Next Article in Journal
The Emulsifying Properties of Hydrogenated Rosin Xylitol Ester as a Biomass Surfactant for Food: Effect of pH and Salts
Previous Article in Journal
Charge Displacement Analysis—A Tool to Theoretically Characterize the Charge Transfer Contribution of Halogen Bonds
Review

Ammi Visnaga L., a Potential Medicinal Plant: A Review

1
Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 11835, Egypt
2
Arab Company for Pharmaceuticals and Medicinal Plants, (Mepaco-Medifood), El-Sharqiya 11361, Egypt
3
Faculty of Pharmacy, Minia University, Al Minya 61519, Egypt
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(2), 301; https://doi.org/10.3390/molecules25020301
Received: 9 December 2019 / Revised: 1 January 2020 / Accepted: 8 January 2020 / Published: 12 January 2020
(This article belongs to the Section Natural Products Chemistry)

Abstract

Ammi visnaga L. (Visnaga daucoides Gaertn., Family Apiaceae), also known as Khella Baldi or toothpick weed, is an annual or biennial herb indigenous to the Mediterranean region of North Africa, Asia, and Europe. The plant is known to have been used in traditional medicine a long time ago. Nowadays, it is used in modern medicine to treat many aliments such as renal colic and coronary insufficiency, and is used as an antioxidant, antifungal, and antibacterial, with a larvicidal effect on mosquito larvae. Peer-reviewed studies show that these pharmacological activities are due its valuable chemical constituents that include mainly essential oil, polyphenolic compounds including flavonoids, as well as γ-pyrones, represented mainly by khellin and visnagin. Its essential oil is reported to have antiviral, antibacterial, and larvicidal effects, while its flavonoid content is responsible for its antioxidant activity. Its γ-pyrone content has a powerful effect on facilitating the passage of kidney stones and relieving renal colic, in addition to having a relaxant effect on smooth muscle including that of the coronary arteries. The current review represents the progress in research on A. visnaga in terms of either its chemistry or biological activities. This review represents scientific support material for the use of the plant by the pharmaceutical industry.
Keywords: Ammi visnaga L.; γ-pyrones; khellin; visnagin; flavonoids; essential oil; muscle-relaxant Ammi visnaga L.; γ-pyrones; khellin; visnagin; flavonoids; essential oil; muscle-relaxant

1. Introduction

Since prehistoric times, plants have been employed in the treatment of many illnesses. Ancient humans used plants for the treatment of diseases by trial and error. They also noticed that animals avoid some plants while consuming others, and they followed their ways in dealing with nontoxic plants. Over time, people in various civilizations used plants in a planned and studied way. The Ancient Egyptians, Greeks, Romans, Chinese, and Indians had their own Planta Medica, which was a part of their materia medica. Many of the drugs mentioned in the Ebers Papyrus are still used today, including Ammi visnaga L., a plant that was known in ancient times as Pharaoh’s bread. Also, during the golden age of the Arabs, well-known physicians such as Avicenna, Al-Razy, Al-Antaki, and others mentioned many plants in their books, in an attempt to preserve, improve, and transmit the knowledge of ancient people [1]. This transferred knowledge is a corner stone for modern pharmacognosy and phytochemistry.
Ammi visnaga L. is a short annual or biennial herb indigenous to the Mediterranean region of North Africa, Asia, and Europe [2,3]. In Egypt, the plant is widely distributed in the Delta region, and surrounds the Nile River, particularly in Assiut and Minia governorates [4]. It is also widely cultivated by many people and companies aiming to use its extracts or active components in the pharmaceutical industry. It has been recently discovered and added to the flora of Croatia at altitudes of 380–460 meters above sea level [5]. The plant is also distributed throughout North America (North Carolina, Pennsylvania, Oregon, Alabama, California, Florida, and Texas), the Atlantic islands, Argentina, Mexico, and Chile. In Asia, the plant is found in Iraq, Iran, and other western and southern countries. The plant, especially its fruit, has a wide range of applications either in traditional or modern medicine. Despite the medical importance and applications of A. visnaga and its chemical constituents, no comprehensive literature review has been made for this plant. This review aims to report on the phytochemical constituents and pharmacological effects, as well as the applications of A. visnaga in the pharmaceutical industry. Data in this review was collected from 100 peer-reviewed articles, book chapters, and a WHO monograph (for the period 1947–2019) found in different online databases, such as PubMed, ScienceDirect, SciFinder, Google Scholar, and Scopus.

1.1. Synonyms

Selinum visnaga E.H.L. Krause, Daucus visnaga L., Sium visnaga Stockes, Visnaga daucoides Gaertn., Ammi daucoides Gaertn., Ammi dilatatum St.-Lag., Apium visnaga L., Crantz, Carum visnaga L., Koso-Pol., Daucus gingidium L. ex DC [6].

1.2. Common Names

In Arabic countries A. visnaga has many common names such as Khella baladi, Khella, Khellah, Khellakl, Chellah, Kella, Gazar sheitani, Kammon habashi, Bizer Al-Khilla, Kulla, and Swak Al-Nabi. In Turkey, it is known as disotu, kilir, and hiltan.
In England, it is known as Pick tooth and Toothpick. In France it is known as Herbe aux cure-dents and in Germany as Zahnstocherkraut. The Berber calls it Tabellaout [6].

1.3. Morphology

Ammi visnaga is an herbaceous annual or sometimes biennial plant growing to a height of up to 1.3 meters and a diameter of the green aerial part of up to 1.2 meters. The root is a cylindrical tap root, and light brown in color. The root is straight or slightly tortuous, growing vertically. The surface of the root shows remnants of secondary fibrous rootlets. The main tap root measures up to 50 cm in length and 1.5 cm in the widest upper part. The stem is cylindrical, erect, highly branched, densely leafy, and glabrous. The alternate internodes are at a distance ranging from 5 to 8 cm in length, where light brown scaly leaves are present at the nodes. The stem measures up to 130 cm in length and 1.5 cm in diameter. Leaves are pinnate or ovate in shape with slender linear segments measuring about 20−30 mm in length and 0.5−1 mm in diameter. The margin of the segment is entire, while the apex is acute. Leaves are sessile in the upper shoots and have short petioles downwards. They are green at the upper region and greyish white in the lower part. Flowers form inflorescent white umbels, each of which is 6−10 cm across; flower stalks are elongated, up to 20 cm in length. With many bracts, the number of rays may be 50, 100, or 150 per umbel; each ray is slender and 2–5 cm long, unequally spreading when young. In the fruiting stage, rays become thick, rigid, and constricted on a discoid thickened base. They are surrounded with an involucre of long tripartite bracts. Bracteoles are numerous, 3–10 mm in length, entire, equaling flowers. Florets have a white corolla and calyx with minute inconspicuous sepals, and are 0.2 mm in length. The foliage part has a very characteristic smell and the flowers have their own special perfume. Fruits are ovoid oblong cremocarps, and brownish green with a violet tinge. They are laterally compressed with thick raised ridges and are glabrous. The umbels become dry and constricted on a discoid torus at the fruiting stage, measuring from 6 to 10 cm in length and 2 to 4 cm in width (at the widest part), and becoming light brown in color with characteristic odor and taste. The photosensitizing power of the plant sap must be taken into consideration, so it is advisable to handle the flowers or the whole plant with gloves or wash hands directly with water after handling [3,4,6].

1.4. Traditional Folk Medicinal Uses

The decoction and/or powdered plant has been traditionally used for the treatment of renal colic, mild anginal symptoms, treatment of abdominal cramps. It is also employed as a supportive treatment for mild obstruction of the respiratory tract in asthma or spastic bronchitis, and postoperative treatment of conditions associated with the presence of urinary calculi. The plant and its extracts are also popular in the treatment of vitiligo and psoriasis, and are used as a lithotriptic agent. It is generally used to dilate bronchial, urinary, and blood vessels without affecting blood pressure. It is also internally used as an emmenagogue to regulate menstruation, as a diuretic, and in the treatment of vertigo, diabetes, and kidney stones. An infusion of the aerial parts has also been used to treat headaches [2,7,8,9].

