Fresh Bilberry fruit – Myrtilli fructus recens (Vaccinium myrtillus L.)
|Latin name of the genus:||Myrtilli fructus recens|
|Latin name of herbal substance:||Vaccinium myrtillus l.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Fresh bilberry fruit|
Latin name of the genus: Myrtilli fructus recens
Botanical name of plant: Vaccinium myrtillus L.
English common name of herbal substance: Fresh Bilberry fruit
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Vaccinium myrtillus (L.), fructus siccus (bilberry fruit, dried): dried ripe fruit of V. myrtillus (L.) (Ph. Eur. 8.0, 2008:1588). It contains minimum 1.0% of tannins expressed as pyrogallol.
Vaccinium myrtillus (L.), fructus recens (bilberry fruit, fresh): fresh or frozen ripe fruit of V. myrtillus (L.) (Ph. Eur. 8.0, 2008:1602). It contains minimum 0.30% of antocyanins, expressed as cyanidin 3-
Bilberry (V. myrtillus L.) is a species of a shrubby perennial plant of the heather family (Ericaceae) reaching from 15 to 60 cm in height. It has many common names, including blueberry. It is widespread in Asia, Europe and North America in the areas with a temperate and arctic climate. The flowers, blooming from April to June, are pollinated by insects. The time from pollination to full ripeness of the fruit is about two months. The plant occurs from lowlands to high mountain positions (even above the tree line) and plant prefers strongly acidic soil in the pine forests, other coniferous forests, oak woods, beech forests and moors. The fruits are the black berries with a bluish, waxy bloom (Frohne, 2006) with sweet and slightly astringent taste (European Pharmacopoeia 8.0, 2008:1588 and 1602).
Dried fruits are traditionally used in therapy of digestive disorders, particularly in diarrhoea. The traditional use and some not controlled studies from 1960 and 1970 suggested the potential benefits of bilberry preparations for improvement of night vision, but more recent
The following substances were found in bilberry fruits:
The amount is oppositely correlated with the degree of fruit ripening.
Anthocyanic compounds are present in plant cells in the form of glycosides (anthocyanins). There are about 400 known anthocyanic glycosides. The most important anthocyanins are the cyanidin glycosides, as they represent 50% of the pigment composition of fruits (Kong et al., 2003). Anthocyanins are present in ripe fruits of Vaccinium species but the highest total anthocyanin content occurs in the bilberry (V. myrtillus L.) (Kalt et al., 1999).
Total anthocyanin amount ranges from 300 to 700 mg per 100 g in ripe fruits of V. myrtillus (Prior et al., 1998; Prior and Cao 2000). There is a great diversity of the total content of anthocyanins in bilberry collected in various geographical areas, from 19.3 to 38.7 mg/g dry weight (Lätti et al., 2008). Moreover, in concentrated bilberry extracts the total content of anthocyanins may amount to 24%
(Zhang et al., 2004). According to the European Pharmacopoeia 8.0 the standardized dry extract of V. myrtillus contains 32.4% to 39.6% of anthocyanins, expressed as cyanidin
Most of the researchers investigating anthocyanin composition of bilberries have reported mainly 14 or 15 anthocyanins (Lätti et al., 2008; Yue and Xu, 2008). Fifteen anthocyanins have been identified in bilberry fruit, juice, and extract (1 – delphinidin
During ripening process, there is an increase in the quantity of anthocyanidins in fruits. Usually the highest content of anthocyanins is found in berries collected late summer, at the end of August and the beginning of September. The levels are approximately
There is a great diversity of the total content of anthocyanins in bilberry collected in various geographical areas of Finland, from 19.3 to 38.7 mg/g dry weight (Lätti et al., 2008). Delphinidin and cyanidin derivatives dominated in the northern and southern berries, respectively (Lätti et al., 2008; Prior and Cao 1998; Bilberry Fruit Extract. Summary of data for chemical selection)
Anthocyanins are pigments highly soluble in water and polar solvents. They are unstable and are oxidized under the influence of various factors (pH, temperature, enzymes, UV radiation, SO2, ascorbic acid, metal ions), resulting in colour change and degradation
In the study of Yue and Xu (2008) the thermal stability and degradation of the anthocyanins derivatives conjugated with a variety of sugars (delphinidin, cyanidin, petunidin, peonidin and malvidin) at the heating temperature of 80, 100, and 125°C were alike. However, when the heating temperature was increased to 125oC, degradation of each compound increased sharply, with
Bilberry anthocyanin content was studied by Kähkönen et al., 2003. Individual compounds were identified and quantified using HPLC and
Table 1: Anthocyanin composition in bilberry raw extract, extraction solvent CH3CN/TFA/H2O 49.5:0.5:50 V/V/V (after Kähkönen et al., 2003)
gal, galactoside; glu, glucoside; ara, arabinoside; rut, rutinoside.
Stability of anthocyanins is affected by several environmental factors, particularly by thermal treatment. Interestingly, some acylated anthocyanins have an unusual stability in neutral or weakly acidic solutions. Packaging can also speed up the
The average amount contained in 100 g of fruits is 14 mg of flavonoid glycosides (Hansel et al., 1994). Since June flavonoids concentration decreases as fruits ripen. The following flavonoids were reported from bilberry: apigenin, luteolin, chrysoriol, kaempferol, hyperoside, quercetin, quercitrin, isorhamnetin, myricetin, laricitrin, syringetin,
The quinolizidine alkaloid myrtine was found. However it is not explained precisely by the authors of the publication, whether it comes from the fruit or the leaves (Slosse and Hootelé, 1978).
Asperuloside and monotropeine are found in immature fruits, but in ripe fruits they are no longer detectable (Friedrich and Schonert 1973).
Condensed and hydrolyzable tannins. Dried ripe fruit contains minimum 1.0% of tannins, expressed as pyrogallol (Ph. Eur. 8.0, 2008:1588).
Oleanolic acid, ursolic acid (0.25%) (Szakiel et al., 2012)
Chlorogenic, ferulic, syringic, caffeic,
In fresh fruits: Vitamin C, B1, panthotenic acid, nicotinamide (Hansel et al., 1994).
Aliphatic alcohols, aldehydes, ketones, terpene derivatives. For the distinctive aroma of the fruits
V. myrtillus (L.), fructus dry extract prepared from fresh bilberry fruit;
Extracts from bilberry are usually refined to the range of 34 to 36% anthocyanosides, which corresponds to a content of 25% anthocyanidins (aglycons). The amount of anthocyanin in many commercial preparations substantially varies fluctuating between 2.0 – 200 mg/g (Prior and Cao 2000).
