Phytochemical info of Ginkgo extract.Ginkgo Biloba extract.:
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Definition:Flavonoids from Ginkgo extract.Ginkgo Biloba extract are majorly composed of .
Chemical information disclosed as following table:
Ginkgo Biloba,Ginkgo Biloba Extract Research and case study:
Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.:World J Gastroenterol. 2004; 10(4):560-6 (ISSN: 1007-9327)
AIM: To investigate the effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.
METHODS: Sprague-Dawley rats were randomly divided into four groups: sham operation without ginkgo, sham operation with ginkgo, duodenal ulcer without ginkgo, and duodenal ulcer with ginkgo. Rats with duodenal ulcer were induced by 500 mL/L acetic acid. Rats with ginkgo were intravenously injected with Ginkgo biloba extract from the tail at a dose of 0.5 mg/(kg/d) for 7 and 14 days.
RESULTS: Pathological result showed that duodenal ulcer rats with ginkgo improved mucosal healing and inflammation compared with those without ginkgo after 7 d treatment. After 14 d treatment, duodenal ulcer rats with ginkgo significantly increased weight gain (34.0+/-4.5 g versus 24.5+/-9.5 g, P<0.05) compared with those without ginkgo. Duodenal ulcer rats significantly increased cell proliferation (27.4+/-4.0 and 27.8+/-2.3 BrdU-labeled cells in duodenal ulcer rats with and without ginkgo versus 22.4+/-3.5 and 20.8+/-0.5 BrdU-labeled cells in sham operation rats with and without ginkgo, P<0.05) compared with sham operation rats. Mucosal prostaglandin E(2) concentration significantly increased by 129% (P<0.05) in duodenal ulcer rats with ginkgo compared with that in those without ginkgo. Duodenal ulcer rats without ginkgo significantly decreased superoxide dismutase activity in the duodenal mucosa and erythrocytes (19.4+/-6.7 U/mg protein versus 38.1+/-18.9 U/mg protein in the duodenal mucosa, and 4.87+/-1.49 U/mg protein versus 7.78+/-2.16 U/mg protein in erythrocytes, P<0.05) compared with sham operation rats without ginkgo. However, duodenal ulcer rats with ginkgo significantly increased erythrocyte superoxide dismutase activity (8.22+/-1.92 U/mg protein versus 4.87+/-1.49 U/mg protein, P<0.05) compared with those without ginkgo. Duodenal ulcer rats without ginkgo significantly increased plasma lipid peroxides (4.18+/-1.12 micromol/mL versus 1.60+/-1.10 micromol/mL and 1.80+/-0.73 micromol/mL, P<0.05) compared with sham operation rats without ginkgo and duodenal ulcer rats with ginkgo during the experimental period.
CONCLUSION: Ginkgo biloba extract can improve weight gain and mucosal healing in duodenal ulcer rats by the actions of cytoprotection and antioxidation.
Effects of Ginkgo biloba on exhaled nasal nitric oxide during normobaric hypoxia in humans.:High Alt Med Biol. 2004; 5(4):445-9 (ISSN: 1527-0297)Jowers C; Shih R; James J; Deloughery TG; Holden WE.Oregon Health and Sciences University, Portland, OR, USA.
Ginkgo biloba, an extract of the ginkgo tree, may prevent or lessen symptoms of acute mountain sickness in humans. The mechanism of this effect is poorly understood. One hypothesis is that ginkgo alters nitric oxide (NO) metabolism, possibly by scavenging NO or altering nitric oxide synthase expression and thereby lessening the vasodilatory effects of NO. To date, an effect of Ginkgo biloba on NO metabolism has not been demonstrated in humans. We measured exhaled nasal NO output in humans (n = 9) during normoxia and then during acute normobaric hypoxia (goal oxyhemoglobin saturation 75% to 85%) before and after administration of a standardized extract of Ginkgo biloba (120 mg twice daily for 5 days). Oxygen saturation, heart rate, and minute ventilation were similar before and after Ginkgo biloba administration. Exhaled nasal NO output was increased during normoxia following ginkgo (p < 0.02) and reduced during normobaric hypoxia both before (p < 0.02) and following (p < 0.003) ginkgo. Exhaled nasal NO output during normobaric hypoxia was lowest following ginkgo (p < 0.003). We conclude that Ginkgo biloba increases exhaled nasal NO output during normoxia and enhances reduced exhaled nasal NO output during normobaric hypoxia. Our results suggest that Ginkgo biloba may act to reduce AMS through an effect on NO metabolism.
Effect of Ginkgo biloba extract on memory deficits in radial maze performance induced by some drugs in rats.:
Ginkgo biloba extract is widely used as a herbal medicine or dietary supplement in Europe, since Ginkgo biloba extract is effective in facilitation of learning and recollection of memories. However, little is known about the mechanism of the action of Ginkgo biloba extract on learning and memory enhancements. On the other hand, it is well known that cholinergic, histaminergic and glutamatergic systems play a crucial role in learning and memory in animals. Therefore, in order to elucidate the mechanism of Ginkgo biloba extract on memory, we studied and clarified the effect of Ginkgo biloba extract on spatial memory deficits induced by scopolamine, diphenhydramine or MK-801 using eight-arm radial maze performance. It was found that Ginkgo biloba extract improved the spatial memory deficits induced by scopolamine. Ginkgo biloba extract also caused repair to spatial memory deficits induced by diphenhydramine. On the other hand, no significant effect was observed with MK-801-induced spatial memory deficits. These findings suggest that the effect of Ginkgo biloba extract is mediated not only by the cholinergic system but also by the histaminergic system to induce learning and memory enhancements.
Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.:Arch Intern Med. 2005; 165(3):296-301 (ISSN: 0003-9926).Chow T; Browne V; Heileson HL; Wallace D; Anholm J; Green SM.Department of Emergency Medicine, Loma Linda University Medical Center and Children's Hospital, Loma Linda, CA 92354, USA. Drtkchow@aol.com
BACKGROUND: Acute mountain sickness (AMS) commonly occurs when unacclimatized individuals ascend to altitudes above 2000 m. Acetazolamide and Ginkgo biloba have both been recommended for AMS prophylaxis; however, there is conflicting evidence regarding the efficacy of Ginkgo biloba use. We performed a randomized, placebo-controlled trial of acetazolamide vs Ginkgo biloba for AMS prophylaxis. METHODS: We randomized unacclimatized adults to receive acetazolamide, Ginkgo biloba, or placebo in double-blind fashion and took them to an elevation of 3800 m for 24 hours. We graded AMS symptoms using the Lake Louise Acute Mountain Sickness Scoring System (LLS) and compared the incidence of AMS (defined as LLS score > or =3 and headache). RESULTS: Fifty-seven subjects completed the trial (20 received acetazolamide; 17, Ginkgo biloba, and 20, placebo). The LLS scores were significantly different between groups; the median score of the acetazolamide group was significantly lower than that of the placebo group (P=.01; effect size, 2; and 95% confidence interval [CI], 0 to 3), unlike that of the Ginkgo biloba group (P=.89; effect size, 0; and 95% CI, -2 to 2). Acute mountain sickness occurred less frequently in the acetazolamide group than in the placebo group (effect size, 30%; 95% CI, 61% to -15%), and the frequency of occurrence was similar between the Ginkgo biloba group and the placebo group (effect size, -5%; 95% CI, -37% to 28%). CONCLUSIONS: In this study, prophylactic acetazolamide therapy decreased the symptoms of AMS and trended toward reducing its incidence. We found no evidence of similar efficacy for Ginkgo biloba.
EST analysis in Ginkgo biloba: an assessment of conserved developmental regulators and gymnosperm specific genes.:
BMC Genomics. 2005; 6:143 (ISSN: 1471-2164)Brenner ED; Katari MS; Stevenson DW; Rudd SA; Douglas AW; Moss WN; Twigg RW; Runko SJ; Stellari GM; McCombie WR; Coruzzi GM.The New York Botanical Garden, 200th St. and Kazimiroff, Bronx, NY 10458-5126, USA. ebrenner@nybg.org
BACKGROUND: Ginkgo biloba L. is the only surviving member of one of the oldest living seed plant groups with medicinal, spiritual and horticultural importance worldwide. As an evolutionary relic, it displays many characters found in the early, extinct seed plants and extant cycads. To establish a molecular base to understand the evolution of seeds and pollen, we created a cDNA library and EST dataset from the reproductive structures of male (microsporangiate), female (megasporangiate), and vegetative organs (leaves) of Ginkgo biloba.
RESULTS: RNA from newly emerged male and female reproductive organs and immature leaves was used to create three distinct cDNA libraries from which 6,434 ESTs were generated. These 6,434 ESTs from Ginkgo biloba were clustered into 3,830 unigenes. A comparison of our Ginkgo unigene set against the fully annotated genomes of rice and Arabidopsis, and all available ESTs in Genbank revealed that 256 Ginkgo unigenes match only genes among the gymnosperms and non-seed plants--many with multiple matches to genes in non-angiosperm plants. Conversely, another group of unigenes in Gingko had highly significant homology to transcription factors in angiosperms involved in development, including MADS box genes as well as post-transcriptional regulators. Several of the conserved developmental genes found in Ginkgo had top BLAST homology to cycad genes. We also note here the presence of ESTs in G. biloba similar to genes that to date have only been found in gymnosperms and an additional 22 Ginkgo genes common only to genes from cycads.
CONCLUSION: Our analysis of an EST dataset from G. biloba revealed genes potentially unique to gymnosperms. Many of these genes showed homology to fully sequenced clones from our cycad EST dataset found in common only with gymnosperms. Other Ginkgo ESTs are similar to developmental regulators in higher plants. This work sets the stage for future studies on Ginkgo to better understand seed and pollen evolution, and to resolve the ambiguous phylogenetic relationship of G. biloba among the gymnosperms.
Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study.:Eur J Neurol. 2006; 13(9):981-5 (ISSN: 1468-1331).Mazza M; Capuano A; Bria P; Mazza S.Department of Psychiatry, Catholic University of Sacred Heart, Rome, Italy. mariannamazza@hotmail.com
The Ginkgo biloba special extract EGb 761 seems to produce neuroprotective effects in neurodegenerative diseases of multifactorial origin. There is still debate about the efficacy of Ginkgo biloba special extract EGb 761 compared with second-generation cholinesterase inhibitors in the treatment of mild to moderate Alzheimer's dementia. Our aim is to assess the efficacy of the Ginkgo biloba special extract E.S. in patients with dementia of the Alzheimer type in slowing down the disease's degenerative progression and the patients' cognitive impairment compared with donepezil and placebo. The trial was designed as a 24-week randomized, placebo-controlled, double-blind study. Patients aged 50-80 years, suffering from mild to moderate dementia, were allocated into one of the three treatments: Ginkgo biloba (160 mg daily dose), donepezil (5 mg daily dose), or placebo group. The degree of severity of dementia was assessed by the Syndrom Kurz test and the Mini-Mental State Examination. Clinical Global Impression score was recorded to assess the change in the patients' conditions and the therapeutic efficacy of tested medications. Our results confirm the clinical efficacy of Ginkgo biloba E.S. (Flavogin) in the dementia of the Alzheimer type, comparable with donepezil clinical efficacy. There are few published trials that have directly compared a cholinesterase inhibitor with Ginkgo for dementia. This study directly compares a cholinesterase inhibitor with Ginkgo biloba for dementia of the Alzheimer type and could be a valid contribution in this debate. Our study suggests that there is no evidence of relevant differences in the efficacy of EGb 761 and donepezil in the treatment of mild to moderate Alzheimer's dementia, so the use of both substances can be justified. In addition, this study contributes to establish the efficacy and tolerability of the Ginkgo biloba special extract E.S. in the dementia of the Alzheimer type with special respect to moderately severe stages.
Ginkgo biloba use in nursing home elderly with epilepsy or seizure disorder.:
Epilepsia. 2006; 47(2):323-9 (ISSN: 0013-9580).Harms SL; Garrard J; Schwinghammer P; Eberly LE; Chang Y; Leppik IE.Division of Health Services Research and Policy, School of Public Health, 420 Delaware Street SE, MMC 729, Minneapolis, MN 55455, U.S.A. harms010@tc.umn.edu
PURPOSE: Ginkgo biloba, among the most widely used herbs, possesses the capacity both to induce and to inhibit seizures. The purpose of this study was to describe the prevalence of ginkgo and other common herb prescribing in a sample of nursing home (NH) elderly diagnosed with epilepsy/seizure (Epi/Sz) disorder and to determine demographic, clinical, and functional factors associated with ginkgo use. METHODS: This was a 1-year prevalence study of 68,403 NH residents living in 557 nursing facilities throughout the United States. RESULTS: Overall, herb use in the NHs was very low (0.41%). Ginkgo was prescribed 162 times, more than any other herb. St. John's wort was prescribed 40 times; garlic, 29 times; and all others, <20 times, for a total of 307 herb orders. Among all residents with an herb order, ginkgo was prescribed for 61.9% of residents with an Epi/Sz diagnosis and 58.0% (p = 0.820) of residents without an Epi/Sz diagnosis. Dementia, educational level, and the interaction of age group with cognitive impairment were all significantly associated with herb use among Epi/Sz residents. Cognitive impairment and the interaction of Epi/Sz disorder with dementia were associated specifically with ginkgo use.
CONCLUSIONS: Ginkgo is the most frequently prescribed herb in this population in which >50% of all herb orders were written for ginkgo. The concern with ginkgo use among elderly with Epi/Sz is the lack of standardization that characterizes ginkgo products. In the absence of standardization, the likelihood is increased that ginkgo products may be adulterated with the Ginkgo biloba plant parts most commonly associated with seizure provocation.
Ginkgo biloba for acute ischaemic stroke.:Cochrane Database Syst Rev. 2005; (4):CD003691 (ISSN: 1469-493X).Zeng X; Liu M; Yang Y; Li Y; Asplund K.Sichuan Provincial Hospital, Department of Neurology, Chengdu, China 610072. zxrma@hotmail.com
BACKGROUND: Ginkgo biloba extract is widely used in the treatment of acute ischaemic stroke in China. We aimed to assess the evidence from randomised controlled trials and quasi-randomised controlled trials on the use of Ginkgo biloba extract in acute ischaemic stroke.
OBJECTIVES: The primary objective was to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischaemic stroke. Secondary objectives were to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials Register of the Cochrane Complementary Medicine Field (last searched October 2004) and the Chinese Stroke Trials Register (last searched June 2004). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED (1985 to May 2002) and the China Biological Medicine Database (CBM-disc, 1979 to August 2004). We searched relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies.
SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled clinical trials comparing Ginkgo biloba extract with placebo or open control (no placebo) in patients with acute ischaemic stroke.
DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. MAIN RESULTS: Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials follow up was performed at 14 to 35 days after stroke. In all studies neurological outcome was assessed but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analysing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI) 1.79 to 3.94). One placebo-controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI -8.9 to 10.52). No deaths or major adverse events were reported during the follow-up period.
AUTHORS' CONCLUSIONS: There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomised controlled trials are needed to test its efficacy.
Spontaneous bleeding associated with ginkgo biloba: a case report and systematic review of the literature: a case report and systematic review of the literature.:
J Gen Intern Med. 2005; 20(7):657-61 (ISSN: 1525-1497).Bent S; Goldberg H; Padula A; Avins AL.Osher Center for Integrative Medicine, University of California, San Francisco, USA. bent@itsa.ucsf.edu
BACKGROUND: Ginkgo biloba (ginkgo) is a herbal remedy used by over 2% of the adult population in the United States. Several review articles have suggested that ginkgo may increase the risk of bleeding.
OBJECTIVE: To report a case of bleeding associated with using ginkgo, to systematically review the literature for similar case reports, and to evaluate whether using ginkgo is causally related to bleeding.
DATA SOURCES: We searched MEDLINE, EMBASE, IBIDS, and the Cochrane Collaboration Database from 1966 to October 2004 with no language restrictions.
REVIEW METHODS: Published case reports of bleeding events in persons using ginkgo were selected. Two reviewers independently abstracted a standard set of information to assess whether ginkgo caused the bleeding event.
RESULTS: Fifteen published case reports described a temporal association between using ginkgo and a bleeding event. Most cases involved serious medical conditions, including 8 episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for bleeding. Only 6 reports clearly described that ginkgo was stopped and that bleeding did not recur. Bleeding times, measured in 3 reports, were elevated when patients were taking ginkgo.
CONCLUSION: A structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events. Given the widespread use of this herb and the serious nature of the reported events, further studies are needed. Patients using ginkgo, particularly those with known bleeding risks, should be counseled about a possible increase in bleeding risk.
Effects of Ginkgo biloba extract on blood pressure and vascular endothelial response by acetylcholine in spontaneously hypertensive rats.:
We previously demonstrated that Ginkgo biloba extract (Ginkgo) produced vasodilation via the nitric oxide pathway in aortic segments isolated from Wistar rats. In this study, we have analysed the effects of daily long-term oral Ginkgo treatment on blood pressure, vascular tone, and calcium mobilization to evaluate the clinical availability. Spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were fed either a control diet or a diet containing 0.05%-0.5% Ginkgo for 30 days. Administration of Ginkgo did not change systolic blood pressure in WKY, but significantly decreased systolic blood pressure in SHR. In thoracic aortic preparations isolated from SHR, diminished relaxation in response to acetylcholine was improved by a Ginkgo-containing diet. This diet significantly decreased the EC50 value and significantly increased maximum relaxation in response to acetylcholine in SHR. In aortic segments isolated from WKY, acetylcholine-induced relaxation was not affected by a Ginkgo-containing diet. Sodium nitroprusside-induced relaxation was unchanged by a Ginkgo-containing diet in SHR and WKY. We also examined the effects of a Ginkgo-containing diet on the intracellular calcium level of aortic endothelium using a fluorescent confocal microscopic imaging system. Calcium Green 1/AM preloading indicated that acetylcholine significantly increased the endothelial intracellular calcium level. The Ginkgo-containing diet significantly enhanced this increase in the aortic endothelium of SHR, but did not change that of WKY. The results suggested that Ginkgo enhanced endothelium-dependent vasodilation and elevation of the endothelial intracellular Ca(2+) level in SHR, resulting in hypotension. This accelerative effect of Ginkgo on Ca(2+) mobilization seemed to be associated with restoration of impaired dilatory function induced by acetylcholine in endothelial cells.
Effects of the flavonoid fraction from Ginkgo biloba extract on the postprandial blood glucose elevation in rats.:Yakugaku Zasshi. 2004; 124(9):605-11 (ISSN: 0031-6903)
The present study investigated the effects of Ginkgo biloba extract and its flavonoid fractions on alpha-amylase and alpha-glucosidase activity in vitro. Ginkgo biloba extracts and their flavonoid fraction significantly inhibited alpha-amylase and alpha-glucosidase activity in vitro. Furthermore, Ginkgo biloba extracts and their flavonoid fraction reduced the elevation of rat plasma glucose level after oral administration of various saccharinity agents. In addition, we examined the effects of the flavonoid fraction isolated from Ginkgo biloba extracts on the plasma glucose level in streptozotocin-induced diabetic rats. When flavonoid fractions were orally administered to the rats three times daily for 9 days, plasma glucose concentrations were decreased compared with those in the water treatment group. Furthermore, flavonoid fractions reduced the elevation of rat plasma glucose levels after oral administration of sucrose and glucose in streptozotocin-induced diabetic rats.
Effect of Ginkgo biloba extract on plasma steroid concentrations in healthy volunteers: a pilot study.:Pharmacotherapy. 2005; 25(10):1337-40 (ISSN: 0277-0008).Markowitz JS; DeVane CL; Lewis JG; Chavin KD; Wang JS; Donovan JL.Department of Pharmaceutical Sciences, Medical University of South Carolina, Children's Research Institute, Charleston, South Carolina 29425, USA. markowij@musc.edu
STUDY OBJECTIVE: To determine if a standardized ginkgo supplement significantly alters concentrations of circulating androgenic steroids in humans.
DESIGN: Open-label, fixed-treatment order, crossover study.
SETTING: University general clinical research center. SUBJECTS: Eleven healthy volunteers (six men, five women).
INTERVENTION: Volunteers received ginkgo biloba 240 mg/day for 14 days.
MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of cortisol, 11-deoxycortisol, 17alpha-hydroxyprogesterone, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, sex hormone-binding globulin, androstenedione, and free testosterone, as well as free androgen index and combined concentrations of androsterone sulfate and epiandrosterone sulfate, were analyzed in all subjects before and after their 14-day course of ginkgo biloba. Ginkgo biloba did not significantly alter endogenous steroid levels compared with baseline values (p < 0.05).
CONCLUSION: A 14-day oral administration of a widely used, standardized ginkgo extract at a generally advocated dosage of 240 mg/day did not significantly alter concentrations of major circulating steroids in men and women.
