Nootropics: Efficacy and tolerability of products from three active substance classes
Journal of Drug Development and Clinical Practice (United Kingdom), 1996, 8/2 (77-94)
This paper reviews and evaluates all the currently available clinical trials on the efficacy of three nootropics. Only randomised, double-blind, placebo- controlled clinical trials were taken into account which produced 44 studies allowing comparison of the patient populations, efficacy and tolerability of Ginkgo biloba special extracts, nimodipine and tacrine. Taking all the studies together, statistically significant results were obtained at three relevant levels of efficacy (psychopathological, psychometric, behavioural) for all three substances. Nine studies produced significant results at all three efficacy levels. One study on Ginkgo biloba and one on tacrine also produced significant rerationalised diagnosis of dementia, inclusion of mild-to- moderate cases, statistical proof at all three levels of efficacy and global clinical evaluation). The clinical efficacy of all three substances has thus been demonstrated.
The effect of ginkgo biloba glycoside on the blood viscosity and erythrocyte deformability
Clinical Hemorheology (USA), 1996, 16/3 (271-276)
In this study, we investigated the effect of ginkgoglycoside in two different doses (19.2 mg/day and 28.8 mg/day) on blood viscosity and erythrocyte deformability in 27 patients suffering from cerebrovascular insufficiency. The patients were divided into two groups randomly consisting of 13 and 14 patients respectively. Both groups received 28.8 mg/day ginkgoglycoside between the 1st and 15th day. The first group received the same dose until the end of the 30th day, whereas the dose administrated to the second group was reduced to 19.2 mg/day. In the first group, during 30 days a significant decrease in blood viscosity and a significant increase in erythrocyte deformability were observed. In the second group on the other hand, after dose reduction, the effect of the drug on blood viscosity and erythrocyte deformability were diminished. Improvement of symptoms including vertigo, tinnutus, headache and forgetfulness in the first group was found to be significantly different from the 2nd group at day 30 in a dose dependent manner.
Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats
Audiology and Neuro-Otology (Germany), 1997, 2/4 (197-212)
The effects of an extract from Ginkgo biloba, EGb 761, on tinnitus were tested using an animal model of tinnitus. Daily oral administration of Egb 761 in doses from 10 to 100 mg/kg/day began 2 weeks before behavioral procedures and continued until the end of the experiment. Tinnitus was induced by daily administration of 321 mg/kg sodium salicylate s.c. (corresponding to 275 mg/kg/day of salicylate acid) in fourteen groupsgmented rats, 6 animals/group. The results from salicylate- and EGb-761- treated animals were compared to control groups receiving either salicylate, saline, or EGb 761 only in doses of 100 mg/kg. Administration of EGb 761 resulted in a statistically significant decrease of the behavioral manifestation of tinnitus for doses of 25, 50 and 100 mg/kg/day.
The treatment of acute cerebral ischemia. Ginkgo: Free radical scavenger and PAF antagonist
THERAPIEWOCHE (Germany), 1994, 44/24 (1394-1396)
There exists no generally recommended treatment concept concerning actue cerebral ischemia. In the presented study we have investigated safety and side effects of intravenously applicated Ginkgo biloba (EGb 761) in patients with an acute ischemic stroke. 20 patients with an acute cerebral infarction in the territory of medial cerebral artery were treated with Egb 761 (Tebonin) within 224 hours after the acute onset of the neurological symptoms. The symptoms improved significantly in 16 of 20 patients during an average observation period of three weeks. There was no fatal outcome. 10 patients recovered completelyor nearly completely. There were no side effects related to the therapy in the investigated population. Treatment of acute ischemic stroke with EGb 761 appears rational from theoretical reasons: EGb 761 has to be regarded as a scavenger of free radicals and in an antagonist of the platelet-activating factor. The efficacy of this treatment in acute stroke should be investigated in ongoing randomized trials.
Efficiency of ginkgo biloba extract (EGb 761) in antioxidant protection against myocardial ischemia and reperfusion injury
Biochemistry and Molecular Biology International (Australia), 1995, 35/1 (125-134)
The cardio-protective mechanisms of EGb 761, an extract of Ginkgo biloba leaves, on myocardial ischemia reperfusion injury were investigated using rabbits subjected to 30 minutes of regional cardiac ischemia and 120 min of reperfusion under anesthesia. Compared to the saline perfused group, Egb 761 treatment (10 mg/kg, injected into the coronary artery) significantly inhibited the increase in lipid peroxidation and maintained total and CuZn-SOD levels in both plasma and tissue during and at the end of reperfusion. Both the decrease in tissue type plasminogen activator (t-PA) and the increase in plasminogen activator inhibitor-1 (PAI-1) caused by ischemia-reperfusion were also significantly suppressed by EGb 761 treatment. Furthermore, the ultrastructure of the myocytes of the EGb 761 treated heart was slightly damaged after ischemia- reperfusion, while the control ischemic-reperfused hearts demonstrated severe histological damages such as swelling and vacuolization of the mitochondria. These results suggest that Egb 761 protects hearts by its antioxidant properties and by its ability to adjust fibrinolytic activity.
