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October 22, 1997, Vol 278, No. 16 >
ARTICLE | October 22, 1997

A Placebo-Controlled, Double-blind, Randomized Trial of an Extract of Ginkgo Biloba for Dementia FREE

Pierre L. Le Bars, MD, PhD; Martin M. Katz, PhD; Nancy Berman, PhD; Turan M. Itil, MD; Alfred M. Freedman, MD; Alan F. Schatzberg, MD
[+] Author Affiliations

Reprints: Pierre L. Le Bars, MD, PhD, New York Institute for Medical Research, 150 White Plains Rd, Tarrytown, NY 10591 (e-mail: NYI@HZI.com).


JAMA. 1997;278(16):1327-1332. doi:10.1001/jama.1997.03550160047037
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Article
References

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 disease and multi-infarct dementia.

Design.  —A 52-week, randomized double-blind, placebo-controlled, parallelgroup, multicenter study.

Patients.  —Mildly to severely demented outpatients with Alzheimer 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 3 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 betterthan 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 4-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 6 months to 1 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.

REFERENCES

1 +
Cott J.  Natural product formulations available in Europe for psychotropic indication . Psychopharmacol Bull . 1995;;31:745-751.
2 +
DeFeudis FG. In: DeFeudis FV, ed. Ginkgo Biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications . Paris, France: Editions Scientifiques Elsevier; 1991;:7-146.
3 +
Packer L, Haramaki N, Kawabata T, et al.  Ginkgo biloba extract (EGb 761) . In: Christen Y, Courtois Y, Droy-Lefaix MT, eds. Effect of Ginkgo Biloba Extract (EGb 761) on Aging and Age-Related Disorders . Paris, France: Editions Scientifiques Elsevier Paris; 1995;:23-47.
4 +
Oyama Y, Fuchs PA, Katayama N, Noda K.  Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca2+-loaded brain neurons . Brain Res . 1994;;635:125-129.
5 +
Richardson JS.  Free radicals in the genesis of Alzheimer's disease . In: Nitsch RM, Growdon JH, Corkin S, Wurtman RJ, volume eds. Alzheimer's Disease: Amyloid Precursor Proteins, Signal Transduction, and Neuronal Transplantation. Ann N Y Acad Sci . 1993;;695:73-76.
6 +
Anderson DK, Thomas CE.  Mechanisms and role of oxygen free radicals in CNS pathology . In: Racagni G, Brunello N, Langer SZ, volume eds. Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Dysfunction. Int Acad Biomed Drug Res . 1994;;7:119-124.
7 +
Behl C, Davis JB, Lesley R, Schubert D.  Hydrogen peroxide mediates amyloid β protein toxicity . Cell . 1994;;77:817-827.
8 +
Benzi G, Moretti A.  Are reactive oxygen species involved in Alzheimer's disease? Neurobiol Aging . 1995;;16:661-674.
9 +
Warburton DM.  Psycho-pharmacologie clinique de l'extrait de Ginkgo biloba . Presse Med . 1986;;15:1595-1604.
10 +
Kleijnen J, Knipschild P.  Ginkgo biloba for cerebral insufficiency . Br J Clin Pharmacol . 1992;;34:352-358.
11 +
Letzel H, Haan J, Feil WB.  Nootropics . J Drug Dev Clin Pract . 1996;;8:77-94.
12 +
Hofferberth B.  The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type, a double-blind, placebo-controlled study on different levels of investigation . Hum Psychopharmacol . 1994;; 9:215-222.
13 +
Kanowski S, Herrmann WM, Stephan K, Wierich W, Hörr R.  Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia . Pharmacopsychiatry . 1996;;29:47-56.
14 +
Folstein MF, Folstein SE, McHugh PR.  Mini-Mental State . J Psychiatr Res . 1975;;12:189-198.
15 +
Reisberg B, Ferris SH, de Leon MJ, et al.  The Global Deterioration Scale for assessment of primary degenerative dementia . Am J Psychiatry . 1982;;39:1136-1139.