2. Chemical Review

The chemical constituents of A. visnaga are well known and have been reported by many researches in numerous studies throughout the years. Previous studies have reported on various chemical constituents in A. visnaga, including γ-pyrones, coumarins flavonoids, and essential oils. The quality and quantity of these secondary metabolites depend on the part of the plant analysed, as well as the growing conditions and the addition of any bioregulators [10].

2.1. γ-Pyrones and Coumarins

γ-Pyrones and coumarins are considered to be the major constituents of A. visnaga. They include:
γ-Pyrones (Furanochromone Derivatives)
Khellin and visnagin are the major ones [11,12,13,14,15], in addition to 4-norvisnagin, khellinol, visamminol, ammiol, and khellol [16]. Other important γ-pyrones include 5,7-dihydroxy-2-methyl-γ-pyrone-7-O-glucoside and pimolin (III) [17], as well as, khellinin, khellinone, and visnaginone [15].
Coumarins, which may be further divided into two sub-groups
Pyranocoumarins: represented by an angular-type dihydro-pyranocoumarin glucoside which was isolated from the fruits and named cis-khellactone-3′-β-d-glucopyranoside [18], in addition to visnadin [19], samidin, and dihydrosamidin [15].
Furanocoumarins such as xanthotoxin, ammoidin, bergapten, and psoralene are present, but only in small amounts [20].
The chemical structures of the aforementioned compounds have been determined using various spectroscopic techniques such as nuclear magnetic resonance, ultraviolet, mass spectroscopy, and infrared spectroscopy. The structures of previously identified γ-pyrones and coumarins are compiled in Table 1 and Figure 1.

2.2. Phenolic Compounds

Phenolic compounds are considered an important group of secondary metabolites that has been identified in A. visnaga, particularly in its aerial parts, by many researchers. They belong mainly to the flavonoids class. They are present in both aglycone and conjugated forms, and may be divided into:

2.2.1. Flavonols

The main aglycones identified in A. visnaga include quercetin, kaempferol, rhamnocitrin, and rhamnetin [21], in addition to rhamnazin [16]. The flavonols in A. visnaga most commonly conjugate with either glucose or rutinose moeities. Flavonoidal glycosides include quercetin-3-glucoside, kaempferol-3-glucoside [21], and isorhamnetin 3-β-d-glucoside [17], as well as rhamnetin-3-O-glucoside, isorhamnetin-3-O-glucoside, rhamnazin-3-glucoside, isorhamnetin-7-O-glucoside, and quercetin-7,3,3’-O-triglucoside [22]. Those conjugated with rutinose comprise quercetin-3-rutinoside, kaempferol-3- rutinoside [21], and isorhamnetin-3-O-rutinoside [22]. A. visnaga is also considered a rich source of flavonoidal sulfates; The most commonly identified ones include quercetin 3-sulfate, rhamnocitrin 3-sulfate, rhamnetin, and isorhamnetin-3-sulfate [21].

2.2.2. Isoflavones

Represented by daidzin, genistin, sissotrin, isoformononetin, formononetin, prunetin, biochaninA, coumestrol, daidzein, and 6,7,4′-trihydroxyisoflavone. Their presence was identified by means of semipreparative HPLC with an enzyme-linked immunosorbent assay (HPLC-ELISA) along with high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) [23].

2.2.3. Flavones as Apigenin, Luteolin and Chrysoeriol

The chemical structures of reported flavonoids are shown in Table 1 and Figure 1.

2.3. Essential Oil

Ammi visnaga L. was found to contain essential oils in different organs, but mainly in the umbels and fruits. Studies used either steam distillation or hydrodistillation to isolate the oil, and then analyse it by means of gas chromatography (GC) and gas chromatography coupled with mass spectrometery (GC-MS) to identify its components. The chemical constituents of the essential oils of A. visnaga are distributed mainly among the following groups: nonterpenes and monoterpenes [24], in addition to diterpenes and sesquiterpenes but only in very small amounts in the case of the latter two [25]. The most abundant constituents of A. visnaga essential oils were found to be isoamyl 2-methylbutyrate, isoamyl isobutyrate, iso-butyl-2-methylbutyrate, 2-methylbutyl 2-methylbutyrate, 2-methylbutyl isobutyrate, and isoamyl isovalerate [14,26]. A large group of the volatiles identified in A. visnaga belong to the monoterpenes class. They are either oxygenated or hydrocarbon monoterpenes, and the major components identified were linalool and thymol. They comprise the highest percentage among other monoterpenes. Other identified monoterpenes include α-thujene, α-pinène, β-pinene, and β-myrcene, but only in small amounts [27,28]. The nature of the main constituents of the essential oils of A. visnaga depend greatly on the plant part and its developmental stage. Many studies have dealt with the differences in the chemical composition of essential oils of A. visnaga and their respective amounts. They suggested that the differences could be associated with differences in biotypes and geographic origins along with variations in the environment such as soil type, solar radiation, and environmental stress. These factors could lead to the activation or inactivation of certain enzymatic groups, resulting in the up- or down-regulation of certain biosynthetic pathways [15]. The structures of the different constituents of the essential oils in A. visnaga are represented in Table 1 and Figure 1.

2.4. Sterols and Fatty Acids

Other classes of chemical compounds were found in various parts of A.visnaga; however, they are considered minor compounds and are found in low percentages in the plant. These include β-sitosterol and β-sitosterol-glucoside [29], in addition to palmitic, palmitoleic, stearic, petroselinic, linoleic, linolinic, arachidic, tetracosanoic acids, which were identified using high performance liquid chromatography-quadrupole time of flight (LC-QTOF) mass spectrometry [30].
Table 1. Secondary metabolites previously isolated from A. visnaga.
Table 1. Secondary metabolites previously isolated from A. visnaga.
No.CompoundPlant OriginPlant PartReference
Furanochromones (γ-Pyrones)
1KhellinItalyFruits[11]
2Visnagin
3KhellinolEgyptFruits[16]
4Ammiol
5Visamminol
6Khellol
7PimolinEgyptFruits[17]
8Khellinin
(khellol glycoside)
TurkeyFruits[13]
9CimifuginTunisiaUmbels[10]
10Prim-O-glucosyl cimifugin
Benzofurans
11KhellinoneEgyptFruits[16]
12Visnaginone
Pyranocoumarines
13VisnadinPolandFruits[19]
14cis-khellactone-3′-β-d-glucopyranosideGermanyFruits[18]
15SamidinAustriaFruits[31]
16Dihydrosamidin
Furanocoumarins
17XanthotoxinEgyptFruits[32]
18Bergapten
19Psoralen
Flavonoids
20Kaempferol-3-rutinosideEnglandLeaf, flower and fruit[21]
21Kaempferol-3-glucoside
22Quercetin3-sulfate
23Rhamnocitrin-3-sulfate
24Rhamnetin-3-sulfate
25Isorhamnetin-3-sulfate
26Quercetin-3-O-rutinosideAlgeriaAerial parts[22]
27Quercetin-3-O-glucoside
28Isorhamnetin 3-O-β-d-glucosideEgyptFruits[17]
29RhamnazinEgyptFruits and aerial parts[16]
30Isorhamnetin
31QuercetinIraqFruits and aerial parts[33]
32KaempferolFruits[33]
33Apigenin
34Luteolin
35Chrysoeriol
36RhamnetinAlgeriaAerial parts[22]
37Rhamnetin-3-O-glucoside
38Isorhamnetin-3-O-glucoside
39Rhamnazin-3-glucoside
40Isorhamnetin-7-O-glucoside
41Isorhamnetin-3-O-rutinoside
42Quercetin 7,3,3′-O-triglucoside
43DaidzinCzech RepublicLeaves and roots[23]
44Genistin
45Sissotrin
46Isoformononetin
47Formononetin
48Prunetin
49Biochanin A
50Coumestrol
51Daidzein
524′,6,7-Trihydroxyiso-flavone
Representatives of essential oil constituents
53LinaloolTunisiaFruits[27]
54Isoamyl-2-methylbutyrate
55α-Thujene
56Butyl isobutyrate
57α-PinèneTunisiaLeaves, stems, flower buds, roots, umbels and fruits[24,27]
58β-Pinene
59α-Terpinene
60Limonene
61α-IsophoroneAlgeriaFresh aerial parts[26]
622-Nonyne
63Hexenyl isobutanoate
64Thymol
65Citronellyl propionate
66Croweacin
67Geranyl acetate
68Isobutyl isovalerateAlgeriaFruits and fresh aerial parts[34]
69NerolFresh aerial parts
70HexanalAlgeriaUmbels[28]
71Sabinene
Fatty acids
72Tetracosanoic acidEgyptAerial parts[29]
73Stearic acid
74Petroselinic acidEgyptFruits[30]
75Arachidic acid
Sterols
76β-sitosterolEgyptAerial parts[29]