Extracts are mainly prepared from the fresh bilberry fruits by a suitable procedure using ethanol (96% V/V) or methanol (minimum 60% V/V) at 10 – 60 °C, diluted with water, filtered and afterwards concentrated and refined usually by means of
According to the European Pharmacopoeia 8.0 the refined and standardized dry extract of fresh bilberry fruit contains 32.4% to 39.6% of anthocyanins, expressed as cyanidin
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2. Search and assessment methodology
Databases assessed up to September 2013:
Science Direct, PubMed, Embase, Medline, Academic Search Complete, Toxnet
Search terms: Vaccinium myrtillus, bilberry, anthocyanins
2. Data on medicinal use
2.1.Information about products on the market
Information about products on the market in the EU/EEA Member
Dry bilberry fruit has been present as single active ingredient in 115 herbal teas on the German market for more than 30 years, traditionally used for unspecific acute diarrhoea, mild inflammation of the oropharyngeal mucosa.
Comminuted dry bilberry fruit has been on the Polish market as single active ingredient for more than 30 years and it is also registered as a herbal tea for unspecific acute diarrhoea in Austria.
A bilberry methanolic dry extract prepared from fresh fruit (DER
Information on medicinal products marketed in the EU/EEA
Table 2: Overview of data obtained from marketed medicinal products
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
Information on relevant combination medicinal products marketed in the EU/EEA
Pharmaceutical form> containing 100 mg V. myrtillus L., anthocyanosidic extract (no further detail available) + 5 mg
Indication: capillary fragility, CVI, visual problems related to circulatory problems
Posology: 3 to 6 times 100 mg a day
On the market from 1965 to 1991.
Soft capsules containing 70 mg V. myrtillus L, fructus recens dry extract; DER
Indication: conditions of capillary fragility
Posology: 4 to 6 capsules a day or according to medical prescription
On the market since 1993.
Information on other products marketed in the EU/EEA (where relevant)
Five single active ingredient herbal teas on the Polish market as food supplements (for unspecific acute diarrhoea).
2.1.2. Information on products on the market outside the EU/EEA
2.2. Information on documented medicinal use and historical data from literature
Bilberry fruits are traditionally used for diarrhoea and in the conditions of increased fragility of blood vessels and chronic venous insufficiency. Anecdotal explanations start back to World War 2, when British pilots supposedly ate bilberry jam before the night flights in order to improve night vision (Kramer 2004).
The use of V. myrtillus L., fructus has been included in the following handbooks: Table 3: Overview of historical data
2.3. Overall conclusions on medicinal use
Table 4: Overview of evidence on period of medicinal use
1)V. myrtillus L., fructus siccus (dry bilberry fruit), whole or comminuted, as herbal tea for oral use as an adjuvant in unspecific acute diarrhoea. Traditional medicinal use of this preparation is substantiated by extensive bibliography and the presence on the German and Polish market for more than 30 years. The daily dose in adults and adolescents over 12 years ranges from 15 to 60 g, divided in
2)V. myrtillus L., fructus siccus (dry bilberry fruit), whole or comminuted, as a decoction for oromocosal use for the topical treatment of mild inflammation of the mucous membranes of the mouth and throat. Traditional medicinal use of this preparation is substantiated by extensive bibliography and the presence on the German and Polish market for more than 30 years. It is used as a 10% decoction to rinse the mouth several times daily.
2) V myrtillus L., fructus recens dry extract; DER
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
In vitro experiments
Effect of the V. myrtillus fresh fruits extract, DER
Contractility of the segments of internal thoracic vein calf preparations induced by barium chloride (50g/ml) was reduced by V. myrtillus extract concentration dependently (25, 50, 75, 100 g/ml). Indomethacin
In other experiment the influence of BEM on contractility of the smooth muscles of the calf splenic arteries segments induced by
caused a concentration dependent decrease in tension of the arterial muscles as the response to the contractions induced by
Effect of the extract of BEM on contractility of calf isolated coronary artery preparations was tested in vitro by Bettini et al., (1985a). Contractions induced by barium chloride (50 g/ml) were concentration dependently mildly suppressed by BEM (25, 50, 75, 100 g/ml). The effect was more pronounced after addition of ascorbic acid
Bettini et al., (1985b) reported the influence of BEM on potentiation of activity of adrenaline on the isolated calf coronary vessels. Adrenaline (0.2 g/ml) vasodilating activity was concentration dependently increased by BEM (25, 50, 75, 100 g/ml) (Table 5). The potentiating effect was completely abolished in the presence of pyrogallol (50 g/ml) a
Table 5: Mean percentage increase (± S.D.) in the response of the preparation of the calf coronary artery to adrenalin (0.2 g/ml) in the presence of BEM (afterBettini et al., 1985b)
In another study Bettini et al., (1991) investigated contractile responses of the isolated calf coronary vessels to acetylcholine (ACh) and methylene blue. Experiments were carried out without removal of the endothelium. BEM
Continuing research of Bettini et al., (1993) found after use of BEM
The direct vasorelaxating activity of a lyophilized dry bilberry extract (BE) (no further details are available) was tested in vitro by Bell and Gochenaur (2006) on coronary arterial rings isolated from pigs. BE contained 15 different anthocyanins including cyanidin, peonidin, delphinidin, petunidin, and malvidin. The total anthocyanin composition was 12.1 g/100 g and total phenolics 35.7 g/100 g. BE produced dose- and
Mechanism of vasodilatation induced by bilberry anthocyanins was investigated by Ziberna et al., (2013). Vascular reactivity was assessed in thoracic aortic rings obtained from male Wistar rats. The endothelium was preserved in the rings.
In vivo experiments
Influence of fresh fruits BEM on the capillary fragility has been studied in the model of rats deprived of dietary flavonoids (Cristoni and Magistretti 1987). Wistar rats were fed for 3 weeks on the diet devoid of flavonoids. On depilated skin the capillary resistance – the lowest negative pressure on the skin that induces petechiae was defined by use of the vacuum gauge. Immediately after the BEM corresponding to 25% anthocyanidins was administered by intraperitoneal injection and the capillary fragility was estimated again after 2, 4 and 6 hours (Table 6).
Table 6: Activity of BEM on the capillary resistance of rats fed on a
In vitro experiments
Triebel et al., (2012) studied the inﬂuence of a lyophilized BE (no further details are available) and comprising anthocyanins on
Table 7: Anthocyanin concentrations in the BE and corresponding initial concentrations in in vitro incubations with 25 μg/ml extract (afterTriebel et al., 2012)
aAccording to the manufacturer’s speciﬁcations. bFor an in vitro incubation with 25 μg/ml extract.