Neuroprotective properties of Ginkgo biloba - Constituents
Z. PHYTOTHER. (Germany), 1994, 15/2 (92-96)
More than 10 years ago it has been demonstrated, that an extract of the leaves of Ginkgo biloba (EGb 761) clearly increased the local cerebral blood flow and the tolerance against hypoxia in rats and mice. Using various models of cerebral ischemia and cultured neurons in vitro ginkgolides A and B as well as bilobalide were shown to be neuroprotective. The ginkgolides are known to be antagonists of the platelet activating factor (PAF) and this activity could be responsible for their neuroprotective potency. Bilobalide reduced the infarct size after focal cerebral ischemiia of mice and rats more efficaciously than the ginkgolides A and B and was capable of protecting neurons and astrocytes against damage, however, its mechanism of action however is still unknown.
Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: Effect of ginkgo biloba extract
Pharmacological Research (United Kingdom), 1995, 32/5 (273- 278)
The influence of ginkgo biloba extract on the lipid peroxide product (malondialdehyde, MDA), glutathione (GSH) and phospholipids levels as well as superoxide dismutase (SOD, 126.96.36.199) and lactate dehydrogenase (LDH, 188.8.131.52) activities in rat brain after occlusion of common carotid arteries was investigated. Two experimental models were studied: 60 min ischaemia without reperfusion and 60 min ischaemia followed by 60 min reperfusion. Compared to sham- operated animals, ischaemia followed by reperfusion increased cytosolic LDH activity and mitochondrial lipid peroxide content and decreased the superoxide dismutase activity and mitochondrial total phospholipids level. Preischaemic administration of ginkgo biloba extract (150 mg kg-1, p.o.) could normalize the SOD activity of the rat brain. The extract was also able to reduce the lipid peroxide and phospholipids contents of the mitochondrial rat brain. These effects could be explained on the basis of the antioxidant property of ginkgo biloba extract and suggests its beneficial role in the protection against post-ischaemic injury.
Protection of hypoxia-induced ATP decrease in endothelial cells by ginkgo biloba extract and bilobalide
Biochemical Pharmacology (United Kingdom), 1995, 50/7 (991- 999)
Due to their localization at the interface between blood and tissue, endothelial cells are the first targets of any change occurring within the blood, and alterations of their functions can seriously impair organs. During hypoxia, which mimics in vivo ischemia, a cascade of events occurs in the endothelial cells, starting with a decrease in ATP content and leading to their activation and release of inflammatory mediators. EGb 761 and one of its constituents, bilobalide, wereshown to inhibit the hypoxia-induced decrease in ATP content in endothelial cells in vitro. Under these conditions, glycolysis was activated, as evidenced by increased glucose transport, as well as increased lactate production. Bilobalide was found to increase glucose transport under normoxic but not hypoxic conditions. In addition, EGb and bilobalide prevented the increase in total lactate production observed after 60min of hypoxia. However, after 120 min of hypoxia, the total lactate production was similar under normoxic and hypoxic conditions, and both compounds increased this production. These results indicate that glycolysis slowed down between the 60th and 120th minute of hypoxia, while EGb and bilobalide delayed the onset of glycolysis activation. In another experimental model, both compounds were shown to increase the respiratory control ratio of mitochondria isolated from liver of rats treated orally. Since ischemia is known to uncouple mitochondria, the protection of ATP content and the delay in glycolysis activation observedduring hypoxia in the presence of EGb 761 or bilobalide is best explained by a protection of mitochondrial respiratory activity, at least during the first 60 min of hypoxia incubation. Both products retain the ability to form ATP, thereby reducing the cell's need to induce glycolysis, probably by preserving ATP regeneration by mitochondria as long as oxygen is available.
