients.Abdel-Fattah 1983

Urolithiasis

The diuretic effect of khellin may be responsible for its ability to facilitate urethral and kidney stone passage.Kilicaslan 2012

Animal and in vitro data

An in vitro study found that a khella extract, as well as the khella compounds khellin and visnagin prevented renal epithelial cell injury caused by oxalate and calcium oxalate monohydrate.Vanachayangkul 2010 In rats, a khella extract administered for 14 days reduced the incidence of calcium oxalate crystal deposition in the kidneys. Urinary excretion of citrate and a reduction in oxalate excretion was associated with khella extract administration.Vanachayangkul 2011 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.Ahsan 1989 Daily treatment with 500 mg/kg of A. visnaga seeds reduced the incidence of nephrolithiasis in Wistar albino rats.Khan 2001

Clinical data

A case report describes the beneficial effects of A. visnaga seed administration in a 50-year-old patient with urethral and kidney stones. Two days after initiation of treatment, the patient reported pain relief and the absence of hematuria. The kidney stone passed on day 5 and the urethral stones on days 7 and 8.Bhagavathula 2015

Vitiligo

Interest in khellin as an adjunct to UV light therapy in the treatment of vitiligo is based on the structural similarity between khellin and the psoralens, but with less phototoxicity and damaging effects on DNA.Abu-Hashem 2015, Morliere 1988

In vitro data

A study evaluating the mechanism of action of khellin in cultured human cells concluded that khellin activated by UVA stimulates melanocyte proliferation and melanogenesis.Carlie 2003

Clinical data

Success in treatment of vitiligo has been reported using oral and topical khellin in clinical studies.Hofer 2001, Valkova 2004, de Leeuw 2003, Orecchia 1992, Saraceno 2009 Studies using oral khellin 100 mg,Hofer 2001 topical khellin 0.005% encapsulated in liposomes,de Leeuw 2003 khellin 5% in water/oil emulsion,Valkova 2004 or khellin 4% topical ointment(Saraceno 2009) plus UVA therapy demonstrated success rates comparable to those with standard psoralen UVA therapy.

Topical therapy with the khellin-UVA combination required a longer duration of therapy than systemic therapy to achieve treatment goals but also demonstrated fewer adverse effects.Valkova 2004 Follow-up (mean, 40 months) of patients who received oral khellin showed no long-term adverse effects.Hofer 2001

Dosing

A typical dose of khella is an amount that provides 20 mg of the khellin constituent per day.Bhagavathula 2015 In safety and efficacy studies of khellin use in combination with UV light therapy for treatment of vitiligo, pure compound khellin was applied topically as a 5% preparation,Valkova 2004 and as 100 mg administered orally.Hofer 2001 In a study evaluating khellin effects on cholesterol regulation, khellin 200 mg/day orally was administered for 4 weeks.Harvengt 1983

Pregnancy / Lactation

Khellin should not be used in women who are pregnant or breastfeeding. It possesses uterine stimulant activity. Insufficient information is available regarding use during breastfeeding.Bhagavathula 2015

Interactions

None well documented.

Adverse Reactions

In patients who received oral khellin to reduce blood lipids and in a study evaluating khellin use in vitiligo, nausea and vomiting were observed frequently (29% of patients in the vitiligo study). Elevated AST and ALT were also reported during therapy (7% to 14%).Hofer 2001, Harvengt 1983 Other potential adverse reactions include dizziness, constipation, headache, itching, insomnia, and lack of appetite.Bhagavathula 2015

A. majus has been associated with the development of severe ophthalmologic changes, particularly pigmentary retinopathy in photosensitized fowl.Shlosberg 1974, Shlosberg 1983 In a study of 28 patients, 1 patient (4%) reported a temporary reduction in visual acuity that resolved upon discontinuation of treatment.Hofer 2001 Patients receiving khella or its extracts should be monitored for ophthalmologic changes.

The furocoumarins (psoralens) may cause photosensitization and dermatitis.Kavli 1984 One study reported 4 irritant compounds from ammi seeds and evaluated their potential contact dermatitic properties.Saeed 1993 A case report described a florist who experienced allergic rhinitis and contact urticaria as a result of exposure to A. majus. She tested positive with a pinprick test as well as had positive immunoglobulin E levels specific to A. majus. Upon cessation of work as a florist, the patient became and remained asymptomatic.Kiistala 1999

Toxicology

The use of oral khellin is limited by its potential for toxicity (eg, elevated liver enzymes, phototoxicity, dermatitis).Hofer 2001, Harvengt 1983, Kavli 1984, Saeed 1993 In a study of rats, the median lethal dose (LD50) was 3.6 g/kg for intraperitoneal administration and 10.1 g/kg for oral administration. Toxic symptoms noted at higher doses included piloerection and diminished locomotor activity.Jouad 2002 Although not lethal, toxicity as evidenced by reduced weight gain, inefficient feed utilization, tissue lesions, and hematological and serological changes were noted in chicks fed 10% A. visnaga seed.Ibrahim 2004

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