Herbal medicines from ginkgo leaf extract in the treatment of mild dementia

  • Silvana Petrović Department of Pharmacognosy, University of Belgrade - Faculty of Pharmacy
  • Ljuboš Ušjak Department of Pharmacognosy, University of Belgrade - Faculty of Pharmacy
Keywords: Ginkgo biloba; leaf extract; mild dementia; herbal medicines; efficacy and safety

Abstract


According to current EU monograph of the Committee on Herbal Medicinal Products of European Medicines Agency (EMA/HMPC) for ginkgo leaf, Ginkgonis folium (Ginkgo biloba, Ginkgoaceae), herbal medicines prepared from refined and quantified dry extract of ginkgo leaf are used for the improvement of (age-associated) cognitive impairment and of quality of life in mild dementia. It was demonstrated in clinical trials that long-term use of the extract is effective mainly in patients more than 50 years old. The precise mode of action is not known. According to Ph. Eur., the extract should contain 22.0-27.0% of flavonoids, 2.8-3.4% of ginkgolides A, B and C, and 2.6-3.2% of bilobalide, which are active constituents, and maximum 5 ppm of ginkgolic acids, which are potential allergens. These herbal medicines are characterized by corresponding posology, duration of use, contraindications, special warnings, and precautions for use, interactions and possible undesirable reactions.

References

World Health Organization (WHO). Global action plan on the public health response to dementia 2017-2025. Geneva: 2017.

O'Brien JT, Thomas A. Vascular dementia. Lancet. 2015;386:1698-706.

Yuan Q, Wang CW, Shi J, Lin ZX. Effects of Ginkgo biloba on dementia: An overview of systematic reviews. J Ethnopharmacol. 2017;195:1-9.

European Medicines Agency (Table of herbal medicines) [Internet] [cited 2020 February 10]. Available from: https://www.ema.europa.eu/en/medicines/download-medicine-data#herbal-medicines-section

European Medicines Agency. EMA/HMPC/321097/2012. European Union herbal monograph on Ginkgo biloba L., folium. London: 28 January 2015.

Del Tredici P. The evolution, ecology, and cultivation of Ginkgo biloba. van Beek TA, editor. London: CRC Press; 2000; pp. 25-42.

Hohmann N, Wolf EM, Rigault P, Zhou W, Kiefer M, Zhao Y, et al. Ginkgo biloba’s footprint of dynamic Pleistocene history dates back only 390,000 years ago. BMC Genomics. 2018;19(1):299.

Zhao YP, Fan G, Yin PP, Sun S, Li N, Hong X, et al. Resequencing 545 ginkgo genomes across the world reveals the evolutionary history of the living fossil. Nat Commun. 2019;10(1):1-10.

Isah T. Rethinking Ginkgo biloba L.: Medicinal uses and conservation. Phcog Rev. 2015;9(18):140-8.

Mahady GB. Ginkgo biloba for the prevention and treatment of cardiovascular disease: a review of the literature. J Cardiovasc Nurs. 2002;16(4):21-32.

Leistner E, Drewke C. Ginkgo biloba and ginkgotoxin. J Nat Prod. 2010;73(1):86-92.

DeFeudis FV. A brief history of EGb 761 and its therapeutic uses. Pharmacopsychiatry. 2003;36 Suppl 1:S2-S7.

Lang F, Hoerr R, Noeldner M, Koch E. Ginkgo biloba extract EGb 761®: From an ancient Asian plant to a modern European herbal medicinal product. Wagner H, Ulrich-Merzenich G, editors. Vienna: Springer; 2013; pp. 431-70.

Gafner S. Adulteration of Ginkgo biloba leaf extract. Botanical Adulterants Bulletin [Internet]. American Botanical Council (ABC), the American Herbal Pharmacopoeia (AHP), and the University of Mississippi's National Center for Natural Products Research (NCNPR): Botanical Adulterants Prevention Program; 2018 [cited 2020 Feb 10]. Available from: http://cms.herbalgram.org/BAP/BAB/GinkgoBulletin.html

Veit M. Pflanzliche Arzneidrogen und einfache Arzneizubereitungen. Sticher O, Heilmann J, Zündorf I, editors. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2015; pp. 141-70.

European Pharmacopoeia 9th Edition. Strasbourg: Council of Europe, published 2016, valid from 1 January 2017.

European Medicines Agency. EMA/HMPC/201116/2005 Rev. 2, 2011. Guideline on quality of herbal medicinal products/traditional herbal medicinal products. London: 31 March 2011.