The authors studied the expression of inﬂammatory bowel
Influence of chosen anthocyanins on expression of
In the study of Song et al. (2010), a newly established human corneal limbal epithelial cell line (HCLEC) was investigated to study the effects of a BE on the cell growth, cell cycle and the expression of hyaluronic acid (HA) and glycosaminoglycans (GAGs) in corneal epithelial cells. A commercially available BE containing 25% total anthocyanins (no further details are available) was used. The content of anthocyanins present in BE was quantified by HPLC using
Hou et al. (2005) investigated
In vivo experiments
In another study Bertuglia et al., (1995) tested activity of BEM from fresh fruits (100 mg per day/kg p.o. for 2 and 4 weeks) in the microcirculation ischemia model. Ischemia was induced by clamping the
hamster cheek pouch for 30 minutes with subsequent reperfusion also lasting 30 minutes. Changes in the microcirculation were visualized by fluorescence method. Ischemia and reperfusion were associated with increased number of leukocytes sticking to venules, decreased number of perfused capillaries and increased permeability. After treatment there was a significant reduction in ischemic symptoms (p<0.01, Table 8).
Table 8: Number of sticking leukocytes (l per 100 μm venules), % of perfused capillary length (capillary perfusion), permeability increase (normalized grey levels) in Control (Con) and in hamsters treated with BEM for 2 (A) and 4 (B) weeks after ischemia reperfusion (Bertuglia et al., 1995).
*p<0.01, compared to controls, †p<0.05 relative to bilberry A group.
Table 9: Overview of the main
A large amount of data from preclinical studies on the beneficial effects of anthocyanins on the regeneration of rhodopsin exist. Such studies, among others, were carried out by Matsumoto et al., 2003; Tirupula et al., 2009; Yanamala et al., 2009. Circadian clock regulation of the pH in the retina of vertebrates showed the pH increased upon exposure to light. It appeared that the pH of the retina is more alkaline during the day. According to the authors this may be important because the pH of the environment plays an important role in the various activities of anthocyanins. Their concentration in the tissues of the eye is very low (Manach et al., 2005; Ichiyanagi et al., 2004a, 2004b; Matsumoto et al., 2003).
As believed by Kalt et al., (2010) other phenolic flavonoids may play an important role in the survival of the cultured human retinal pigment epithelial cells and regeneration of rhodopsin. These could be the flavanone eriodictyol (Johnson et al., 2009, Maher and Haneken 2005, 2008) baicalein, luteolin, galangin, fisetin or quercetin.
3.1.2. Secondary pharmacodynamics
Impact on lipid peroxidation
In vitro experiments
The comprehensive and extensive monograph by Upton et al., (2001) showed that an extract of bilberries protected microsomes from rat liver against oxidative damage and apolipoprotein B before brought about by UV radiation.
An anthocyanoside complex extract from V. myrtillus was tested for its ability to inhibit lipid peroxidation and to scavenge hydroxyl and superoxide radicals
Laplaud et al., (1997) tested in vitro an aqueous extract of V. myrtillus on human low density lipoproteins. They found, that the extract, which contained 74.2±4.9 mg/g of total polyphenols with a proportion of catechin of 17.3±3.3% caused potent protective action on LDL particles during in vitro
In vitro experiments
In in vitro studies conducted by Cluzel et al. (1969; 1970) it was found that anthocyanins of
V. myrtillus affected the activity of various enzymes of retina in pig and in rabbit (inhibiting the activity of phosphoglucomutase, and increasing the activity of lactate dehydrogenase,
It was found, that the extract scavenged superoxide anion and inhibited microsomal lipid peroxidation at all concentrations (25, 50 75 and 100 μg/ml) (p<0.01) and a 50% inhibition of rate of reaction was observed with a final concentration of 25 μg/ml. The anthocyanoside complex extract was able to inhibit lipid peroxidation (IC50=50.28 mg/ml) and to scavenge superoxide anion (IC50<25 mg/ml). The ability to remove hydroxyl radical exerted by this extract was detectable from 50 mg/ml of extract in the reaction mixture
According to Prior et al. (1998), comparison of the antioxidant capacity in a variety of Vaccinium species have shown high activity of V. myrtillus (Table 10). Bilberries were extracted with acetonitrile/acetic acid for the analysis of ORAC, total anthocyanins, and total phenolics. In conclusion the increased maturity at harvest increased the ORAC, the anthocyanin, and the total phenolic content. A linear relationship existed between ORAC and anthocyanin (rxy=0.77) or total phenolic (rxy=0.92) content.
Table 10: Antioxidant activity of V. myrtillus L. (after Prior et al., 1998).
V. myrtillus L.
aExpressed as micromole Trolox equivalents per gram of fresh fruit. Oxygen radical absorbance capacity (ORAC ROO). Data in parentheses expressed per gram of dry matter. Bilberry was harvested on 7/2/97.
bConcentration based upon
Direct in vitro influence of the bilberry fruit extracts on the oxidative phosphorylation of isolated rat heart mitochondria was tested by Trumbeckaitè et al. (2013). For testing, two types of extracts were used: the hydroethanolic extract (BEE) of the crushed plant material was prepared by maceration with 50% ethanol at room temperature (1:10, V/V), initially for 48 hours and thereafter until exhaustion; the aqueous extract (BAE) was prepared using repercolation method (1:10, V/V). The obtained hydroethanolic extract was ﬁltered and concentrated under vacuum (at 50oC) and then subjected to freeze drying. Freeze dried bilberry powder was packed into a glass jar and dissolved before experiments. The levels of anthocyanidins, measured by use of HPLC, varied in the two extracts (see Table 11)
Table 11: Anthocyanidins in the two extracts tested by Trumbeckaitè et al. (2013)
Amount of anthocyanidins (ng/ml) in 1 μl) of bilberry fruit extracts
BAE, bilberry aqueous fruit extract; BEE, bilberry ethanolic fruit extract.