Effect of Ginkgo biloba extract on procarcinogen-bioactivating human CYP1 enzymes: identification of isorhamnetin, kaempferol, and quercetin as potent inhibitors of CYP1B1.:
Toxicol Appl Pharmacol. 2006; 213(1):18-26 (ISSN: 0041-008X).Chang TK; Chen J; Yeung EY.Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. tchang@interchange.ubc.ca
In the present study, we investigated the effect of Ginkgo biloba extracts and some of its individual constituents on the catalytic activity of human cytochrome P450 enzymes CYP1B1, CYP1A1, and CYP1A2. G. biloba extract of known abundance of terpene trilactones and flavonol glycosides inhibited 7-ethoxyresorufin O-dealkylation catalyzed by human recombinant CYP1B1, CYP1A1, and CYP1A2, and human liver microsomes, with apparent Ki values of 2 +/- 0.3, 5 +/- 0.5, 16 +/- 1.4, and 39 +/- 1.2 microg/ml (mean +/- SE), respectively. In each case, the mode of inhibition was of the mixed type. Bilobalide, ginkgolides A, B, C, and J, quercetin 3-O-rutinoside, kaempferol 3-O-rutinoside, and isorhamentin 3-O-rutinoside were not responsible for the inhibition of CYP1 enzymes by G. biloba extract, as determined by experiments with these individual chemicals at the levels present in the extract. In contrast, the aglycones of quercetin, kaempferol, and isorhamentin inhibited CYP1B1, CYP1A1, and CYP1A2. Among the three flavonol aglycones, isorhamentin was the most potent in inhibiting CYP1B1 (apparent Ki = 3 +/- 0.1 nM), whereas quercetin was the least potent in inhibiting CYP1A2 (apparent Ki = 418 +/- 50 nM). The mode of inhibition was competitive, noncompetitive, or mixed, depending on the enzyme and the flavonol. G. biloba extract also reduced benzo[a]pyrene hydroxylation, and the effect was greater with CYP1B1 than with CYP1A1 as the catalyst. Overall, our novel findings indicate that G. biloba extract and the flavonol aglycones isorhamnetin, kaempferol, and quercetin preferentially inhibit the in vitro catalytic activity of human CYP1B1.
Effects of Ginkgo biloba extract on number and activity of endothelial progenitor cells from peripheral blood.:J Cardiovasc Pharmacol. 2004; 43(3):347-52 (ISSN: 0160-2446)
The aim of this study is to investigate whether Ginkgo biloba extract can augment endothelial progenitor cells numbers, and promote the cells' proliferative, migratory, adhesive, and in vitro vasculogenesis capacity. Total mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture dishes. After 7 days culture, attached cells were stimulated with Ginkgo biloba extract (to make a series of final concentrations: 10 mg/L, 25 mg/L, and 50 mg/L) or vehicle control for the respective time points (6 hours, 12 hours, 24 hours, and 48 h). Endothelial progenitor cells were characterized as adherent cells double positive for DiLDL-uptake and lectin binding by direct fluorescent staining under a laser scanning confocal microscope. They were further documented by demonstrating the expression of KDR, VEGFR-2, and AC133 with flow cytometry. Endothelial progenitor cells proliferation, migration, and in vitro vasculogenesis activity were assayed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, modified Boyden chamber assay, and in vitro vasculogenesis kit, respectively. Endothelial progenitor cells adhesion assay was performed by replating those on fibronectin-coated dishes, and then counting adherent cells. Incubation of isolated human mononuclear cells with Ginkgo biloba extract dose- and time-dependently increased the number of endothelial progenitor cells, maximum at 25 mg/L, 24 hours (approximately 1-fold increase, P < 0.01). In addition, Ginkgo biloba extract also dose- and time-dependently promoted endothelial progenitor cells proliferative, migratory, adhesive, and in vitro vasculogenesis capacity. The results of the present study defined a novel functional effect of Ginkgo biloba extract: the augmentation of endothelial progenitor cells with enhanced functional activity.
Ginkgo biloba for acute ischaemic stroke.:
Background:Ginkgo biloba extract is widely used in the treatment of acute ischaemic stroke in China. We aimed to assess the evidence from randomised controlled trials and quasi 每 randomised controlled trials on the use of Ginkgo biloba extract in acute ischaemic stroke.
Objectives:The primary objective was to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischaemic stroke. Secondary objectives were to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life.
Search strategy:We searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials Register of the Cochrane Complementary Medicine Field (last searched October 2004) and the Chinese Stroke Trials Register (last searched June 2004). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) ( Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED (1985 to May 2002) and the China Biological Medicine Database (CBM 每 disc, 1979 to August 2004). We searched relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies.
Selection criteria:Randomised controlled trials or quasi 每 randomised controlled clinical trials comparing Ginkgo biloba extract with placebo or open control (no placebo) in patients with acute ischaemic stroke.
Data collection and analysis:Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data.
Main results:Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials follow up was performed at 14 to 35 days after stroke. In all studies neurological outcome was assessed but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analysing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI) 1.79 to 3.94). One placebo 每 controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI 每 8.9 to 10.52). No deaths or major adverse events were reported during the follow 每 up period.
Authors' conclusions:There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High 每 quality and large 每 scale randomised controlled trials are needed to test its efficacy.
Cochrane Rev Abstract. 2006
Ginkgo biloba for tinnitus.:M Hilton
Background:Tinnitus can be described as the perception of sound in the absence of external acoustic stimulation. At present no specific therapy for tinnitus is acknowledged to be satisfactory in all patients. There are a number of reports in the literature suggesting that Ginkgo biloba may be effective in the management of tinnitus. However, there also appears to be a strong placebo effect in tinnitus management.
Objectives:To assess the effect of Ginkgo biloba in patients who are troubled by tinnitus.
Search strategy:The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4 2003), MEDLINE (1966 每 2003), EMBASE (1974 每 2003), and reference lists of identified publications. Date of the most recent search was December 2003.
Selection criteria:Adults (18 years and over) complaining of tinnitus. Adults with a primary complaint of cerebral insufficiency where tinnitus forms part of the syndrome.
Data collection and analysis:Both reviewers independently extracted data and assessed trials for quality.
Main results:Twelve trials were identified from the search as being relevant to the review. Ten trials were excluded on methodological grounds. No trials of tinnitus in cerebral insufficiency reached a satisfactory standard for inclusion in the review. There was no evidence that Ginkgo biloba was effective for the primary complaint of tinnitus. The incidence of side effects was small.
Authors' conclusions:The limited evidence did not demonstrate that Ginkgo biloba was effective for tinnitus which is a primary complaint. There was no reliable evidence to address the question of Ginkgo biloba for tinnitus associated with cerebral insufficiency.
Ginkgo Biloba extract for age ‐ related macular degeneration.:
Background:Ginkgo is used in the treatment of peripheral vascular disease and 'cerebral insufficiency'. It is thought to have several potential mechanisms of action including increased blood flow, platelet activating factor antagonism and prevention of membrane damage caused by free radicals. Vascular factors and oxidative damage are thought to be two potential mechanisms in the pathology of age 每 related macular degeneration (AMD).
Objectives:The objective of this review was to determine the effect of Ginkgo Biloba extract on the progression of AMD.
Search strategy:We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) on (2005, Issue 4), MEDLINE (1966 to January 2006, week 3), EMBASE (1980 to January 2006), SIGLE (1980 to 2005/03), AMED (1985 to January 2006), NRR (2005, Issue 4), reference lists of identified trial reports, and the Science Citation Index. We also contacted investigators of included studies for additional information.
Selection criteria:All randomised trials where Ginkgo Biloba extract had been compared to control in people with AMD were included.
Data collection and analysis:The review author extracted data using a standardised form. The data were verified with the trial investigators. Trial quality was assessed.
Main results:Two published trials were identified. However, these trials were small (20 and 99 participants) and their results could not be pooled because they had different control groups. Adverse effects and quality of life for people with AMD have not been addressed.
Authors' conclusions:The question as to whether people with AMD should take Ginkgo Biloba extract to prevent progression of the disease has not been answered by research to date.
Ginkgo Extract Efficacious for Alzheimer's/Dementia Within 26 Weeks.:
New York (MedscapeWire) Aug 3 〞 New analysis of the breakthrough study published in The Journal of the American Medical Association (JAMA) shows that a patented Ginkgo biloba extract, EGb 761, effectively improves the mental function of patients with Alzheimer's disease and multi-infarct dementia within the first 26 weeks of treatment.
In a double-blind, placebo-controlled, parallel group, multicenter study, changes in the cognitive function, daily living, and social behavior of 309 patients were evaluated using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC). The 26-week results of the intent-to-treat analysis was published in the July/August issue of Dementia and Geriatric Cognitive Disorders.
Study participants receiving 120 mg per day of EGb 761 exhibited clinically relevant improvement in ADAS-Cog and GERRI evaluations, but the placebo group showed significant worsening in these 2 areas of assessment. Regarding safety, no differences between the 2 groups were observed.
Specifically, 26% of the patients in the EGb 761 group achieved at least a 4-point improvement in the ADAS-Cog and 30% improved on the GERRI. The study states: "Comparison of the current results with those reported in a German study testing a higher dose of EGb might suggest that an increased EGb dose would result in an even more favorable treatment effect. After a similar treatment duration...240 mg EGb showed...a higher percentage of improved patients, i.e. 38% of the EGb group reached the highest cutoff point on the cognitive scale versus 26% in the current study."
Study coauthor Dr. Meinhard Kieser commented, "Previous US research comparing [EGb 761] against other extracts, showed that only [EGb 761] increased activity in all areas of the brain. As pointed out in this present publication, researchers attribute the activity spectrum of EGb761 to the synergistic effects of multiple constituents of the total extract. Other Ginkgo extracts do not have the same composition as EGb761 and the results of this and other studies cannot be extrapolated to any other Ginkgo extract."
Ginkgo biloba for Dementia: A Systematic Review of Double-Blind, Placebo-Controlled Trials.:from Clinical Drug Investigation [TM]E. Ernst , M.H. Pittler, Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, England
Abstract and Introduction:
Objective: To systematically review the clinical evidence of Ginkgo biloba preparations as a symptomatic treatment for dementia.
Methods: Computerised literature searches were performed to identify all double-blind, randomised, placebo-controlled trials assessing clinical end-points of Ginkgo biloba extract as a treatment for dementia. Databases included Medline, Embase, Biosis and the Cochrane Library. There were no restrictions regarding the language of publication. Data were extracted in a standardised, predefined fashion, independently by both authors.
Results: Nine double-blind, randomised, placebo-controlled trials met the inclusion criteria and were reviewed. These studies are of varying methodological quality. They collectively suggest that Ginkgo biloba extract is more effective for dementia than placebo. However, a number of caveats pertain. Few, generally mild, adverse effects were reported.
Conclusion: These findings are encouraging and warrant independent, large scale confirmatory and comparative trials.
Introduction:
Complementary/alternative therapies (CATs) are used by a considerable number of the general population. In the USA about 40% of the general population have used CATs within the preceding year, while in Germany this figure is about 65%. In orthodox physicians this level of popularity may raise several concerns, particularly questions regarding the efficacy and tolerability of such treatments.
