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Gingko biloba extract (EGb 761): Pharmacological activities and clinical applications
TiPS - Augusf 1992 [Vol. 131
334
Acknowledgements
Contributions from many collaborators, including the illustration by Mr Michael Phillips, are gratefully acknowledged. Parts of the original research described in this review were supported by grants to D.H.M. from the Canadian MRC and the Muscular Dystrophy Association of Canada.
1 Britt, B. A. (1991) in Thermoregulafion: Pathology, Phanaacology and Therapy (Schonbaum, E. and Lomax, P. eds), pp. 179-292, Pergamon Press 2 O%rien, P. j. (1987) Vet. Res. Commun. 11.527-559 3 Denboxuugh, M. A. and LoveII, R. R. H. (1960) htcet ii, 45-47 4 BrItt, B. A. (1984) Can. Anaesth. Sot. J. 31.61-7s 5 EG&ow, W., Brie, B. A., Terreau, M. E. and Haist, C (1970) Lpncet ii, 895-898 6 Ellis, F. R., H&m& D. G. F., Keaney, N. P., Kyei-Mensah, K, and TyrreII, J. H. (197l) Br. J. Anaesth. 43,721-m 7 Larach, M. G. (1989) Anestk. A&g. 69,
A clinical tale: Gingko bitoba goes west Gingko biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications by F. V. DeFeudis, Elsevier, 2992. FFr250.00 in France, FFr280.00 elsewhere (xii + 287 pages) ISBN 2 906077 24 0 kbk, 2 906077 21 6 pbk Anything that survives 4000 years must have a few tricks up its leaves. The Gingko biloba tree has a life span of between 2000 and 4000 years and is regarded as a living fossil, since this species has been in existence for between 150 and 200 million years. Chinese herbal pharmacopoeias, both ancient and modern, contain references to the extract of Gingko biloba leaves as being ‘good for the heart and lung’. In this monograph, DeFeudis describes more recent investigations of the basic and clinical pharmacology of the extract of
511-515 8 The European Malignant ~yperthe~ia Group (1984) Br. 1. Anaesth. 56, 1267-1269 9 Webb, A. 1. and Simuson. S. I?. (1986) Anim..Prod: 43,493-563 10 Harrison, G. G. (1979) ht. Anesthesiof. Ctin. 17,25-62 11 Eikelenb~m, G. and Minkema, D. (1974) Netherlands J. Vet. Sci. 99,421-426 12 Gahne, B. and Juneja, R. K. (1985) Anim. Blood Groups Biochem. Genet. 16, 265-283 13 Endo, M. et al. (1983) Biomed. Res. 4, 83-92 14 Ohnishi, S. T., Taylor, S. and Gronert, G. A. (1983) FEBS Left. 161,103-107 15 O’Brien, P. J. (1986) Can. J. Vet. Res. 50, 318-328 16 Carrier, L., VilIaz, M. and DuPont, Y. (1991) Biochim. Biophys. Acfa 1064, 175-183 17 FiII. M. ef al. (1990) Biophys. J. 50, 471-475 18 Fill, M., Stefani, E. and Nelson, T. E. (1991) Bioohus. 1. 59.108!?-1090 19 &udson:C:M.; Micketson, J. R., Louis, C. F. and Camubeli, K. P. (1990) I. BioL Ckem, 265,24%2424 . 20 Ohta, T., Ito, 5. and Ohga, A. (1990) Eur. J. Pharmacol. 178, 11-19 21 FIeischer, S. and Inui, M. (1989) Annu.