3. Pharmacological Review

3.1. Kidney Diseases

Ammi visnaga L. has been used in folk medicine by the Middle Eastern population since ancient times. The fruit decoction was used for the treatment of renal colic by the ancient Egyptians [35], as a treatment of kidney inflammation in Iraq [36] and Palestine [37], and in the treatment of urolithiasis and prostatic pain in Algeria [38]. Its use had spread to the extent that it was regarded as the most recommended species for the treatment of urinary tract infections [39]. Several studies have focused on the diuretic activity of A. visnaga; it has been shown to be effective in the treatment of nephrolithiasis and uremia [40]. Its use in the treatment of kidney disorders is commonly coupled with khellin and visnagin, i.e., the major γ-pyrones of A. visnaga. They have been shown to protect the renal epithelial cell damage from oxalate and calcium oxalate monohydrate crystals, and to prevent the oxalate formation that is associated with hyperoxaluria by increasing the urinary pH and citrate concentration, along with a decrease of urinary oxalates [41,42,43,44,45]. The pleiotropic effects of khellin and visnagin on urolithiasis have been intensively studied by many researchers [46,47,48]. Bhagavathula reported that a patient suffering from recurrent urethral stones showed complete recovery after treatment with A.visnaga fruit for ten days [49]. Recently, an experiment was conducted in an approach aiming to further explain the mode of action of A. visnaga in inhibiting the nucleation and preventing the crystallization of kidney stone [50].

3.2. Antispasmodic and Vasodilating Effects

The vasodilating properties of A. visnaga have been investigated by several researches. It has been established as a bronchodilator and coronary medication in the treatment of angina pectoris due to its peripheral and coronary vasodilator activity [51], in addition to being an antiasthmatic and a vasodilator, as well as an effective muscle relaxant agent without affecting blood pressure [3,52]. The vasodilating properties of A. visnaga are associated with its two major γ-pyrones, khellin and visnagin, along with the pyranocoumarin, visnadin. Both khellin and visnadin have been proven to possess calcium antagonistic activity, which, in turn, yields vasodilating activities. Visnadin has been shown to possess both peripheral and coronary vasodilator activities, and is thus used for the treatment of angina pectoris. It preferentially inhibits the contractile responses mediated by Ca2+ entry through L-type Ca2+ channels, and at high concentrations, it may also interfere with other sites involved in vascular smooth muscle contraction [53,54,55,56,57,58]. The vasodilating effect of visnagin is a result of inhibiting the vascular smooth muscle contractility at multiple sites, and weakly inhibiting the hydrolytic activity of the cyclic nucleotide phosphodiesterase (PDE) isozymes [59,60,61].

3.3. Antidiabetic Activities

The use of A. visnaga as an antidiabetic agent is considered famous in many cultures, such as those of Palestine, Moroco, and the Sefrou region [35,62,63,64]. An aqueous extract of A. visnaga was shown to possess a significant hypoglycemic effect when given to both normal and streptozotocin diabetic rats [65]. additionally, a decoction prepared from the fruits of the A.visnaga had the ability to reduce blood glucose levesl by 51% in normoglycemic rats, compared to an oral hypoglycaemic agent (tolbutamide) [66].

3.4. Treatment of Vitiligo

Since 1982, khellin has been shown to be effective in both oral and topical photochemotherapy for the treatment of vitiligo. A study done by Orecchia indicated that treatment with a gel formulation of khellin based upon a water/2-propanolpropylene glycol (khellin-WPG) system combined with ultraviolet A (UVA) significantly improved the clinical outcome of patients with vitiligo by facilitating the availability of the drug in the skin [67]. The treatment was proven to be safe for both short- and long-term treatments [68]. Later on, an open clinical trial was conducted to investigate the efficacy and safety of treatment with khellin encapsulated in L-phenylalanine stabilized phosphatidylcholine liposomes in combination with ultraviolet A/ultraviolet B (UVA/UVB) light therapy (KPLUV) in 74 patients suffering from vitiligo. The treatment was shown to be highly effective, and did not cause any side effects [69]. Furthermore, the melanin biosynthesis inhibitory effects of khellin were investigated using a B16 melanoma cell line, and showed a potent inhibitory activity compared to arbutin, which was used as a positive control in the experiment [29]. Moreover, the additional value of combining blister roof transplantation (BRT) with khellin in liposomes and ultraviolet light (KLUV) in the treatment of recalcitrant vitiligo patches has been investigated; the results showed that almost 75% of the treated patients were extremely satisfied with the result [70].

3.5. Anti-inflammatory Effect

The anti-inflammatory effects of A. visnaga have been investigated, and it was shown that, depending on its visnagin content, it caused a decrease in mRNA expression and the release of TNF-α, IL-1β, and IFNγ. In addition, visnagin reduced LPS-induced IL-6 and MCP-1 mRNA level, thus suggesting that the anti-inflammatory effect of visnagin may be due to the inhibition of transcription factors such as AP-1 and NF-κB [71]. Moreover, Kwon et al. suggested that visnagin had a neuroprotective effect in terms of suppressing kainic acid-induced pathogenesis in the brain, and that these neuroprotective effects are associated with its anti-inflammatory effects [72].

3.6. Antimicrobial Effect

Several studies have reported on the antimicrobial effects of the different extracts of A.visnaga The alkaloidal and sesquiterpene lactone fractions have shown activity against Candida species [73], while the ethanolic extracts of fruits showed a significant inhibition of the growth of Mycobacterium tuberculosis [74]. In addition, the fruit’s aqueous extract inhibited the growth and aflatoxin production of Aspergillus flavus in a dose-dependent manner [75]. Additionally, remarkable activity was revealed for the aqueous and hydroalcoholic stem extracts of A. visnaga against Streptococcus mutans, Streptococcus salivarius, and Streptococcus sanguis [76]. In an approach aimed to evaluate the possibility of using A. visnaga extracts in pharmaceutical and food preservation systems, a study showed that the fruit ethanolic extract was the most active extract against the Gram-positive bacteria Enterococcus faecalis. Moreover, the same extract revealed antimicrobial activity against the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae [77]. Several studies have focused on the antimicrobial effects of the essential oils of the A. visnaga L., showing their effectiveness against various microorganisms such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae strains [25,26,78,79]; however, they showed weak antifungal activities [34]. Razzaghi-Abyaneh identified components that strongly inhibited aflatoxin formation in toxigenic fungi, e.g., khellin, xanthotoxin, and bergapten [20].

