A medical herbalist would prescribe Ginkgo for the following: to increase blood flow, tissue oxygenation and tissue nutrition, platelet-activation factor (PAF) antagonism, as an antioxidant i.e. prevention of membrane damage caused by free radicals, enhances memory and cognitive function, especially in the elderly, and its use is associated with an increase in longevity
Abstract
Ginkgo Biloba is one of the most researched medicinal herbs in the last 20 years. With wonderful results from the research time and time again it opens the gate for more detailed research to better understand how this amazing herb works and what human conditions it can treat. As the research is being updated on a weekly basis for Ginkgo the purpose of this literature review is to highlight the most significant clinical trials carried out on ginkgo while presenting the most recent research from En vitro and En vivo animal and human trials, conducted on Ginkgo or one of its extracts . The majority of the pharmacological studies and clinical trials have been conducted using a special concentrated standardized extract called EGb761, which is chemically complex, containing at least 26 identified components and standardized to contain 24% flavonoid glycosides (Ginkgo flavone glycosides) and 6% terpinoids (ginkgolides and bilbalide)
Introduction
Ginkgo Biloba is a deciduous tree which has survived unchanged for about 150 million years. The living fossil may have been saved from extinction by the Chinese who revered the tree and planted it along their temples. In the 1960s a group of German scientists were investigating the effects of exotic herbs on circulation and found that the leaves of Ginkgo were particularly active. A special highly concentrated extract standardized for flavonoid content was patented soon after. In the years that followed standardized extracts of Ginkgo leaves became widely used in Europe.(1) Though there is some evidence to confirm the use of the nuts of the ginkgo tree in Chinese tradition, remarkably Ginkgo leaves are one of the few medicinal herbs with no traditional use.
Since its discovery in the 1960’s a number of constituents in the leaves have been the focus of scientists. The phytochemical constituents of most interest are the Terpene lactones (terpenoids), including bilobalide and ginkgolides A, B, C, J; the Bioflavonoids, ginkgolic acid, sterols, procyanidins and polysaccharides and Flavones: quercetin, Kaempferol and isorhamnetin and coumaric acid esters of flavonoids. As a result of this research, today Ginkgo is mainly prescribed to increase blood flow, for tissue oxygenation and tissue nutrition, platelet-activation factor (PAF) antagonism, prevention of membrane damage caused by free radicals and enhancing memory and cognitive function, especially in the elderly.(1)
Human Trials
Dementia:
In a randomised, double-blind, controlled trial by Mazza et al in 2006, a standardised Ginkgo extract was as efficacious as the cholinesterase inhibitor donepezil in the treatment of mild to moderate Alzheimer's dementia(2). Patients received one of three treatments: standardised Ginkgo extract (160 mg/day), donepezil (5 mg/day) or placebo for a period of 24 weeks, after first having undergone a 4-week run-in phase to exclude placebo-responders. Outcome measures included MMSE (Mini-Mental State Examination), SKT (Syndrome Kurz test) and CGI (Clinical Global Impression) which are the most common tests used in the clinical evaluation of cognitive impairment. Both treatments (Ginkgo and donepezil) produced significant improvement from baseline for the SKT and CGI. These results also showed a significant difference when compared with the placebo group. No difference in response was found between the Ginkgo and donepezil groups. Adverse events were recorded for those patients receiving donepezil but not for Ginkgo. The trial included a small number of patients (n =60). The authors concluded that Ginkgo is as efficacious as donepezil in the treatment of mild to moderate Alzheimer's dementia, and has a lower side effect profile, and that a trial with larger numbers should be preformed to confirm this result. In a number of similar studies the efficacy of four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 in Alzheimer's disease were compared(3). The differences in the effects of the active substance and placebo on cognition were measured on the ADAS-Cog scale, taking into account the different degrees of dementia in the various studies and the dropout rate due to adverse drug reactions. Efficacy, expressed as the delay in symptom progression or the difference in response rate between active substance and placebo, showed no major differences between the four cholinesterase inhibitors and the Ginkgo special extract. Only tacrine exhibited a high dropout rate due to adverse drug reactions. In view of this, the subject of new prescriptions should be critically reviewed. Second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 should be considered equally effective in the treatment of mild to moderate Alzheimer's dementia. Le Bars et al conducted a 52-week randomised, double-blind, placebo controlled, multicentre study involving 309 patients with mild to severe dementia from Alzheimer’s disease or multi-infarct dementia(4). Treatment with EGb 761(120 mg/day) stabilized the condition in a substantial number of cases, improving cognitive performance and social functioning. Although the visible effects were described as modest, they were sufficiently noticeable to the caregivers. Moreover, safety over this period was established. Another trial by Le Bars et al explored the treatment effect of EGb 761 in Alzheimer's disease depending on baseline severity, in an intent-to-treat data set collected during a 52-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study with 120 mg of EGb (n = 236)(5). The results