Download Vaccinium myrtillus (Bilberry) | (HE 1:1 | 42-85ml)

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Vaccinium myrtillus (Bilberry) | (HE 1:1 | 42-85ml)
The bilberry plant is a deciduous, leafy, freely branched, perennial shrub that is native to northern Europe, the
northern United States, and Canada. It is found in heaths, moors, and woods in most of Europe, northern Asia,
and in the mountain and subalpine areas of western North America. Bilberry grows 35-60cm in height and
flowers from April through June. It produces a fruit similar to the American blueberry, and the ripe fruits can be
collected from July through September. The name bilberry is derived from the Danish word bollebar, which
means "dark berry." The berries are purple-black in color and coarsely wrinkled. The berries contain many small,
shiny, brownish-red seeds. The applicable parts of bilberry are the fruit and leaf. The dried, ripe fruit contains
tannins and several anthocyanidin (anthocyanoside) constituents including cyanidin, delphinidin, peonidin,
petunidin, malvidin, and others. Bilberry leaves also contain polyphenols such as resveratrol, flavonoids such as
quercetin, and a relatively high concentration (9.0 ppm) of chromium (1265, 16628). Orally, bilberry is used for
improving visual acuity including night vision, cataracts, degenerative retinal conditions, varicose veins,
atherosclerosis, venous insufficiency, chronic fatigue syndrome (CFS), and hemorrhoids. It is also used orally
for angina, diabetes, osteoarthritis, gout, dermatitis, gastrointestinal (GI) disorders, kidney disease, and urinary
tract infections (UTIs). Topically, it is used for mild inflammation of the mouth and throat mucous membranes.
ANTIPLATELET / ANTICOAGULANTS: Anthocyanidin extracts may inhibit platelet aggregation (16631,
35455, 35478, 35503, 35504, 35505). Combining bilberry with antiplatelet or anticoagulant drugs may increase
risk of bleeding. Some of these drugs include aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin
(Lovenox), heparin, indomethacin (Indocin), ticlopidine (Ticlid), warfarin (Coumadin), ngelica, clove, danshen,
garlic, ginger, ginkgo, glucosamine, Panax ginseng. ANTIDIABETIC: Bilberry leaf extract might have blood
glucose-lowering activity (1264, 35463, 35468). May have additive effects when used by patients taking
antidiabetic drugs. Doses of diabetes medications may need to be adjusted. Some antidiabetes drugs include
glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, metformin (Glucophage),
pioglitazone (Actos), rosiglitazone (Avandia). CHROMIUM-CONTAINING HERBS AND
SUPPLEMENTS: Bilberry contains chromium and could increase risk of chromium toxicity when taken with
chromium supplements or chromium-containing herbs such as brewer's yeast, cascara, or horsetail. HERBS
AND SUPPLEMENTS WITH HYPOGLYCEMIC POTENTIAL: Might have additive effects with herbs
that decrease blood glucose levels (1264, 35468, 35643) - devil's claw, fenugreek, garlic, guar gum, horse
chestnut, Panax ginseng, psyllium, Siberian ginseng. GENERAL: May cause gastrointestinal discomfort,
nausea or heartburn. CARDIVASCULAR: Bilberry may have hypotensive effect (drop) blood pressure, based
on vascular smooth muscle-relaxing properties (35454, 35514, 35515). ENDOCRINE: Hypoglycemia has been
demonstrated - alcoholic extract of Vaccinium myrtillus increases serum glucose levels (35508). May inhibited
absorption of estrogens in the intestine by 75.5% (p<0.01) (35450). GASTROINTESTINAL: Mild-to-moderate
flatulence (91506). May have laxative effect. May increase frequency of bowel movements (when combined
with aerial agrimony, cinnamon quills, powdered bilberry fruit, and slippery elm bark (35462). Only dried
bilberry suggested for diarrhoea. Large consumption may cause constipation. OTHER: May increase tumor
necrosis factor-alpha (TNF-alpha) (35459), although opposite effects have been seen using frozen whole berries
(35463). May cause dark-bluish to black discoloration of feces and tongue (91506). TOXICOLOGY: May
cause hydroquinone poisoning, anticoagulation, or gastrointestinal distress (35485). PATIENT HANDOUT |
Family: Ericaceae.