When measured the effects of BEs on complex
respiration rate by BEs may be the inhibition of mitochondrial respiratory chain at complexes I and II. Pure anthocyanins, the main components of used extracts,
A BE from dried fruits containing anthocyanins (25.0%, w/w) (no further details are available) reduced
In the other experiments of the same group HaCaT keratinocytes were used to assess the effects of
concentrations the protection decreased to 50% and 40% at a concentration of 25 mg/l. The phenolic fraction of Vaccinium myrtilli berries signiﬁcantly decreased generation of reactive oxygen and nitrogen species (RONS), of oxidizing lipids, proteins and DNA. Application of the BE (4 hours) to
Antioxidant activity of bilberry (Vaccinium myrtillus L.) and blueberry (Vaccinium corymbosum L.) was examined at the cellular level in different cell lines: human colon cancer
Table 12: Half maximal effective concentrations (EC 50) of the extracts in 4 cell lines (afterBornsek et al., 2012)
Data were expressed as mean±SEM, number of independent measurements was n=6. Statistical analysis was performed using one- way ANOVA with
The effective concentrations achievable after oral administration (Mazza et al., 2002; Felgines et al., 2008) are in the range of plasma anthocyanin concentrations in the presented experiments, showing cellular antioxidant activity at very low concentrations in different human cell lines. Such values in the range of 1nM are attained after consumption of ordinary servings of berries (McGhie and Walton 2007).
Cytoprotective effect of a BE from fresh fruits against oxidative damage in primary cultures of rat hepatocytes was studied by Valentová et al., (2007). The BE analysed by HPLC contained 25% of total anthocyanins. Activity of BE against oxidative cell damage induced by
Table 13: Protective effect of the bilberry extract on
After 30 minutes of
Antiradical activity was evaluated spectrophotometrically like the ability of the tested substances to reduce
Ogawa et al., (2011) studied the lipid peroxidation and free radical scavenging activity of a BE (containing more than 25%
Table 14: Superoxide anion radical scavenging activity of the bilberry extract and its main anthocyanidins (delphinidin, cyanidin and malvidin) (afterOgawa et al., 2011)
IC50, 50% inhibitory concentration. The parentheses show 95% confidence limits
Table 15: Hydroxyl radical scavenging activity of the bilberry extract and its main anthocyanidins (delphinidin, cyaniding and malvidin) (afterOgawa et al., 2011)
IC50, 50% inhibitory concentration. The parentheses show 95% confidence limits.
Different berry phenolics, V. myrtillus included, and their antioxidant activity were investigated by Kähkönen et al., (2001). Extraction methods for berries and apples were examined to create phenolic extracts with high antioxidant activity. Evaluation of antioxidant activity was performed by auto- oxidazing methyl linoleate (40°C, in the dark). The extraction method affected prominently both the phenolic composition and the antioxidant activity (Table 16). However, from the observation of the results obtained the effects cannot be clearly related with the content of phenolic of the individual subgroups.
Table 16: Anthocyanin, flavonol, hydroxycinnamic acid (HCA), hydroxybenzoic acid (HBA), ellagitannin, flavanol and procyanidin, and total phenolic contents (data expressed as mg per 100 g of weight), and antioxidant activity (data expressed as inhibition percentage) of bilberry extracts produced using different extraction methodsa) (afterKähkönen et al., (2001).
aMeans (SD of duplicate assays. Values in the same column for each berry having the same letter are not significantly different at p<0.05. ND, not detected. NA, not analyzed. bConcentration based upon
The antioxidant activity of phenolics (at concentrations of 1.4, 4.2, and 8.4 μg of purified extracts/ml of liposome sample) such as anthocyanins, ellagitannins, and proanthocyanidins from bilberry was studied by Viljanen et al. (2004) in a
Table 17: Inhibition of lipid and protein oxidation (after 6 days of oxidation) by bilberry phenolics incorporated into
aSD, standard deviation. Negative values indicate
Bilberry phenolics exhibited good overall antioxidant activity toward protein oxidation. The antioxidant effect toward lipid oxidation was more pronounced than the effect on protein oxidation (Table 18).
Table 18: Phenolic profiles of bilberry extract (expressed as % of total phenolics measured using HPLC; ND, not detected) (afterViljanen et al., 2004)
Anthocyanins; amount based upon
It has long been known that several phenolic substances such as flavonoids, phenolic acids, tannins and lignans have antimicrobial activity (Heinonen 2007). It is believed that it is the flavonoid anthocyanins component in V. myrtillus that exerts such an effect. The mechanism of antimicrobial activity may include antiadhesion activity, destruction of the cytoplasmic phospholipid bilayer of the cell wall in microbes, damage of the outer membrane with disintegration of the liposaccharide (LPS) layer by phenolics, tannins complexation of metal ions and inhibition of plasma coagulation by bacteria. Another mechanism is the inhibition of antibacterial multidrug resistance (MDR) and impairment of the efflux pump activity in bacteria
In vitro experiments
Rauha et al. (2000) evaluated the antimicrobial activity of a number of plants, including bilberry. To the in vitro studies, an aqueous solution of the dry extract prepared from the dry plant material (acetone/methanol 70%
Candida albicans (i. z. of
The antimicrobial activity of many plants, including V. myrtillus extract
Staphylococcus aureus (Nohynek et al., 2006).
Binding of Neisseria meningitidis pili to V. myrtillus berries and juice polyphenolic fractions containing anthocyanins, proanthocyanidins and flavonols have been identified by Toivanen et al. (2009; 2011). Prevention of adhesion of pathogenic bacteria to host cell surfaces may constitute the protection from the activity of bacteria that use adhesins to colonize the host cells.
Activity of bilberry against Gram positive and Gram negative intestinal pathogens was examined in in vitro cultures of Salmonella, Staphylococcus, Listeria and Lactobacillus bacteria
Stronger inhibition of growth was also seen against Salmonella enterica Typhimurium
Influence of various preparations of BE prepared from fresh berries, on trophozoites of Giardia duodenalis viability and spontaneous excystation of Cryptosporidium parvum oocysts was examined in in vitro experiments by Anthony et al., (2007, 2011). The water soluble extracts of bilberry containing polyphenols (167 µg/ml of gallic acid equivalents) killed 90.4+2.8% of Giardia duodenalis trophozoites. Increase of the spontaneous excystation of Cryptosporidium parvum oocysts observed after administration of the BE (equivalent to 213 µg/ml of the gallic acid). Because anthocyanins represent more than 70% of the polyphenols, it was concluded that they could be responsible for antiprotozoan activity of bilberry.
In vitro experiments
Similar experiments were conducted by Huttunen et al. (2011) who found through in vitro studies that a
In contrary, juice fractions of V. myrtillus of the higher molecular weight with the dominance of anthocyanins, proanthocyanidins and flavonol glycosides exerted antiaggregation effect on the pairs of bacteria common in the pathology of the dental plaque in the oral cavity: Streptococcus mutans with
Fusobacterium nucleatum or Actinomyces naeslundi (Riihinen et al., 2011).