of this retrospective analysis indicated that a treatment effect favorable to EGb could be observed with respect to cognitive performance (p = 0.02) and social functioning (p = 0.001) regardless of the stage of dementia, whether mild or moderately severe. The authors concluded that the relative changes from baseline measured at endpoint depended heavily on the severity at baseline. Improvement was observed in the group of patients with very mild to mild cognitive impairment, while in more severe dementia, the mean EGb effect should be considered more in terms of stabilization or slowing down of worsening, as compared to the greater deterioration observed with placebo A 1998 meta-analysis of clinical trials using Ginkgo biloba for Alzheimer’s disease concluded that a small but significant effect occurred after 3-6 months of treatment with 120-140mg of Ginkgo extract on objective measures of cognitive function(6). In another study to determine the clinical efficacy of GbE on 513 outpatients of mild to moderate dementia of the Alzheimer type(7), Schneider et al concluded that the trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE. In a study on health individuals Mix et al examined the effectiveness of Ginkgo biloba extract for enhancing cognitive abilities in 48 individuals with no history of significant neurocognitive dysfunction. The purpose of this research was to examine the relatively short-term (i.e., 6 weeks) efficacy of EGb 761 on the cognitive functioning of cognitively intact persons over the age of 55 years via a diverse battery of neuropsychologic tests and measures(8). Participants were randomly assigned to either EGb 761 (180 mg/d) or placebo control group. Participants who received 180 mg of EGb 761 daily for 6 weeks exhibited significantly more improvement on a task assessing speed of processing abilities by the end of treatment as compared to participants who received placebo, also more participants in the Ginkgo biloba extract group rated their overall abilities to remember by the end of treatment as "improved," as compared to the placebo group. Mix concluded that the findings from standardized neuropsychologic assessment and a subjective, self-report questionnaire suggested that relatively short-term (i.e., 6 weeks) utilization of EGb 761 may prove efficacious in enhancing certain neurocognitive functions/processes of cognitively intact older adults. More recently a study on EGb761 was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years(9). The authors concluded that Ginkgo treatment has a valid place in caretaking structure of health services. Ginkgo attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.
Vascular disease:
Ginkgo has demonstrated an inhibitory effect on nanoplaque formation. For a period of 2 months eight patients who had undergone an aortocoronary bypass operation received standardised Ginkgo extract (120 mg, twice daily)(10). Analysis of blood samples indicated a reduction of atherosclerotic nanoplaque formation of 11.9% from baseline. Nanoplaque size was reduced to 24.4%, and the concentration of lipoprotein(a), an atherothrombotic risk factor was decreased by 23.4%. The free radical scavenging activity of Ginkgo reduced the amount of oxidized low-density lipoprotein. (Nanoplaque generation represents the very earliest stages of an atherosclerotic plaque, which consists of proteoglycan-receptor, lipoprotein and calcium). Treatment with Ginkgo may have partially repaired endothelial dysfunction at the very earliest stages in atherosclerosis. The discovery that Ginkgo can cause a marked reduction in lipoprotein(a) is potentially a significant development in the management of cardiovascular risk with natural agents. Some cases of spontaneous bleeding have been reported in patients treated with Ginkgo biloba. A prospective, double-blind, randomized, placebo-controlled study was carried out in 32 young male healthy volunteers to evaluate the effect of three doses of Ginkgo biloba extract (120, 240 and 480 mg/day for 14 days) on hemostasis, coagulation and fibrinolysis(11). This study did not reveal any alteration of platelet function or coagulation. This suggests that the reported clinical bleeding events in patients receiving Ginkgo biloba extract are not related to pharmacological properties of EGb761. It should be noted that the study period was deemed too short for Ginkgo to create an affect on coagulation. Qualified herbalists will always prescribe Ginkgo as long term treatment to create an anti - platelet-activation factor effect. Pittler et al performed a meta-analysis of the efficacy of Ginkgo biloba extract for intermittent claudication (typically an aching pain, cramping, or numbness in the calf, buttock, hip, thigh, or arch of the foot – due mainly to Peripheral arterial disease) based on the results of randomized, placebo-controlled, double-blind trials(12). Eight randomized, placebo-controlled, double-blind trials were included. Meta-analysis found a significant difference in the increase in pain-free walking distance in favour of Ginkgo biloba. Adverse effects were rare, mild, and transient. Pittler concluded that these results suggest that Ginkgo biloba extract is superior to placebo in the symptomatic treatment of intermittent claudication. However, the size of the overall treatment effect is modest and of uncertain clinical relevance. In a randomized, placebo-controlled, double-blind, parallel study of 20 patients, the antiischemic effect of EGb 761 was studied by measuring the transcutaneous partial pressure of oxygen (TcPo2) during exercise(13) This provides an estimation of local arterial perfusion and local and regional capillary perfusion. It was found that a 320mg dose of EGb761 taken for four weeks decreased the amount of ischaemic area by 38% compared to no change in the placebo group – a statistically significant difference.