The extract of Ginkgo biloba is an ancient plant remedy and may be of particular interest to neurologists. This extract was reported in the Journal of the American Medical Association to improve symptoms in patients suffering from dementia. Most of the evidence relating to this subject is, however, scattered in less accessible journals and published in languages other than English.
This systematic review is therefore aimed at summarising the evidence from randomised, controlled trials for or against the clinical effectiveness of Ginkgo biloba extract as a symptomatic treatment for dementia.
Methods:
Computerised literature searches were performed to identify all randomised, controlled trials of Ginkgo biloba for dementia. The search strategy included Medline, Embase, Biosis and the Cochrane Library (all from their respective inception to March 1998). The search terms used were ginkgo, gingko, Ginkgo biloba, dementia and Alzheimer. A manual search was performed using the bibliographies of studies located through the computer search and through scanning our own extensive files and books related to the topic. In addition, manufacturers of Ginkgo biloba preparations were asked to contribute published and unpublished material.
Only double-blind, randomised, placebo-controlled trials on human patients were included in this review. There were no restrictions regarding the language of publication. Only trials of Ginkgo biloba extract for dementia (Alzheimer type, multi-infarct dementia or mixed types) were included. Studies performed on 'cerebral insufficiency' were excluded. Trial outcomes, methodological details and quality of each trial were assessed in a predefined fashion. This was done independently by the two reviewers using a standard scoring system (table I).
The authors met to agree consensus on the assessed data. The initial plan to perform a meta-analysis was abandoned as it became obvious that the available data were too heterogeneous for statistical pooling.
Results:
Eighteen double-blind, randomised, placebo-controlled trials were identified. Nine studies were excluded from this investigation, eight because patients with cerebral insufficiency were assessed and one because it assessed patients with cerebro-organic syndrome.Nine studies met all of the aforementioned inclusion/exclusion criteria and were reviewed. Four studies scored the maximum of 5 points on the Jadad scale assessing methodological quality, while all studies scored at least 3 points (table II). Key data of all trials are presented in table III.
Intervention of 6 Months and Longer:
The most recent trial is also the largest in the dataset and originates from the USA. 327 patients were randomised to receive either oral Ginkgo biloba extract or placebo, but only 137 patients completed the trial. 50% of the patients in the Ginkgo biloba group and 38% in the placebo group finished the 52-week treatment period per protocol. Assessments were performed at baseline and at 2, 12, 26 and 52 weeks. The intention-to-treat analysis implied significant advantages for Ginkgo biloba extract over placebo in two of the rating scales. However, clinicians were unable to detect differences between Ginkgo and placebo by means of global rating of clinical symptoms.
Alzheimer patients seemed to benefit slightly more than multi-infarct dementia patients. The results also suggested that the effect size was independent of age or severity of symptoms at baseline. Five serious adverse effects, including three deaths (one in the placebo group, two in the Ginkgo group) were reported during the treatment phase. They were not found to be causally related to the administration of Ginkgo biloba extract. When only causally related adverse effects were considered, 16 and 12% of the patients attributed adverse effects to Ginkgo biloba extract or placebo, respectively. Kanowski et al. included 222 patients aged 55 years or older in a multicentre trial, of which 156 finished the trial. During a 4-week run-in phase all patients received placebo. Therapeutic success was assessed by three validated rating scales. The per protocol and intention-to-treat analyses both favoured the active medication. In particular, there was a significant difference in the number of treatment responders at the end of the treatment (28% for Ginkgo biloba compared with 10% for placebo).
A subgroup analysis according to type of dementia revealed that both patients with Alzheimer and those with multi-infarct dementia responded to the treatment with Ginkgo biloba extract; the response in the Alzheimer subgroup was, however, consistently larger. The study reported no further follow-up after the treatment phase. In total, 122 adverse effects were recorded, seven serious. In the experimental group 63 adverse effects were reported of which five were judged as serious. A causal relationship of Ginkgo biloba medication and serious adverse effects was, according to the authors, ruled out, with the exception of a patient who suffered a suspected acute stroke.
Intervention of Less than 6 Months:
In 1986, Weitbrecht and Jansen randomised 60 patients with a mean age of 72 years into three groups to receive either oral standardised Ginkgo biloba extract, placebo or ergot alkaloid for 12 weeks. Three rating scales served as outcome measures. The results of this early trial suggested no significant differences between the two active treatments in terms of clinical efficacy. Both, however, led to a treatment response that was significantly superior compared with placebo. There was no follow-up and no mention of adverse effects.
Hartmann and Frick randomised 52 outpatients with mild vascular dementia to receive either 150mg oral Ginkgo biloba extract or placebo daily for 3 months. The diagnosis was supported by computed tomographic (CT) images in each case. Patients who had received prior treatment with nootropic or psychopharmacological drugs were excluded. Therapeutic success was evaluated by physician-rated symptom score, a memory test and a psychometric test. The results showed a decrease in signs and symptoms in both groups, but no statistically significant intergroup differences. However, a trend favoured Ginkgo biloba extract over placebo.
Halama treated a group of 50 patients with either 150mg oral Ginkgo biloba extract daily or placebo for 12 weeks. All patients were diagnosed with either vascular dementia or Alzheimer's disease. There were eight drop-outs (five in the Ginkgo biloba group). The per protocol analysis showed significant advantages in favour of Ginkgo biloba extract compared with placebo as judged by patient- and doctor-rated symptom scores.
Hofferberth randomised 40 hospitalised patients with Alzheimer's disease. Oral Ginkgo biloba extract 3 x 80mg daily or placebo were given for 12 weeks. The diagnosis was confirmed using dementia rating scales and CT. Patients receiving vasoactive, nootropic or psychopharmacological drugs were excluded. The 'Syndrom Kurz Test', as the predefined primary end-point, showed a significant difference between the two treatment groups at 1, 2 and 3 months after the start of treatment.
Maurer et al. randomised 20 patients with mild to moderate Alzheimer's disease to two groups. A 7-day run-in phase preceded the treatment phase of 240mg of oral Ginkgo biloba extract daily or placebo for a 12-week study period. The diagnostic criteria of the American Psychiatric Association (1987) were used to verify the diagnosis. After randomisation, there was a slight difference in terms of disease severity in disfavour of the Ginkgo biloba group. The results, however, showed an advantage of Ginkgo biloba over placebo. The 'Syndrom Kurz Test' demonstrated an improvement in patients receiving Ginkgo biloba extract and a deterioration in those receiving placebo. This resulted in a significant inter-group difference at the end of the treatment period.
Mancini et al. randomised 80 patients with 'psycho-organic senile dementia of arteriosclerotic origin' to two groups. One group received oral Ginkgo biloba extract while the other group received placebo for 6 weeks. The Sandoz Geriatric Scale served as a primary end-point, and the results showed a significant benefit for the experimental compared with the placebo group.
Haase and colleagues treated 40 patients aged 45 to 87 years with moderate forms of Alzheimer or multi-infarct dementia (stages 4 or 5 according to Reisberg's Global Deterioration Scale) with daily (4 times weekly) infusions of Ginkgo biloba extract. Three validated scales served as primary end-points. After 4 weeks of treatment, patients receiving active medication scored significantly better compared with placebo on all three scales (e.g. 3.6 vs 0.3 points average improvement in the Nuremberg Geriatric Score, respectively). 85% of the patients showed an improvement according to Clinical Global Impressions, while this figure was only 35% in the placebo group. The authors reported that no adverse effects were observed and that tolerability parameters were unaffected by the treatment. This was the only study where Ginkgo biloba extract was not given orally.
Discussion:
Collectively the results generated by these nine randomised, double-blind, placebo-controlled trials are encouraging. The US study is perhaps the most convincing trial, not least because of its large sample size and long treatment period - longer than for most trials of conventional drugs for dementia. Nevertheless, this trial, like all the others, may not convince sceptics. On the global rating the clinicians were unable to distinguish the effects of Ginkgo biloba extract from placebo. This finding relating to the Clinical Global Impression Scale is supported by another trial, while two studies reported significant differences in favour of Ginkgo biloba extract concerning this end-point. Despite these conflicting results, British and German Pharmacopoeias list dementia as one of the indications for Ginkgo biloba extract.
The clinical relevance of the hypothesis that Ginkgo biloba delays the clinical deterioration of patients with dementia is considerable. Based on the study by Le Bars et al.,one can calculate that about seven patients have to take Ginkgo biloba for 1 year for a patient's family member to notice an improvement in the patient's daily living and social behaviour or for one patient of the seven to experience an improvement on the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-Cog) score of 4 points. Four points, in turn, are equivalent to a 6 months' delay in progression of the disease.
However, how can regular intake of Ginkgo biloba exert beneficial effects in patients with dementia? It is conceivable that compensatory mechanisms could be stimulated by the actions of Ginkgo biloba in mild to moderate forms of dementia. The whole plant extract with ginkgolides and bilobalides as its main constituents appear to exert more powerful effects than single sub-fractions. In various test models Ginkgo biloba has shown anti-ischaemic, anti-oedemic, anti-hypoxic, radical-scavenging and metabolic actions. In addition, it increases disturbed microcirculatory blood flow by increasing blood fluidity.
Recent in vitro experiments also suggest that Ginkgo biloba is a potent inhibitor of nitric oxide production under tissue-damaging conditions. The relative importance of these actions regarding the clinical effects of Ginkgo biloba in dementia is, however, uncertain at present.
According to the above trial data, Ginkgo biloba extract seems to be well tolerated. The incidence rate of adverse effects was not relevantly different from placebo. In a large postmarketing surveillance study including 10 815 patients with dementia treated with Ginkgo biloba, 183 (1.7%) reported only mild adverse effects.This incidence rate was similar to those observed in comparable circumstances with placebo. However, the size of the samples studied so far may be too small for rare adverse effects to emerge. Two cases of spontaneous bleeding after medication with Ginkgo biloba have been reported. This could be related to the anti-platelet activity of ginkgolides. It needs to be stressed, however, that due to the anecdotal nature of these cases no firm cause-effect relationship could be established. Even if this were possible, such complications would seem to constitute extremely rare events.
The notion that Ginkgo biloba is effective for dementia is indirectly supported by a sizeable amount of clinical trials demonstrating that it alleviates the symptoms of 'cerebral vascular insufficiency', an inadequately defined syndrome that includes some of the symptoms of dementia.These data have recently been reviewed by Dutch and German authors.
The Dutch group found 40 controlled clinical trials of varying rigour, the vast majority of which suggested that Ginkgo biloba extract was effective in treating symptoms such as impaired memory or concentration. Furthermore, there is a body of evidence suggesting that Ginkgo may be effective in mild cases of peripheral vascular disease and some indications that it might benefit critical leg ischaemia. Such evidence may indirectly support the hypothesis that Ginkgo biloba extract benefits vascular diseases by enhancing blood flow.