Lipid peroxidation in experimental spinal cord injury. Comparison of treatment with Ginkgo biloba, TRH and methylprednisolone
Research in Experimental Medicine (Germany), 1995, 195/2 (117-123)
Ischaemia-induced lipid peroxidation is one of the most important factors producing tissue damage in spinal cord injury. In our study, the protective effects of Ginkgo biloba, thyroid releasing hormone (TRH) and methylprednisolone (MP) on compression injury of the rat spinal cord were investigated. For this study 45 rats in four groups, including control, MP, TRH and Gingko biloba, were used to determine the formation of malondialdehyde (MDA). All the animals were made paraplegic by the application clip method of Rivlin and Tator. Rats were divided randomly and blindly to one of four treatment groups (ten animals in each). MP and Ginkgo biloba treatments significantly decreased MDA levels (F=54.138, P<0.01). These results suggest that MP and Ginkgo biloba may have a protective effect against ischaemic spinal cord injury by the antioxidant effect.
Effects of natural antioxidant Ginkgo biloba extract (EGb 761) on myocardial ischemia-reperfusion injury
FREE RADIC. BIOL. MED. (USA), 1994, 16/6 (789-794)
Recently, it was reported that Ginkgo bilboa extract (EGb 761), which is known to have antioxidant properties, also has antiarrhythmic effects on cardiac reperfusion-induced arrhythmias. In the present study, effects of EGb 761 on cardiac ischemia-reperfusion injury were investigated from the point of view of recovery of mechanical function as well as the endogenous antioxidant status of ascorbate. Isolated rat hearts were perfused using the Langendorff technique, and 40 min of global ischemia were followed by 20 min of reperfusion. EGb 761 improved cardiac mechanical recovery and suppressed the leakage of lactate dehydrogenase LDH) during reperfusion. Furthermore, EGb 761 diminished the decrease of myocardial ascorbate content after 40 min of ischemia and 20 min of reperfusion. Interestingly, EGb 761 also suppressed the increase of dehydroascorbate. These results indicate that EGb 761 protects against cardiac ischemia-reperfusion injury and suggest that the protective effects of EGb 761 depend on its antioxidant properties.
Experimental model of cerebral ischemia. Preventive activity of Ginkgo biloba extract
SEM. HOP. (FRANCE), 1979, 55/43-44 (2047-2050)
Unilateral embolization of the brain was performed in rats by intracarotid injection of 4000 radioactive microspheres (50 mu). Local blood flow in hippocampus, striatum, hypothalamus and remainder of the brain were determined using the iodoantipyrine technique. Embolization resulted in a decrease in blood flow and modification of lthe distribution of microflow. Furthermore, embolization produces changes in energy metabolism: particularly a fall in ATP and glucose levels and an increase in lactate level. Subsequently, severe vasogenic edema development. There was a correlation between the number of microspheres injected and the amount of edema. Pretreatment using an extract of Ginkgo biloba leaves partially suppressed the effect of embolization. An improvement of the flow in the ischemic areas associated with an improvement of the energy metabolism explain the decrease of the edema.
Myocardium-protective effects of Ginkgo biloba extract (EGb 761) in old rats against acute isobaric hypoxia. An electron microscopic morphometric study. II. Protection of microvascular endothelium.
Welt K; Fitzl G; Schaffranietz L. Institute of Anatomy, University Leipzig, Germany. Exp Toxicol Pathol (GERMANY) Jan 1996, 48 (1) p81-6
Aim of this electron microscopic morphomere protective properties of Gin kgo biloba extract EGb 761 on myocardial microvessels of old rats during acute hypoxic stress. Hypoxia of 20 minutes duration with N2O/O2 mixture (5 vol% O2) was performed using a hypoxia chamber combined with a commercial narcosis apparatus. EGb 761-pretreatment diminished significantly the percentage of endothelial cells exhibiting edema, luminal blebs and of capillaries surrounded by pericapillary debris. Hypoxia-related decrease in plasmalemmal vesicle frequency was prevented by EGb 761, formation of vacuoles non significantly diminished against the hypoxic group. Volume density of mitochondrial cristae was significantly less diminished, the volume fraction of degenerated areas less increased in the EGb 761-protected group. The results give some evidence that EGb 761 protects endothelial cell ultrastructure of myocardial microvasculature against hypoxic alterations, probably by its radical scavenging properties.
Myocardium-protective effects of Ginkgo biloba extract (EGb 761) in old rats against acute isobaric hypoxia. An electron microscopic morphometric study. I. Protection of cardiomyocytes.
