Pharmacological properties

2.5.2.1 Pharmacodynamic Properties

2.5.2.2 Anti-Inflammatory Effects

2.5.2.1.1 In vitro studies

Ethanolic (48% V/V) and isopropanolic (48% V/V) extracts of matricaria flower inhibited 5-lipoxygenase, cyclooxygenase, and the oxidation of arachidonic acid with IC50 values of 0.05-0.3%, while a supercritical carbon dioxide extract had an IC50 of 6-25 jg/ml for these activities [22]. Investigation of individual constituents revealed that apigenin inhibited 5- and 12-lipoxygenase (IC50: 8 and 90 jM, respectively); chamazulene and (-)-a-bisabolol inhibited only 5-lipoxygenase (IC50: 13 and 40 jM, respectively); apigenin, cis-en-yn-spiroether and (-)-a-bisabolol inhibited cyclooxygenase (IC50: 70-80 jM); only chamazulene had antioxidative activity (IC50: 2 jM) [22].

2.5.2.1.2 In vitro studies

The anti-inflammatory effects of orally administered (-)-a-bisabolol have been demonstrated in carrageenan-induced rat paw edema, adjuvant arthritis of the rat, ultraviolet-induced erythema of the guinea pig, and yeast-induced fever of the rat [72]. In the carrageenan-induced rat paw edema test the following ED50 values (mmol/kg) were obtained after oral administration: (-)-a-bisabolol 2.69, chamazulene 4.48, guaiazulene 4.59, matricin 2.69, and salicylamide 1.53 [71].

An extract prepared from infusion of 20 g of matricaria flower in 100 ml of ethanol 42%, topically applied at a dose of 750 jg dry extract per ear, inhibited croton oil-induced edema of mouse ear by 23.4% compared to controls; benzydamine at 450 jg/ear showed comparable inhibition of 26.6% [66]. In the same test system, two polysaccharides from matricaria flower at a dose of 300 jg/ear inhibited edema by 14 and 22%, respectively [53].

2.5.2.3 Antispasmodic Effects

2.5.2.3.1 In vitro studies

A hydroethanolic extract of matricaria flower showed antispasmodic activity on isolated guinea pig ileum stimulated by various spasmogens. The ED50 (mg/ml) and the strength of activity relative to papaverine (= 1.0), respectively, were 1.22 and 0.0011 with barium chloride, 1.15 and 0.0019 with histamine dihydrochloride, 2.24 and 0.00074 with bradykinin, and 2.54 and ca. 0.00062 with serotonin. Pure constituents were also investigated: with barium chloride, (-)-a-bisabolol (ED50 = 136 |g/ml) showed activity comparable to papaverine, while apigenin (ED50 = 0.8 |g/ml) was more than three times as active [17].

2.5.2.4 Antiulcerogenic Effects

2.5.2.4.1 In vivo studies

The development of ulcers induced in rats by indomethacin stress or ethanol was inhibited by an orally administered extract of matricaria flower with an ED50 of 1 ml per rat and by (-)-a-bisabolol with an ED50 of 3.4 mg/kg body weight. These substances also reduced healing times for ulcers induced in rats by chemical stress (acetic acid) or heat coagulation [103].

2.5.2.5 Wound Healing Effect

2.5.2.5.1 In vivo studies

The wound healing activity of azulene has been demonstrated in studies on the thermally damaged rat tail [40] and of matricaria flower constituents in accelerated healing of experimental injuries [115].

2.5.2.6 Sedative Effects

2.5.2.6.1 In vitro studies

Apigenin competitively inhibited the binding of flunitrazepam to the central benzodiazepine receptor (Ki = 4 |M) but had no effect on muscarinic receptors, aradreno-receptors, or the binding of muscimol to GABAa receptors [109].

HPLC fractions of a methanolic extract of matricaria flower were able to displace flunitrazepam from its receptors in rat cerebellar membranes, the ligand RO 5-4864 from "peripheral" benzodiazepine receptors in rat adrenal gland membranes, and muscimol from GABA receptors in rat cortical membranes. This last activity is mainly due to GABA present in the fractions [23].