16 +
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer's disease . Am J Psychiatry . 1984;;141:1356-1364.
17 +
Stern RG, Mohs RC, Davidson M, et al.  A longitudinal study of Alzheimer's disease . Am J Psychiatry . 1994;;151:390-396.
18 +
Schwartz GE.  Development and validation of the Geriatric Evaluation by Relative's Rating Instrument (GERRI) . Psychol Rep . 1983;;53:479-488.
19 +
Morich FJ, Bieber F, Lewis JM, et al.  Nimodipine in the treatment of probable Alzheimer's disease . Clin Drug Invest . 1996;;11:185-195.
20 +
Clinical Global Assessment Scale (CGI). In: Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rockville, Md: US Dept of Health Education and Welfare, National Institute of Mental Health; 1976:218-222.
21 +
Gillings D, Koch G.  The application of the principle of intention-to-treat to the analysis of clinical trials . Drug Inform J . 1991;;25:411-424.
22 +
Jorm AF, Korten AE, Henderson AS.  The prevalence of dementia . Acta Psychiatr Scand . 1987;;76:465-479.
23 +
Katzman R, Lasker B, Bernstein N.  Advances in the diagnosis of dementia . In: Terry RD, ed. Aging and the Brain . New York, NY: Raven Press; 1988;: 17-62.
24 +
Anthony JC, LeResche L, Niaz U, Von Korff MR, Folstein MF.  Limits of the 'Mini-Mental State' as a screening test for dementia and delirium among hospital patients . Psychol Med . 1982;;12:397-408.
25 +
Crum RM, Anthony JC, Bassett SS, Folstein MF.  Population-based norms for the Mini-Mental State Examination by age and education level . JAMA . 1993;;269:2386-2421.
26 +
Welsh K, Butters N, Hughes J, Mohs R, Heyman A.  Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures . Arch Neurol . 1991;;48:278-281.
27 +
Agresti A.  Tutorial on modeling ordered categorical response data . Psychol Bull . 1989;;105:290-301.
28 +
Kramer-Ginsberg E, Mohs RC, Aryan M, et al.  Clinical predictors of course for Alzheimer patients in a longitudinal study: a preliminary report . Psychopharmacol Bull . 1988;;24:458-462.
29 +
Davis LK, Thal LJ, Gamzu ER, et al.  A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease . N Engl J Med . 1992;;327:1253-1259.
30 +
Farlow M, Gracon SI, Hershey LA, et al.  A controlled trial of tacrine in Alzheimer's disease . JAMA . 1992;;268:2523-2529.
31 +
Knapp MJ, Knopman DS, Solomon PR, et al.  A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease . JAMA . 1994;;271:985-991.
32 +
Morris JC, McKeel DW, Fulling K, Torack RM, Berg L.  Validation of clinical diagnosis criteria for Alzheimer's disease . Ann Neurol . 1988;;24:17-22.
33 +
Baldereschi M, Amato MP, Nencini P, et al.  Crossnational interrater agreement on the clinical diagnostic criteria for dementia . Neurology . 1994;;44:239-242.
34 +
Victoroff J, Mack WJ, Lyness SA, Chui HC.  Multicenter clinicopathological correlation in dementia . Am J Psychiatry . 1995;;152:1476-1484.
35 +
Dahlke F, Lohaus A, Gutzmann H.  Reliability and clinical concepts underlying global judgments in dementia . Psychopharmacol Bull . 1992;;28:425-432.
36 +
Knopman DS, Knapp MJ, Gracon SI, Davis CS.  The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease . Neurology . 1994;;44:2315-2321.
37 +
Itil TM, Eralp E, Tsambis E, Itil KZ, Stein U.  Central nervous system effects of Ginkgo biloba, a plant extract . Am J Ther . 1996;;3:63-73.
38 +
Leber P.  Observations and suggestions on antidementia drug development . Alzheimer Dis Assoc Disord . 1996;;10( (suppl 1) ):31-35.
39 +
Chui H, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R.  Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) . Neurology . 1992;;42:473-480.
