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November 2002

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Ginkgo biloba

Ginkgo for memory enhancement: a randomized controlled trial.

CONTEXT: Several over-the-counter treatments are marketed as having the ability to improve memory, attention and related cognitive functions in as little as four weeks. These claims, however, are generally not supported by well-controlled clinical studies. OBJECTIVE: To evaluate whether ginkgo, an over-the-counter agent marketed as enhancing memory, improves memory in elderly adults as measured by objective neuropsychological tests and subjective ratings. DESIGN: Six-week randomized, double-blind, placebo-controlled, parallel-group trial. SETTING AND PARTICIPANTS: Community-dwelling volunteer men (n = 98) and women (n = 132) older than 60 years with Mini-Mental State Examination scores greater than 26 and in generally good health were recruited by a U.S. academic center via newspaper advertisements and enrolled over a 26-month period from July 1996 to September 1998.

INTERVENTION: Participants were randomly assigned to receive ginkgo, 40 mg three times per day (n = 115), or matching placebo (n = 115). MAIN OUTCOME MEASURES: Standardized neuropsychological tests of verbal and nonverbal learning and memory, attention and concentration, naming and expressive language, participant self-report on a memory questionnaire and care giver clinical global impression of change as completed by a companion. RESULTS: Two hundred three participants (88%) completed the protocol. Analysis of the modified intent-to-treat population (all 219 participants returning for evaluation) indicated that there were no significant differences between treatment groups on any outcome measure. Analysis of the fully evaluable population (the 203 who complied with treatment and returned for evaluation) also indicated no significant differences for any outcome measure. CONCLUSIONS: The results of this six-week study indicate that ginkgo did not facilitate performance on standard neuropsychological tests of learning, memory, attention and concentration or naming and verbal fluency in elderly adults without cognitive impairment. The ginkgo group also did not differ from the control group in terms of self-reported memory function or global rating by spouses, friends and relatives. These data suggest that when taken following the manufacturer’s instructions, ginkgo provides no measurable benefit in memory or related cognitive function to adults with healthy cognitive function.

JAMA 2002 Aug 21;288(7):835-40

A placebo-controlled, double-blind, randomized trial of an extract of ginkgo biloba for dementia. North American EGb Study Group.

CONTEXT: EGb 761 is a particular extract of ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior. OBJECTIVE: To assess the efficacy and safety of EGb in Alzheimer’s disease and multi-infarct dementia. DESIGN: A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study. PATIENTS: Mildly to severely demented outpatients with Alzheimer’s disease or multi-infarct dementia, without other significant medical conditions. INTERVENTION: Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every three months with complete outcome evaluation at 12, 26 and 52 weeks. PRIMARY OUTCOME MEASURES: Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative’s Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC). RESULTS: From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGb group had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a four-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events. CONCLUSIONS: EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for six months to one year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.

JAMA 1997 Oct 22-29;278(16):1327-32

Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity.

Antioxidant therapy has been shown to be beneficial in neurological disorders including Alzheimer’s disease and cerebral ischemia. Glutamate-induced cytotoxicity in HT-4 neuronal cells has been previously demonstrated to be due to oxidative stress caused by depletion of cellular glutathione (GSH). The present study demonstrates that a wide variety of antioxidants inhibit glutamate-induced cytotoxicity in HT-4 neuronal cells. Low concentrations of alpha-tocopherol and its analogs were highly effective in protecting neuronal cells against cytotoxicity. Purified flavonoids and herbal extracts of gingko biloba (EGb 761) and French maritime pine bark (Pycnogenol) were also effective. We have previously shown that pro-glutathione agents can spare GSH and protect cells from glutamate insult in a C6 glial cell model. The protective effects of nonthiol-based antioxidants tested in the HT-4 line were not mediated via GSH level modulation. In contrast, protective effects of thiol-based pro-glutathione agents alpha-lipoic acid (LA) and N-acetyl cysteine (NAC) corresponded with a sparing effect on GSH levels in glutamate-treated HT-4 cells. Glutamate-induced cytotoxicity in HT-4 cells is a useful model system for testing compounds or mixtures for antioxidant activity.

Free Radic Res 2000 Feb;32(2):115-24

Mitochondria, oxidative stress and aging.