Fitzl G; Welt K; Schaffranietz L. Institute of Anatomy, University Leipzig, Germany. Exp Toxicol Pathol (GERMANY) Jan 1996, 48 (1) p33-9
Ginkgo biloba extract EGb 761 was used in hypoxia experiments with old rats to investigate its ultrastructure-preserving effects on the myocardium. Hypoxia was performed by means of a hypoxia chamber combined with a commercial narcosis apparatus. N2O/O2- mixture was applied with O2 at 5 vol.% for 20 minutes under normobaric conditions. Ultrastructural-morphometric analysis revealed that Egb 761-pretreatment was able to diminish hypoxic damage at mitochondrial cristae and matrix and also distension of the sarcoplasmic reticulum during acute hypoxic stress. Whereas formation of vacuoles was depressed below thed. The preservation of mitochondrial cristae was confirmed by independent secondary morphometric parameters and by cytophotometrically measured activities of mitochondrial enzymes.
Treatment of senile macular degeneration with Ginkgo biloba extract. A preliminary double-blind, drug versus placebo study
PRESSE MED. (FRANCE), 1986, 15/31 (1556-1558)
Senile macular degeneration is a frequent cause of blindness for which there is no satisfactory medical treatment. A double-blind trial comparing Ginkgo biloba extract with placebo was conducted in 10 out-patients at the Hopital Foch. Drug effectiveness was assessed on the results of fundoscopy and of measurements of visual acuity and visual field. In spite of the small population sample, a statistically significant improvement in long distance visual acuity was observed after treatment with Ginkgo biloba extract. The assumed pathogenesis of senile macular degeneration is discussed with emphasis on free oxygenated radicals.
[The influence on sound damages by an extract of ginkgo biloba]
Arch Otorhinolaryngol (UNITED STATES) Jul 8, 1975, 209 (3) p203-15
A fraction of Ginkgo biloba, used in experiments with animals ensured significantly the diminution of sound damages caused by white noise or by a pure tone of 4.5 kHz. Higher amplitudes of the acoustic nerve potentials show the protective effect of this fraction of Ginkgo biloba at acute sound damages. It is moreover possible to hold physiologically the adaptation of excitation of the hair cells of the organ of Corti by the fraction of Ginkgo biloba before andafter sound damage caused by white noise or during a pure tone of 4.5 kHz. The influence of the fraction of Ginkgo biloba can be seen by a significantly slower recovery of the noise damaged evoked potentials of the acoustic cortex. An efferent protective influence on the neurons of the acoustic cortex is discussed. The fraction of Ginkgo biloba in this form of solution has not been tested for clinical use but it seems to be rich in meaning.
[Ginkgo extract EGb 761 (tenobin)/HAES versus naftidrofuryl A randomized study of therapy of sudden deafness]
Laryngorhinootologie (GERMANY) Mar 1994, 73 (3) p149-52
80 patients with idiopathic sudden hearing loss existing no longer than 10 days were included in a randomised reference-controlled study. The therapeutic value of Ginkgo EGb 761 (Tebonin) + HAES was compared to that of Naftidrofuryl (Dusodril)+HAES. The main mechanisms of action of EGb 761 are a vasoregulating activity (increased blood flow), the platelet activating factor antagonism and a prevention of membrane damage caused by free radicals. Naftidrofuryl has antiserotonergic and therefore vasodilatory properties. The statistical analysis of the audiometric data was performed in measuring the relative hearing gain as described by Eibach 1979. After one week of observation, 40% of the patients in each group showed a complete remission of hearing loss. This was also observed by other authors who had compared other drugs. Therefore, in these cases, it is most likely that spontaneous recovery is the most important factor. After two and three weeks of observation, measuring the relative hearing gain, there was a significant borderline benefit of EGb 761 (p = 0.06) without any side effects. Some patients of the reference group developed side effects such as orthostatic dysregulation or headache or sleep disturbances. Minimising side effects should be one of the most important goals in therapy of sudden hearing loss until the efficiency of infusion therapy is proved.
[Therapeutic trial in acute cochlear deafness. A comparative study of Ginkgo biloba extract and nicergoline]
Presse Med (FRANCE) Sep 25 1986, 15 (31) p1559-61
Ischemia and the metabolic disorder it entails would seem to be the pathogenic mechanism behind acute cochlear deafness, irrespective of the triggering process. The prognosis is entirely dependent on the rapid initiation of an effective treatment. At the end of a double-blind therapeutic trial comparing Ginkgo biloba extract and a standard alpha blocker (nicergoline), a significant recovery was observed in both therapeutic groups, but improvement was distinctly better in the Ginkgo biloba group.