40 +
Lopez OL, Larumbe MR, Becker JT, et al.  Reliability of NINDS-AIREN clinical criteria for the diagnosis of vascular dementia . Neurology . 1994;;44:1240-1245.
41 +
Huguet F, Tarrade T.  α2-Adrenoceptor change during cerebral ageing: the effect of Ginkgo biloba extract . J Pharm Pharmacol . 1992;;44:24-27.
42 +
Krištofiková Z, Klaschka J.  In vitro effect of Ginkgo biloba extract (EGb 761) on the activity of presynaptic cholinergic nerve terminals in rat hippocampus . Dement Geriatr Cogn Disord . 1997;;8:43-48.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Cott J.  Natural product formulations available in Europe for psychotropic indication . Psychopharmacol Bull . 1995;;31:745-751.
2 +
DeFeudis FG. In: DeFeudis FV, ed. Ginkgo Biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications . Paris, France: Editions Scientifiques Elsevier; 1991;:7-146.
3 +
Packer L, Haramaki N, Kawabata T, et al.  Ginkgo biloba extract (EGb 761) . In: Christen Y, Courtois Y, Droy-Lefaix MT, eds. Effect of Ginkgo Biloba Extract (EGb 761) on Aging and Age-Related Disorders . Paris, France: Editions Scientifiques Elsevier Paris; 1995;:23-47.
4 +
Oyama Y, Fuchs PA, Katayama N, Noda K.  Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca2+-loaded brain neurons . Brain Res . 1994;;635:125-129.
5 +
Richardson JS.  Free radicals in the genesis of Alzheimer's disease . In: Nitsch RM, Growdon JH, Corkin S, Wurtman RJ, volume eds. Alzheimer's Disease: Amyloid Precursor Proteins, Signal Transduction, and Neuronal Transplantation. Ann N Y Acad Sci . 1993;;695:73-76.
6 +
Anderson DK, Thomas CE.  Mechanisms and role of oxygen free radicals in CNS pathology . In: Racagni G, Brunello N, Langer SZ, volume eds. Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Dysfunction. Int Acad Biomed Drug Res . 1994;;7:119-124.
7 +
Behl C, Davis JB, Lesley R, Schubert D.  Hydrogen peroxide mediates amyloid β protein toxicity . Cell . 1994;;77:817-827.
8 +
Benzi G, Moretti A.  Are reactive oxygen species involved in Alzheimer's disease? Neurobiol Aging . 1995;;16:661-674.
9 +
Warburton DM.  Psycho-pharmacologie clinique de l'extrait de Ginkgo biloba . Presse Med . 1986;;15:1595-1604.
10 +
Kleijnen J, Knipschild P.  Ginkgo biloba for cerebral insufficiency . Br J Clin Pharmacol . 1992;;34:352-358.
11 +
Letzel H, Haan J, Feil WB.  Nootropics . J Drug Dev Clin Pract . 1996;;8:77-94.
12 +
Hofferberth B.  The efficacy of EGb 761 in patients with senile dementia of the Alzheimer type, a double-blind, placebo-controlled study on different levels of investigation . Hum Psychopharmacol . 1994;; 9:215-222.
13 +
Kanowski S, Herrmann WM, Stephan K, Wierich W, Hörr R.  Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia . Pharmacopsychiatry . 1996;;29:47-56.
14 +
Folstein MF, Folstein SE, McHugh PR.  Mini-Mental State . J Psychiatr Res . 1975;;12:189-198.
15 +
Reisberg B, Ferris SH, de Leon MJ, et al.  The Global Deterioration Scale for assessment of primary degenerative dementia . Am J Psychiatry . 1982;;39:1136-1139.
16 +
Rosen WG, Mohs RC, Davis KL.  A new rating scale for Alzheimer's disease . Am J Psychiatry . 1984;;141:1356-1364.
17 +
Stern RG, Mohs RC, Davidson M, et al.  A longitudinal study of Alzheimer's disease . Am J Psychiatry . 1994;;151:390-396.
18 +
Schwartz GE.  Development and validation of the Geriatric Evaluation by Relative's Rating Instrument (GERRI) . Psychol Rep . 1983;;53:479-488.
19 +
Morich FJ, Bieber F, Lewis JM, et al.  Nimodipine in the treatment of probable Alzheimer's disease . Clin Drug Invest . 1996;;11:185-195.
20 +