Despite the good average methodological quality, the above trials are by no means beyond criticism. The inclusion/exclusion criteria varied greatly between studies. In most trials they were ill-defined. Thus it is possible, even likely, that a heterogeneous array of conditions, some not dementia-related, were included. This obviously limits the conclusiveness of the results. Few studies provide sufficient details on the randomisation procedure or report the use of proper power calculations to estimate sample size. Deblinding of studies is a possibility that has not been adequately accounted for. Often the treatment periods were too short to yield ultimately compelling results.
Similarly, the outcome measures used were not generally accepted for dementia. This is particularly true for the early trials, carried out at a time when universally accepted end-points did not exist. The validity and reliability of the clinical end-points is therefore unclear for several of the trials included in this review. The dose of Ginkgo biloba extract varied greatly, and there were no trials aimed at defining the optimal treatment regimen. It has been speculated that the dose used in the study by Le Bars et al. could be increased to yield better clinical outcomes.
Even though statistically significant, the results may not necessarily be clinically meaningful. It is also unclear whether Ginkgo biloba truly delays clinical deterioration, as suggested by most authors, or whether it merely leads to a symptomatic improvement. The above data are not sufficient to be sure. All trials included in this review were sponsored by manufacturers of Ginkgo biloba preparations. It is conceivable that bias may have been introduced by the predominant publication of positive results. The tendency for negative trials to remain unpublished is a recognised phenomenon, and may also be relevant in journals of complementary or alternative medicine, where studies with positive findings may be over-represented.
Conclusion:
In conclusion, the majority of randomised, controlled trials available to date support the notion that Ginkgo biloba is efficacious in delaying the clinical deterioration of patients with dementia or in bringing about symptomatic improvement. Unfortunately, none of the current studies is flawless and ultimately convincing. The tolerability profile of Ginkgo biloba is reassuring. More research is needed to establish the clinical value of Ginkgo biloba for dementia and to answer the multitude of open questions which remain.
Herbals and Vitamin Supplements as Prophylaxis for Stroke and Heart Disease.:
Is there any risk in taking 1500 IU of vitamin E daily, 80 mg of aspirin daily, and 3 tablets of Ginkgo biloba daily? I have a patient who would like to start these drugs as prophylaxis against stroke and heart disease, but is concerned that all 3 drugs can decrease platelet cohesion. She is otherwise well and fit. I do not think there is a risk, but am not sure. Can you advise me?
There has been a lot of interest in vitamin supplementation to reduce atherosclerotic disease ever since the results of several large, prospective, cohort studies were reported. The Nurses' Health Study, in which 87,245 female nurses in the United States were followed for 8 years, and the Health Professionals Study, in which 39,910 male health professionals in the United States were followed, both suggested significantly lower risk for coronary artery disease (CAD) events in supplemental vitamin E users. Otherstudies, such as the Iowa Postmenopausal Women's Study that followed 34,486 women, and large studies from Finland, suggested benefits associated with vitamin E obtained from food sources.[1]
The problem with large, prospective, cohort studies (observational studies) is that these can only suggest a linkage between 2 items; in this case, vitamin E and decreased atherosclerotic disease. However, until an interventional study is conducted, the relationship between 2 items cannot be proven.
The interventional studies (placebo-controlled) specific to vitamin E have met with poor results. Two worth mentioning are the CHAOS study (Cambridge Heart Anti-Oxidant Study, 2002 participants) and the HOPE trial (Heart Outcomes Prevention Evaluation study, 9541 participants). The CHAOS study (400 IU to 800 IU per day) showed strong reduction of nonfatal myocardial infarctions, but a trend toward increased cardiovascular deaths. The HOPE trial was looking primarily for outcomes related to ramipril (Altace), but also included a vitamin E arm (400 IU per day) that showed no significant beneficial effect.[2] If one adds up all the clinical trials conducted with vitamin E (52,000 subjects), the overall results show an insignificant effect on atherosclerotic disease.
In addition, there are the issues of toxicity and bleeding. Large doses of vitamin E have been correlated with bleeding problems -- which should be of particular concern in a patient who is already using aspirin (even 80 mg per day). Ginko has also been cited in 3 case reports of intercerebral bleeding.[3] The current literature would suggest that 400 IU to 800 IU per day of vitamin E would be reasonable and present a minimal risk, although benefits and dosage do not have the scientific support that aspirin has. I would recommend the 400 IU per day dosage in that it minimizes risk and has been most frequently tested.
Ginkgo is a fascinating plant that appears to have real medicinal benefit. It has been shown to be as effective as donepezil (Aricept) to help delay progression of dementia[4] and improve symptoms for claudication.[5] However, I could not find any published information for its use to prevent stroke or heart disease. The real concern with Ginkgo is that there is the real risk of bleeding. I would be particularly careful when using it in conjunction with other "blood thinners" such as aspirin and vitamin E.
Use of Herbal Medicine and Other Dietary Supplements in Community-Dwelling Older People: Baseline Data from the Ginkgo Evaluation of Memory Study.:
Richard L. Nahin, PhD, MPH*; Annette L. Fitzpatrick, PhD?; Jeff D. Williamson, MD, MHS?; Gregory L. Burke, MD, MS?; Steven T. DeKosky, MD∫; Curt Furberg, MD, PhD? for the GEM Study Investigators
Abstract:
Objectives: To analyze baseline data from the Ginkgo Evaluation of Memory (GEM) study, in which information was collected on the use of all dietary supplements.
Design: Cross-sectional regression analysis.
Setting: GEM study sites in California, Maryland, North Carolina, and Pennsylvania.
Participants: The GEM study enrolled 3,072 ambulatory individuals aged 75 and older between September 2000 and June 2002.
Measurements: Self-reported use of dietary supplements and use identified through bottles brought to the clinic.
Results: Respectively, 59.4%, 66.6%, and 27.4% of the GEM study cohort used a multivitamin, at least one individual vitamin or mineral supplement, and some type of nonvitamin onmineral dietary supplement (NVNMDS). In logistic regression models, multivitamin use was associated with female sex, a higher income, a higher modified Mini-Mental State Examination score, difficulty with mobility, and asthma history; use of any other vitamin or mineral was associated with female sex, white race, nonsmoking, more years of schooling, difficulty walking, a history of osteoporosis, and reading health and senior magazines; and NVNMDS use was associated with residing in California, having difficulties with muscle strength, and reading health and senior magazines.
Conclusion: There were substantial differences between individuals who used vitamins and minerals and those who used NVNMDS. These data require that trial investigators pay close attention to participant use of off-protocol dietary supplements. In addition, these findings may help identify elderly individuals likely to combine NVNMDS and prescription drugs.
Introduction:
The purported health benefits and aggressive marketing of herbal products have dramatically increased their use during the last decade.[1-3] Recognition of this trend has prompted increasing concerns about the safety and efficacy of herbal products and other dietary supplements.[4,5] Given that herbal products are usually complex mixtures of multiple active ingredients and that they are not subject to the same regulatory requirements as pharmaceuticals,[6] it is not surprising that little is known about the biological effects of these compounds. Nevertheless, because a substantial portion of the public perceives these products as safe,[7] it is likely that many adverse effects associated with herbal medicine and other dietary supplement use have not been recognized or reported.
Several national surveys of the U.S. populace have reported on the use of nonvitaminonmineral dietary supplements (NVNMDSs), which include herbal medicines, hormones, oils, and cartilage products, in those aged 70 and older.[3,8-10] Prevalence rates from these surveys range from 2.9% for those aged 75 to 84[8] to 11.6% for individuals aged 75 to 79.[10] None of these research reports related NVNMDS use to specific diseases or conditions in older people or examined as comprehensive a list of potential correlates as in the present study.
There are many reasons to confirm and expand these findings in older people. First, older people represent the fastest-growing segment of the population.[11] Second, this population has the highest prevalence of polypharmacy,[12] which reflects their greater prevalence of chronic disease and somatic complaints.[13,14] Third, adverse drug reactions can have a greater effect on the health and functional status of older adults,[15,16] probably as a result of altered drug pharmacokinetics and pharmacodynamics.[16,17] For these reasons, data were analyzed from the Ginkgo Evaluation of Memory (GEM) study cohort,[18] in which information was collected on the use of all medications, including prescription and over-the-counter drugs, herbal preparations, vitamins, and other dietary supplements. The proportion of GEM study participants who used various dietary supplements is described, and whether use of dietary supplements (or particular classes of supplements) was associated with demographic characteristics, health status, health behaviors, or cognitive status is assessed.
Methods:
Study Population:
The GEM study is a double-blind, placebo-controlled, randomized clinical trial evaluating the effectiveness of ginkgo biloba (240 mg/d) in reducing the incidence of dementia〞specifically Alzheimer's disease〞in older adults (≡75).[18] Eligibility requirements for this trial included being free of dementia, being aged 75 and older, having English as one's primary language, and being able to find a proxy to represent and provide parallel evaluation of the participant. Potential participants were excluded if they were taking the anticoagulant warfarin, any antipsychotic medications, or cholinesterase inhibitors. The use of vitamin E or ginkgo biloba was also a potential exclusion; individuals who were unwilling to reduce their vitamin E intake to 400 IU/d and stop taking ginkgo biloba were excluded from the trial. Only 4% of more than 12,000 individuals screen were excluded, because they refused to reduce their use of vitamin E or ginkgo biloba.[18,19] Additional exclusions included having a history of bleeding disorders; having cancer within the past 5 years, congestive heart failure with disability, or untreated depression; being hospitalized for depression in the past year; or having prevalent Parkinson's disease. Recruitment occurred between September 2000 and June 2002 and yielded 3,072 participants who were enrolled at four clinical centers: Johns Hopkins University, University of California at Davis, University of Pittsburgh, and Wake Forest University.[19] All sites obtained approval from their institutional review boards. Informed consent was obtained from GEM study participants and from identified proxies. At baseline, the participants self-identified race as follows: 95% white, 3% black, 1% Asian, and 1% other; 1.2% of study participants reported Hispanic ethnicity. The majority of participants were aged 75 to 79.
Use of Vitamins and Other Dietary Supplements:
Use of vitamins, minerals, and other dietary supplements were assessed using a medications inventory,[20] as well as independently according to self-report in a medical history questionnaire mailed to participants 2 weeks before the baseline visit. The questionnaire asked specifically about use of 11 dietary supplements within the previous 2 weeks (multivitamins; vitamins A, B, C, D, and E; iron; echinacea; ginkgo biloba; ginseng; and St. John's wort) and provided opportunities to list all "other vitamin or mineral supplements" and all "other herbal supplements" used in this same time period. For the baseline visit, participants were instructed to bring in all medications taken in the previous 2 weeks, including prescription and over-the-counter medicines. Instructions to participants specifically asked that all dietary supplements be included. A trained interviewer recorded the name of the drug or supplement, dose, and frequency of use. The interviewer discussed the medications and supplements brought in with the participant and ascertained that all products currently being used (i.e., within previous 2 weeks) by the participant were brought to the clinic.