In vitro experiments
Bilberry fruit extracts were screened to antineoplastic activity by in vitro tests to determine the ability to induce phase II detoxification of quinone reductase and inhibition of the induction of ornithine decarboxylase. Raw extracts containing anthocyanin and proanthocyanidin fractions showed little activity (Bomser et al., 1996).
Esselen et al., (2011) investigated the influence of BE on topoisomerases activity in a
to significantly diminish
In vitro experiments
Lamy et al., (2007) studied the activity of anthocyanidins (aglycons of anthocyanins) in prevention of migration of glioblastoma cells. Because the full resection of malignant glioblastomas is not possible due to their diffuse structure, the development of new projects for cancer therapy and prevention is very important. It was found that aglycons of the anthocyanins: cyanidin, delphinidin, and petunidin acts as potent glioma
In vivo experiments
Antiulcer activity of a BE (corresponding to 25% anthocyanidins) was tested in vivo in Wistar rats in experimental models of pyloric ligature induced ulcers, ulcers induced with the use of reserpine, phenylbutazone, ulcers caused by restraint and a local application of acetic acid to the gastric mucosa (Cristoni and Magistretti 1987). The results of experiments were compared with the control groups and groups of rats receiving carbenoxolone and cimetidine. The results of the performed experiments were analyzed by the
Table 19: Activity of V. myrtillus extract in pyloric ligature ulcer model in rats (afterCristoni and Magistretti 1987)
Substances were given 50, 30, 25, 6 hours before and immediately after pyloric ligature (*) p<0.05; (**) p<0.01; Mann Whitney U test.
Table 20: Activity of V. myrtillus extract in reserpine ulcer model in rats (afterCristoni and Magistretti 1987)
Substances were given once a day for 8 days; (**) p<0.01
Table 21: Activity of V. myrtillus extract in phenylbutazone ulcer model in rats (Cristoni and Magistretti 1987)
Substances were given twice a day for 4 days (*) p<0.05; (**) p<0.01; Mann Whitney U test.
Table 22: Activity of V. myrtillus extract in restraint ulcer model in rats (Cristoni and Magistretti 1987)
Substances were given once a day. (*) p<0.05; (**) p<0.01; Mann Whitney U test.
Table 23: Activity of V. myrtillus extract in acetic acid ulcer model in rats (Cristoni and Magistretti 1987)
Smooth muscles contractility
In vivo experiments
Influence of a BE (corresponding to 25% of anthocyanidins on rat stomach muscles to stimulation of
hexamethonium (20 μg/ml) partially decreased the facilitatory response (Table 24). Authors concluded that the BE enhances the liberation of ACh at the level of the postganglionic nerve endings.
Table 24: Mean percentage increase in the response of the preparation to transmural stimulation (after Bettini et al., 1986)
A) in standard Krebs solution; B) with hexamethonium (20 g/ml); note that the percentage increase is greater in the absence of hexamethonium.
3.1.3. Safety pharmacology
Effects of BE (containing 36% of anthocyanosides) on platelet aggregation in humans was studied by initially by Bottecchia et al., (1987), later by Pulliero et al., (1989) and by Morazzoni and Magistretti (1990) in rabbit and rats.
In preliminary in vitro studies Bottecchia et al. (1987) showed 50% inhibition of the clot retraction at concentration of 75 µg/ml of the BE. Moreover, the platelet aggregation induced by ADP, collagen and arachidonic acid was inhibited in a concentration dependent manner (50, 100 and 150 µg/ml). The researchers believed that BE stimulates the release of prostacyclin (PGI2), which has the effect of increasing the concentration of the intracellular cAMP or reducing the level of thromboxane A2 in platelets.
In experiments conducted by Morazzoni and Magistretti (1990) in rabbits and rats in vitro and in vivo, not only the activity of the BEM was tested, but also three principal anthocyanosides occurring in the extract. BE, as dipyridamole and aspirin inhibited platelet aggregation (Table 25). Both cyanidin
Table 25: Inhibition of rabbit platelet aggregation by BEM, dipyridamole and aspirin (after Morazzoni and Magistretti 1990)
Tab 26: Inhibition of rabbit platelet aggregation by cyanide
BEM significantly and dose dependently
Table 27: Time course of the effects of single oral doses of BEM (100 mg/kg) on bleeding time in rats (after Morazzoni and Magistretti 1990)
Bleeding time (sec) (Mean±S.E.)
*p≤0.05; **p≤0.01 with Student’s test for paired data. The experiment was performed on groups of 10 rats for each time.
Similar to ticlopidine change in platelet adhesiveness was found in male mouse after single oral administration of BEM at the dose 400 mg/kg 2 hours before the test. In the treated group marked decrease in the number of the adhesive platelets was found compared to control values (Table 28)
Table 28: Effect of single oral dose of BEM and ticlopidine hydrochloride on male mouse platelet adhesiveness (after Morazzoni and Magistretti 1990).
BEM and ticlopidine hydrochloride were administered orally 2 hours before the test (**p≤0.01 with Dunnett’s t test).
3.1.4. Pharmacodynamic interactions
Fuchikami et al. (2006) studied in vitro the influence of the water/ethanol bilberry extract on the uptake
Except this single report no animal studies of the bilberry fruit or extracts interactions were identified (Gardner and McGuffin 2013).
As dried ripe fruits of bilberry contain at least 1% of tannins, the traditional use of the dry fruit preparations in diarrhea and topically in mild inflammation of the mucosa is justified on the basis of their astringent properties.
Bilberry is also recommended for the treatment of vascular disorders. Many therapeutic proprieties of bilberry is ascribed to anthocyanin activity. This concerns both the relaxing action on blood vessels like arteries and veins, an improvement of capillaries after microcirculation injury and protective effects of the BE and anthocyanins against oxidative damage. Preclinical studies have also reported their antimicrobial, antinflammatory, antiplatelet and antineoplastic activity.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
In the study of Talavéra et al., (2003) anthocyanins from BEM (88 µM/l) were injected directly into the stomach of anaesthetized rats for 30 minutes and their appearance in plasma was a measure of absorption from the stomach. The absorption of anthocyanins was very diverse
Other bioavailability studies in rats demonstrated that after oral administration of a single dose of 400 mg/kg of BEM (mixture of 15 anthocyanosides) they were quickly absorbed with a Cmax=2.5 µg/ml at the plasma peak Tmax value of 15 minutes (absorption rate constant=0.13 /min). After 2 hours after administration no detectable concentrations were observed. According to the authors, despite the low bioavailability of BEM the concentration of
Anthocyanins have a low bioavailability as evaluated by urinary excretion, appear very quickly after ingestion in systemic circulation (peak plasma concentrations appear after 1.5 hours). Several data showed that only less than 1% of the consumed anthocyanins can be detected in the plasma and urine (Felgines et al., 2005; Kay et al., 2005; Nielsen et al., 2003). Intact anthocyanidin glycosides have been detected in plasma indicating that
This high level of anthocyanins absorption was comparable to the studies of Felgines et al., (2006) (about 20% in the stomach and 7% in the small intestine). It can generally be assumed on the basis of these results that about 10% total the anthocyanins administered can be absorbed from the stomach and small intestine (Talavéra et al., 2004).