[Improvement of hemorheology with ginkgo biloba extract. Decreasing a cardiovascular risk factor]
Fortschr Med (GERMANY) May 10 1992, 110 (13) p247-50
STUDY DESIGN: Open prospective study. Patients: 20 outpatients with a long history of elevated fibrinogen levels and plasma viscosity, and a variety of underlying diseases.
INTERVENTION: Treatment with the special ginkgo biloba extract (Egb 761), 240 mg tablets a day for a period of 12 weeks.
RESULTS: The clinical diagnoses included coronary heart disease, hypertension, hypercholesterolemia and diabetes mellitus. A significant improvement in the fibrinogen levels and hemorrheological properties was seen. The medication can thus positively influence these cardiovascular risk factors over the long term.
Natural product formulations available in Europe for psychotropic indications
Psychopharmacology Bulletin (USA), 1995, 31/4 (745-751)
Until the middle of this century, development of medical treatment for human disease was intimately connected with the plant kingdom. Despite advances of the last three decades in utilizing chemical synthetic approaches to drug design and sophisticated structure-activity studies, there is still a great need for novel compounds with unique mechanisms of action in the field of medicine. While many thousands of structural analogs have been synthesized and tested, numerous gaps remain in the therapeutic armamentarium for psychiatric illnesses. Most new drugs marketed for psychotherapeutic indications in recent years have been only incremental improvements on existing medications. Major breakthroughs have resulted primarily from the study of natural products. Some of our most valuable drugs have been isolated from plant and animal sources, including aspirin, morphine, reserpine (the first antipsychotic), almost all of our antibiotics, digitalis, and such anti-cancer agents as vincristine, vinblastine, and taxol. Recent political and social events suggest that new emphasis will be placed on natural product research in the years to come. This article highlights therapeutic applications of Ginkgo biloba, Hypericum perforatum, Valerian officinalis, and Panex ginseng.
Inhibitory effects of a novel platelet activating factor (PAF) antagonist (BN 52021) on antigen-induced prostaglandin and thromboxane formation by the guinea-pig lung
PHARMACOL. RES. COMMUN. (UK), 1986, 18/SUPPL. (111-117)
The effects of a new Platelet-Activating Factor (PAF- acether) antagonist (BN52021) extracted from Ginkgo biloba leaves have been studied on the release of metabolites of arachidonic acid in IgG-dependent guinea pig pulmonary anaphylaxis in vitro. Prostaglandin Esub 2 (PGEsub 2) and thromboxane Bsub 2 (TxBsub 2) were assayed using a novel ELISA technique. The release of PGEsub 2 and TxBsub 2 from anaphylactic lungs reached a maximum 4-5 min following the antigen challenge (about 3.2 and 31.0 ng/ml respectively) and decayed slowly during the following 25 min. BN52021 (1, 3 and 30 mug/ml) produced dose-dependent decreases of the release of PGEsub 2 and TxBsub 2. These results suggest that there are some interactions between the release of icosanoids and PAF-acether in anaphylaxis.
Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents
J. ETHNOPHARMACOL. (Ireland), 1991, 32/1-3 (135-139)
Ginkgolides are unique twenty-carbon terpenes, occurring naturally only in the roots and leaves of Ginkgo biloba. The molecules incorporate a tert-butyl group and six 5- membered rings, and are specific and potent antagonists of platelet-activating factor (PAF), a potent inflammatory autacoid. Studies in animal models with the most potent ginkgolide, BN 52021, and other specific PAF antagonists have demonstrated that PAF plays an important role in pathologies such as asthma, shock, ischemia, anaphylaxis, graft rejection, renal disease, CNS disorders and numerous inflammatory conditions. Ginkgolides are now being developed as therapeutic agents and very promising results have been obtained in clinical trials on shock, organ preservation and thermal injury. In addition to ginkgolides, several other types of natural PAF antagonists have been identified from various medicinal plants. These compounds have not only helped to explain the pharmacological basis of several traditional medicines, but have also provided man with a valuable new class of therapeutic agents.
Effects of Ginkgo biloba extract (EGb 761) on cochlear vasculature in the guinea pig: morphometric measurements and laser Doppler flowmetry.
Eur Arch Otorhinolaryngol (GERMANY) 1996, 253 (1-2) p25-30
Ginkgo biloba extract (EGb 761) was administered orally for 4 or 6 weeks to healthy adult guinea pigs. Animals were then decapitated under deep ketamine anesthesia. Post- mortem morphometric measurements of cochlear vessels in the spiral lamina revealed a vasodilating effect of the extract in four of ten animals following 6 weeks of treatment. In vivo testing of the effect of 4 or 6 weeks of treatment with EGb 761 was monitored with laser Doppler flowmetry of the cochlear blood flow under pathological conditions. Results demonstrated that EGb 761 partly counteracted sodium salicylate-induced decreases in cochlear blood flow (CBF) and enhanced CBF increases induced by hypoxia. These findings indicate that EGb 761 may help to improve oxygenation in cochleas with compromised blood flow.