Rev. Biophys. Biophys. Chem. 18,3X+-364 22 Takeshima, H. ef al. (19893 Nufure 339, 439+z5 23 Zorzato, F. et al. (1990) 1. Biol. Chem. 265, 224&22% 24 Fujii, J. et al.(1991) Science 253,44&-451 25 MacKenzie, A. E. et al. (1990) Am. 1. Ham. Genef. 46,1082-1089 26 Harbitz, I. et at. (1990) Genomics 9, 243-248 27 Davies, W., Harbitz, I., Fries, R, Stranzinger, G. and Hauge, J. G. (1988) Anim. Genet. 19,203-212 28 MacLennan, D. H. et al. (1990) Nature 343,559-561 29 McCarthy, T. V. et al. (1990) Nature 343, 562-564 30 Otsu, K., Khanna, V. K., Archibald, A. L. and MacLennan, D. N. (1991) Genomics 11,744-750 31 Gillard. E. F. ef al. 11990 Genomics 11, . 751-755 32 Levitt, R. C. et al. (1991) Genomics 11, 543-547 33 Deufel, T. et al. Am. 1. Hum. Genet. (in press) 34 MacKenzie, A. E. et al. (1991) Anaestkes~oiagy 75,4-B 35 Brownell, A.K. W. (1988) Br. 1. Anaestk. 660,303-308 36 Mulley, J. C. et al. (1991) Cytogenet. Cell Genef. 58,2022
Gingko biloba leaves (EGb 761) that has been in use in Europe since 1965. Specific indications include stroke, vasospastic and ischaemic disorders and primary degenerative or vascular dementia. My particular interest in this book derives from the fact that Gingko biloba extract contains active amounts of gingkolides A, B and C. Gingkolide B, also known as BN52021, is a relatively potent platelet-activating factor (PAF) receptor antagonist. The prologue suggests that the monograph has been written for both the ‘average’ person and the health specialist - an ambitious undertaking and one that I do not believe has been achieved in the pages that follow. The language and detail of the treatise are clearly directed at a scientifi~y literate and clinical readership and consequently should prove of most value to prescribers of Gingko biloba extract and to those interested in researching further the fascinating activities of the extract. Those with an interest in the
pharmacology of PAF and PAF antagonists would also find the monograph of value. The first chapter provides a brief and interesting history of the use of Gingko biloba extract, initially in Chinese herbal medicine followed by some detail of its first use in Western medicine. The chemical composition, though not yet fully elucidated, is described and much attention is focused on standardization of the content of the extract to specific percentages of flavonoids and terpenoids, the former possessing antioxidant activity, the latter comprising some PAF antagonists, There is, however, no description of the chemical stability of this complex mixture. The limited amount of pharmacokinetic data is reviewed, but given the number of potentially active substances in the extract, any systematic pharmacokinetic evaluation would be impractical. Subsequent chapters deal with in vitro, in viva and clinical studies, with a further four chapters covering clinical perspectives, safety, proposed mechanisms of action and general conclusions. The monograph is well organized with a number of useful diagrams. Extensive reproduction of published data in both tabular
I
TiPS - August 1992 IVol. 131
335
and graphical form is of great help to the reader in examining the claims made for this herbal extract. The author assiduously pursues the theme that many of the actions of the extract are multivalent, i.e. the clinical response is the net effect of interactions between the various biologically active principles. As a generalization of the reported data, this conclusion is sustained. However, there is emerging evidence, at least from animal studies, that the PAF antagonists used alone may have application in the treatment of ischaemic disorders. The nootropic actions of Gingko biloba extract are undoubtedly the most controversial aspect of the clinical claims for this agent, and the relevant literature is critically reviewed in detail. Some perplexing data on the safety of the Gingko biloba extract are discussed. It appears that despite an increase in use of the extract of at least tenfold between 1983 and 1988, the incidence of reported adverse reactions has remained constant. Moreover, in a double-
blind, placebo-controlled
clinical
trial, Gingko biloba extract appeared to have no more adverse effects than placebo treatment. Not so much a magic bullet as a magic cartridge of shotgun pellets! Finally, I am not entirely convinced that a more orthodox approach (for the purposes of a reductionist pharmacologist) involving the isolation of the most active constituents, optimization of their potency and selectivity,
and their recombination at optimal dose leveis, would not provide a superior therapeutic regimen. Nevertheless, the major aim of this book to provide a synthesis of existing data and a framework for future studies has been achieved in a lucid manner.
Desperately seeking definition
rats exposed to a wide variety of insults responded with adrenocortical hypertrophy and he formulated from these findings a theory giving promir.ence to corticosteroids. Walter Cannon, from his separate line of investigation, concluded that catecholamine release was the pharmacological hallmark of stress. He used the phrase ‘the necessities of fighting or flight’, to describe the acute protective functions of adrenergic activation, a phrase that has passed into common language as the ‘fight or flight’ response. These days we have
Perturbing the Organism: The Biology of Stressful Experience by Herbert Weiner, University of Chicago Press, 1992. $35.00 (xiii + 351 pages) ISBN 0 226 89041 4 The ghosts of Cannon and Selye haunt nearly every page of this volume on stress, locked in immortal combat over the pharmacological correlates of this commonly used but poorly formulated concept. Hans Selye showed that
A. G. STEWART Deparhnent
Melbourne, Australia.
of Physiology, Parkville,
Uniuersity
Victoria
of
3052,
334
Acknowledgements
Contributions from many collaborators, including the illustration by Mr Michael Phillips, are gratefully acknowledged. Parts of the original research described in this review were supported by grants to D.H.M. from the Canadian MRC and the Muscular Dystrophy Association of Canada.