Dichotomous variables were created to collect information on the use (vs nonuse) of multivitamins, individual vitamins, individual minerals, herbal medicines, and other types of NVNMDSs. The source of information (e.g., self-report, medications brought into the clinic, or both) was retained for comparisons. Data were grouped into three major categories for analyses: multivitamins, other vitamins/minerals, and NVNMDSs. Use of any vitamin included a participant taking individual supplements of vitamins A, any B (B6, B12, or B-complex formulas), C, D, E, folate, or "eye vitamins" (mixtures of lutein, vitamins A, C, and E). Use of any mineral was defined as use of calcium, magnesium, zinc, iron, potassium, selenium, or "bone formulations" (mixtures of calcium, magnesium, zinc, potassium). Use of NVNMDSs included use of ginseng, garlic, St. John's wort, echinacea, saw palmetto, coenzyme Q10, ginkgo biloba (because before the baseline visit for the GEM study, participants were required to discontinue use of ginkgo biloba, these data were based on self-report only), and glucosamine/chondroitin formulations. One type of "bone formulation" used by only two participants contained glucosamine in addition to vitamins and minerals. These products were counted under vitamins/minerals and NVNMDSs. In total, participants used more than 100 types of NVNMDSs, which included not only herbal medicine, but also oils, cartilage products, and yeast products. Because three or fewer individuals used most of these supplements, analyses of individual NVNMDSs were limited to those previously identified as having a high prevalence in the U.S. population,[11] although data for all NVNMDSs combined are presented in the tables.
Demographic and Other Data:
Demographic data collected at baseline included age, race, sex, and education. Income data were not collected directly from participants but were estimated from the 2000 Census based on median income for the ZIP code in which each participant resided. Also collected was self-reported information on comorbidities and health and social behaviors using questions specific to and appropriate for older adults.[21] Prevalence of the following conditions was calculated: history of myocardial infarction, angina pectoris, stroke, asthma, osteoporosis, hypertension, diabetes mellitus, and cancer in the previous 5 years. Physical function was evaluated using a self-report questionnaire to identify difficulty with specific activities of daily living (ADLs) or instrumental activities of daily living (IADLs).[22] Specific subscores from the ADL questionnaire, including mobility, strength, ability to walk 1 mile, and ability to walk around the home, were also extracted for use in these analyses. Also assessed was the frequency of attending religious services, reading the Bible, participating in social clubs, and reading health or senior magazines; the first three variables are associated with mortality, morbidity or both,[23,24] whereas the last is associated with positive health-seeking behaviors.[25] Body mass index (BMI) was calculated from the baseline anthropometry measurements as (weight (kg)/height (m)2). Vision and hearing problems were assessed based on participants' responses to a series of questions on ability to see or hear with or without correction (e.g., watch television, recognize a person from across a room). Use of tobacco, alcohol, and level of physical activity were assessed according to self-report from the personal history questionnaire. For this study, cognition was evaluated using the Modified Mini-Mental Examination (3MSE) score.[26] Depression was assessed using the Centers for Epidemiologic Studies Depression Scale,[27] and use of any selective serotonin reuptake inhibitor was identified from the medication inventory.
Statistical Analyses:
Descriptive statistics were calculated by comparing the number and percentage of persons using specific and categories of dietary supplements according to age, race, sex, education, and income. Chi-square tests were used to determine group differences. Kappa statistics for specific items were calculated to assess agreement between self-reported use of medications and supplements and documentation using the medication inventory.
Cross-sectional baseline correlates of use of multivitamins, any other vitamins or minerals, and NVNMDSs were determined using logistic regression.
A forward stepwise methodology with criteria of 0.10 for entering each model and 0.05 for exiting was specified. Three specific models were run addressing use of a multivitamin, use of any other vitamin or mineral, and use of any NVNMDS for all participants. Because sex is related to use of all three categories of supplements in the general population,[3,9,28-30] interactions between sex and the other demographic variables in the model were also tested for; no interactions were significant at P>.05. The stepwise procedure evaluates variables in the model for collinearity at each step and adds or removes variables based on the presence of collinearity. Thus, variable collinearity was not present in the final models, with each variable an independent predictor of the dependent variable being investigated. Odds ratios and 95% confidence intervals comparing specific levels of covariates to the reference value were calculated. All statistics were computed using SPSS, version 12.0 (Advanced Statistics, SPSS Inc., Chicago, IL).
Results:
Table 1 presents levels of agreement between self-reported dietary supplement use and use identified through transcription of bottle labels brought to the clinic. The overall kappa for any use of dietary supplements was 0.73. The kappa value for multivitamin use was slightly higher at 0.78, whereas values for use of other vitamins and minerals and NVNMDSs were lower. Kappa values for individual supplements ranged from 0.41 to 0.87. Kappa values did not appear to be associated with a particular group of supplements; good agreement and poor agreement were seen in each category. For instance, the five supplements with the highest kappa values included multivitamins, single vitamins and minerals (vitamins C and E), and NVNMDSs (saw palmetto and St. John's wort). Similarly, single vitamins and minerals and NVNMDSs were also among the five supplements with the worst agreement (vitamin A and D, calcium, magnesium, and glucosamine/chondroitin). NVNMDSs that were specifically queried in the participant medical history (echinacea, ginseng, St. John's wort) tended to have higher kappa values than those identified through the "other, specify" questions (e.g., garlic, glucosamine/chondroitin, lecithin). This did not seem to be the case for vitamins mentioned in the medical history, which had high or low values. The nature of the disagreements varied across supplements, with vitamins generally showing more cases in the "high self-report but low label transcription" category (with the exception of vitamin D), whereas minerals had more cases in the "low self-report but high label transcription" category. NVNMDSs were mixed, with some appearing in each category of disagreement.
Use of Supplements According to Sociodemographic Variable:
At baseline, 59.4% of the GEM study cohort reported current use of a multivitamin, 66.6% reported use of at least one individual vitamin or mineral supplement, and 27.4% reported use of some type of NVNMDS. Table 2 presents the unadjusted prevalence of use of the three categories of dietary supplements stratified by sex, age, race, education, and estimated income. Women were more likely than men to take multivitamins and individual vitamins or minerals but not NVNMDSs. Generally, men and women used the same products, the seven most prevalent products being a multivitamin; vitamins B, C, D, and E; calcium; and glucosamine/chondroitin, although there were some notable differences in the use of individual supplements by sex. Women were more than twice as likely to take calcium and vitamin D. Women were also more likely to use magnesium, whereas men were more likely to take garlic. As expected, no women used saw palmetto, given that its purported application is prostate health.
Although there were no racial differences in the use of multivitamins or overall use of NVNMDSs, whites were more likely to use single vitamins or minerals than nonwhites. In particular, white participants were more likely to use vitamin B, vitamin E, calcium, zinc, ginseng, ginkgo biloba, and glucosamine/chondroitin than nonwhite participants. Although not statistically significant, 2.3% of whites used coenzyme Q10, whereas there was no reported use by nonwhites.
Higher levels of education were associated with greater use of multivitamins and single vitamins and minerals but not with overall NVNMDS use. Individuals with more than 17 years of education were more likely to use vitamins A, C, D, and E, but no differences in education were associated with use of minerals. The use of garlic was inversely related to level of education, with those having less than 12 years of schooling showing the highest use.
The association between income and supplement use was mixed. Those making less than $40,000 or more than $55,000 were more likely to use multivitamins than those making $40,000 to $54,999. Participants with incomes above $55,000 were more likely to use vitamin A and saw palmetto. The use of other individual supplements was not associated with estimated income.
Age was not associated with an appreciable difference in the use of any dietary supplements, with similar distributions for multivitamins, other vitamins or minerals, and NVNMDS supplements seen in the three age groups examined (75每79, 80每84, and ≡85).
Use of Supplements According to Health Status and Health Behaviors:
Table 3 (on-line manuscript only) presents bivariate analyses examining the association between dietary supplement use and variables related to health status and health behaviors. Self-reported health status was not related to use of any of the three dietary supplement categories. Having a history of a specific disease could be associated with greater use (e.g., asthma and osteoporosis for multivitamin use; osteoporosis for specific vitamin or mineral use; stroke and osteoporosis for use of NVNMDS) or less use (e.g., myocardial infarction for multivitamin use; hypertension for specific vitamin or mineral use; diabetes mellitus for use of NVNMDS). Being obese (BMI ≡30.0) was inversely related to multivitamin use or use of specific vitamin or mineral supplements. Having difficulties with mobility was related to less use of a multivitamin but greater use of NVNMDSs. Difficulties in muscle strength and walking were associated with use of specific vitamins and minerals and NVNMDSs. Persons with ADL difficulty were more likely to report using NVNMDS but not vitamins or minerals. Conversely, persons exercising regularly were more likely to report using vitamins or minerals but not NVNMDSs. Higher 3MSE scores and lower depression (Centers for Epidemiologic Studies Depression Scale) scores were associated with using multivitamins. Those who had never smoked were more likely to use single vitamins or minerals than former or current smokers. Participants who attended religious services more than once per week were more likely to use vitamins or minerals than individuals who attended services less frequently, although reading the bible regularly was not associated with the use of vitamins or minerals. Use of alcohol and social club attendance were not associated with any of the dietary supplement categories. The most consistent finding seen across dietary supplement categories was a strong association between reading health or senior magazines and using supplements.
Predictors of Supplement Use:
Table 4 presents adjusted odds ratios with 95% confidence intervals for variables independently associated with the three groups of dietary supplements. Different patterns of associations were found between users of the three groups and the various demographic, health-status, and health-behavior measures investigated. Multivitamin use was associated with female sex, higher income, higher cognition as measured according to the 3MSE score, less difficulty with mobility, and a history of asthma. Use of any other vitamin or mineral was associated with female sex, white race, former smoker, not residing in rural Maryland (Hagerstown and vicinity), more years of schooling, less difficulty walking, a history of osteoporosis, and reading health or senior magazines. Finally, using NVNMDSs was associated with residing in California (Sacramento and vicinity), having greater difficulties with muscle strength, and reading health or senior magazines.