Anthocyanin specific transporter is the bilitranslocase, a membrane carrier in the liver responsible for the transport of the dye bromosulphophtalein. This transporter is located on luminal side in the apical domain of epithelial cells of the stomach and intestines. Experimental simulation of antocyanins absorption with the use of intestinal epithelial
This phenomenon may explain why the bioavailability of anthocyanins is so low. When the anthocyanins come into contact with the bacterial microflora of the colon, rapid deglycosylation occurs with conversion to phenolic metabolites (Fleschhut et al., 2006; Keppler and Humpf 2005; Kemperman et al., 2010; Nurmi et al., 2009; Selma et al., 2009). Most anthocyanins do not appear to undergo extensive metabolism of the parent glycosides to glucuronic, sulfo- or methyl- derivatives (Mc Ghie and Walton 2007; Ichiyanagi et al., 2004a, 2004b).
Lietti and Forni (1976) studied the tissue distribution of anthocyanidins after the administration to rats of the extract of V. myrtillus equivalent to 25% of anthocyanidins dissolved in saline in doses of 25 mg/kg i.p. or 20 – 40 mg/kg i.v. Bilberry anthocyanidins were rapidly distributed in the tissues especially to skin and kidney as compared to plasma (Table 29). The calculated estimated volume of distribution in the rat as extrapolated from the plots was 22 ml, which corresponds approximately to the sum of the plasma plus the interstitial fluid volume.
Table 29: Tissue distribution of anthocyanidins in rat 1 hour after i.p. administration of 200 mg of V. myrtillus anthocyanosides (equivalent to 25% of anthocyanidins). Mean±SE of five animals per group (after Lietti and Forni 1976).
Anthocyanidins seem to have longer persistence in the skin compared with the plasma (Table 29). This
Table 30: Relationship between plasma and skin level of anthocyanidins and pharmacological activity of V. myrtillus anthocyanosides (200 mg/kg i.p.) on rat capillary resistance. Mean±SE of five rats per group (after Lietti and Forni 1976)
The distribution of bilberry anthocyanidins was tested in mice (Sakakibara et al., 2009). After single oral administration of 100 mg/kg of BE (obtained by use of 80% ethanol acidified with hydrochloric acid) with the total concentration of anthocyanins 67.3 µmol/100 mg of the extract the total plasma concentration has attained a maximum of 1.18±0.3 µM after 15 minutes and afterwards rapidly decreased almost to basal levels after 120 minutes (Table 31).
aValues are indicated as the mean
When mice received a diet containing 0.5% BE for 2 weeks, anthocyanins were detected in the liver, kidney, testes and lung.
Table 32: Anthocyanin concentrations in tissues of mice fed a 0.5% bilberry diet for 2 weeks (after Sakakibara et al., 2009)
aValues are indicated as the mean
Binding of anthocyanins to plasma albumin
Cahyana and Gordon (2013) have found that the effect of the structure of anthocyanins (pelargonidin, cyanidin, delphinidin, malvidin) on the affinity to human plasma albumins was
The above experiments have shown that the most common anthocyanins in plasma and tissues were malvidin glycosides, and in second place followed by peonidin glycosides. These and other anthocyanins are converted to methoxyl or glucosyl substituents with subsequent result on the interaction with serum albumin. Since the pH at inflammatory sites is acidic it can determine their beneficial health effects (Cahyana and Gordon 2013).
Elimination of anthocyanidins proceeds quite fast regardless of the route of administration (Lietti and Forni 1976). After 4 hours, approximately 20% of the administered dose was eliminated in the urine.
After 24 hours, 15% of the intravenous dose and 18% of the administered via the intraperitoneal route was excreted in the bile.
Anthocyanins are readily reactive compounds and therefore are easily deteriorating or reacting with the other ingredients in the mixtures to form colourless or brown compounds. After the passage through the gastrointestinal tract after oral administration they are exposed to different pH and temperature conditions and to different chemical substances. Their different molecular forms are in dynamic equilibrium. Most of the anthocyanins are transformed in the colon to phenolic acids by bacteria (Aura et al., 2005; Keppler & Humpf, 2005). The enzymatic reactions include ring cleavage, hydrolysis of glycosides, glucuronides, amides and esters, and reduction, decarboxylation, demethylation and hydroxylation (Aura 2008; Dall’Asta et al., 2012; Kay et al., 2005; Kay 2006; Manach et al., 2005; Williamson and Manach 2005). On the other hand, anthocyanins given to patients with an ileostomy are accumulating mostly unchanged in the bag (85%), giving little evidence of metabolism after gastrointestinal transfer up to ileum (Kahle et al., 2006). Known mammalian metabolites of anthocyanidins are presented in the Table 33 (after Williamson and Clifford 2010).
Table 33: Known mammalian metabolites of anthocyanidins (after Williamson and Clifford 2010).
The metabolites of anthocyanins most likely are the C6,
In vitro studies with anaerobic human microflora demonstrated that protocatechuic acid is the most probable main degradation product of anthocyanins (Galvano et al., 2008). Also, studies in humans with the administration of orange juice and administration of
The oral intake by volunteers of oats added to a purée of bilberries (glycosides of delphinidin, accompanied by small amounts of malvidin, peonidin and petunidin glycosides) and lingonberries (cyanidin glycosides) (Ek et al., 2006) resulted in urinary excretion of
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
The acute oral toxicity of BE was studied in mice and rats and no signs of toxicity were observed at doses higher than 2000 mg/kg (Eandi, Data on file 1987; quoted after Morazzoni and Bombardelli 1996).
Oral administration of a single dose of BEM (no further details) (3000 mg/kg, equivalent to 1.08 g/kg anthocyanins) to dogs, besides a clear darkening stool and urine, did not result in adverse reactions (Eandi, Data on file 1987; quoted after Morazzoni and Bombardelli 1996). This symptom gave evidence that the absorption and elimination of the preparation are via the kidney.