2.5.2.6.2 In vitro studies

A sedative effect of matricaria flower was demonstrated through prolongation of hexobarbital-induced sleep, reduction of spontaneous mobility, and reduction of explorative activity in mice [43, 44].

Restricted stress-induced increases in plasma ACTH levels in normal and ovariectomized rats were decreased by administration of diazepam and inhalation of matricaria flower oil vapor. Inhaling the vapor induced greater decreases in plasma ACTH levels in ovariectomized rats than treatment with diazepam; this difference was not observed in normal rats. Furthermore, the inhalation of matricaria flower oil vapor induced a decrease in plasma ACTH level that was blocked by pretreat-ment with flumazenil, a potent and specific benzodiazepine receptor antagonist [113].

2.5.2.7 Antimicrobial Effects

Matricaria flower essential oil exerted a bactericidal effect against Gram-positive bacteria and a fungicidal effect against Candida albicans at a concentration of 0.7% V/V [98]. The essential oil was not active against Gram-negative bacteria, even in concentrations as high as 8% V/V [19].

An infusion of matricaria flower, a hydroethanolic extract, and pure herniarin showed antimicrobial activity against various bacteria and fungi in the presence of near UV light [37, 82].

2.5.2.8 Clinical Studies

2.5.2.8.1 Anti-inflammatory effects

In a bilateral comparative study, 161 patients with inflammatory dermatoses, who had been treated initially with 0.1% diflucortolone valerate, were treated during maintenance therapy with a cream containing matricara flower extract or one of three alternatives: 0.25% hydrocortisone, 0.75% fluocortin butyl ester, or 5% bufexamac. The therapeutic results with the extract were equivalent to those of hydrocortisone and superior to those of fluocortin butyl ester and bufexamac [18].

In a comparative study on 20 healthy volunteers with chemically induced toxic dermatitis, the smoothing effect on the skin of an ointment containing matricara flower extract was significantly superior (p < 0.01) to that of 0.1% hydrocortisone acetate or the ointment base [87].

In a study on 12 healthy subjects, a cream containing matricaria flower extract (20 mg/g) did not suppress UV-induced erythema but it reduced visual scores of skin redness in the adhesive tape stripping test (p = 0.0625) [76]. In an analogous study, the cream produced 69% of the effect of a hydrocortisone-27-acetate ointment [20].

In a randomized, double-blind study, 25 healthy volunteers with UVB light-induced erythema were treated with various matricara flower preparations, hydrocortisone cream, or the respective vehicle. Ranking the preparations according to visual assessment scores and mean values from chromametry, a cream containing a hydroalcoholic extract of matricaria flower gave the best result [75].

In an open study on 98 cancer patients, a matricaria flower extract preparation containing 50 mg of a-bisabolol and 150-300 mg of apigenin-7-glucoside per 100 g, applied three times daily, reduced oral mucositis caused by localized irradiation or systemic chemotherapy [30].

In a phase III double-blind, placebo-controlled clinical trial involving 164 patients, a mouthwash containing matricaria flower extract did not decrease 5-fluorouracil-induced stomatitis [49].

2.5.2.8.2 Anti-inflammatory and antispasmodic effects

In an open multicentric study, 104 patients with gastrointestinal complaints such as gastritis, flatulence, or minor spasms of the stomach were treated orally for 6 weeks with a matricaria flower extract preparation (standardized to 50 mg a-bisabolol and 150-300 mg apigenin-7-glucoside per 100 g) at a daily dose of 5 ml. Subjectively evaluated symptoms improved in all patients and disappeared in 44.2% of patients [98, 100].

2.5.2.8.3 Wound healing effects

In an open study, 147 female patients episiotomized during childbirth were treated for 6 days with either an ointment containing matricaria flower extract or a 5% dexpanthenol cream. The healing effect of the two preparations was comparable [73].