Discussion:
This is the first analysis of associations between a wide spectrum of dietary supplements and a number of health behaviors and lifestyle factors in a large cohort of community-dwelling elderly persons. The GEM study population was more likely to use any type of dietary supplement, as well as specific supplements such as multivitamins; calcium; vitamins A, C, and E;[9,29-31] echinacea; garlic; ginkgo biloba; ginseng; and St. John's wort than participants in earlier national surveys of dietary supplement use.[8-10] In particular, the rate of use of glucosamine/chondroitin by the GEM study cohort was six times the rate reported by 2002 National Health Interview Survey participants age 65 and older.[10]
Even after adjusting for demographic variables, health status, and health access, the profiles of multivitamin, other vitamin and mineral, and NVNMDS users differed in substantial ways. The only common factor was that the use of all three groups was related to degree of self-reported functional impairment, with participants reporting higher functionality more likely to be users of multivitamins and vitamins or minerals. Conversely, participants reporting more impairment were more likely to be NVNMDS users. These data suggest that, as function declines, older adults may seek more alternative forms of medications for improvement. Differences were also apparent between individuals using multivitamins and those using other types of vitamin and mineral supplements, with greater use by women being the only common predictor.
The literature has consistently identified several demographic factors associated with the use of vitamins and minerals, including sex, age, race, education, and income.[9,28-47] Specific positive health behaviors were also associated with vitamin and mineral use: having a healthy BMI or weight, not smoking, moderate or no use of alcohol, and regular physical activity.[9,30,31,33,36,37,40-44] Therefore, it was surprising in this study that sex was the only variable associated with multivitamin use and the use of other vitamins and minerals in the adjusted analysis.
Specific vitamin and mineral use appears more prevalent in individuals with particular diseases or conditions such as cardiovascular disease,[36,39,43] osteoporosis,[36] and cancer[36,39] and less prevalent in other diseases such as diabetes mellitus.[39] Some of these observations were confirmed in the GEM study cohort (i.e., greater use with osteoporosis, less use with diabetes mellitus) but not others (less use with myocardial infarction and hypertension, no association with a history of cancer).
Although the observation of higher vitamin and mineral use in women is consistent with the literature (see above), the lack of association between sex and NVNMDS use contradicts the few previous reports examining this issue.[10,12] In fact, the percentage of men using NVNMDSs in the GEM study cohort is slightly higher than that of women. The higher use of garlic, glucosamine/chondroitin, and saw palmetto in men appears to drive this difference.
The strong association that reading health or senior magazines had with NVNMDS use is intriguing. The media is a primary source through which individuals obtain information about NVNMDS.[44] It may be that what they saw in health or senior magazines influenced participants who used NVNMDSs. Magazines popular among older people often contain articles and advertisements for a variety of dietary supplements, including NVNMDSs used by participants such as garlic, ginkgo biloba, and glucosamine/chondroitin.[45] Unfortunately, these magazines do not provide complete information on the safety and use of these supplements, especially the potential for adverse interactions with prescription drugs.[45]
A number of factors might explain the discrepancies between the associations seen in the current study and those cited in the literature for the use of dietary supplements. First, the previous associations were assessed in much younger cohorts than the GEM study cohort. Second, participants were predominately Caucasian and well educated, had a low rate of current smoking, and had lower prevalence of asthma, cancer, diabetes mellitus, hypertension, myocardial infarction, or stroke than participants in the 2002 National Health Interview Survey, who were representative of the general U.S. population for individuals aged 65 and older.[10] Finally, because participants volunteered to participate in a clinical trial of an herbal medicine, they might have differed in significant ways from the general elderly population in demographic and health factors. The exclusion criteria for the clinical trial also limit generalizability of the results. For instance, 4% of individuals screened for the study were excluded, because they wanted to continue taking ginkgo biloba or high-dose vitamin E.[18,19] It can be hypothesized that these individuals who were committed to ginkgo biloba or vitamin E were more avid users of dietary supplements in general. Their exclusion likely reduced the overall effect of dietary supplements in the analyses. Nevertheless, the data were still able to clearly describe a subpopulation of older people who are high users of dietary supplements.
To the authors' knowledge, this is the first study in elderly persons that has compared data on dietary supplement use collected through an in-person questionnaire with that derived from transcribing the labels of supplement bottles brought to the clinic, and it is the first in any age group to compare data on the use of NVNMDSs using these two complementary methods. Two previous studies[46,47] also compared questionnaire data with label transcription, but their populations were much younger, and data were limited to the use of vitamins and minerals. Nevertheless, the data from the current study are compatible with those from these early studies. All of these studies found, in general, higher correspondence for vitamins than minerals. The current study and one of the earlier studies[47] found higher correspondence for vitamins C and E than vitamins A and D, with B vitamins falling in between. Supplements most commonly packaged as individual ingredients, such as vitamin E and C, might elicit better recall than supplements commonly packaged as mixtures (e.g., vitamin D with calcium, zinc, or magnesium). Some of the differences observed between supplements may be a result of recall bias in that NVNMDSs specifically mentioned in the GEM study medical history questionnaire had, in general, better agreement than those collected through the "other, specify" question. What is clear from all three studies is that use of a single method for collecting data on dietary supplements is inadequate.
The current study had several limitations. As previously mentioned, the GEM study cohort may not be representative of the general population of adults aged 75 and older. Second, participant health status and health behaviors were self-reported. Third, although every effort was made to collect information on all dietary supplements used by GEM study participants, it is still possible that use was underreported. However, the net effect of underreporting would be to reduce observed differences between groups; thus, it is likely that the predictors of dietary supplement use identified would remain in the regression model. Fourth, actual income data were not collected for members of the GEM study cohort; instead participant income was estimated based on the median household income for specific ZIP codes. This compressed the range of incomes in the analysis, making it harder to see differences between the upper and lower income categories, although it was unlikely that there were many participants at either extreme. Fifth, since the primary focus was to identify factors associated with the use of each class of dietary supplement, dichotomous dependent variables were used. By doing so, information on the frequency and dose of use was lost. It is conceivable that heavy users of dietary supplements have different demographic and health behavior than light users. Future analyses will attempt to determine this. Sixth, the number of individuals using some types of NVNMDSs was small (St. John's wort), reducing the power to determine differences between groups and stability of the kappa estimates. Finally, cross-sectional data were used for this analysis. As a result, causal pathways underlying the observed associations between demographic and health variables and lifestyle behaviors and use of dietary supplements cannot be determined with certainty.
The regression models adjusted for a wide range of covariates, allowing the associations between such variables as age, ethnicity, education, and income and the use of dietary supplements to be assessed. The use of both dietary supplement questionnaires and transcription of supplement bottle labels allowed for more complete and accurate data than the use of telephone interviews or mailed questionnaires. This increased confidence that these findings were valid.
Conclusion:
Many adults aged 75 and older use a wide variety of dietary supplements. Given the multitude of ongoing clinical trials enrolling elderly participants, the current data provide a warning that trial investigators should pay close attention to participant use of off-protocol dietary supplements and how such use might affect the drug or supplement under study. The current data also help healthcare providers to identify elderly individuals likely to combine NVNMDSs and drugs and thus avoid potentially harmful interactions.[4,5] Longitudinal analysis of the GEM study cohort will provide important insights into the effects of this polypharmacy on health status, as well as the longitudinal effect of a range of dietary supplements on the health and functional status of community-dwelling older adults.
Author Contributions: Richard L. Nahin, Annette L. Fitzpatrick, and Curt Furberg: study concept and design, analysis and interpretation of data, and preparation of manuscript. Jeff D. Williamson: study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Gregory L. Burke: study concept and design, acquisition of subjects and data, and preparation of manuscript. Steven T. DeKosky: acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript.
Botulinum Toxin, Ginkgo Show Promise for Relieving Diabetic Neuropathy.:By Karla Gale
SAN DIEGO (Reuters Health) Apr 11 - Injections of botulinum toxin type A relieve pain in an animal model of diabetic neuropathy, according to research reported at the American Academy of Neurology's annual meeting in San Diego.
A second presentation at the meeting suggests that a combination of Ginkgo biloba extract and folate is superior to placebo in reducing symptoms of diabetic neuropathy, even though nerve conduction velocities are unaffected.
"We previously showed that botulinum toxin reduces hypersensitivity in a model of surgical neuropathy," Dr. Zdravko Lackovic, from Zagreb University in Croatia, said in an interview with Reuters Health.
His team's current research involved what they considered an animal model that more closely represents diabetic neuropathy, he said. They injected alloxan subcutaneously into rats, and used those that developed blood glucose levels > 15 mmol/L after 5 days. "About 60% of the diabetic rats developed mechanical hyperalgesia," which is similar to diabetic neuropathy, Dr. Lackovic noted.
Five days after they injected the plantar surface of the paw pad of diabetic rats with 5 or 7 U/kg of botulinum toxin, the animals became less sensitive to formalin injection, as demonstrated by reductions in flinches and shaking of the injected paw, compared with diabetic rats treated with saline instead of the toxin.
Mechanical sensitivity was also reduced in the diabetic rats treated with botulinum toxin, an effect that lasted 15 days.
"To our knowledge, this is the first demonstration that a single peripheral injection of botulinum toxin might have a long-lasting antinociceptive effect in diabetic neuropathy," the investigators conclude in their meeting abstract.
For the research reported in the second presentation, Dr. Susanne Koeppen, from the University of Essen in Germany, and her colleagues recruited 60 diabetic patients with polyneuropathy. The subjects were randomly assigned to Ginkgo biloba extract (EGb), folate, both agents, or placebo.
EGb 50 mg and folate 15 mg and placebo were administered by IV for 14 days, then as tablets three times daily for 14 days (EGb, 80 mg and/or folate 4 mg or placebo).
"We found out that all three active treatments were superior to placebo, with the best effect seen with the combination of folate and EGb," Dr. Koeppen told Reuters Health.
"I think it is important to know that even a short treatment period can have an effect on neuropathic symptoms," she added, even though there were no changes in electrophysiologic tests.
Safety and Toxicity of Ginkgo Biloba:
Acute toxicity(LD50):Ginkgo Biloba
LD50: Lethal dose,50 percent kill.Oral.mice.7.73 g/kg (This corresponds to 2.3 g/kg of active ingredients, 1.9 g/kg of flavone glycosides, and 464 mg/kg of terpene lactones).
LD50: Lethal dose,50 percent kill.Intravenous.1.1 g/kg.
Subacute/Subchronic Studies. In rats and mice, orally administered GBE did not produce evidence of organ damage or impairment of hepatic and renal functions when administered over 27 weeks in doses ranging from 100 to 1,600 mg/kg (Salvador, 1995).
Chronic/Carcinogenicity Studies. No 2-year carcinogenicity studies of GBE were identified in the available literature
GBE has been a subject of intense research for 20-30 years. Toxicologic studies are underway at the National Toxicology Program. Previous studies reported in the literature indicate little potential for acute toxicity: oral LD50 in mice of 7.73 g/kg (1.9g/kg of flavone glycosides, 464 mg/kg of terpene glycosides), I.V. LD50 1.1g/kg. Evidence of mutagenicity and carcinogenicity of quercetin and kaempferol at high doses in some animal species are documented. In rats, radiolabled GBE was concentrated in glandular, neuronal, eye tissues; 38% exhaled, 22% excreted in urine, 29% in feces at 72 hours.