Dosage used, however, broadly exceeds the human exposure (usually around
3.3.2. Repeated dose toxicity
No toxic effects were noted in guinea pigs received daily BEM for 2 weeks and rats for 6 weeks at doses up to 43 mg/kg (Pourat et al., 1967, quoted in Upton 2001).
Similarly no abnormalities were found in rats receiving BEM for 4 weeks up to 36 mg/kg i.v. daily or in dogs treated for 13 weeks 12 mg/kg daily. There was, however, a dark blue colour of the urine, skin, eyes, and, in certain cases, liver, kidney and the ovaries (Eandi, Data on file 1987, quoted in Morazzoni and Bombardelli 1996).
Both oral daily administration of the BEM to rats for 6 months
No 2 years toxicity studies of BE were identified in the available literature.
Toxicological studies of anthocyanins are limited and are made using extracts from the various species. Human population is naturally affected by exposure to anthocyanins as regularly eating fruits and vegetables.
Weak mutagenic activity in the Ames test was observed after application of an extract of V. myrtillus (Schimmer et al., 1994). However, the results refer to the extract of the leaves of the plant and not to fruit preparations.
In the study of Malaveille et al., (1996) cyanidin chloride inhibited hepatic
On the contrary, cyanidin, malvidin, and delphinidin were inactive in prevention of the
Laboratory and clinical studies provide strong evidence that increased intake of berries which have among others a high content of anthocyanins, may contribute to a reduced risk of certain cancers, especially colorectal cancer (Brown et al., 2012; Stoner et al., 2008; Wang and Stoner 2008).
3.3.5. Reproductive and developmental toxicity
In the study of Pourrat et al., (1967) anthocyanin glycosides from the currants, blueberries and elderberries, when given in doses of 1.5, 3, or 9 g/kg for 3 successive generations did not induce teratogenic activity in rats, mice and rabbits (http://www.inchem.org/documents/jecfa/jecmono/v17je05.htm).
Bhargava (1990) reported that malvidin chloride inhibited the spermatogenesis in langur monkeys receiving 50 mg/kg for 60 days. Testicular and epididymal mass was diminished and the disappearance of Leydig cells was seen. The level of total RNA protein, sialic acid, the acid/alkaline phosphatase in the testes was reduced as the amount of cholesterol in epididymides.
3.3.6. Local tolerance
No data available.
3.3.7. Other special studies
No data available
Toxicological studies are limited.
Tests on reproductive toxicity and genotoxicity were performed almost 50 years ago and are not in accordance with the current standards.
Adequate tests on toxicity, genotoxicity and carcinogenicity have not been performed. No reason of concern is arisen from data of human consumption.
3.4. Overall conclusions on
Results from relevant experimental studies are very limited, but the antimicrobial, astringent and antihadesive properties of the tannins present in the herbal substance can explain the traditional uses of the dried fruit as a decoction for symptomatic treatment of mild diarrhoea and for symptomatic treatment of minor inflammations of the oral mucosa.
Pharmacokinetic studies showed that anthocyanin glycosides are rapidly absorbed from the stomach after ingestion and they enter the central compartment after first pass through the liver. In the liver they undergo methylation and glucuronidation reactions and some of the metabolites are transported to the bile. Anthocyanin glycosides which are not absorbed from the stomach move to the jejunum, and are absorbed to systemic circulation. Anthocyanins that reach the colon are exposed to a microbial transformation with production of phenolic compounds, later they are degraded to aldehydes and phenolic acids.
As there is no valid information on reproductive and developmental toxicity the use during pregnancy and lactation cannot be recommended.
Toxicological studies are limited and were performed using extracts from the various species.
Adequate tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.
Oral administration and oromucosal use of decoction of dried bilberry fruit can be regarded as safe at traditionally used doses and adequate duration of use.
4. Clinical Data
4.1. Clinical pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
In clinical study Puliero et al., (1989) 30 volunteers of both sexes (mean age 45 years) were involved. They were divided into three groups, of which received orally for 60 days : A) BEM 480 mg/day in 3 divided doses; B) Ascorbic acid 3 g in three divided doses, C) BEM 480 mg/day in 3 divided doses + ascorbic acid 3 g in three divided doses. Blood samples were taken before treatment and after 30, 60 and 120 days after the beginning of treatment. The combination of BEM and ascorbic acid concentration dependently reduced the platelet aggregation induced by either collagen
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
In vitro studies with anaerobic human microflora demonstrated that protocatechuic acid is one of the most probable main degradation products of anthocyanins (Galvano et al., 2008). Also, studies in humans with the administration of orange juice and administration of
The oral intake of oats added to a purée of bilberries by volunteers (glycosides of delphinidin, accompanied by small amounts of malvidin, peonidin and petunidin glycosides) and lingonberries (cyanidin glycosides) (Ek et al., 2006) resulted in urinary excretion of
4.2. Clinical efficacy
4.2.1. Dose response studies
No data available.
4.2.2. Clinical studies (case studies and clinical trials)
Table 34: Clinical studies on humans
Treatment of disorders of the circulatory system (e.g. altered microcirculation and peripheral venous insufficiency) Non Randomised Studies
Dry eye syndrome (DES) (keratoconjunctivitis sicca) – Controlled study
Bilberry OSDI group showed a statistically significant improvement (p<0.01)
4.3. Clinical studies in special populations (e.g. elderly and children)
No data available.
4.4. Overall conclusions on clinical pharmacology and efficacy
Bilberry fruits are traditionally used for diarrhoea and in the conditions of increased fragility of blood vessels and chronic venous insufficiency. Bilberry intake is claimed to produce improvement of microcirculation.
Numerous clinical trials have been carried out since the early 1960s, involving the treatment of vascular fragility and improvement of vision.
The systematic review of clinical studies dedicated to improving vision in conditions of reduced light (Canter and Ernst 2004) does not provide clear conclusions. Of the 12 studies with placebo, five studies were randomized. Unfortunately, four of these recent studies gave negative results. The only positive study (Jayle and Aubert 1964) showed an increase in the area of the visual field. In this study patients received, however, a complex product containing BE and
In most discussed publications the age of the patients varied greatly from young to advanced age. It is known, however, that normal night vision begins to decline in middle age. In addition, it has not been mentioned anywhere at what time of day research was carried out. Rigorous clinical trials are needed to prove the effects of BE on subjects suffering from impaired night vision (Canter and Ernst 2004).
The problem of stability of anthocyanins is essential, as improper storage leads to their degradation. It is especially relevant when carrying out long, ongoing clinical trials.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
No data available.