In the 1980’s, Miquel and Fleming suggested that mitochondria play a key role in cellular aging. Mitochondria, and especially mitochondrial DNA (mtDNA), are major targets of free radical attack. At present, it is well established that mitochondrial deficits accumulate upon aging due to oxidative damage. Thus, oxidative lesions to mtDNA accumulate with age in human and rodent tissues. Furthermore, levels of oxidative damage to mtDNA are several times higher than those of nuclear DNA. Mitochondrial size increases whereas mitochondrial membrane potential decreases with age in brain and liver. Recently, we have shown that treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E or the ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and oxidation of mitochondrial glutathione. Moreover, the extract EGb 761 also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver. Thus, mitochondrial aging may be prevented by antioxidants. Furthermore, late onset administration of certain antioxidants is also able to prevent the impairment in physiological performance, particularly motor co-ordination, that occurs upon aging.

Free Radic Res 2000 Mar;32(3):189-98

Ginkgo biloba inhibits hydrogen peroxide-induced activation of nuclear factor kappa B in vascular endothelial cells.

The present study determined the effects of ginkgo biloba extract (GBE) on the activation of nuclear factor kappa B (NF-kappaB) and the level of hydrogen peroxide (H2O2) in bovine pulmonary artery endothelial cells (PAEC). H2O2 showed a concentration-dependent activation of NF-kappaB. GBE demonstrated a concentration-dependent suppression of NF-kappaB activated by H2O2. GBE directly scavenged H2O2 in a cell-free system; it also decreased H2O2 levels in PAEC. These results suggest that the inhibitory effect of GBE on H2O2-induced NF-kappaB activation may be caused by its scavenging and suppression of H2O2. Our experiments demonstrate that GBE can inhibit NF-kappaB activation induced by H2O2 and may thus be effective for the prevention or treatment of atherosclerosis and other disorders related to NF-kappaB activation.

Gen Pharmacol 1999 Nov;33(5):369-75

Vitamin K

Inhibition of human platelet aggregation by vitamin K.

The effect of several vitamin K (Vit K) analogues on the aggregation of human platelets was examined. The analogues were potent inhibitors of aggregation induced by ADP, thrombin, collagen and arachidonate but were less active against aggregation induced by the calcium ionophore A23187. Vit K3 also prevented platelet membrane phosphatide breakdown induced by collagen. These effects were not due to a direct inhibition of enzymes involved in the liberation of arachidonate or its subsequent transformation. The analogues exerted no effects on enzymes regulating intraplatelet cAMP. However, these effects could be overcome by increasing extracellular Ca++ levels, indicating a possible interaction with Ca++ regulation in platelets.

Thromb Res 1985 Jan 1;37(1):103-14

Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver.

OBJECTIVE: Bone loss frequently appears in the natural history of liver disease. The effects of therapy for osteoporosis associated with cirrhosis of the liver are still controversial. We evaluated the effects of vitamin K2 on osteopenia in women with cirrhosis. METHODS: The subjects were 50 women with cirrhosis who had underlying hepatitis viral infections. Half of the patients were randomly assigned to receive vitamin K2 (menatetrenone). The bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry at entry and at 1-yr intervals for 2 yr. RESULTS: The percentages of change from the initial BMD at 1 and 2 yr after initiation of the study were, respectively, +0.1 +/- 2.6% and -0.5 +/- 3.5% for the vitamin K2-treated group and -2.2 +/- 2.4% and -4.6 +/- 3.9% for the control group. The changes in BMD at each timepoint differed significantly between the control and treated groups (p = 0.008 for 1 yr and p = 0.002 for 2 yr). In the vitamin K2-treated group, the ratio of osteocalcin to undercarboxylated osteocalcin in those patients with increases in BMD after 1 yr of treatment was significantly lower than that in patients showing decreases in BMD (p = 0.017). No adverse effects of vitamin K2 were noted. CONCLUSIONS: Vitamin K2 can prevent bone loss and may therefore be useful in the management of bone disease in women with cirrhosis of the liver.

Am J Gastroenterol 2002 Apr;97(4):978-81

Effects of vitamin K(2) on bone of ovariectomized rats and on a rat osteoblastic cell line.

The effects of vitamin K(2) on bone mineral density (BMD) and bone metabolic markers of ovariectomized rats, and those on mRNA expression of osteocalcin and IL-6 on a rat osteoblastic cell line, were investigated. BMD and bone metabolic markers were examined in ovariectomized rats after 2 months’ treatment with vitamin K(2), and mRNA expression of osteocalcin and IL-6 were measured in the cell line after 24-hour treatment with vitamin K(2). Vitamin K(2) attenuated the decline in BMD after ovariectomy in the rats, and suppressed serum deoxypyridinoline levels of the ovariectomized rats. No effect on osteocalcin and IL-6 mRNA expression on the cell line was observed. In conclusion, vitamin K(2) has a bone-protective effect on ovariectomized rats.

Gynecol Obstet Invest 2002;53(3):144-8

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