Mechanism of Action
Constituents: Bilberry contains several compounds that have demonstrated biological activity. The main
chemicals contained in bilberry extract have been shown to be antocyans, anthocyanidins, anthocyanins, and
anthocyanosides (35451, 35452, 35464); as well as flavonoids, quercetin, epicatechin, hydroquinone, oleanolic
acid, neomyrtillin, sodium, tannins, and ursolic acid (8141, 35459, 35485, 35494, 35518, 35519). Bilberry also
contains resveratrol (16053, 35447, 35459, 35458).
Flavonoids have been shown to inhibit prostacyclin synthesis, reduction of capillary permeability and fragility,
free radical scavenging, inhibition of a wide range of enzymes, impairment of coagulation and platelet
aggregation, and anticarcinogenicity (35499, 35518).
Antibacterial effects: A study using Staphylococcus aureus, Staphylococcus aureus, Enterococcus faecalis,
Bacillus subtilis, and Escherichia coli, showed minimum inhibitory concentration (MIC) of 12.7-17.8mg/mL,
and an aqueous extract of bilberry fruit had an MIC of 15.4-30.7mg/mL (35489).
Anticancer effects: Anthocyanin-rich extracts inhibit growth of a colon cancer cell line (35448).
Bomser et al. screened fruit extracts of bilberry for potential anticarcinogenic compounds by a combination of
fractionation and in vitro testing of their ability to induce the phase 2 xenobiotic detoxification enzyme
quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting
enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA) (35499). The
crude extracts, anthocyanin, and proanthocyanidin fractions were not found to be highly active in phase 2
xenobiotic detoxification enzyme QR induction, whereas the ethyl acetate extracts were active QR inducers.
The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of bilberry
were 1.0mcg of tannic acid equivalents (TAE). Further fractionation of the bilberry ethyl acetate extract
revealed that the majority of inducer potency was contained in a hexane-chloroform subfraction
(CDqr=0.07mcg of TAE). The anthocyanidin and ethyl acetate extracts of bilberry were either inactive or
relatively weak inhibitors of ODC activity. The authors concluded that components of the hexane-chloroform
fraction of bilberry exhibited potential anticarcinogenic activity, as evaluated by in vitro screening tests.
Anti-inflammatory effects: In human research, a supplement containing mixed berry-derived anthocyanin
isolates (Medox) decreased levels of various proinflammatory chemokines (interleukin-8 [IL-8], regulated
upon activation, normal T cell expressed and secreted [RANTES], and interferon-alpha [IFN-alpha]) and
cytokines (IL-4 and IL-13) (35453). Dietary supplementation of bilberry, either alone or as part of a "healthy
diet," has also been shown to lower serum levels of high-sensitivity C-reactive protein (hs-CRP), IL-6, IL-12,
IL-15, lipopolysaccharide (LPS), E-selectin, and monokine induced by IFN-gamma (MIG) (35467, 35459,
35473). Mixed findings have been found with regard to tumor necrosis factor-alpha (TNF-alpha), with some
research demonstrating decreased levels following dietary bilberry consumption (frozen whole berries)
(35463) and others demonstrating increases (bilberry juice) (35459). Inhibition of nuclear factor-kappa B (NFkappaB) activation has been purported as a possible mechanism of action underpinning bilberry's observed
anti-inflammatory effects (35453, 35459).