Ginkgo biloba extract (EGb 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery
Cardiovascular Drugs and Therapy (USA), 1997, 11/2 (121- 131)
A growing body of evidence supports the trigger role of free radicals in the delayed functional and metabolic myocardial recovery following cardiopulmonary bypass (CPB) in humans, thus opening the field to specific therapies. This clinical study was designed to evaluate, in 15 patients undergoing aortic valve replacement, whether the extent of CPB- and reperfusion-induced lipid peroxidation, ascorbate depletion, tissue necrosis, and cardiac dysfunction is reduced by orally administered EGb 761, a Ginkgo biloba extract with potent in vitro antiradical properties. Patients received either EGb 761 (Tanakan, 320 mg/day, 8) or a matching placebo (n = 7) for 5 days before surgical intervention. Plasma samples were obtained from the peripheral circulation and the coronary sinus at crucial stages of the operation (i.e., before incision, during ischemia, and within the first 30 minutes post- unclamping) and up to 8 days postoperatively. Upon aortic unclamping, EGb 761 inhibited the transcardiac release of thiobarbituric acid-reactive species (p < 0.05), as assessed by high-performance liquid chromatography, and attenuated the early (5-10 minute) decrease in dimethylsulfoxide/ascorbyl free radical levels, an electron spin resonance index of the plasma ascorbate pool (p < 0.05). EGb 761 also significantly reduced the more delayed leakage of myoglobin (p = 0.007) and had an almost significant effect on ventricular myosin leakage (p = 0.053, 6 days ostoperatively). The clinical outcome of recovery of treated patients was improved, but not significantly, compared with untreated patients. Our results demonstrate the usefulness of adjuvant EGb 761 therapy in limiting oxidative stress in cardiovascular surgery and suggest the possible role of highly bioavailable terpene constituents of the drug.
Inhibition of antigen-induced lung anaphylaxis in the guinea-pig by BN 52021, a new specific paf-acether receptor antagonist isolated from Ginkgo biloba
AGENTS ACTIONS (SWITZERLAND), 1986, 17/3-4 (371-372)
Paf-acether appears to be a potent mediator released in response to allergen exposure in sensitized animals and it could contribute to clinical manifestations of allergic asthma. In order to ascertain this assumption the inhibition of antigen-induced lung anaphylaxis in guinea pig by BN 52021, a new highly specific paf-acether antagonist, was studied. Ovalbumin injected into passively sensitized guinea pig induced a large bronchoconstriction that was accompanied by thrombocytopenia and leukopenia. Treatment of animals with BN 52021 i.v., 5 minutes before challenge, strongly (at the doses of 1 and 2 mg/kg) or totally (at 0.1 mg/kg) inhibited the bronchoconstriction and partially reduced the thrombocytopenia and leukopenia, the thrombocytopenia occurring after challenge.These results confirm that paf-acether and platelets might play a key role in asthma. BN 52021 and other paf-acether antagonists could provide a new group of potent prophylactic anti-asthma drugs.
Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse.
Pharmacopsychiatry (GERMANY) Jul 1996, 29 (4) p144-9
Decreases in cell membrane fluidity may be a major mechanism of age-related functional decline. A prime cause for the decline of membrane fluidity may be the presence of free radicals. Gingko biloba extract Egb 761 protects neuronal cell membranes from free radical damage in vitro. Further, EGb 761 has repeatedly been shown to improve cognitive functions in man and in laboratory animals. To test if there is a link between these two actions we assessed the effects of EGb 761 on passive avoidance learning and on neuronal membrane fluidity in vivo in young (three-month-old), middle-aged (12-month-old) and aged (22 to 24-month-old) female NMRI mice. The animals were treated daily with 100 mg/kg EGb 761 for three weeks. There was a significant improvement in short-term memory, measured by the avoidance latency 60 seconds after the aversive stimulus (p < 0.0311), and of membrane fluidity (p < 0.01) in the aged animals, but no improvement in long-term memory as measured by the avoidance latency 24 hours after shock. However, no significant correlation between membrane fluidity and short-term memory performance was found. Taken together, these results indicate that EGb 761 independently improves changes in passive avoidance learning and brain membrane fluidity.