Sticher O. Phenolische Verbindungen. Sticher O, Heilmann J, Zündorf I, editors. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 2015; pp. 741-858.

Rotblatt MD. Herbal medicine: a practical guide to safety and quality assurance. West J Med. 1999;171(3):172-5.

van Beek TA, Montoro P. Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals. J Chromatogr A. 2009;1216(11):2002-32.

Stockler S, Plecko B, Gospe Jr SM, Coulter-Mackie M, Connolly M, van Karnebeek C, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104(1-2):48-60.

Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2009;(1):CD003120.

European Medicines Agency. EMA/HMPC/321095/201228. Assessment report on Ginkgo biloba L., folium. London: 28. January 2014.

Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke S. Ginkgo biloba extract EGb 761 ® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012;46(6):716-23.

Ihl R, Tribanek M, Bachinskaya N. Baseline neuropsychiatric symptoms are effect modifiers in Ginkgo biloba extract (EGb 761®) treatment of dementia with neuropsychiatric features. Retrospective data analyses of a randomized controlled trial. J Neurol Sci. 2010;299(1-2):184-7.

Ihl R, Bachinskaya N, Korczyn AD, Vakhapova V, Tribanek M, Hoerr R, Napryeyenko O. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: A randomized controlled trial. Int J Geriatr Psychiatry. 2011;26(11):1186-94.

Ihl R, Tribanek M, Bachinskaya N. Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761 ® in Alzheimer's disease and vascular dementia: Results from a randomised controlled trial. Pharmacopsychiatry. 2012;45(2):41-6.

Napryeyenko O, Borzenko I. Ginkgo biloba special extract in dementia with neuropsychiatric features: A randomised, placebo-controlled, double-blind clinical trial. Arzneim -Forsch Drug Res. 2007;57(1):4-11.

Napryeyenko O, Sonnik G, Tartakovsky I. Efficacy and tolerability of Ginkgo biloba extract EGb 761® by type of dementia: Analyses of a randomised controlled trial. J Neurol Sci. 2009;283(1-2):224-9.

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(2):47-56.

Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761® in dementia: Intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry. 2003;36(6):297-303.

Le Bars PL, Kieser M, Itil KZ. A 26-week analysis of a double-blind, placebo-controlled trial of the Ginkgo biloba extract EGb 761® in dementia. Dementia Geriatr Cogn Disord. 2000;11(4):230-7.

Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R. Ginkgo biloba extract EGb 761, donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: A randomised, double-blind, exploratory trial. Aging Ment Health. 2009;13(2):183-90.

Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology. 8th ed. Edinburgh: Elsevier Churchill Livingstone; 2016. 489-90 p.

van Dongen MCJM, van Rossum E, Kessels AGH, Sielhorst HJG, Knipschild PG. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: New results of a randomized clinical trial. J Am Geriatr Soc. 2000;48(10):1183-94.

McCarney R, Fisher P, Iliffe S, van Haselen R, Griffin M, van der Meulen J, Warner J. Ginkgo biloba for mild to moderate dementia in a community setting: A pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry. 2008;23(12):1222-30.

Schneider LS, DeKosky ST, Farlow MR, Tariot PN, Hoerr R, Kieser M. A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type. Curr Alzheimer Res. 2005;2(5):541-51.

Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG) A05-19B. Ginkgohaltige Präparate bei Alzheimer Demenz. Köln: 29. September 2008.

Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010;10:14.

Blumenthal M, Busse WR, Goldberg A, Gruenwald J, Hall T, Klein S, et al. The Complete German Commission E Monographs. Austin: American Botanical Council; 1998. pp. 136-8.

World Health Organization (WHO). Folium Ginkgo. WHO Monographs on Selected Medicinal Plants, Vol. 1. Geneva: 1999. pp. 154-67.

European Scientific Cooperative On Phytotherapy (ESCOP). Ginkgo folium. ESCOP Monographs, 2nd ed. Exeter: 2003. pp. 178-210.

DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, et al. Ginkgo biloba for prevention of dementia: A randomized controlled trial. J Am Med Assoc. 2008;300(19):2253-62.

Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B, et al. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): A randomised placebo-controlled trial. Lancet Neurol. 2012;11(10):851-9.

Stefanova E, Pavlović A, Semnic M, Janjić V, Petrović M, Milošević V, et al. Vodič za Alchajmerovu bolest. Belgrade: June 2013.