3.7. Cytotoxic Activity

In recent years, focus has been directed to the discovery of new cytotoxic agents, and attempts have been made to investigate the cytotoxic activities of many medicinal plants, including A. visnaga. In 2004, khellin was isolated, and its cytotoxicity was evaluated against four human tumour cell lines: HT-29 (colorectal cancer), MCF-7 (breast cancer), HEp-2 (larynx cancer), and MKN-45 (gastric cancer). However, the results were not promising, and the substance did not show significant cytotoxic activity at the tested concentrations against the four cell lines [80]. On the other hand, khellin showed mild to moderate activity when tested against the hepatocarcinoma cell line (HepG2) [81]. An ethanolic extract of A. visnaga also showed inhibitory effects on both Hela (cervical cancer) and MCF7 cell lines [82]. The cytotoxic activity of isolated khellin and visnagin against four human cell lines, Hela (cervical carcinoma), Hep-G2 (liver carcinoama), HCT 116 (colon carcinoma), and MCF7 (breast carcinoma), was further investigated; the results revealed good cytotoxic activity of both γ-pyrones against the Hep-G2 cell line [83].

3.8. Antioxidant Activity

Very few studies have examined the antioxidant properties of A. visnaga. The free radical scavenging activity of the butanol extracts of the aerial parts of A. visnaga has been investigated, showing equivalent antioxidant activity, i.e., an IC50 equals to 8.77 ± 0.2 µg/mL, to the standard antioxidant rutin (IC50 = 3.01 ± 0.2 µg/mL) [22]. Another study examined the antioxidant activity of essential oils isolated from the umbels of A. visnaga; however, the results showed only very weak activity [28].

3.9. Hair Loss

The topical application of A. visnaga for hair loss has been studied. A lotion for hair scalp composed of visnadin and other constituents led to an increase in arterial and arteriolar sphygmic activity in the subpapillary plexus, leading to an improvement in local microcirculatory flow [84].

3.10. Antimutagenic Effect

In a study aiming to evaluate the antimutagenicity spectrum of A. visnaga, khellin showed inhibition to mutagenicity of promutagens benzo[a]pyrene, 2-aminofluorene, and 2-aminoanthracene in Salmonella typhimurium T98, while visnagin showed higher toxic activity. Meanwhile, the total extract from A. visnaga fruit showed higher inhibition potency than khellin alone against 2-aminoanthracene, 1-nitropyrene, and daunomycin. This was attributed to the presence of additional inhibitors such as coumarins, or to the synergistic effects with the accompanying compounds [85].

3.11. Cardiovascular Activity

It is well known that A. visnaga extract or its active principals exert a relaxant effect on smooth muscles, even those of coronary arteries. It was found that intravenous injection of visnagin lowered the blood pressure with no change in the heart rate. It was also found that samidin and khellol glycoside induced a positive inotropic effect on the heart, while visnadin in a concentration 60 µg/mL increased coronary blood flow in isolated guinea pig heart. On the other hand, it was found that khellin, samidin, dihydrosamidin, and visnadin effectively normalized the electrocardiogram of ischemic myocardia in a dog. It seems that khella extracts or active principals improve the blood supply to coronary smooth muscles, where it dilates the coronary arteries without affecting the heart rate. The administration of khellin by oral or intramuscular injection gave good results in treating angina pectoris, and is favored in case of coronary thrombosis. As a result, khellin in a concentration of 50 mg/mL can help prevent angina pectoris with no side effects, although it is weaker than glyceryl trinitrate [54,59,60,61].

3.12. Immunostimulatory Activity

A. visnaga total and protein extracts were found to have immunostimulatory effects. Extracts were tested using an MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay on splenocytes with or without stimulation by concanavalin-A (Con-A), a mitogenic agent used as a positive control. This could explain the traditional use of such a plant [86].

3.13. Other Reported Activities on Human

Gouda obtained results that suggested that A. visnaga, among other plants, might have analgesic activity [87]. Also, Bhagavathula et al. suggested that A. visnaga fruits have a significant effect on increasing HDL-cholesterol levels, highlighting the hypothesis that it could be used in treating hypertriglyceridemia [49].

3.14. Larvicidal and Insecticidal Activities

Many natural products isolated from plants could be used as alternative treatments with larvicidal and insecticidal activities. For this purpose, the larvicidal and insecticidal properties of A. visnaga were studied, and the toxicity of khellin was investigated against nymphs Oncopeltus fasciatus (Hemiptera) and the larvae of Aedes aegypti (Diptera), where it showed great activity [88]. Studying the acaricidal and ovicidal activity of khellin and visnagin against Tetranychus urticae showed that both khellin and visnagin were highly promising, and could be used for the development of new botanical acaricides from A. visnaga [89], as well as that they were both phytotoxic to model species lettuce (Lactuca sativa) and duckweed (Lemna paucicostata) [90]. The fruit extract was found to possess an inhibitory action on the lipid content in haemolymph of nymphs and adults [91], while the n-butanolic extract of A.visnaga was also shown to prevent the activity of Glutamic oxaloacetic transaminase (GOT) and Glutamic pyruvic transaminase (GPT) in haemolymph and fat bodies of last instar nymphs and newly-emerged adult females of the dangerous desert locust, Schistocerca gregaria [92].

3.15. Herbicidal Activity

A study done in Argentina found that the dichloromethane extract of A. visnaga had a significant herbicidal effect. Phytotoxicity fractionation was done, and the fraction that contained khellin and visnagin was found to be responsible for its significant herbicidal activity [90].

4. Standardization of A. visnaga Fruit

Several pharmacognostic and phytochemical parameters for the standardization of A.visnaga fruit have been mentioned in the WHO monograph, among which the most important is that the fruit should contain not less than 1% γ-pyrones calculated as khellin, as determined using spectrophotometry [6].

5. Methods for Analysis of γ-Pyrones (Khellin and Visnagin)

Several methods have been applied for the determination of the γ-Pyrones percentage in A. visnaga (i.e., in the root, aerial parts, umbel, and fruit) extracts or pharmaceutical products. These methods include the spectrophotometric method, the colorimetric method, GC, and HPLC:

5.1. Spectrophotometric Method

This depends on the chromatographic adsorption of the impurities from the alcoholic extract, and then determining the extinction coefficient in the region of 220−350 nm. A calibration curve for standard Khellin was prepared for such a quantitative determination [93].

5.2. Gas Chromatography

This simple, fast, and precise method was applied using a capillary column DB-17 and injecting a chloroform extract of khellin with an internal standard [94].

5.3. Capillary Electrophoresis

Capillary electrophoresis has been employed for the analysis of A. visnaga extracts. Capillary electrophoresis is considered a useful, simple, and rapid technique for the identification and determination of khellin and visnagin in A. visnaga fruits. This method needs only a minute sample without any preseparation process. The process is time and reagent efficient. In order to separate the nonionic khellin in capillary electrophoresis, an interaction with a charged carrier in the buffer should be provided by including a surfactant in the mobile phase [95].

5.4. HPLC Methods

Several validated HPLC methods have been applied for the separation and simultaneous quantitation of different γ-pyrones. A calibration curve is prepared and validated methods are applied using reversed phase technique. These methods are selective, time saving, and widely applicable in quality control for the herb, its extracts, or pharmaceutical products [96,97,98,99].