Reference:NTP (2004): Ginkgo biloba Extract (GBE), National Toxicology Program, National Institute of Environmental Health Sciences. Accessed: 5/4, http://ntp-server.niehs.nih.gov/cgi/iH_Indexes/ALL_SRCH/iH_ALL_SRCH_Frames.html Reference:Moreau J. P., Eck C. R., McCabe J. and Skinner S. (1986): [Absorption, distribution and elimination of a labelled extract of Ginkgo biloba leaves in the rat]. Presse Med. 15(31): 1458-61 [cited in NTP summary].
Acute toxicity(LD50):Component of Ginkgo Biloba
Quercetin.CAS.117-39-5.:
Acute toxicity(LD50):Quercetin
LD50: Lethal dose,50 percent kill.Oral.Rodent-rat.161 mg/kg.
Details of toxic effects not reported other than lethal dose value.
Reference:RCTOE4 Reviews of Environmental Contamination and Toxicology.(Springer-Verlag New York,Inc.,Service Center,44 Hartz Way,Secaucus,NJ07094)V.98-1987-Volume(issue)/page/year:113,47,1990
LD50: Lethal dose,50 percent kill.Oral.Rodent-mouse.159 mg/kg.
Toxic Effects:
Behavioral:somnolence(general depressed activity).
Behavioral:muscle weakness.
Lungs,Thorax,or Respiration-respiratory depression.
Reference:PSEBAA Proceedings of the Society for Experimental Biology and Medicine.(Academix Press,Inc.,1E.First St.,Duluth,MN55802)V.1-1903/04-Volume(issue)page/year:77,269,1951.
LD50: Lethal dose,50 percent kill.Subcutaneous.Rodent-mouse.97 mg/kg.
Toxic Effects:
Behavioral:muscle weakness.
Behavioral:somnolence (general depressed activity)
Lungs,Thorax,or Respiration-respiratory depression.
Reference:PSEBAA Proceedings of the Society for Experimental Biology and Medicine.(Academix Press,Inc.,1E.First St.,Duluth,MN55802)V.1-1903/04-Volume(issue)page/year:77,269,1951.
LD50: Lethal dose,50 percent kill.Intravenous.Rodent-mouse.18 mg/kg.
Details of toxic effects not reported other than lethal dose value.
Reference:CSLNX*U.S.Army Armament Research & Development Command,Chemical Systems Laboratory,NIOSH Exchange Chemicals.(Aberdeen Proving Ground,MD21010)Volume(issue)page/year:NX#02589.
LD50: Lethal dose,50 percent kill.Intravenous.Rodent-rabbit.100 mg/kg.
Details of toxic effects not reported other than lethal dose value.
Reference:FAONAU FAO Nutrition Meetings Report Series.(Rome,Italy) No.?-57,1948-77.Discontinued.Volume(issue)page/year:46A,18,1969.
Tumorigenic Data.:Quercetin
TDLo-Lowest published toxic dose.Oral.Rodent-rat.33610mg/kg/58W-C.
Toxic Effects:
Tumorigenic:Carcinogenic by RTECS criteria.
Gastrointestinal:tumors.
Kidney,Ureter,Bladder:tumors.
Reference: CNREA8 Cancer Research.(Public Ledger Building,Suit 816,6th & Chestnut Sts.,Philadelphia,PA19106) V.1-1941-Volume(issue)/page/year:40,3468,1980.
TDLo-Lowest published toxic dose.Oral.Rodent-mouse.966 mg/kg/23W-C.
Toxic Effects:
Tumorigenic:equivocal tumorigenic agent by RTECS criteria.
Lungs,Thorax, or Respiration: tumors.
Reference:GANNA2 Gann.Japanese Journal of Cancer Research.V.1-75,1907-84.For publisher information,see JJCREP.Volume(issue)/page/year:72,327,1981.
TD-Toxic dose(other than lowest).Oral.Rodent-rat.38235 mg/kg/58W-C.
Toxic Effects:
Tumorigenic:Carcinogenic by RTECS criteria.
Gastrointestinal:tumors.
Kidney,Ureter,Bladder: tumors.
Reference:CNREA8 Cancer Research.(Public Ledger Building,Suit 816,6th & Chestnut Sts.,Philadelphia,PA19106) V.1-1941-Volume(issue)/page/year:40,3468,1980.
TD-Toxic dose(other than lowest).Oral.Rodent-rat.243 mg/kg/3Y-C.
TD-Toxic dose(other than lowest).Oral.Rodent-rat.487 mg/kg/3Y-C.
Toxic Effects:
Tumorigenic:neoplastic by RTECS criteria.
Liver;tumors.
Reference:PAACA3 Proceedings of the American Association for Cancer Research.(Waverly Press,428 E.Preston St.,Baltimore,MD21202)V.1-1954-Volume(issue)/page/year:25,95,1984.
Reproductive Data.:Quercetin
TDLo-Lowest published toxic dose.Oral.Rodent-rat.20 mg/kg.Sex/Duration:female 6~15 day(s) after conception.
Toxic Effects:
Reproductive: effects on Embryo or Fetus-fetotoxicity (except death,e.g,stunted fetus).
Reference: FCTOD7 Food and chemical Toxicology.(Pergamon Press Inc.,Maxwell House,Fairview Park,Elmsford,NY 10523) V.20-1982-Volume(issue)/page/year:20,75,1982.
Cytogenetic analysis.Rodent-hamster Fibroblast.1 mg/L.
Sister chromatid exchange.Rodent-hamster Fibroblast.5 mg/L.
Reference:PJABDW Proceedings of the Japan Academy,Series B:Physical and Biological Sciences.(Maruzen Co.Ltd.POB 5050,Tokyo International,Tokyo 100-31,JP)V.53-1977-Volume(issue)/page/year:56,443,1980
Mutation test systems-not otherwise specified.Mammal-cattle Cells.not otherwise specified.5 umol/L.
DNA inhibition.Mammal-cattle Cells.not otherwise specified.12 umol/L.
Reference:EXPEAM Experientia.(Birkhaeuser Verlag,POB 133,CH-4010 Basel,Switzerland)V.1-1945-Volume(issue)/page/year:44,882,1988
Kaempferol.CAS.520-18-3.:
Mutagenic Data.:Kaempferol.
Mutation in microorganisms.Bacteria-Salmonella typhimurium.166 nmol/plate.
DNA adduct.Bacteria-Escherichia coli. 100 umol/L.
Micronucleus test.Human Lymphocyte.10 mg/L.
Sister chromatid exchange.Human Lymphocyte.20 mg/L.
Sex chromosome loss and nondisjunction.Human Lymphocyte. 20 mg/L.
Micronucleus test.Intraperitoneal.Rodent-mouse.200 mg/kg.
Cytogenetic analysis.Rodent-hamster Ovary. 25 mg/L.
Sister chromatid exchange.Rodent-hamster Ovary.45 mg/L.
Mutation in mammalian somatic cells.Rodent-hamster Ovary.25 mg/L.
Reference:MUREAV Mutation Research.(Elsevier Science Pub.B.V.,POB 211,1000 AE Amsterdam,Netherlands)V.1-1964-Volume(issue)/page/year: 54,297,1978;89,95,1981;246,205,1991;89,69,1981;113,45,1983.
DNA inhibition.Human Fibroblast. 50 mg/L.
Mutation test systems-not otherwise specified.Human Fibroblast.100 mg/L.
Reference:BCPCA6 Biochemical Pharmacology.(Pergamon Press Inc.,Maxwell House,Fairview Park,Elmsford,NY 10523)V.1-1958-Volume(issue)/page/year:33,3823,1984.
General Info:Kaempferol.
IARC Cancer Review:animal Inadequate Evidence.
IARC Cancer Review: Human No Adequate Data.
IARC Cancer Review: Group 3
Reference:IMSUDL IARC Monographs,Supplement.(WHO Publications Centre USA,49 Sheridan Ave.,Albany,NY 12210)No.1-1979-Volume(issue)/page/year:31,171,1983;7,56,1987
Isorhamnetin.CAS.480-19-3.:
Acute toxicity(LD50): LD50: Lethal dose,50 percent kill.Intravenous.Rodent-rat.11100 mg/kg.
Details of toxic effects not reported other than lethal dose value.
Reference:NIIRDN Drugs in Japan(Ethical Drugs).Volume(issue)/page/year:6,63,1982.
Mutagenic Data.: Mutation in microorganisms.
Test Systems:Bacteria-Salmonella typhimurium. Dose/Period:1 mg/plate.
Reference:JOPHDQ Journal of Pharmacobio-Dynamics.V.1-1978-Volume(issue)/page/year:3,236,1980.
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Scientific References:
1.What is Ginkgo Biloba? What is Ginkgo Biloba Extract or GBE?What is super water soluble ginkgo biloba extract?
2.Research update of Ginkgo Biloba,Ginkgo Biloba Extract or GBE.
Claims & Warning:
Claims: Information this web site presented is meant for Nutritional Benefit and as an educational starting point only, for use in maintenance and promotion good health in cooperation with a common knowledge base reference...Furthermore,it based solely on the traditional and historic use or legend of a given herb from the garden of Adonis. Although every effort has been made to ensure its accurate, please note that some info may be outdated by more recent scientific developments......
Pharmakon Warning: The order of knowledge is not the transparent order of forms and ideas,as one might be tempted retrospectively to interpret it; it is the antidote....(Dissemination,Plato's Pharmacy,II.The Ingredients:Phantasms,Festivals,and Paints;138cf. Jacques Derrida.).
And as it happens,the technique of imitation,along with the production of the simulacrum,has always been in Plato's eyes manifestly magical,thaumaturgical:......and the same things appear bent and straight to those who view them in water and out,or concave and convex,owing to similar errors of vision about colors, and there is obviously every confusion of this sort in our souls.And so scene painting (skiagraphia) in its exploitation of this weakness of four nature falls nothing short of witchcraft (thaumatopoia), and so do jugglery and many other such contrivances.(Republic X,602c-d;cf.also 607c).
seminal trace...Ginkgo extract.Ginkgo Biloba extract.CAS.NO.090045-36-6.Ginkgo Biloba Leaf extract.24/6,Flavone 24% Lactone 6%HPLC.Extract of maidenhair tree; Ginkgo extract; Ginkgo biloba, ext......
Phytochemical info of Ginkgo extract.Ginkgo Biloba extract.:
Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.:World J Gastroenterol. 2004; 10(4):560-6 (ISSN: 1007-9327)
Scientific References:
Claims & Warning:
