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Vol 6|Issue 2| 2016 |89-95.

Asian Journal of Pharmaceutical Science & Technology

e-ISSN: 2248 – 9185 www.ajpst.com Print ISSN: 2248 – 9177

MEDICAL IMPORTANCE OF NOBILIS ( NOBILE) - A REVIEW

Ali Esmail Al-Snafi

Department of Pharmacology, College of Medicine, Thi qar University, Iraq.

ABSTRACT Anthemis nobilis (), the so-called Roman , is a perennial herb of the family. It possessed antibacterial, antifungal, insecticidal, hypotensive, anti- platelet aggregation, anti-inflammatory, hypoglycaemic, antioxidant, nervous, cytotoxic, brochodilatory, endocrine and many other effects. This review highlights the chemical constituents and pharmacological effects of Anthemis nobilis.

Key words: Chemical constituents, Pharmacology, Anthemis nobilis.

INTRODUCTION Since the dawn of civilization, man utilized de jardín, manzanilla fina, manzanilla romana, Swedish: for their medicinal and edible value. Recent reviews showed romersk kamomill [43]. that plants produce many secondary metabolites which are Distribution: It was widely distributed in Asia, bio-synthetically derived from primary metabolites and , Africa and Northern America. The cultivated constitute an important source of many drugs [1-42]. in Africa: , ; Europe: Ireland, United Anthemis nobilis (Chamaemelum nobile), the so-called Kingdom, , , , Austria, Belarus, Roman chamomile, is a perennial herb of the Asteraceae Moldova, Ukraine, Bulgaria; ; Serbia, Belgium; Czech family. It possessed antibacterial, antifungal, insecticidal, Republic; Germany; Slovakia; Switzerland; Australasia: hypotensive, anti- platelet aggregation, anti-inflammatory, Australia, New Zealand; Northern America: United states hypoglycaemic, antioxidant, nervous, cytotoxic, [44]. brochodilatory, endocrine and many other effects. This Traditional use : The cold infusion was used in review will highlight the chemical constituents and gastric debility, with flatus; the hot infusion was used as pharmacological effects of Anthemis nobilis. diaphoretic, emetic, to relieve colds due to sudden Synonyms : Chamaemelum nobile (L.) cutaneous chilling, in dysmenorrhea to decrease pain and facilitate the flow, as antiemetic, antispasmodic, and TAXONOMIC CLASSIFICATION sedative. The oil was used as carminative, and for intestinal Kingdom: Plantae, Subkingdom: Viridaeplantae, cramps and colic due to flatulency [45-47]. Infrakingdom: Streptophyta, Division: Tracheophyta, Sub division: Spermatophytina, Infradivision: Angios DESCRIPTION permae, Class: Magnoliopsida, Superorder: Asteranae, Anthemis nobilis is a low-growing plant, creeping Order: , Family: Asteraceae, : or trailing, its tufts of leaves and flowers a foot high. The Chamaemelum, Species: Chamaemelum nobile [43,44]. root is perennial, jointed and fibrous, the stems, hairy and freely branching are covered with leaves which are divided COMMON NAMES into thread-like segments, the fineness of which gives the Arabic: babonaj Romani, babanq Romani, babanaq whole plant a feathery appearance. The blooms appear in Itri, babanaq shareef; English: chamomile, common the later days of summer, from the end of July to chamomile, corn chamomile, English chamomile, garden September, and are borne solitary on long, erect stalks, chamomile, noble chamomile, Roman chamomile, drooping when in bud. With their outer fringe of white ray- Russian chamomile, sweet chamomile; French: camomille florets and yellow centers, they are remarkably like the romaine; German: römische Kamille; Spanish: camomila daisy. There are some eighteen white rays arranged round a

Corresponding Author: Ali Esmail Al-Snafi E-mail: [email protected]

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Vol 6|Issue 2| 2016 |89-95. conical center, botanically known as the receptacle, on and constituents such as α-bisabolol and its which the yellow, tubular florets are placed- the centre of oxides and azulenes [59]. the daisy is, however, considerably flatter than that of the Chamomile. All the have a tiny, chaffy scale Antimicrobial effect between each two florets, which is very minute and has to The extract and essential oil of Roman chamomile be carefully looked for but which all the same is a vital flower head showed antibacterial activity against P. characteristic of the genus Anthemis. The distinction gingivalis. The antimicrobial effects were evaluated by disk between A. nobilis and other species of Anthemis is the diffusion method. The results indicated that the means of shape of these scales, which in A. nobilis are short and inhibition zone for chamomile extract and essential oil were blunt. The fruit is small and dry, and as it forms, the hill of 13.33±3.4 and 20.5±0.5 respectively [60]. the receptacle gets more and more conical. The whole plant Azulenes and bisabolol were anti-inflammatory is downy and grayish green in colour. It prefers dry and antispasmodic, reducing histamine-induced reactions, commons and sandy soil [48,49]. including hay fever and asthma. Flavonoids, especially anthemidin, were also antispasmodic. Valerianic acid and CHEMICAL CONSTITUENTS cyanogenic glycosides were sedative [61]. Two A. nobilis contained 80% water , 6-7% mineral hydroperoxides compounds isolated from Anthemis nobilis materials , volatile oil, sesquiterpenes, hydroperoxides, showed a medium antibacterial activity. In a clinical study , flavonoids, catechins, coumarins, polyacetylenes, phenolic Anthemis nobelis showed a good result in the treatment of acids, triterpenes and steroids and polysaccharides [46, 50]. recurrent aphthous stomatitis as estimated by the time of However, many authors [47, 51, 52] mentioned that pain elimination and the duration of the healing [62]. different parts of the plant contained: The antimicrobial activity of an essential oils of the Volatile oils (0.4-1.75%): angeiic and tiglic acid flower of Anthemis nobilis from the Provence (France) was esters (85%) and 1,8 cineole, l-trans-pinocarveol, l-trans- tested against various strains of Gram-positive bacteria pinocarvone, chamazulene, farnesol, and nerolidol. (Staphylococcus aureus and Enterococcus faecalis) and Flavonoids: apigenin,luteolin, quercetin and their glycosides Gram-negative bacteria (Escherichia coli, Pseudomonas (apiin, luteolin-7-glucoside and rutin); Coumarins: aeruginosa, Proteus vulgaris, Klebsiella scopoletin-7-glucoside; Germacranolide-type sesquiterpene pneumoniae and Salmonella sp.) as well as against the lactones(0.6%): nobilin, 3-epinobilin, 1,10-epoxynobilin, yeast Candida albicans using a modified agar dilution and and 3-dehydronobilin; Various alcohols: amyl and isobutyl agar diffusion method. In addition, some pure main and alcohols. minor compounds (chemical composition obtained by It also contained: angelic and tiglic acid esters, means of GC and GC/MS measurements), such as isobutyl anthemic acid, choline, phenolic, phytosterols, inositol and angelate (32.1%), 2-methylbutyl angelate (16.2%), isobutyl fatty acids. The essential oil of A. nobilis is a light blue isobutyrate (5.3%), methyl 2-methylbutyrate (1.9%), prenyl color due to the terpenoid chamazulene [53]. The amount of acetate (1.4%), 2-methylbutyl 2-methylbutyrate (1.2%) and the constituents isolated were differ according to the origin 2-methylbutyl acetate (1.2%), were also studied for their and the age of the flowers . The essential oils of the aerial antimicrobial effects. The Roman chamomile sample parts of the plants were included: isobutyl isobutanoate showed high antimicrobial activity against all strains of (4.4%), 2-methylbutyl isobutanoate (4.3%), isobutyl tested microbes. A similar result was found for 2- angelate (24.5%), 2-butenyl angelate (7.3%), 2- methylbutyl methylbutyl 2-methylbutyrate, 2-methylbutyl acetate and angelate (17.4%), trans-pinocarveol (4.5%), isoamyl prenyl acetate [63]. The volatile oil of Anthemis nobilis angelate (7.6%) and estragol (5.0%) [53-55]. showed activity against Gram-positive bacteria, especially C. nobile proved to be an equilibrated valuable Bacillus subtilis, B. anthracis, Micrococcus glutamicus, B. herb rich in carbohydrates and proteins, and poor in fat, sacchrolyticus, B. thuringiensis, Sarcina lutea, B. providing tocopherols, carotenoids and essential fatty acids. stearothermophilus, Lactobacillus plantarum, Moreover, the herb and its infusion are a source of phenolic Staphylococcus aureus, Staphylococcus sp. and L. casei, and organic acids (oxalic, quinic, malic, citric and fumaric whereas the oil showed no activity against Gram-negative acids) [56]. Six octulosonic acid derivatives were isolated bacteria species including Salmonella group B, Citrobacter from the flower heads of Roman chamomile sp., Enterobacter sp., Esheria. coli, Pseudomonas sp., (Chamaemelum nobile) [57]. Six new hydroperoxides were Salmonella saintpaul and Salmonella weltevreden. The isolated from the ethanol extract of the blossoms of volatile oil also inhibited the growth of dermatophytons, Anthemis nobilis L., besides the known 1 beta- Alternaria sp., Aspergillus fumigatus and A. parasiticus. hydroperoxyisonobilin [58]. Volatile oil was inactive against Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum and PHARMACOLOGICAL EFFECTS Aspergillus niger. Hydroperoxides [Z-2-methyl-2-butyric The biological activity of chamomile was mainly acid-(2-hydroperoxy-2-methyl-3-butenyl) ester, and Z-2- due to the flavonoids apigenin, luteolin, quercetin, patuletin methyl-2-butyric acid-(3-hydroperoxy-2-methylidenebutyl)

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Vol 6|Issue 2| 2016 |89-95. ester], isolated from the ethanolic extract of the Anthemis headed) variety. The oils caused 22.8 to 38.7% inhibition of nobilis flowers, showed antibacterial activity against E. coli, the carrageenan induced increase in paw volume [71]. P. aeruginosa and E. faecalis. The MIC values of first Six octulosonic acid derivatives were isolated from compound were 256 μg/ml against E. coli and 512 μg/ml the flower heads of Roman chamomile (Chamaemelum against P. aeruginosa. The MIC values of the second nobile). The biological activity of the isolated compounds compound were 512 and 128 μg/ml against the same was evaluated toward multiple targets related to microorganisms, respectively [64]. inflammation and metabolic disorder such as NAG-1, NF- κB, iNOS, ROS, PPARα, PPARγ, and LXR. Similar to the Insecticidal effect action of NSAIDs, all the six compounds increased NAG-1 Volatile oil of Anthemis nobilis showed high activity 2-3-fold. They also decreased cellular oxidative activity against the whitefly (Trialeurodes vaporariorum) stress by inhibiting ROS generation. Three of the nymphs at 0.0047 and 0.0093 μg/ml using an impregnated compounds activated PPARγ 1.6-2.1-fold, while PPARα filter paper test, whereas it was ineffective against the adult was activated 1.4-fold by compounds two compounds. None or egg forms [65]. of the compounds showed significant activity against iNOS or NF-κB. Hypotensive effect The hypotensive effect of Chamaemelum nobile Hypoglycemic effect: aqueous extract (CNAE) in spontaneously hypertensive The effect of both a single dose and daily oral was studied in rats. Single oral administration of CNAE administration dose (20mg/kg body weight) for 15 days of (140 mg/kg) produced a significant reduction (p < 0.05) in the aerial part of Chamaemelum nobile aqueous extract on systolic blood pressure (SBP) after 24 h of the blood glucose concentrations and basal insulin levels in administration. Daily oral administration of CNAE (140 normal and streptozotocin-induced diabetic rats (STZ) were mg/kg) during 3 weeks produced a significant reduction in studied. Single oral administration of C. nobile aqueous SBP in the day 8 (p < 0.01) of treatment. Furthermore, extract reduced blood glucose levels from 6.0 ± 0.3 mmol/l CNAE produced a significant increase in urinary output and to 4.9 ± 0.09 mmol/l (P < 0.05) 6h after administration in electrolytes excretion (p < 0.01) from the day 8 to the end of normal rats and from 21.1 ± 1.3 mmol/l to 14.5 ± 0.9 treatment [66]. The in vitro vasorelaxant effect of C. nobile mmol/l (P < 0.001) in STZ diabetic rats. Furthermore, blood aqueous extract was evaluated using aortic ring isolated glucose levels were decreased from 6.1 ± 0.06 mmol/l to 4.6 from Wistar rats. C. nobile aqueous extract at doses of 5, 10 ± 0.17 mmol/l (P < 0.01) and from 21.1 ± 1.31 mmol/l to and 20 mg/ml possessed in vitro vasorelaxant effect. 13.7 ± 0.9 mmol/l (P < 0.01) in normal and STZ diabetic Incubation of aqueous C. nobile extract for 30 minutes rats, respectively, after 15 days of treatment. Basal plasma produced a significant shift of the dose-response curve to insulin concentrations remain unchanged after treatment in norepinephrine (NE) (10-8 to 10-5) M (p < 0.001) [67]. both normal and STZ diabetic rats, which means that the mechanism of this pharmacological activity seems to be Anti-inflammatory effect independent of insulin secretion [72]. Flavonoid glucoside The anti-inflammatory effect of the chamaemeloside, has been determined to have in vivo polysaccharides isolated from the aqueous extract of Roman hypoglycaemic activity [73]. chamomile flowers and herb was investigated in rats, Inflammation was induced with subplantar injection of Nervous effect viscarine. The flower and herb polysaccharide was given ip In mice, apigenin had a clear affinity for central as 10 mg/kg dose. They reduced the inflammation of the benzodiazepine receptors. Apigenin competitively inhibited paw by 36.2 and 37.7%, respectively compared with the binding of flunitrazepam, a benzodiazepine, but had no untreated control [68,69]. effect on muscarinic receptors, alpha 1-adrenoceptors, or the The volatile oil have been documented as having binding of muscimol to GABA receptors. Apigenin had anti inflammatory activity (carrageenan rat paw odema test clear anxiolytic activity in mice without incidence of ) and produced antidiuretic and sedative effects sedation or muscle relaxation effects at doses similar to following intraperitoneal administration of doses up to 350 those used for classical benzodiazepines; no anticonvulsant mg/kg to rats. The mechanism of antiallergic and anti action was detected. Increasing dosages produced mild inflammatory effects of azulenes is thought to involve sedation and a reduction in ambulatory locomotor activity inhibition of histamine release [70]. [71,74]. Two varieties of Anthemis nobilis, named (white- The essential oil of Roman chamomile decreased headed) or double flowered and (yellow-headed) yield the mobility of male Wistar rats with 51-76% for 50 essential oils with different composition. These essential minutes, compared to untreated control, when given oils proved to possess interesting anti-inflammatory and subcutaneously in a dose of (350, 1250 and 2500 mg/kg) sedative properties, especially that derived from the (White- and i.p in a dose of (175 and 350 mg/kg).

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Antioxidant effect cervical and hepatocellular carcinomas). The plant material Chamazulene affected free radical processes and extract was more potent than the infusion sample in all the inhibited lipid peroxidation in a concentration- and time- tested cell lines, presenting GI50 values that ranged from dependent manner [75]. 82.52 to 168.40 μg/mL for the MCF-7 and HepG2 cells, The antioxidant properties of essential oils were respectively. Decoction preparation had no antitumour investigated for A. nobilis from Italy. The results indicated effects at the maximal concentration used (400 μg/mL), that the volatile oils from Roman chamomile possessed which could indicate that these effects might be related to high antioxidant activity [76]. The aqueous extracts (crude compounds (including phenolic compounds) that are not and decoction) of A. nobilis button flowers showed high extracted or affected by the decoction [50]. antioxidant activity, as evaluated by ABTS, TBARS and From fresh and dried herb (without inflorescences) haemolysis of red blood cells assays. Moreover, this activity of Anthemis nobilis L. a new sesquiterpene lactone was higher for the decoction extract, and it was in good C20H26O6 was isolated. This compound showed a agreement with its greater phenolic content. As revealed by cytotoxic activity at a level of ED50 HeLa 0-56 -6 the mass spectrometry analysis, the potent antioxidant microgram/ml (1-5 x 10 M), and ED50 KB 1.23 ability of aqueous A. nobilis extracts can result from the microgram/ml (3-5 x 10-6 M) [79]. presence of quinic acid and caffeic acid derivatives [77]. Nobilin, 1,10-epoxynobilin, 3-dehydronobilin and One hundred and twenty, one day old unsexed hydroxyisonobilin, isolated from Roman chamomile flower, Lohman broiler chicks were used to study the effect of showed in vitro cytostatic activity against human HeLa supplementing aqueous extract and powder of chamomile (cervix carcinoma cell line) and KB (nasopharyngeal flowers to diet and drinking water on some physiological carcinoma) cell lines [80]. characters of broiler exposed to high environmental temperature 28 – 30 – 28 ◦ C to alleviate heat stress. Five Effect in asthma treatments were carried out, treatment T0 without In an open clinical study carried out on 54 supplementing chamomile to drinking water or diet, patients with chronic bronchial asthma, A. nobilis showed treatments T1 and T2 supplementing with 0.3 and 0.6% of antiasthmatic effects, it caused significant elevation in the aqueous extract to drinking water, treatments with T3 and values of forced expiratory volume in first second (FEV1%) T4 supplementing 0.6 and 0.9% of chamomile flowers and forced volume capacity (FVC) with marked reduction powder to diet. This supplementation of chamomile to in asthmatic attacks [81]. drinking water and diet had been given to birds daily for 6 hours from 1200-1800 and during the highest environmental Effect in poly cystic ovary temperature and during the experiment period from 4 – 8 The effectiveness of Anthemis nobilis aqueous- weeks of age. The result revealed that body temperature alcoholic extract was studied in polycystic ovary syndrome reduced significantly in the group T3 and T4 compared induced in rats by a single dose of estradiol valerate. with other treatments however heterophil lymphocyte ratio Histological investigations revealed that the animal reduced significantly while hemoglobin increased in all administered with dose of 50 mg/day showed small cysts treatments compared with T0, also glucose reduced and less inflammation, with decreasing of serum estrogen significantly in the group T1, T2 and T3 compared with T0. hormone(P<0.029) [82]. The study confirmed that supplementing the aqueous extract and powder of chamomile flowers lead to alleviate heat Contraindications and adverse effects stress. The results pointed that chamomile flowers powder The US Food and Drug Administration (FDA) supplementation gave better results than aqueous extract have classified the oil and extract of Roman chamomiles as [78]. safe substances . Large doses are emetic. Acute LD50 in The antioxidant effects of Anthemis nobilis were rabbits (dermal) and rats exceed 5g/kg. evaluated by four different tests: DPPH radical scavenging Dosage : Flower heads 1-4 g by infusion three times a day capacity, reducing power and inhibition of lipid [47]. peroxidation using β-carotene–linoleate model system in liposomes and TBARS assay in brain homogenates. Herbal CONCLUSION sample gave the highest β-carotene bleaching activity and This review discusses the chemical constituent, lipid peroxidation inhibition (lowest EC50 values) which pharmacological and therapeutic effects of Anthemis nobilis related to its higher content of phenolic compounds, while as promising herbal drug because of its safety and infusion showed the highest DPPH scavenging activity effectiveness. which related to their higher levels of organic acids [50] ACKNOWLEDGEMENT: None Cytotoxic effects The antitumour potential of Anthemis nobilis was CONFLICT OF INTEREST tested in human tumour cell lines (breast, lung, colon, The authors declare that they have no conflict of interest.

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