Other conditions:
A 1999 systematic review of five randomised, controlled trials suggests that treatment with Ginkgo biloba may result in significant improvements in tinnitus(14). Conditions of shorter duration appeared to have a better response, and tolerability was excellent.
A previous study suggested that Ginkgo biloba extracts (GBE) have estrogenic activity and might be suitable as an alternative to HRT. However, there are no reports of the preventive effect of GBE on breast cancer, which is the side effect of classical HRT. In a study by Oh et al it was confirmed that GBE exhibits estrogenic and antiestrogenic activity depending on the E2 and GBE concentration, via estrogen receptor (ER)-dependent and ER-independent pathways(15). In conclusion, GBE has a biphasic effect on estrogen, and can be considered as a potential alternative to HRT with chemopreventive effects on breast cancer. However, further studies on animals and humans will be required.
In previous studies EGb 761 had been found to alleviate symptoms of anxiety in people with mental decline. Woelk et al therefore tested for clinical efficacy in younger patients suffering from anxiety. One hundred and seven patients with generalized anxiety disorder (GAD, n=82) or adjustment disorder with anxious mood (ADWAM, n=25) according to the diagnostic and statistical manual of mental disorders, third edition - revised (DSM-III-R) were randomized to daily doses of 480mg EGb 761, 240mg EGb 761 or placebo for 4 weeks(16). EGb 761 was significantly superior to placebo on all secondary outcome measures. It was safe and well tolerated and may thus be of particular value in elderly patients with anxiety related to cognitive decline.
In a pilot study by Johnson et al it was to determined whether a EGb 761 improved functional performance in individuals with Multiple Sclerosis(17). This study used a double-blind, placebo-controlled, parallel group design where half of the subjects received 240 mg per day of EGb 761, and the other half received placebo. The authors concluded that this exploratory pilot study showed that no adverse events or side effects were reported and that ginkgo exerted modest beneficial effects on select functional measures (eg, fatigue) among some individuals with MS.
Wolf et al conducted a study to determine whether EGb 761 amplifies the known effects of acetylsalicylic acid (ASA) on platelet aggregation, bleeding time or other coagulation parameters in healthy subjects(18). In a double-blind, double-dummy procedure, 50 healthy male subjects (20-44 years) were randomly allocated in equal numbers to one of two possible treatment sequences, i.e. ASA followed by ASA + EGb 761 or ASA + EGb 761 followed by ASA. Each treatment lasted 7 days; the washout period between treatments was 3 weeks. Study medication was taken twice daily (ASA group: ASA 500 mg tablet + placebo-coated tablet in the morning and placebo tablet + placebo-coated tablet in the evening; ASA + EGb 761 group: ASA 500 mg tablet + EGb 761 120 mg-coated tablet in the morning and placebo tablet + EGb 761 120 mg-coated tablet in the evening), resulting in a daily dose of ASA 500 mg in the ASA group and 500 mg ASA + 240 mg EGb 761 in the ASA + EGb 761 group. The findings suggest that co-administration of ASA and EGb 761 does not constitute a safety risk, including in an elderly patient population undergoing treatment with EGb 761.
EGb 761 has been shown to ameliorate some defects associated with the insulin resistance syndrome and so patients with Type 2 diabetes mellitus (T2DM) may be inclined to co-ingest the herb with their medications, such as metformin. A study by Kudolo et al was designed to determine if the co-ingestion of EGb 761 and metformin would alter the pharmacokinetic properties of metformin in T2DM patients and persons without diabetes, who may ingest it for other purposes(19). The co-ingestion of 120 mg of EGb 761 and 500 mg of metformin did not significantly affect the pharmacokinetic properties of metformin. Further studies are required to verify this observation for smaller and larger dose of metformin with other doses of EGb 761, since T2DM patients on medication constitute a very heterogeneous group.