5.5. Supercritical Carbon Dioxide Fluid Chromatography

Supercritical fluid chromatography (SFC) is a separation technique which uses instrumentation that is almost identical to that used in HPLC. Complex mixtures can be separated and the amount, and sometimes the identity, of the individual components in the mixture can be determined. A solution of the sample is injected into a high-pressure flow stream that sweeps the sample into a tube or column filled with fine particles. The individual components in the sample interact differently with the surface of the particles, and are separated in time and space as they pass through the column. The components emerge from the column at different times, as Gaussian or pseudo-Gaussian peaks, and pass through a detector. As a rule of thumb, any compound that is soluble in methanol or a less polar solvent is a good candidate for separation by SFC; therefore, it is very suitable for the determination of closely related structures and complex mixtures of γ-Pyrones in A. visnaga [100]

6. Pharmaceutical Products

Worldwide, many pharmaceutical products contain A. visnaga extract or active principals. The following are some examples.
Egypt
  • Kellagon® (capsules and effervescent sachets), produced by Arab Company for Pharmaceuticals and Medicinal Plants (Mepaco).
  • Khellalgin® ampoules, produced by Misr Company.
  • Glucolynamine®, produced by Memphis Company.
Germany
  • Aesrutal® S tablets, produced by Steigerwald Company.
  • Carduben® capsules, produced by Madaus Company.
  • Khellangan N® tablets, produced by Ardeypharm Company.
  • Steno-logs N® tablets, produced by Loges Company.
  • Dr. Reckweg R66 arrythmin liquid, produced by Reckweg&Co.
France
  • Ammi visnaga drops, produced by Biotron Laboratories.
  • Ammi visnaga granules, produced by Biotron Laboratories.
  • Ammi visnaga globules, produced by Biotron Laboratories.
Spain
  • Vibeline®, produced by Promesa Company.
  • United States of America
  • Ammi visnaga Pellets, produced by Washington Homeopathic products.
  • CL-N liquid, produced by Vitality Works, Inc.
  • CN-Tone liquid, produced by Apotheca Company.
  • Dr. Reckweg R66 arrythmin liquid, distrubed by Dr. Reckweg America Inc.
  • GB-TONE liquid, produced by Apotheca Company.
  • Liver Tonic II liquid, produced by Apotheca Company.
Romania
  • Kellagon® capsules, produced by Mepaco Egypt and distributed by Sprint Pharma Company.

7. Dosage, Contraindications and Warnings

The daily recommended dose from A. visnaga fruit ranges from 0.05 to 0.15 g. For other dosage forms, the dose must be mentioned in the insert leaflet, as directed by the physician. It is expected to be the equivalent to the aforementioned dose of the fruit. Nothing has been reported regarding contraindications, except that such treatments must be avoided during pregnancy. Also, there are no warnings regarding the dried drug or its preparations, but it is advisable that patients receiving Khella treatment are not exposed to direct sun light. Care must be taken while handling the fresh plant to avoid the photosensitizing effect of the sap which is present in various organs.

8. Conclusions

Ammi visnaga has been used in traditional medicine for millennia. At present, it is widely cultivated by many peoples and companies aiming to use its extracts or active principals in the pharmaceutical industry. It is used in modern medicine to treat many aliments such as renal colic and coronary insufficiency, and as an antioxidant, antifungal, and an antibacterial with a larvicidal effect on mosquito larvae. The current review aimed to report on the main phytochemical constituents and pharmacological effects, as well as applications of A. visnaga in the pharmaceutical industry. The literature reviewed in this study recommends new research on and applications of this plant, especially in the field of the reliable production of herbal medicine.