Clinical Global Assessment Scale (CGI). In: Guy W, ed. ECDEU Assessment Manual for Psychopharmacology. Rockville, Md: US Dept of Health Education and Welfare, National Institute of Mental Health; 1976:218-222.
21 +
Gillings D, Koch G.  The application of the principle of intention-to-treat to the analysis of clinical trials . Drug Inform J . 1991;;25:411-424.
22 +
Jorm AF, Korten AE, Henderson AS.  The prevalence of dementia . Acta Psychiatr Scand . 1987;;76:465-479.
23 +
Katzman R, Lasker B, Bernstein N.  Advances in the diagnosis of dementia . In: Terry RD, ed. Aging and the Brain . New York, NY: Raven Press; 1988;: 17-62.
24 +
Anthony JC, LeResche L, Niaz U, Von Korff MR, Folstein MF.  Limits of the 'Mini-Mental State' as a screening test for dementia and delirium among hospital patients . Psychol Med . 1982;;12:397-408.
25 +
Crum RM, Anthony JC, Bassett SS, Folstein MF.  Population-based norms for the Mini-Mental State Examination by age and education level . JAMA . 1993;;269:2386-2421.
26 +
Welsh K, Butters N, Hughes J, Mohs R, Heyman A.  Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures . Arch Neurol . 1991;;48:278-281.
27 +
Agresti A.  Tutorial on modeling ordered categorical response data . Psychol Bull . 1989;;105:290-301.
28 +
Kramer-Ginsberg E, Mohs RC, Aryan M, et al.  Clinical predictors of course for Alzheimer patients in a longitudinal study: a preliminary report . Psychopharmacol Bull . 1988;;24:458-462.
29 +
Davis LK, Thal LJ, Gamzu ER, et al.  A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease . N Engl J Med . 1992;;327:1253-1259.
30 +
Farlow M, Gracon SI, Hershey LA, et al.  A controlled trial of tacrine in Alzheimer's disease . JAMA . 1992;;268:2523-2529.
31 +
Knapp MJ, Knopman DS, Solomon PR, et al.  A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease . JAMA . 1994;;271:985-991.
32 +
Morris JC, McKeel DW, Fulling K, Torack RM, Berg L.  Validation of clinical diagnosis criteria for Alzheimer's disease . Ann Neurol . 1988;;24:17-22.
33 +
Baldereschi M, Amato MP, Nencini P, et al.  Crossnational interrater agreement on the clinical diagnostic criteria for dementia . Neurology . 1994;;44:239-242.
34 +
Victoroff J, Mack WJ, Lyness SA, Chui HC.  Multicenter clinicopathological correlation in dementia . Am J Psychiatry . 1995;;152:1476-1484.
35 +
Dahlke F, Lohaus A, Gutzmann H.  Reliability and clinical concepts underlying global judgments in dementia . Psychopharmacol Bull . 1992;;28:425-432.
36 +
Knopman DS, Knapp MJ, Gracon SI, Davis CS.  The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease . Neurology . 1994;;44:2315-2321.
37 +
Itil TM, Eralp E, Tsambis E, Itil KZ, Stein U.  Central nervous system effects of Ginkgo biloba, a plant extract . Am J Ther . 1996;;3:63-73.
38 +
Leber P.  Observations and suggestions on antidementia drug development . Alzheimer Dis Assoc Disord . 1996;;10( (suppl 1) ):31-35.
39 +
Chui H, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R.  Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) . Neurology . 1992;;42:473-480.
40 +
Lopez OL, Larumbe MR, Becker JT, et al.  Reliability of NINDS-AIREN clinical criteria for the diagnosis of vascular dementia . Neurology . 1994;;44:1240-1245.
41 +
Huguet F, Tarrade T.  α2-Adrenoceptor change during cerebral ageing: the effect of Ginkgo biloba extract . J Pharm Pharmacol . 1992;;44:24-27.
42 +
Krištofiková Z, Klaschka J.  In vitro effect of Ginkgo biloba extract (EGb 761) on the activity of presynaptic cholinergic nerve terminals in rat hippocampus . Dement Geriatr Cogn Disord . 1997;;8:43-48.

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