Ingestion of EGb 761 may increase pancreatic beta-cell function in both healthy subjects with normal glucose tolerance (NGT) as well as patients with Type 2 Diabetes mellitus (T2DM). Since hyperinsulinemia is a hallmark of T2DM, a study was conducted to verify that increased insulin production is not due to increased insulin resistance(20). It studied 28 individuals for a 3 month period. Kudolo et al concluded that the ingestion of 120 mg of EGb 761 as a single for 3 months did not produce insulin resistance in the non-diabetic or pre-diabetic subjects or exacerbate the disease in the T2DM subjects.
Several studies have tested the efficacy of ginkgo biloba using compromised visual systems and have found improvement in vision. Page et al measured functional changes in the visual system of older, healthy adults to see if ginkgo extract EGb 761 would increase performance in the normal visual system(21). The results suggest that the higher order processing stages of visual response, which may be influenced by cognition, decline more rapidly than do lower level processing stages in healthy adults as a function of age, and that the use of ginkgo biloba extract may improve the functioning of this system.
En Vivo animal studies
Antioxidant effects:
An experimental study was to investigate the effect of standardized preparation of EGb 761 on the hyperlipidemic nephrotoxicity and oxidative stress induced by a single intravenous injection (5 mg/kg) of adriamycin on rats(22). It was shown that EGb 761 was received daily thereafter by a gavage at the dose of 100 mg/kg for 35 consecutive days. EGb 761 administration significantly attenuated adriamycin-induced renal dysfunction as assessed by estimating serum lipid profile, serum total protein, serum urea, and creatinine clearance. EGb 761 was studied for its nephroprotective effects in experimentally diabetic and hypoxic rats(23). The daily dose of 100mg EGb/kg bodyweight started 1 month after induction of the diabetes. EGb reduced the relative total symptoms of diabetes(SOD) activity from 163% in diabetic kidney to 46%. Additional hypoxia-induced ultrastructural damage was also diminished. A study was carried out to determine if EGb 761 exerts a beneficial effect against cisplatin-induced renal failure in rats(24) In conclusion EGb 761 has been shown to protect against cisplatin-induced nephrotoxicity.
Other Conditions:
Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. In a study(25), Walesiuk et al investigated the efficacy of EGB 761 in prevention and treatment of the post-stress memory dysfunctions. Preventive doses of EGB 761 (100 mg kg(-1)), given 30 min before each restraint stress episode or corticosterone injection, abolished cognitive deficits seen in unprotected rats
He et al conducted a study to test the effects of extract from Ginkgo biloba (EGb) containing 22% flavonoid and 5% terpenoid on chronic liver injury and liver fibrosis of rats induced by carbon tetrachloride (CCl(4)).(26) It was concluded that EGb resists oxidative stress and thereby reduces chronic liver injury and liver fibrosis in rats with liver injury induced by CCl(4).
An experimental animal model was used to assess spinal cord injury following lateral hemitransection at thoracic spinal cord level to determine whether EGb could have a neuroprotective effect in spinal cord injury (SCI)(27). It was concluded that EGb 761 could inhibit iNOS expression and have neuroprotective effect by preventing nerve cells from apoptosis after SCI in rats.
Conclusion
As one can see, the herb Ginkgo biloba and more specifically EGb761 is a remarkable medicine with multiple applications. The research is ongoing and is moving at a rapid pace. I feel Ginkgo has already established its place as a possible front line medicine for treating Dementia and vascular disease, and with the continuous positive results form more current research I feel it will soon be established for use in the treatment and prevention of oxidative stress and possible many more common health problems.