Snitz BE, O'Meara ES, Carlson MC, Arnold AM, Ives DG, Rapp SR, et al. Ginkgo biloba for preventing cognitive decline in older adults a randomized trial. J Am Med Assoc. 2009;302(24):2663-70.

Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN), Deutsche Gesellschaft für Neurologie (DGN). S3-Leitlinie "Demenzen": Langversion. January 2016.

Deutsche Gesellschaft für Neurologie (DGN). Leitlinien für Diagnostik und Therapie in der Neurologie. Vaskuläre Demenzen. 2017.

Savaskan E, Mueller H, Hoerr R, von Gunten A, Gauthier S. Treatment effects of Ginkgo biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: meta-analysis of randomized controlled trials. Int Psychogeriatr. 2018;30(3):285-93.

Nikolova G, Yancheva S, Raychev I, Hoerr R. PLAGIN Study Group Ginkgo biloba extract in dementia: a 22-week randomised, placebo-controlled, double-blind trial. Bulgarian Neurol. 2013;14:139-43.

Spiegel R, Kalla R, Mantokoudis G, Maire R, Mueller H, Hoerr R, Ihl R. Ginkgo biloba extract EGb 761® alleviates neurosensory symptoms in patients with dementia: a meta-analysis of treatment effects on tinnitus and dizziness in randomized, placebo-controlled trials. Clin Interv Aging. 2018;13:1121-7.

Gessner B, Voelp A, Klasser M. Study of the long-term action of a Ginkgo biloba extract on vigilance and mental performance as determined by means of quantitative pharmaco-EEG and psychometric measurements. Arzneimittelforschung. 1985;35(9):1459-65.

Santos RF, Galduróz JC, Barbieri A, Castiglioni ML, Ytaya LY, Bueno OF. Cognitive performance, SPECT, and blood viscosity in elderly non-demented people using Ginkgo biloba. Pharmacopsychiatry. 2003;36(4):127-33.

Guinot P, Caffrey E, Lambe R, Darragh A. Tanakan inhibits platelet-activating-factor-induced platelet aggregation in healthy male volunteers. Haemostasis. 1989;19(4):219-23.

Mehlsen J, Drabaek H, Wiinberg N, Winther K. Effects of a Ginkgo biloba extract on forearm haemodynamics in healthy volunteers. Clin Physiol Funct Imaging. 2002;22(6):375-8.

Oberpichler H, Beck T, Abdel-Rahman MM, Bielenberg GW, Krieglstein J. Effects of Ginkgo biloba constituents related to protection against brain damage caused by hypoxia. Pharmacol Res Commun. 1988;20(5):349-68.

Ahlemeyer B, Krieglstein J. Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry. 2003;36 Suppl 1:S8-S14.

Janssens D, Michiels C, Delaive E, Eliaers F, Drieu K, Remacle J. Protection of hypoxia-induced ATP decrease in endothelial cells by Ginkgo biloba extract and bilobalide. Biochem Pharmacol. 1995;50(7):991-9.

Janssens D, Delaive E, Remacle J, Michiels C. Protection by bilobalide of the ischaemia-induced alterations of the mitochondrial respiratory activity. Fundam Clin Pharmacol. 2000;14(3):193-201.

Braquet PG, Spinnewyn B, Braquet M, Bourgain RH, Taylor JE, Etienne A, Drieu K. BN 52021 and related compounds: A new series of highly specific PAF-acether receptor antagonists isolated from Ginkgo biloba L. Blood & Vessel. 1985;16(6):558-72.

Akiba S, Kawauchi T, Oka T, Hashizume T, Sato T. Inhibitory effect of the leaf extract of Ginkgo biloba L. on oxidative stress-induced platelet aggregation. Biochem Mol Biol Int. 1998;46(6):1243-8.

Koch E. Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications after oral intake of Ginkgo biloba extracts. Phytomedicine. 2005;12(1-2):10-6.

Koltermann A. Influence of Ginkgo biloba extract EGb 761® on signaling pathways in endothelial cells [dissertation]. [Munich (DE)]: Ludwig-Maximilians-Universität; 2007. 155 p.

Shi C, Liu J, Wu F, Yew DT. Ginkgo biloba extract in Alzheimer's disease: from action mechanisms to medical practice. Int J Mol Sci. 2010;11(1):107-23.

Du ZY, Li XY. Effects of ginkgolides on interleukin-1, tumor necrosis factor-alpha and nitric oxide production by rat microglia stimulated with lipopolysaccharides in vitro. Arzneimittelforschung. 1998;48(12):1126-30.