1 Britt, B. A. (1991) in Thermoregulafion: Pathology, Phanaacology and Therapy (Schonbaum, E. and Lomax, P. eds), pp. 179-292, Pergamon Press 2 O%rien, P. j. (1987) Vet. Res. Commun. 11.527-559 3 Denboxuugh, M. A. and LoveII, R. R. H. (1960) htcet ii, 45-47 4 BrItt, B. A. (1984) Can. Anaesth. Sot. J. 31.61-7s 5 EG&ow, W., Brie, B. A., Terreau, M. E. and Haist, C (1970) Lpncet ii, 895-898 6 Ellis, F. R., H&m& D. G. F., Keaney, N. P., Kyei-Mensah, K, and TyrreII, J. H. (197l) Br. J. Anaesth. 43,721-m 7 Larach, M. G. (1989) Anestk. A&g. 69,
A clinical tale: Gingko bitoba goes west Gingko biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications by F. V. DeFeudis, Elsevier, 2992. FFr250.00 in France, FFr280.00 elsewhere (xii + 287 pages) ISBN 2 906077 24 0 kbk, 2 906077 21 6 pbk Anything that survives 4000 years must have a few tricks up its leaves. The Gingko biloba tree has a life span of between 2000 and 4000 years and is regarded as a living fossil, since this species has been in existence for between 150 and 200 million years. Chinese herbal pharmacopoeias, both ancient and modern, contain references to the extract of Gingko biloba leaves as being ‘good for the heart and lung’. In this monograph, DeFeudis describes more recent investigations of the basic and clinical pharmacology of the extract of
511-515 8 The European Malignant ~yperthe~ia Group (1984) Br. 1. Anaesth. 56, 1267-1269 9 Webb, A. 1. and Simuson. S. I?. (1986) Anim..Prod: 43,493-563 10 Harrison, G. G. (1979) ht. Anesthesiof. Ctin. 17,25-62 11 Eikelenb~m, G. and Minkema, D. (1974) Netherlands J. Vet. Sci. 99,421-426 12 Gahne, B. and Juneja, R. K. (1985) Anim. Blood Groups Biochem. Genet. 16, 265-283 13 Endo, M. et al. (1983) Biomed. Res. 4, 83-92 14 Ohnishi, S. T., Taylor, S. and Gronert, G. A. (1983) FEBS Left. 161,103-107 15 O’Brien, P. J. (1986) Can. J. Vet. Res. 50, 318-328 16 Carrier, L., VilIaz, M. and DuPont, Y. (1991) Biochim. Biophys. Acfa 1064, 175-183 17 FiII. M. ef al. (1990) Biophys. J. 50, 471-475 18 Fill, M., Stefani, E. and Nelson, T. E. (1991) Bioohus. 1. 59.108!?-1090 19 &udson:C:M.; Micketson, J. R., Louis, C. F. and Camubeli, K. P. (1990) I. BioL Ckem, 265,24%2424 . 20 Ohta, T., Ito, 5. and Ohga, A. (1990) Eur. J. Pharmacol. 178, 11-19 21 FIeischer, S. and Inui, M. (1989) Annu.