Author Contributions

All authors contributed equally to data collection, analysis, manuscript design, preparation and revision of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Woodward, E.F. Botanical Drugs: A Brief Review of the Industry with Comments on Recent Developments. Econ. Bot. 1947, 1, 402–414. [Google Scholar] [CrossRef]
  2. Batanouny, K.H. Wild Medicinal Plants in Egypt: An Inventory to Support Conservation and Sustainable Use; Acad. of Scientific Research & Technology: Cairo, Egypt, 2001. [Google Scholar]
  3. Chevallier, A. The Encyclopedia of Medicinal Plants; Dorling Kindersley: London, UK, 1996. [Google Scholar]
  4. Boulos, L. Flora of Egypt; Al Hadara Publishing: Cairo, Egypt, 2000; Volume 2. [Google Scholar]
  5. Trinajstić, I. Supplements to the flora of island of Korčula (Croatia). Acta Bot. Croat. 1998, 57, 95–98. [Google Scholar]
  6. WHO. WHO Monographs on Selected Medicinal Plants; World Health Organization: Geneva, Switzerland, 2007; Volume 3. [Google Scholar]
  7. Rose, J.; Hulburd, J. The Aromatherapy Book: Applications and Inhalations; North Atlantic Books: Berkely, CA, USA, 1992. [Google Scholar]
  8. Farnsworth, N.R.; Krause, E.C.; Bolton, J.L.; Pauli, G.F.; van Breemen, R.B.; Graham, J.G. The University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research for Women’s Health: from plant to clinical use. Am. J. Clin. Nutr. 2008, 87, 504S–508S. [Google Scholar] [CrossRef] [PubMed]
  9. Miara, M.; Bendif, H.; Rebbas, K.; Rabah, B.; Hammou, M.; Maggi, F. Medicinal plants and their traditional uses in the highland region of Bordj Bou Arreridj (Northeast Algeria). J. Herb. Med. 2019, 16, 100262. [Google Scholar] [CrossRef]
  10. Sellami, H.K.; Napolitano, A.; Masullo, M.; Smiti, S.; Piacente, S.; Pizza, C. Influence of growing conditions on metabolite profile of Ammi visnaga umbels with special reference to bioactive furanochromones and pyranocoumarins. Phytochemistry 2013, 95, 197–206. [Google Scholar] [CrossRef]
  11. Franchi, G.G.; Ferri, S.; Bovalini, L.; Martelli, P. 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. [Google Scholar] [CrossRef]
  12. Mesbah, M.K. Determination 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. [Google Scholar]
  13. Guenaydin, K.; Beyazit, N. The chemical investigations on the ripe fruits of Ammi visnaga (Lam.) Lamarck growing in Turkey. Nat. Prod. Res. 2004, 18, 169–175. [Google Scholar] [CrossRef]
  14. Zrira, S.; Elamrani, A.; Pellerin, P.; Bessiere, J.M.; Menut, C.; Benjilali, B. Isolation of Moroccan Ammi visnaga oil: comparison between hydrodistillation, steam distillation and supercritical fluid extraction. J. Essent. Oil-Bear. Plants 2008, 11, 30–35. [Google Scholar] [CrossRef]
  15. Hashim, S.; Jan, A.; Marwat, K.B.; Khan, M.A. Phytochemistry and medicinal properties of Ammi visnaga (Apiacae). Pak. J. Bot. 2014, 46, 861–867. [Google Scholar]
  16. Abou-Mustafa, E.A.; Saleh, N.A.; Elgamal, M.H.; Shalaby, N.M.; Duddeck, H. A Further Contribution to the gamma-Pyrone Constituents of Ammi visnaga Fruits. Planta Med. 1990, 56, 134. [Google Scholar] [CrossRef] [PubMed]
  17. Elgamal, M.H.A.; Shalaby, N.M.M.; El-Hagrassy, A.M.; Toth, G.; Simon, A.; Duddeck, H. A further contribution to some gamma-pyrone constituents of Ammi visnaga. Fitoterapia 1998, 69, 549–550. [Google Scholar]
  18. Sonnenberg, H.; Kaloga, M.; Eisenbach, N.; Froemming, K.K. Isolation and characterization of an angular-type dihydropyranocoumarine glycoside from the fruits of Ammi visnaga (L.) Lam. (Apiaceae). Z. Fur Nat. 1995, 50, 729–731. [Google Scholar]
  19. 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. [Google Scholar] [CrossRef]
  20. Razzaghi-Abyaneh, M.; Shams-Ghahfarokhi, M.; Rezaee, M.B.; Sakuda, S. Natural Aflatoxin Inhibitors from Medicinal Plants. In Mycotoxins in Food, Feed and Bioweapons; Rai, M., Varma, A., Eds.; Springer: Berlin/Heidelberg, Germany, 2010; pp. 329–352. [Google Scholar]
  21. Harborne, J.B.; King, L. Flavonoid sulphates in the Umbelliferae. Biochem. Syst. Ecol. 1976, 4, 111–115. [Google Scholar] [CrossRef]
  22. Bencheraiet, R.; Kherrab, H.; Kabouche, A.; Kabouche, Z.; Jay, M. Flavonols and antioxidant activity of Ammi visnaga L. (Apiaceae). Rec. Nat. Prod. 2011, 5, 52–55. [Google Scholar]
  23. Abdulmanea, K.; Prokudina, E.A.; Lanková, P.; Vaníčková, L.; Koblovská, R.; Zelený, V.; Lapčík, O. Immunochemical and HPLC identification of isoflavonoids in the Apiaceae family. Biochem. Syst. Ecol. 2012, 45, 237–243. [Google Scholar] [CrossRef]
  24. Abdul-Jalil, T.Z.; Saour, K.; Nasser, A.A. Phytochemical Study of some Flavonoids Present in the Fruits of Two Ammi L. Species Wildly Grown in Iraq. Iraqi J. Pharma. Sci. 2010, 19, 48–57. [Google Scholar]
  25. Sellami, H.; Flamini, G.; Cioni, P.; Smiti, S. Composition of the essential oils in various organs at different developmental stages of Ammi visnaga (L.) Lam. from Tunisia. Chem. Biodivers. 2011, 8, 1990–2004. [Google Scholar] [CrossRef]
  26. Soro, K.N.; Sabri, L.; Amalich, S.; Khabbal, Y.; Zair, T. Chemical composition of Moroccan Ammi visnaga L. (Lam.) and antibacterial activity of its essential oil against extended-spectrum beta-lactamase–producing and not producing bacteria. Phytotherapie 2015, 13, 168–175. [Google Scholar] [CrossRef]
  27. Khalfallah, A.; Labed, A.; Semra, Z.; Al kaki, B.; Kabouche, A.; Touzani, R.; Kabouche, Z. Antibacterial activity and chemical composition of the essential oil of Ammi visnaga L. (Apiaceae) from Constantine, Algeria. Inter. J. Med. Aromat. Plants 2011, 1, 302–305. [Google Scholar]
  28. Khadhri, A.; ElMokni, R.; Mguis, K.; Ouerfelli, I.; Araujo, M. Variability of two essential oils of Ammi visnaga (L.) Lam. a traditional Tunisian medicinal plant. J. Med. Plants Res. 2011, 5, 5079–5082. [Google Scholar]
  29. Keddad, A.; Baaliouamer, A.; Hazzit, M. Chemical Composition and Antioxidant Activity of Essential Oils from Umbels of Algerian Ammi visnaga (L.). J. Essent. Oil-Bear. Plants 2016, 19, 1243–1250. [Google Scholar] [CrossRef]
  30. Ashour, A.; El Sharkawy, S.; Amer, M.; Abdelbar, F.; Kondo, R. Melanin Biosynthesis Inhibitory Activity of Compounds Isolated from Unused Parts of Ammi visinaga. J. Cosmet. Dermatol. Sci. Appl. 2013, 3, 40–43. [Google Scholar]
  31. Nguyen, T.; Aparicio, M.; Saleh, M. Accurate mass GC/LC-quadrupole time of flight mass spectrometry analysis of fatty acids and triacylglycerols of spicy fruits from the Apiaceae Family. Molecules 2015, 20, 21421–21432. [Google Scholar] [CrossRef] [PubMed]
  32. Winderl, B.; Schwaiger, S.; Ganzera, M. Fast and improved separation of major coumarins in Ammi visnaga (L.) Lam. by supercritical fluid chromatography. J. Sep. Sci. 2016, 39, 4042–4048. [Google Scholar] [CrossRef] [PubMed]
  33. Mabrouk, S.S.; El-Shayeb, N.M.A. Inhibition of aflatoxin production in Aspergillus flavus by natural coumarins and chromones. World J. Microbiol. Biotechnol. 1992, 8, 60–62. [Google Scholar] [CrossRef] [PubMed]
  34. Feirouz, B.; Salima, K. Antibacterial activity and chemical composition of Ammi visnaga l. Essential oil collected from Boumerdes (Algeria) during three periods of the plant growth. J. Essent. Oil-Bear. Plants 2014, 17, 1317–1328. [Google Scholar] [CrossRef]