The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet- activating factor (PAF).
J Ethnopharmacol (IRELAND) Mar 1996, 50 (3) p131-9
Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree which has been cultivated and held sacred for its health- promoting properties. There is substantial experimental evidence to support the view that Ginkgo biloba extracts have neuroprotective properties under conditions such as hypoxia/ischemia, seizure activity and peripheral nerve damage. Research on the biochemical effects of Ginkgo biloba extracts is still at a very early stage. One of the components of Ginkgo biloba, ginkgolide B, is a potent platelet-activating factor (PAF) antagonist. Although the terpene fraction of Ginkgo biloba, which contains the ginkgolides, may contribute to the neuroprotective properties of the Ginkgo biloba leaf, it is also likely that the flavonoid fraction, containing free radical scavengers, is important in this respect. Taken together, the evidence suggests that Ginkgo biloba extracts are worthy of further investigation as potential neuroprotectant agents are.
Memory effects of standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701).
Planta Med (GERMANY) Apr 1993, 59 (2) p106-14
In experiments on young (aged 3 months) and old (aged 26 months) rats, using some conditioned-reflex methods with punishment or positive reinforcement for active and passive avoidance (shuttle-box, step-down, step-through, and water maze), we studied the effects of the standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK501) and their combination Gincosan (PHL-00701). The extracts were administered orally for 7 days before training at three increasing doses: 17, 50, and 150 mg/kg for G115; 10, 30, and 90 mg/kg for GK501; and 27, 80, and 240 mg/kg for PHL-00701. The two extracts and their combination improved the retention of learned behavior. This effect varied considerably with the extracts, with the dose and with the behavioral method used. The results suggest that the Panax ginseng G115 and the Ginkgo biloba GK501 extracts possess properties similar in every respect to those of nootropic drugs. The favorable effects on learning and memory of the combination of G115 plus GK501 and the other pharmacological activities inherent in the extracts characterize this combination, offered as Gincosan as a particularly promising drug in geriatric practice.
[Activity of Ginkgo biloba extract on short-term memory]
Presse Med (FRANCE) Sep 25 1986, 15 (31) p1592-4
Eight healthy female volunteers were included in a double- blind, cross-over trial comparing Ginkgo biloba extract in acute and ascending doses (120, 240, 600 mg) with a placebo. One hour after treatment they were subjected to a battery of tests, including: critical flicker fusion, choice reaction time, subjective rating scale, and Sternberg memory scanning test. No statistically significant differences with the placebo were observed in the first three tests. In contrast, short term memory, as assessed by the Sternberg technique, was very significantly improved following 600 mg of Ginkgo biloba extract, as compared with the placebo. These results differentiate Ginkgo biloba extract from sedative and stimulant drugs and suggest a specific effect on memory processes.
Therapy of dementia - Neurologic and psychiatric aspects
Wiener Medizinische Wochenschrift (Austria), 1996, 146/21- 22 (546-548)
According to the latest research the therapy of dementia includes following strategies: Above all there is a neccessity for thoroughly diagnostic tests to exclude diseases which secondarily induce reduced brain function. The early onset of non pharmacological treatments e.g. 'brain-jogging' is essential. Pharmacological therapy with nootropics (e.g. Codergocrin, Nicergolin, Ginkgo biloba, Piracetam, Pyritinol, Naftidrofuryl) is recommended as early as possible, because they have no relevant side effects. Calcium antagonists may also be administered because of their neuroprotective properties. One pharmacological approach to enhance cholinergic functions involves inhibiting acetylcholine-degradation by inhibiting acetylcholinesterase. Although this relatively new therapy has benefits, in some patients it has not been effective and has a potential to cause serious adverse (hepatic) events; only mild to medium severe dementias of Alzheimer's disease should be treated with this therapeutic principle. In the case of personality disorders there are psychotherapy and the administration of psychoactive drugs necessary.
Prescribing practice with cognition enhancers in outpatient care: are there differences regarding type of dementia?--Results of a representative survey in lower Saxony, Germany.