Rev. Biophys. Biophys. Chem. 18,3X+-364 22 Takeshima, H. ef al. (19893 Nufure 339, 439+z5 23 Zorzato, F. et al. (1990) 1. Biol. Chem. 265, 224&22% 24 Fujii, J. et al.(1991) Science 253,44&-451 25 MacKenzie, A. E. et al. (1990) Am. 1. Ham. Genef. 46,1082-1089 26 Harbitz, I. et at. (1990) Genomics 9, 243-248 27 Davies, W., Harbitz, I., Fries, R, Stranzinger, G. and Hauge, J. G. (1988) Anim. Genet. 19,203-212 28 MacLennan, D. H. et al. (1990) Nature 343,559-561 29 McCarthy, T. V. et al. (1990) Nature 343, 562-564 30 Otsu, K., Khanna, V. K., Archibald, A. L. and MacLennan, D. N. (1991) Genomics 11,744-750 31 Gillard. E. F. ef al. 11990 Genomics 11, . 751-755 32 Levitt, R. C. et al. (1991) Genomics 11, 543-547 33 Deufel, T. et al. Am. 1. Hum. Genet. (in press) 34 MacKenzie, A. E. et al. (1991) Anaestkes~oiagy 75,4-B 35 Brownell, A.K. W. (1988) Br. 1. Anaestk. 660,303-308 36 Mulley, J. C. et al. (1991) Cytogenet. Cell Genef. 58,2022
Gingko biloba leaves (EGb 761) that has been in use in Europe since 1965. Specific indications include stroke, vasospastic and ischaemic disorders and primary degenerative or vascular dementia. My particular interest in this book derives from the fact that Gingko biloba extract contains active amounts of gingkolides A, B and C. Gingkolide B, also known as BN52021, is a relatively potent platelet-activating factor (PAF) receptor antagonist. The prologue suggests that the monograph has been written for both the ‘average’ person and the health specialist - an ambitious undertaking and one that I do not believe has been achieved in the pages that follow. The language and detail of the treatise are clearly directed at a scientifi~y literate and clinical readership and consequently should prove of most value to prescribers of Gingko biloba extract and to those interested in researching further the fascinating activities of the extract. Those with an interest in the
pharmacology of PAF and PAF antagonists would also find the monograph of value. The first chapter provides a brief and interesting history of the use of Gingko biloba extract, initially in Chinese herbal medicine followed by some detail of its first use in Western medicine. The chemical composition, though not yet fully elucidated, is described and much attention is focused on standardization of the content of the extract to specific percentages of flavonoids and terpenoids, the former possessing antioxidant activity, the latter comprising some PAF antagonists, There is, however, no description of the chemical stability of this complex mixture. The limited amount of pharmacokinetic data is reviewed, but given the number of potentially active substances in the extract, any systematic pharmacokinetic evaluation would be impractical. Subsequent chapters deal with in vitro, in viva and clinical studies, with a further four chapters covering clinical perspectives, safety, proposed mechanisms of action and general conclusions. The monograph is well organized with a number of useful diagrams. Extensive reproduction of published data in both tabular
I
TiPS - August 1992 IVol. 131
335
and graphical form is of great help to the reader in examining the claims made for this herbal extract. The author assiduously pursues the theme that many of the actions of the extract are multivalent, i.e. the clinical response is the net effect of interactions between the various biologically active principles. As a generalization of the reported data, this conclusion is sustained. However, there is emerging evidence, at least from animal studies, that the PAF antagonists used alone may have application in the treatment of ischaemic disorders. The nootropic actions of Gingko biloba extract are undoubtedly the most controversial aspect of the clinical claims for this agent, and the relevant literature is critically reviewed in detail. Some perplexing data on the safety of the Gingko biloba extract are discussed. It appears that despite an increase in use of the extract of at least tenfold between 1983 and 1988, the incidence of reported adverse reactions has remained constant. Moreover, in a double-
blind, placebo-controlled
clinical
trial, Gingko biloba extract appeared to have no more adverse effects than placebo treatment. Not so much a magic bullet as a magic cartridge of shotgun pellets! Finally, I am not entirely convinced that a more orthodox approach (for the purposes of a reductionist pharmacologist) involving the isolation of the most active constituents, optimization of their potency and selectivity,
and their recombination at optimal dose leveis, would not provide a superior therapeutic regimen. Nevertheless, the major aim of this book to provide a synthesis of existing data and a framework for future studies has been achieved in a lucid manner.
Desperately seeking definition
rats exposed to a wide variety of insults responded with adrenocortical hypertrophy and he formulated from these findings a theory giving promir.ence to corticosteroids. Walter Cannon, from his separate line of investigation, concluded that catecholamine release was the pharmacological hallmark of stress. He used the phrase ‘the necessities of fighting or flight’, to describe the acute protective functions of adrenergic activation, a phrase that has passed into common language as the ‘fight or flight’ response. These days we have
Perturbing the Organism: The Biology of Stressful Experience by Herbert Weiner, University of Chicago Press, 1992. $35.00 (xiii + 351 pages) ISBN 0 226 89041 4 The ghosts of Cannon and Selye haunt nearly every page of this volume on stress, locked in immortal combat over the pharmacological correlates of this commonly used but poorly formulated concept. Hans Selye showed that
A. G. STEWART Deparhnent
Melbourne, Australia.
of Physiology, Parkville,
Uniuersity
Victoria
of
3052,