  35. Sayed, M.D. Traditional medicine in health care. J. Ethnopharmacol. 1980, 2, 19–22. [Google Scholar] [CrossRef]
  36. Al-douri, N.A. A Survey of Medicinal Plants and Their Traditional Uses in Iraq. Pharm. Biol. 2000, 38, 74–79. [Google Scholar] [CrossRef]
  37. Said, O.; Khalil, K.; Fulder, S.; Azaizeh, H. Ethnopharmacological survey of medicinal herbs in Israel, the Golan Heights and the West Bank region. J. Ethnopharmacol. 2002, 83, 251–265. [Google Scholar] [CrossRef]
  38. Azaizeh, H.; Saad, B.; Khalil, K.; Said, O. The State of the Art of Traditional Arab Herbal Medicine in the Eastern Region of the Mediterranean: A Review. Evid. -Based Complementary Altern. Med. 2006, 3, 229–235. [Google Scholar] [CrossRef]
  39. Jaradat, N.A.; Zaid, A.; Al-Ramahi, R.; Alqub, M.A.; Hussein, F.; Hamdan, Z.; Mustafa, M.; Qneibi, M.; Ali, I. Ethnopharmacological survey of medicinal plants practiced by traditional healers and herbalists for treatment of some urological diseases in the West Bank/Palestine. BMC Complementary Altern. Med. 2017, 17, 255. [Google Scholar] [CrossRef]
  40. Khan, Z.A.; Assiri, A.M.; Al-Afghani, H.M.A.; Maghrabi, T.M.A. Inhibition of oxalate nephrolithiasis with Ammi visnaga (AI-Khillah). Int. Urol. Nephrol. 2002, 33, 605–608. [Google Scholar] [CrossRef] [PubMed]
  41. Vanachayangkul, P. Ammi visnaga L. for the Prevention of Urolithiasis. Ph.D. Thesis, University of Florida, Gainesville, FL, USA, 2008. [Google Scholar]
  42. Vanachayangkul, P.; Byer, K.; Khan, S.; Butterweck, V. An aqueous extract of Ammi visnaga fruits and its constituents khellin and visnagin prevent cell damage caused by oxalate in renal epithelial cells. Phytomedicine 2010, 17, 653–658. [Google Scholar] [CrossRef] [PubMed]
  43. Charafi, S.; Kzaiber, F.; Hafid, A.; Berkani, M.; Oussama, A. Study of Ammi visnaga Lam on oxalocalcic crystallization. Glob. J. Tradit. Med. Sys. 2012, 1, 7–12. [Google Scholar]
  44. Nagal, A.; Singla, R.K. Herbal Resources with Antiurolithiatic Effects: A Review. Indo Glob. J. Pharm. Sci. 2013, 3, 6–14. [Google Scholar]
  45. Nirumand, M.C.; Hajialyani, M.; Rahimi, R.; Farzaei, M.H.; Zingue, S.; Nabavi, S.M.; Bishayee, A. Dietary Plants for the Prevention and Management of Kidney Stones: Preclinical and Clinical Evidence and Molecular Mechanisms. Int. J. Mol. Sci. 2018, 19, 765. [Google Scholar] [CrossRef]
  46. Kilicaslan, I.; Coskun, S. Spontaneous stone passage: Is it Ammi visnaga effect? Urol. Res. 2012, 40, 799–800. [Google Scholar] [CrossRef]
  47. Khater, S.I.; Kandil, S.A.; Hussien, H. Preparation of radioiodinated khellin for the urinary tract imaging. J. Radioanal. Nucl. Chem. 2013, 295, 1939–1944. [Google Scholar] [CrossRef]
  48. Haug, K.G. Exploring the effects of Ammi visnaga L. on Nephrolithiasis Prevention: In vivo Pharmacokinetic and Pharmacodynamic Evaluation of Ammi visnaga L. Extract and Visnagin. Ph.D. Thesis, University of Florida, Gainesville, FL, USA, 2013. [Google Scholar]
  49. Bhagavathula, A.S.; MahmoudAlKhatib, A.J.; Elnour, A.A.; AlKalbani, N.M.S.; Shehab, A. Ammi visnaga in treatment of urolithiasis and hypertriglyceridemia. Pharmacogn. Res. 2015, 7, 397–400. [Google Scholar]
  50. Abdel–Aal, E.A.; Yassin, A.M.K.; El-Shahat, M.F. Inhibition of nucleation and crystallisation of kidney stone (calcium oxalate monohydrate) using Ammi visnaga (Khella) plant extract. Int. J. Nano Biomaterial. 2016, 6, 110–126. [Google Scholar]
  51. Balandrin, M.F.; Kinghorn, A.D.; Farnsworth, N.R. Plant-Derived Natural Products in Drug Discovery and Development. In Human Medicinal Agents from Plants; American Chemical Society: Washington, DC, USA, 1993; Volume 534, pp. 2–12. [Google Scholar]
  52. Al-Snafi, A.E. A Review of Medicinal Plants with Broncho-Dilatory Effect-Part 1. Sch. Acad. J. Pharm. 2016, 5, 297–304. [Google Scholar] [CrossRef]
  53. Rauwald, H.W.; Brehm, O.; Odenthal, K.P. The involvement of a Ca2+ channel blocking mode of action in the pharmacology of Ammi visnaga fruits. Planta Med. 1994, 60, 101–105. [Google Scholar] [CrossRef] [PubMed]
  54. Duarte, J.; Vallejo, I.; Perez-Vizcaino, F.; Jimenez, R.; Zarzuelo, A.; Tamargo, J. Effects of visnadin on rat isolated vascular smooth muscles. Planta Med. 1997, 63, 233–236. [Google Scholar] [CrossRef] [PubMed]
  55. Venugopala, K.N.; Rashmi, V.; Odhav, B. Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity. BioMed Res. Inter. 2013, 2013, 1–14. [Google Scholar] [CrossRef] [PubMed]
  56. Ubeda, A.; Tejerina, T.; Tamargo, J.; Villar, A. Effects of khellin on contractile responses and 45Ca2+ movements in rat isolated aorta. J. Pharm. Pharmacol. 1991, 43, 46–48. [Google Scholar] [CrossRef]
  57. Campos-Toimil, M.; Orallo, F.; Santana, L.; Uriarte, E. Synthesis and Vasorelaxant Activity of New Coumarin and Furocoumarin Derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 783–786. [Google Scholar] [CrossRef]
  58. Tripathi, Y.; Pandey, A. Bioprospecting of Phytodiversity for New Therapeutic Products:Trends, Potential and Challenges. Org. Med. Chem. 2017, 2, 1–7. [Google Scholar]
  59. Duarte, J.; Perez-Vizcaino, F.; Torres, A.I.; Zarzuelo, A.; Jimenez, J.; Tamargo, J. Vasodilator effects of visnagin in isolated rat vascular smooth muscle. Eur. J. Pharm. 1995, 286, 115–122. [Google Scholar] [CrossRef]
  60. Duarte, J.; Lugnier, C.; Torres, A.I.; Pérez-Vizcaino, F.; Zarzuelo, A.; Tamargo, J. Effects of Visnagin on Cyclic Nucleotide Phosphodiesterases and Their Role in its Inhibitory Effects on Vascular Smooth Muscle Contraction. Gen. Pharm. Vasc. Sys. 1999, 32, 71–74. [Google Scholar] [CrossRef]
  61. Duarte, J.; Torres, A.I.; Zarzuelo, A. Cardiovascular Effects of Visnagin on Rats. Planta Med. 2000, 66, 35–39. [Google Scholar] [CrossRef] [PubMed]
  62. Jarald, E.; Joshi, S.B.; Jain, D.C. Diabetes VS Herbal Medicines. Iran. J. Pharm. Ther. 2008, 7, 97–100. [Google Scholar]
  63. Dalila, B.; Smahane, B.; Abderrahman, A.; Mohamed, G.; Latifa, E. Ethnopharmacological Study of anti–diabetic medicinal plants used in the Middle-Atlas region of Morocco (Sefrou region). Int. J. Pharma. Res. Health Sci. 2014, 2, 75–79. [Google Scholar]
  64. Yaniv, Z.; Dafni, A.; Friedman, J.; Palevitch, D. Plants used for the treatment of diabetes in Israel. J. Ethnopharma. 1987, 19, 145–151. [Google Scholar] [CrossRef]
  65. Hassan, J.; Mhamed, M.; Mohammed, E. Hypoglycemic effect of aqueous extract of Ammi visnaga in normal and streptozotocin-induced diabetic rats. J. Herb. Pharma. 2002, 2, 19–29. [Google Scholar]
  66. Bnouham, M.; Mekhfi, H.; Abdelkhaleq, L.; Ziyyat, A. Ethnopharmacology Forum Medicinal Plants used in the treatment of diabetes in Morocco. Int. J. Diabetes Metab. 2002, 10, 33–50. [Google Scholar]
  67. Orecchia, G.; Sangalli, M.; Gazzaniga, A.; Giordano, F. Topical photochemotherapy of vitiligo with a new khellin formulation. J. Dermatol. Treat. 1998, 9, 65–69. [Google Scholar] [CrossRef]
  68. 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. [Google Scholar]
  69. De Leeuw, J.; Van der Beek, N.; Maierhofer, G.; Neugebauer, W.D. 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. [Google Scholar]