Antioxidant effects: Bilberry contains anthocyanosides that are flavonoid derivatives of anthocyanins (the
blue, red, or violet pigments found in many berry varieties), which are closely related in structure and activity
to flavonoids (35485) and possess free radical-scavenging and antioxidant properties. Antioxidant properties
have been attributed to bilberry in in vitro studies (35457, 35495, 35496, 35497, 35498). Specifically,
anthocyanins and other phenolics from bilberry upregulated the oxidative stress defense enzymes hemeoxygenase-1 and glutathione S-transferase-p in cultured human retinal pigment epithelial cells, suggesting that
they stimulate signal transduction pathways, influencing genes controlled by the antioxidant response element
(35452). In human research, dietary consumption of 160g of mixed berries (bilberries, black currants,
chokeberries, lingonberries) daily for eight weeks increased the plasma level of various polyphenols compared
to placebo, including quercetin, caffeic acid, p-coumaric acid, protocatechuic acid, homovanillic acid, vanillic
acid, 3-hydroxyphenylacetic acid, and 3-(3-hydroxyphenyl)propionic acid (35458).
Antiplatelet effects: In a clinical study of 30 subjects with normal platelet aggregation, 480mg of Myrtocyan
(Vaccinium myrtillus anthocyanins) daily, 3g of ascorbic acid daily, or both treatments all reduced platelet
aggregation after 30 and 60 days (35503). Bilberry anthocyanins reduced platelet aggregation more than
ascorbic acid alone, but bilberry anthocyanins and ascorbic acid together were the most effective. In other
human research, a diet rich in various types of berries including bilberry inhibited platelet function as assessed
by a platelet function analyzer, in spite of a lack of change in plasma biomarkers of coagulation, fibrinolysis,
and platelet activation (35455). Similarly, in in vitro studies, anthocyanins extracted from bilberry inhibited
platelet aggregation (35478, 35505, 35502, 35504).
Flavonoids have been shown in vitro to inhibit prostacyclin synthesis. In one animal model, Vaccinium
myrtillus anthocyanosides were studied for their effects on prostacyclin-like activity in rat arterial issue
(35500).
Antiproliferative effects: According to one laboratory study, anthocyanins were the predominant phenolic
compounds in bilberry extracts (35451). Compared to other plants with anthocyanins, such as black currant or
lingonberry, cell growth inhibition was greater for bilberry than other plants studied. The proapoptosis marker
Bax increased 1.3-fold in bilberry-treated cells, whereas the prosurvival marker Bcl-2 was detected only in
control cells. The results demonstrated that bilberry and other berry extracts containing anthocyanins inhibited
cancer cell proliferation, mainly via the p21WAF1 pathway.
Antiulcer effects: Bilberry extract has been suggested as a promoter of gastric ulcer healing, with support
from animal data (35474). In an animal study, large doses of cyanidin chloride from bilberry significantly
increased gastric mucosal release of prostaglandin E2 (35465). In animal models of gastric ulcers, cyanidin
chloride showed antiulcer activity (16629, 35474), as did IdB1027, a natural flavonoid from Vaccinium
myrtillus (bilberry) anthocyanoside (VMA) extract (8141, 16629, 35465, 35494). H. pylori bacteria have been
implicated in many cases of gastric and duodenal ulcers. Berry extracts have been shown to inhibit H. pylori
bacteria in vitro and to enhance susceptibility to clarithromycin (35449).
Connective tissue-stabilizing effects: An in vitro study has suggested that anthocyanosides appear to stabilize
connective tissue by enhancing collagen synthesis, inhibiting collagen degradation, and enhancing collagen
cross-linking (35486). In contrast, Boniface et al. found a significant decrease in connective tissue synthesis
(collagen and glycoproteins) in gingival tissue samples of 12 adult diabetics treated with 600mg of
anthocyanosides daily for two months (35493).
Endothelial effects: In human research, mixed-berry derived anthocyanins have been shown to increase both
flow-mediated dilation (FMD) and cGMP, and decrease soluble vascular adhesion molecule-1 (sVCAM-1)
(35469). However, the effects of anthocyanins on endothelial function were abrogated upon exposure to NOcGMP inhibitors, suggesting a possible NO-cGMP-mediated mechanism of action. One dietary intervention
study in individuals with impaired glucose metabolism also reported a decrease in plasma E-selectin following
the coadministration of a "healthy diet" of bilberries, whole grains, and fatty fish (35467).