Taylor JE. Binding of neuromediators to their receptors in rat brain. Effect of chronic administration of Ginkgo biloba extract. Fünfgeld EW, editor. Berlin, Heidelberg: Springer-Verlag; 1988; pp. 103-8.

Kehr J, Yoshitake S, Ijiri S, Koch E, Nöldner M, Yoshitake T. Ginkgo biloba leaf extract (EGb 761®) and its specific acylated flavonol constituents increase dopamine and acetylcholine levels in the rat medial prefrontal cortex: possible implications for the cognitive enhancing properties of EGb 761®. Int Psychogeriatr. 2012;24 Suppl 1:S25-S34.

Granger AS. Ginkgo biloba precipitating epileptic seizures. Age Ageing. 2001;30(6):523-5.

Härtter S, Sennewald R, Nehmiz G, Reilly P. Oral bioavailability of dabigatran etexilate (Pradaxa®) after co-medication with verapamil in healthy subjects. Br J Clin Pharmacol. 2013;75(4):1053-62.

Fan L, Mao XQ, Tao GY, Wang G, Jiang F, Chen Y, et al. Effect of Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers. Xenobiotica. 2009;39(3):249-54.

Fan L, Tao GY, Wang G, Chen Y, Zhang W, He YJ, et al. Effects of Ginkgo biloba extract ingestion on the pharmacokinetics of talinolol in healthy Chinese volunteers. Ann Pharmacother. 2009;43(5):944-9.

Yoshioka M, Ohnishi N, Koishi T, Obata Y, Nakagawa M, Matsumoto T, et al. Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of Ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers. Biol Pharm Bull. 2004;27(12):2006-9.

Naccarato M, Yoong D, Gough K. A potential drug-herbal interaction between Ginkgo biloba and efavirenz. J Int Assoc Physicians AIDS Care (Chic). 2012;11(2):98-100.

Elmazoudy RH, Attia AA. Efficacy of Ginkgo biloba on vaginal estrous and ovarian histological alterations for evaluating anti-implantation and abortifacient potentials in albino female mice. Birth Defects Res B Dev Reprod Toxicol. 2012;95(6):444-59.

DeFeudis FV. Ginkgo biloba extract (EGb 761): from chemistry to the clinic. Wiesbaden: Ullstein Medical; 1998.

Shiao NH, Chan WH. Injury effects of ginkgolide B on maturation of mouse oocytes, fertilization, and fetal development in vitro and in vivo. Toxicol Lett. 2009;188(1):63-9.

Chan WH. Ginkgolides induce apoptosis and decrease cell numbers in mouse blastocysts. Biochem Biophys Res Commun. 2005;338(2):1263-7.

Baron-Ruppert G, Luepke NP. Evidence for toxic effects of alkylphenols from Ginkgo biloba in the hen's egg test (HET). Phytomedicine. 2001;8(2):133-8.

Gauthier S, Schlaefke S. Efficacy and tolerability of Ginkgo biloba extract EGb 761® in dementia: a systematic review and meta-analysis of randomized placebo-controlled trials. Clin Interv Aging. 2014;9:2065-77.

Hashiguchi M, Ohta Y, Shimizu M, Maruyama J, Mochizuki M. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia. J Pharm Health Care Sci. 2015;1:14.

Tan MS, Yu JT, Tan CC, Wang HF, Meng XF, Wang C, et al. Efficacy and adverse effects of Ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis. 2015;43(2):589-603.

Joseph N, Abhishai B, Thouseef MF, Abna A, Juneja I. A multicenter review of epidemiology and management of varicose veins for national guidance. Ann Med Surg (Lond). 2016;8:21-7.

Rha SW, Choi SH, Kim DI, Jeon DW, Lee JH, Hong KS, et al. Medical resource consumption and quality of life in peripheral arterial disease in Korea: PAD outcomes (PADO) research. Korean Circ J. 2018;48(9):813-25.

European Medicines Agency. EMA/HMPC/322570/2011 Rev. 7. Uptake of the traditional use registration scheme and implementation of the provisions of Directive 2004/24/EC in EU Member States. Status: 31 December 2016. London: 18 April 2017.

Medicines and Medical Devices Agency of Serbia [Internet]. Search for human medicines [cited 2020 April 27]. Available from: https://www.alims.gov.rs/eng/medicinal-products/search-for-human-medicines/

Published
2020/05/15
Section
Review articles