  70. De Leeuw, J.; Assen, Y.J.; van der Beek, N.; Bjerring, P.; Martino Neumann, H.A. Treatment of vitiligo with khellin liposomes, ultraviolet light and blister roof transplantation. J. Eur. Acad. Dermatol. Venereol. 2011, 25, 74–81. [Google Scholar] [CrossRef] [PubMed]
  71. Lee, J.; Jung, J.; Park, S.; Sim, Y.; Kim, S.; Ha, T.; Suh, H. Anti-inflammatory effect of visnagin in lipopolysaccharide-stimulated BV-2 microglial cells. Arch. Pharma. Res. 2010, 33, 1843–1850. [Google Scholar] [CrossRef] [PubMed]
  72. Kwon, M.; Lee, J.; Park, S.; Sim, Y.; Jung, J.; Won, M.; Kim, S.; Suh, H. Neuroprotective effect of visnagin on kainic acid-induced neuronal cell death in the mice hippocampus. Korean J. Physiol. Pharma. 2010, 14, 257–263. [Google Scholar] [CrossRef] [PubMed]
  73. Jawad, A.M.; Jaffer, H.J.; Alnaib, A.; Naji, A. Antimicrobial Activity of Sesquiterpene Lactone and Alkaloid Fractions from Iraqi-Plants. Int. J. Crude Drug Res. 1988, 26, 185–188. [Google Scholar] [CrossRef]
  74. Grange, J.M.; Davey, R.W. Detection of antituberculous activity in plant extracts. J. Appl. Bacteriol. 1990, 68, 587–591. [Google Scholar] [CrossRef]
  75. Mahmoud, A.L.E. Inhibition of growth and aflatoxin biosynthesis of Aspergillus flavus by extracts of some Egyptian plants. Lett. Appl. Microbiol. 1999, 29, 334–336. [Google Scholar] [CrossRef]
  76. Semyari, H.; Owlia, P.; Farhadi, S.; Tabrizi, S. Evaluation of antimicrobial effect of “Ammi visnaga” against oral streptococci. J. Microbiol. Antimicrob. 2011, 3, 126–129. [Google Scholar]
  77. Ghareeb, A.M.; Zedan, T.H.; Gharb, L.A. Antibacterial and antifungal activities of Ammi visnaga extracts against pathogenic microorganisms. Iraqi J. Sci. 2011, 52, 30–36. [Google Scholar]
  78. Satrani, B.; Farah, A.; Fechtal, M.; Talbi, M.; Bouamrani, M.L. Chemical composition and antibacterial and antimycotic activities of the essential oil of Ammi visnaga (L.) Lam. from Morocco. Acta Bot. Gall. 2004, 151, 65–71. [Google Scholar] [CrossRef]
  79. Rasooli, I.; Taghizadeh, M.; Astaneh, S.D.A.; Rezaei, M.B.; Jaimand, K. Phytobiological properties of Ammi visnaga L. and Lavandula angustifolia Mill. essential oils. Int. J. Essent. Oil Ther. 2007, 1, 72–78. [Google Scholar]
  80. Cordero, C.P.; Gómez-González, S.; León-Acosta, C.J.; Morantes-Medina, S.J.; Aristizabal, F.A. Cytotoxic activity of five compounds isolated from Colombian plants. Fitoterapia 2004, 75, 225–227. [Google Scholar] [CrossRef] [PubMed]
  81. Abdel-Monem, A.; Maged, A.; Zeinab, E.; Fawkia, A. Biological Activity of the Egyptian Medicinal Plants: Part 4 Cytotoxicity of 50 Egyptian Plants and Spices Against Hepatocellular Carcinoma. Am. J. Ethnomed. 2014, 1, 56–63. [Google Scholar]
  82. Pakfetrat, H.; Nemati, N.; Shiravi, A. Cytotoxicity effects OF Ammi visnaga extract on Hela and MCF7 cancer cell lines. J. Anim. Bio. 2015, 7, 25–33. [Google Scholar]
  83. Beltagy, A.M.; Beltagy, D.M. Chemical composition of Ammi visnaga L. and new cytotoxic activity of its constituents Khellin and Visnagin. J. Pharma. Sci. Res. 2015, 7, 285–291. [Google Scholar]
  84. Curri, S.B.; Bombardelli, E. Pharmaceutical compositions having activity on the cutaneous microcirculation. US patent 5,176,919, 1 May 1993. [Google Scholar]
  85. 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. [Google Scholar] [CrossRef] [PubMed]
  86. Daoudi, A.; Aarab, L.; Abdel-Sattar, E. Screening of immunomodulatory activity of total and protein extracts of some Moroccan medicinal plants. Toxicol. Ind. Health 2013, 29, 245–253. [Google Scholar] [CrossRef]
  87. Gouda, Y.G.; Hamam, F.S.; AlRemawi, M.M.; Abdallah, M.A.; AlAbbadi, M.A.; AlShehary, S.M.; AlGohary, R.T.; Mohamed, K.M. Study of analgesia caused by some commonly used herbs in the kingdom of Saudi Arabia. Ann. Biol. Sci. 2014, 2, 48–55. [Google Scholar]
  88. Maleck, M.; Dos Santos, F.C.C.; Serdeiro, M.T.; Guimaraes, A.E.; Ferreira, B.; Gunaydin, K.; de Almeida, A.P. Khellin: a furanochromone with toxicity against Oncopeltus fasciatus (Hemiptera) and Aedes aegypti (Diptera). J. Nat. Pharma. 2013, 4, 32–36. [Google Scholar] [CrossRef]
  89. Pavela, R. Acaricidal properties of extracts and major furanochromenes from the seeds of Ammi visnaga Linn. against Tetranychus urticae Koch. Ind. Crop. Prod. 2015, 67, 108–113. [Google Scholar] [CrossRef]
  90. Travaini, M.L.; Sosa, G.M.; Ceccarelli, E.A.; Walter, H.; Cantrell, C.L.; Carrillo, N.J.; Dayan, F.E.; Meepagala, K.M.; Duke, S.O. Khellin and Visnagin, Furanochromones from Ammi visnaga (L.) Lam., as Potential Bioherbicides. J. Agric. Food Chem. 2016, 64, 9475–9487. [Google Scholar] [CrossRef]
  91. Ghoneim, K.; Al-Daly, A.; Amer, M.; Mohammad, A.; Khadrawy, F.; Mahmoud, M.A. Effects of Ammi visnaga L. (Apiaceae) extracts on the main metabolites in haemolymph and fat bodies of Schistocerca gregaria (Forskal)(Orthoptera: Acrididae). J. Adv. Zool. 2014, 1, 11–23. [Google Scholar]
  92. Ghoneim, K.; Al-Daly, A.; Khadrawy, F.; Amer, M.; Mahmoud, M.A. Efficacy of the toothpick weed Ammi visnaga L. (Apiaceae) fruit extracts on transaminase activity in certain tissues of Schistocerca gregaria (Forskal)(Orthoptera: Acrididae). Int. J. Entomol. Res. 2016, 1, 19–28. [Google Scholar]
  93. Buriak, V.P.; Kurinna, N.V. Spectrophotometric determination of kellin and santonin. Farmatsevtychnyi Zhurnal 1971, 26, 39–42. [Google Scholar]
  94. Carlin, A.S.; Simmons, J.E.; el-Arini, S.K.; Shiu, G.K. Determination of khellin in serum by gas chromatography. J. Chromatogr. 1993, 614, 324–327. [Google Scholar] [CrossRef]
  95. Gunaydin, K.; Erim, F.B. Determination of khellin and visnagin in Ammi visnaga fruits by capillary electrophoresis. J. Chromatogr. A 2002, 954, 291–294. [Google Scholar] [CrossRef]
  96. Badr, J.M.; Hadad, G.M.; Nahriry, K.; Hassanean, H.A. Validated HPLC method for simultaneous estimation of khellol glucoside, khellin and visnagin in Ammi visnaga L. fruits and pharmaceutical preparations. Nat. Prod. Res. 2015, 29, 593–601. [Google Scholar] [CrossRef]
  97. El-Domiaty, M.M. Improved high-performance liquid chromatographic determination of khellin and visnagin in Ammi visnaga fruits and pharmaceutical formulations. J. Pharm. Sci. 1992, 81, 475–478. [Google Scholar] [CrossRef] [PubMed]
  98. Alqasoumi, S.; Alam, P.; Anwer, M.; Abdel-Kader, M. Qualitative and quantitative analysis of khellin in Ammi visnaga fruits and pharmaceutical preparations using HPTLC and HPLC. J. Liq. Chromatogr. Relat. Tech. 2014, 37, 61–72. [Google Scholar] [CrossRef]
  99. Bishr, M.; El Degwy, M.; Amin, M.; Salama, O. HPLC Simultaneous Determination of Khellin and Visnagin in Ammi visnaga L. Fruits. J. Pharm. Bio. Sci. 2016, 11, 110–115. [Google Scholar]
  100. Bishr, M.; El-Degwy, M.; Abdel Hady, M.; Amin, M.; Salama, O. Supercritical fluid extraction of γ-Pyrones from Ammi visnaga L. fruits. Future J. Pharm. Sci. 2018, 4, 57–62. [Google Scholar] [CrossRef]
Figure 1. Metabolites previously isolated from A. visnaga.
Figure 1. Metabolites previously isolated from A. visnaga.
Molecules 25 00301 g001
Back to TopTop