Gastrointestinal effects: In humans with diarrhea-predominant irritable bowel syndrome (IBS), a combination
formulation containing aerial agrimony parts, cinnamon quills, powdered bilberry fruit, and slippery elm bark
was shown to mitigate various IBS symptoms (e.g., abdominal pain, bloating, flatulence, straining) in spite of a
lack of efficacy in improving bowel habit; the frequency of bowel movements was increased following
combination bilberry treatment (35462). In humans with mild to moderate ulcerative colitis, a bilberry
formulation (Symrise GmbH & Co, Holzminden, Germany),improved patient symptoms. It is possible bilberry
has direct anti-inflammatory effects on the intestinal mucosa, as well as antioxidant properties (91506).
Hepatoprotective effects: In an animal study, anthocyans exerted a protective effect on liver cells (35491).
Preliminary research in an animal model shows that a specific bilberry extract containing 42% anthocyanidins
decreases alanine aminotransferase (ALT) in experimentally induced liver damage (16625).
Hypoglycemic effects: Limited animal data suggest that bilberry leaf extract possesses hypoglycemic and
lipid-lowering properties that may be beneficial in patients with diabetes (1264). In normal and depancreatized
dogs, oral administration of bilberry leaves reduced hyperglycemia, even when the glucose was injected
intravenously concurrently (35506, 35507). Conversely, in an oral glucose tolerance test in healthy rats, an
alcoholic extract of Vaccinium myrtillus leaves increased serum glucose levels compared to controls (35508).
In a dietary intervention study involving individuals with impaired glucose metabolism, decreased glucose
concentration and glucose area under the curve were observed following the coadministration of a "healthy
diet" of bilberries, whole grains, and fatty fish (35468). Dietary consumption of whole, frozen bilberries has
also been shown to decrease adiponectin and increase both insulin and glycated hemoglobin (HbA1C) (35463).
Bilberry polyphenols may inhibit intestinal alpha-glucosidase activity and glucose transport in vitro. Phenolic
acids and flavonols with inhibitory activity against intestinal glucose uptake are common polyphenolic
constituents of berries. Thus, both a reduced breakdown of carbohydrates and lowered intestinal absorption
may contribute to the improved glycaemic excursions (91507).
Hypotensive effects: Bilberry has been theorized to potentially drop blood pressure, based on preclinical
evidence of vascular smooth muscle-relaxing properties (35454, 35514, 35515). In human research, a diet rich
in various types of berries demonstrated reductions in systolic blood pressure, particularly in individuals with
an elevated baseline blood pressure (35455).
Immunosuppressant effects: In human research, dietary consumption of fresh bilberries decreased expression
of CCR2 and MMD transcripts in genes associated with monocyte and macrophage function (35473).
Insulin effects: In healthy humans, a fermented oatmeal drink with 10% added bilberry fruit reduced
postprandial insulin demand in spite of an elevated glucose response (35466).
Intracellular signaling effects: Anthocyanosides have been shown to inhibit cAMP phosphodiesterase, which
is involved in intracellular signal transduction pathways (16629).
Lipid effects: In human research, mixed berry-derived anthocyanins and mixed berry-rich diets have been
shown to increase plasma concentration of high-density lipoprotein (HDL) cholesterol and decrease lowdensity lipoprotein (LDL) cholesterol (35455, 35469). However, other human studies have reported a lack of
effect on lipid metabolism (35473).
Musculoskeletal effects: In individuals with primary fibromyalgia, anthocyanidins derived from various types
of berries including bilberry improved self-reported symptoms of sleep disturbances, investigator-assessed
symptoms of fatigue, and overall health, as assessed by a General Health Questionnaire (GHQ28) (35520).
