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This page was exported from The Apothecarium [ http://www.thewellbeingfarmacy.com.au ] Export date: Thu Aug 10 3:01:17 2017 / +0000 GMT 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 Mirtogenolâ„¢ (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)