5.2. Patient exposure
Aside from market presence and data from studies, an epidemiological study has been published concening patient exposure. Bilberry is often used in
5.3. Adverse events, serious adverse events and deaths
In the clinical trials no serious adverse events were reported, in Biedermann et al (2013) 33% of patients reported mild to moderate flatulence. No cases of death were reported.
5.4. Laboratory findings
Very limited data are available.
5.5. Safety in special populations and situations
5.5.1. Use in children and adolescents
Particular use in children has not been reported. Therefore, the use in children up to 6 years is not recommended.
According to the instruction of the package leaflet of the products marketed in Poland and in Germany the use in children of comminuted dry bilberry fruit is not recommended.
In Germany the use of in children up to 2 years is contraindicated.
5.5.3. Special Warnings and precautions for use
When used to relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances, if there is inflammation of the skin, thrombophlebitis or subcutaneous induration, severe pain, ulcers, sudden swelling of one or both legs, cardiac or renal insufficiency, a doctor should be consulted.
5.5.4. Drug interactions and other forms of interaction
Peris et al., (2008) described the case of the patient (age and sex not stated) after the
Paoletti et al., (2011) reported a case about the reduction to 1.6 of INR (time to onset 4 days) in 80 years old woman, who was receiving
Aktaş et al., (2011) published a case history of the 77 years old man with hypertension, who consumed for 5 years large amounts of bilberries. The patient for 6 years suffered from hypertension, and because it was found recently that he has an atrial fibrillation and a year before he had a stroke, he received an anticoagulant treatment. In emergency he sought medical assistance because of rectal bleeding and dizziness, which occurred 16 days after introduction of warfarin therapy. His prothrombin time (PT) was 110.5 seconds, INR=15.0, and the activated partial thromboplastin time (APTT) 76.4
seconds. He was given intravenous plasma, but the next day he returned with abundant haematuria and dizziness. His INR was 6.24, and the prothrombin time (PT) was 55.7 seconds. So again he was the subject of further hospitalization.
Despite the presented anecdotal cases it has not been possible to prove a genuine threat of interactions with anticoagulants and antiplatelet agents at the recommended dose of bilberry preparations.
5.5.5. Fertility, pregnancy and lactation
No adverse effects were registered in more than 200 women receiving BEM (no further details) equivalent to
However the safe use of BE and BEM in pregnancy and lactation has not been adequately investigated and established. In the absence of sufficient data, the use of the dry extract of fresh bilberry fruit during pregnancy and lactation is not recommended.
No concern has arisen about any malformation in humans, following the consumption of dried bilberry fruit.
No fertility data available.
No cases of overdose have been reported.
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.5.8. Safety in other special situations
5.6. Overall conclusions on clinical safety
Some reports presented in section 5.4.4. do not provide real threat to confirm interactions with anticoagulants and antiplatelet drugs at the recommended doses of bilberry. However, some attention is needed in patients treated with antiplatelet agents or anticoagulants.
6. Overall conclusions
The results of clinical data available for bilberry fruit preparations are not considered sufficient to support a
The systematic review, conducted in 2004 by Canter and Ernst, of clinical trials designed to improve vision in conditions of poor light with preparations of bilberry fruits did not provide clear conclusions. Out of 12 studies with placebo, only five studies were randomized. Unfortunately, four of these recent studies gave negative results. The only positive study (Jayle and Aubert 1964) showed an increase in
the area of the visual field. In this study patients received, however, a complex product containing BE and
Several clinical studies on disorders of the circulatory system (e.g. altered microcirculation and peripheral venous insufficiency) were performed about 30 – 40 years ago and were not randomized. Hence, despite the conviction of the beneficial effects of the anthocyanins therapy in cardiovascular diseases, the medicinal use of bilberry preparations is based on tradition.
All the requirements for TU
The traditional medicinal use of bilberry dried fruit and bilberry fruit extract has been documented in several medicinal handbooks with indications consistent with the existing pertinent pharmacological experiments performed in vitro and in vivo and it is substantiated by the presence of medicinal products on the European market.
The experimental toxicological data are limited, but given the history of
1)V. myrtillus L., fructus siccus (dry bilberry fruit), whole or comminuted
a)Traditional herbal medicinal product for symptomatic treatment of mild diarrhoea. Daily dose in adults and adolescents over 12 years as an herbal tea for oral use: 15 to 60 g, divided in
b)Traditional herbal medicinal product for symptomatic treatment of minor inflammations of the oral mucosa. It is used as a 10% decoction for oromocosal use to rinse the mouth several times daily. Therapeutic area for browse search with TU indications: mouth and throat disorders.
2)V. myrtillus L., fructus recens dry extract; DER
a)Traditional herbal medicinal product to relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances.
b)Traditional herbal medicinal product to relieve symptoms of cutaneous capillary fragility. Single dose: 80 – 180 mg; Daily dose: up to 160 – 540 mg.
Therapeutic area for browse search with TU indications: venous circulatory disorders.
Whole or comminuted dried bilberry fruit
As a general precaution related to the therapeutic indication “for symptomatic treatment of mild diarrhoea”, the product information should include a warning text advising the patient to consult a doctor or a qualified health care practitioner if the symptoms worsen or persist longer than 3 days during the use of the product. In case of the oromucosal use “for symptomatic treatment of minor inflammations of the oral mucosa” the warning should refer to 1 week.
Bilberry fruit cannot be recommended for oral use in children under 12 years of age due to lack of adequate data.
No concern has arisen about any malformation in humans, following the consumption of dried bilberry fruit. They can be used during pregnancy and lactation if clinically needed. No data on fertility is available.
Fresh bilberry fruit dry extract; DER
The recommended duration of use of the fresh bilberry fruit dry extract “to relieve symptoms of discomfort and heaviness of legs related to minor venous circulatory disturbances” or “to relieve symptoms of cutaneous capillary fragility” is 4 weeks. However, if the symptoms persist for more than 2 weeks during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.
The following warnings are included in section 4.4. of the monograph on bilberry dry extract: “If there is inflammation of the skin, thrombophlebitis or subcutaneous induration, severe pain, ulcers, sudden swelling of one or both legs, cardiac or renal insufficiency, a doctor should be consulted.”
Bilberry dry extract cannot be recommended for oral use in children and adolescents under 18 years of age due to lack of sufficient safety data.
Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the use during pregnancy and lactation is not recommended. No fertility data is available.
On the basis of the available information anthocyanins are considered by the HMPC as contributing to the activity of the V. myrtillus L., fructus recens dry extract (DER
A European Union list entry is not supported due to lack of adequate data on genotoxicity.