Ocular effects: Anthocyanosides have been shown to exert direct effects on the retina (35476), including the
alteration of local enzymatic reactions and enhancement of the recovery of rhodopsin (35479). The multiingredient product Mirtogenol™ (combination of Pycnogenol, a French maritime pine bark extract, and
Mirtoselect, a standardized bilberry extract) has been reported to lower intraocular pressure and improve ocular
blood flow (35456). Other combination bilberry supplements have been shown to improve symptoms of
asthenopia (e.g., combination bilberry, docosahexaenoic acid [DHA], eicosapentaenoic acid [EPA], and lutein)
(35470) or positively affect visual acuity and visual field in individuals with dry form age-related macular
degeneration (e.g., Focus) (35471). One retrospective analysis of glaucoma patients demonstrated
improvements in Humphrey Visual Field (HVF) and the minimal angle of resolution logarithm for bestcorrected visual acuity (logMAR BCVA) following bilberry anthocyanin supplementation (35472). Bilberry
seems to improve the amplitude of accommodation and mesopic contrast sensitivity It is possible the
accelerated resynthesis of rhodopsin, modulation of retinal enzyme activity, and improved microcirculation
may play a role in the improvement of visual function (91505).
Renal effects: Administration of a bilberry extract reduces blood urea nitrogen (BUN) and creatinine levels in
experimentally induced kidney damage (16627). Bilberry is thought to reduce liver and kidney damage
through free radical scavenging and reducing lipid peroxidation (16625).
Smooth muscle relaxant effects: Anthocyanoside extracts have been shown to have smooth muscle-relaxing
activity, which may account for their purported effects in one series of women with dysmenorrhea (35512).
Bioflavonoids and extracts of anthocyanosides (such as those present in bilberry) have been shown to relax
vascular smooth muscles in experimental models, possibly via stimulation of prostaglandins (35454, 35514,
35515).
Vasoprotective effects: Flavonoids have been shown in vitro to reduce capillary permeability and fragility.
Anthocyanosides have been studied for their potential protective effect in disorders due to abnormal capillary
fragility (35518, 35521). Preliminary evidence from numerous in vitro and animal studies has suggested that
bilberry extracts may be useful in the prevention of vascular disease (35454, 35475, 35480) and may reduce
platelet aggregation and oxidation of LDL (1264, 35492, 35495, 35501, 35522). In an animal experiment
looking at ischemia-reperfusion injury in hamster cheek microcirculation, bilberry anthocyanoside (VMA)
extract was shown to reduce microvascular impairment after reperfusion (35488). In another animal study,
VMA extract was shown to reduce vascular permeability in the setting of hypertension (35475). Decreases in
lipid deposition and intimal proliferation have also been demonstrated in VMA-treated animals (35483).
Pharmacokinetics
There are limited data regarding the pharmacodynamics and kinetics of Vaccinium myrtillus (bilberry)
anthocyanosides (VMA).
Bioavailability: Bioavailability in animals is low. Following oral doses in rats, plasma levels of VMA reached
a peak at 15 minutes and declined rapidly within two hours, and the absolute bioavailability was 1.2% of the
administered dose (35461). The gastrointestinal absorption of VMA was 5% of the administered dose. After
administration of a specific bilberry extract (Bilberon 25, Tokiwa Phytochemical Co.) containing 15 different
anthocyanidinsBioavailability for the anthocyanidins ranged from 0.61% to 1.82%. For all anthocyanidins
combined, bioavailability was 0.93% (16624).
Distribution: In one animal study, bilberry anthocyanosides were rapidly distributed after intraperitoneal
injection and intravenous administration (35461). Another study found a differential affinity of VMA for
certain tissues (especially skin and kidney) (35494). This suggests that different tissues may have more
persistent local concentrations.
Elimination: In an animal study, bilberry anthocyanosides were found to be eliminated via the bile and urine
with a modest level of liver extraction (8141)