In a double-blind study on 14 patients, weeping dermatoses following dermabrasion of tattoos were treated with a matricaria flower extract preparation (standardized to 50 mg of a-bisabolol and 3 mg of chamazulene per l00 g). The decrease in the weeping wound area and the improvement in drying tendency were statistically significant (p < 0.05) [54].

In a randomized, open, placebo-controlled study, 120 patients with second-degree hemorrhoids were treated with rubber band ligature alone, rubber band ligature with anal dilator and vaseline, or rubber band ligature with anal dilator and an ointment containing matricaria flower extract. The last group showed the best results in amelioration of hemorrhage, itching, burning, and oozing [50].

2.5.2.9 Pharmacokinetic Properties

After cutaneous administration of [14C](-)-a-bisabolol on mice, 82% of the radioactivity was found in the urine [59, 66].

Apigenin and luteolin were also readily absorbed by the skin. In vivo skin penetration studies of hydroethanolic solutions of apigenin and luteolin with nine healthy female volunteers gave a steady-state flux of 10.31 and 6.11 ng/min.cm2, respectively [84].

After oral administration of apigenin-7-glucoside to rats free apigenin was detected in the urine [57].

After oral administration of 40 ml of a hydroethanolic matricaria flower extract (containing 225.52 mg% apigenin-7-glucoside, 22.51 mg% apigenin, 15.14 mg% herniarin) to a female volunteer, no flavones could be detected in blood plasma nor in 24-h urine, while herniarin was found in both (max. plasma concentration: ±35 mg/ml and 0.324 mg in 24-h urine) [106].

In germ-free rats no hydrolysis of flavone glycosides could be observed; obviously, intestinal microflora can affect the cleavage of the glycosidic bonds [56, 57]. Furthermore, orally administered apigenin was detected in the blood serum of animals [91].

2.5.2.10 Preclinical Safety Data

The acute oral LD50 of matricaria flower essential oil in rats and the acute dermal LD50 in rabbits exceeded 5 g/kg. No irritant effects of the oil were observed after application to the skin of nude mice [88].

In a 48-h patch test in volunteers, matricaria oil neither caused skin irritation nor were there any discernible sensitization reactions or phototoxic effects. Matricaria oil was granted "generally recognized as safe" (GRAS) status by FEMA and has been approved by the FDA for use in food and cosmetics [88].

The acute oral toxicity of (-)-a-bisabolol in mice and rats was very low with an LD50 of about 15 ml/kg. A 6-week subacute toxicity study showed that the lowest toxic oral dose of (-)-a-bisabolol in rats and dogs was between 1 and 2 ml/kg. Oral doses up to 1 ml/kg of (-)-a-bisabolol produced no discernible effects on the prenatal development of rats or rabbits. No malformations were found at any of the tested dose levels [58].

The acute intraperitoneal LD50 of cis- and trans-en yn-dicycloether is 670 mg/kg [17]. In the Ames test, apigenin and an aqueous matricaria flower extract showed no mutagenic or toxic activity [26, 95].

2.5.2.10.1 Allergenicity

Based on the fact that "German"-matricaria flower generally contains no, or only traces of, the sesquiterpene lactone anthecotulide and that millions of people come into contact with matricaria flower daily, allergic reactions due to matricaria flower can be considered to be extremely rare [64]. However, cross-reactions with other sesquiterpene lactone-containing plants are common [64]: a patient allergic to Artemisia vulgaris underwent severe anaphylactic reactions following ingestion of matricaria flower infusions and after eye washing with similar infusions [97]; 18 of 24 patients with Compositae allergy were also allergic to an ether extract of matricaria flower [89]; 96 patients of 4800 showed contact hypersensitivity to an ethanolic matricaria flower extract [39].

In a study on contact allergy performed with 540 type IV allergic patients, some of whom gave positive reactions to standard phytogenic allergens, an anthecotulide-free matricaria flower extract gave a positive reaction in none. This demonstrates the importance of using anthecotulide-free matricaria flower [70, 98].

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