To obtain Ginkgo biloba standardized extract EGb761 contact the clinic on (+353)0719142940
References
(1) Bone K, A Clinical guide to blending liquid herbs, st. louis, Missouri 63146 USA, 375-378 , 2003 :Churchill Livingstone
(2) [Abstract] Mazza M, Capuano A, Bria P et al. ‘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): 981-985
(3) Wettstein A. ‘Cholinesterase inhibitors and Gingko extracts--are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration’ Phytomedicine Jan 2000; 6(6):393-401)
(4) Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. ‘A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group’ JAMA ; 278(16):1327-32
(5) Le Bars PL, Velasco FM, Ferguson JM, Dessain EC, Kieser M, Hoerr R. ‘Influence of the severity of cognitive impairment on the effect of the Gnkgo biloba extract EGb 761 in Alzheimer's disease’ Neuropsychobiology 2002; 45(1):19-26
(6) Oken BS, Storzbach DM, Kaye JA. ‘The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease’ Arch Neurol Nov 1998; 55(11):1409-15
(7) 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 Dec 2005; 2(5):541-51
(8) Mix JA, Crews WD. ‘An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults’ J Altern Complement Med Jun 2000; 6(3):219-29)
(9) [Abstract] Heinen-Kammerer T, Motzkat K, Daniel D, Gertz HJ, Koller M, Lorenz W, Pilartz H, Zimmer B, Habs M, von den Driesch V, Rychlik R. ‘The situation of patients with dementia may be rectified by Ginkgo biloba. Results of a health services research study concerning the ability of patients with dementia, quality of life of the nursing family members and total treatment costs’ MMW Fortschr Med Oct 2005; 147 Suppl 3:127-33
(10)[Abstract] Schafer P, Rodriguez M, Just S et al. ‘The effect of Ginkgo biloba (EGb 761) on arteriosclerotic nanoplaque formation and size in a long-term clinical trial’ Desalination 2006; 191: 426-431
(11) Bal Dit Sollier C, Caplain H, Drouet L. ‘No alteration in platelet function or coagulation induced by EGb761 in a controlled study’ Clin Lab Haematol Aug 2003; 25(4):251-3)
(12) [Abstract] Pittler MH, Ernst E. ‘Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials’ Am J Med Mar 2000; 108(4):276-81)
(13) Mouren X, Caillard P, Schwartz F. ‘Study of the antiischemic action of EGb 761 in the treatment of peripheral arterial occlusive disease by TcPo2 determination’ Angiology Jun 1994; 45(6):413-7
(14) [Abstract] Ernst E, Stevinson C. ‘Ginkgo biloba for tinnitus: a review’ Clin Otolaryngol Allied Sci Jun 1999; 24(3):164-7)
(15) Oh SM, Chung KH. ‘Antiestrogenic activities of Ginkgo biloba extracts’ J Steroid Biochem Mol Biol Aug 2006; 100(4-5):167-76
(16) [Abstract] Woelk H, Arnoldt KH, Kieser M, Hoerr R. ‘Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: A randomized, double-blind, placebo-controlled trial’ J Psychiatr Res Jun 2006;
(17) [Abstract] Johnson SK, Diamond BJ, Rausch S, Kaufman M, Shiflett SC, Graves L. ‘The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial’ Explore (NY) Jan 2006; 2(1):19-24
(18) Wolf HR. ‘Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily?’ Drugs R D 2006; 7(3):163-72
(19) Kudolo GB, Wang W, Javors M, Blodgett J. ‘The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharmacokinetics of metformin in non-diabetic and type 2 diabetic subjects--a double blind placebo-controlled, crossover study’ Clin Nutr Aug 2006; 25(4):606-16
(20) [Abstract] Kudolo GB, Wang W, Elrod R, Barrientos J, Haase A, Blodgett J. ‘Short-term ingestion of Ginkgo biloba extract does not alter whole body insulin sensitivity in non-diabetic, pre-diabetic or type 2 diabetic subjects--a randomized double-blind placebo-controlled crossover study’ Clin Nutr Feb 2006; 25(1):123-34
(21) [Abstract] Page JW, Findley J, Crognale MA. ‘Electrophysiological analysis of the effects of ginkgo biloba on visual processing in older healthy adults’ J Gerontol A Biol Sci Med Sci Oct 2005; 60(10):1246-51
(22) Abd-Ellah MF, Mariee AD. ‘Ginkgo biloba leaf extract (EGb 761) diminishes adriamycin-induced hyperlipidemic nephrotoxicity in rats: association with nitric oxide production’ Biotechnol Appl Biochem Jul 2006
(23) Welt K, Weiss J, Martin R, Hermsdorf T, Drews S, Fitzl G. ‘Ginkgo biloba extract protects rat kidney from diabetic and hypoxic damage’ Phytomedicine Jun 2006;
(24) Gulec M, Iraz M, Yilmaz HR, Ozyurt H, Temel I. ‘The effects of ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity’ Toxicol Ind Health Apr 2006; 22(3):125-30
(25) Walesiuk A, Trofimiuk E, Braszko JJ. ‘Ginkgo biloba normalizes stress- and corticosterone-induced impairment of recall in rats’ Pharmacol Res Feb 2006; 53(2):123-8
(26) He SX, Luo JY, Wang YP, Wang YL, Fu H, Xu JL, Zhao G, Liu EQ. ‘Effects of extract from Ginkgo biloba on carbon tetrachloride-induced liver injury in rats’ World J Gastroenterol Jun 2006; 12(24):3924-8
(27) Ao Q, Sun XH, Wang AJ, Fu PF, Gong K, Zuo HZ, Gong YD, Zhang XF. ‘Protective effects of extract of Ginkgo biloba (EGb 761) on nerve cells after spinal cord injury in rats’ Spinal Cord Jan 2006
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