Pharmacopsychiatry (GERMANY) Jul 1996, 29 (4) p150-5
Previous studies of cognition enhancers have mainly focused on insufficiently defined groups of cognition disorders, e.g., cerebral insufficiency. With regard to the various biological changes in senile dementia of Alzheimer's type (SDAT) and in vascular dementia (VD), which together make up the great majority of senile dementias, many authors have encouraged different studies of these types of dementias, especially since both can be diagnosed clinically with satisfying certainty. Since primary care physicians treat the majority of elderly and demented patients, they have their own experience with cognition enhancers. We were therefore interested to know, how far these physicians differ in their treatment of SDAT and VD. We performed a representative survey (response rate 83.2%; 145 family physicians and 14 neuropsychiatrists) in the Goettingen area. A written case vignette described a 70-year-old widow with moderate dementia and vascular risk factors which are easily treated with drugs. Two versions were randomly assigned, in which (version A) either a typical VD history or a typical SDAT history (version B) were described. After perusal, the physician was asked whether and which drugs he would choose to treat the cognitive disorders in this patient. Most frequently, piracetam (A/B: 25.6%/30.9%), ginkgo biloba (24.4%/28.4%), and nimodipine (14.1%/25.9%) were considered. Aspirin was cited by 29.5%(A) and 17.3% (B) of the physicians respectively. As far as the type of dementia was concerned, significant differences were found only for co-dergocrine, which was preferred in SDAT. The following inter-group trends were observed: family physicians considered ginkgo biloba more often than nimodipine or co-dergocrine. The results show the apparent importance of cost-and safety aspects, while the type of dementia has hardly any impact. The latter impression corresponds to the results of drug trials demonstrating no different efficacy. In our opinion, aspirin was not sufficiently taken into consideration.
[Effectiveness of brief infusions with Ginkgo biloba Special Extract EGb 761 in dementia of the vascular and Alzheimer type]
Z Gerontol Geriatr (GERMANY) Jul-Aug 1996, 29 (4) p302-9
In a placebo-controlled, randomized, double-blind clinical trial, 40 patients with a mean age of 68 (+/- 12.5) years suffering from moderate dementia (Alzheimer, vascular, or mixed type) according to DSM-III-R criteria were included. Severity of the disease had to correspond to stages 4 or 5 of Reisberg's Global Deterioration Scale. Infusions of either EGb 761 or placebo were administered 4 days per week for 4 weeks. Primary outcome measure was the activities of daily living as assessed by the Nurnberger- Alters-Beobachtungsskala (NAB). The Clinical Global Impressions of change (CGI, item 2) and the actual intelligence as assessed by the Kurztest fur Allgemeine Intelligenz (KAI) were further target variables. No relevant group differences could be detected at baseline. After therapy, patients of the active substance group scored significantly better (p < 0.05) on each outcome measure than those who received placebo. Using a sequential testing procedure, a global significance level of p < 0.05 could be assured. Superiority of EGb 761 therapy was also found with respect to a self-rating scale for instrumental activities of daily living (Nurnberger- Alters-Alltagsaktivitatenskala), the improvement of the most prominent symptom of illness, and the decrease of depression. Thus clinical efficacy of EGb 761 could be shown on three planes of assessment: the behavioral, the psychopathologic and the psychometric plane. It could be confirmed that, in patients with moderate dementia, short- term intravenous infusion therapy with EGb 761 results in an improvement of psychopathology and cognitive performance, which is reflected in an increased ability to cope with the demands of daily living.
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 (GERMANY) Mar 1996, 29 (2) p47-56
The efficacy of the ginkgo biloba special extract EGb 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multi-center study. After a 4-week run- in period, 216 patients were included in the randomized 24- week treatment period. These received either a daily oral dose of 240 mg EGb 761 or placebo. In accordance with the recommended multi-dimensional evaluation approach, three primary variables were chosen: the Clinical Global Impressions (CGI Item 2) for psychopathological assessment, the Syndrom-Kurztest (SKT) for the assessment of the patient's attention and memory, and the Nurnberger Alters-Beobachtungsskala (NAB) for behavioral assessment of activities of daily life. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761, with p < 0.005 in Fisher's Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type and multi-infarct dementia was confirmed. The investigational drug was found to be well tolerated.
MORE ON GINKGO BILOBA
An Ancient Tree For The Young and Old
This amazing tree is the source of great hope for aging patients with signs and symptoms of insufficient blood supply to the brain. These symptoms include sterility, short term memory loss, vertigo, headache, ringing in the ears, lack of cerebral blood flow extremely common in the geriatric population due to the presence of atherosclerolic cardiovascular disease.
The Ginkgo is the worlds oldest living tree, a species whose existence can be traced back over 200 million years! For this reason, the Ginkgo is often referred to as the The Living Fossil. Even individual trees may live as long as 1,000 years or older.
The Ginkgo is associated with longevity and it has incredible resistance to environmental factors. It also appears that taking a concentrated extract of Ginkgo Biloba leaves may promote longevity and resistance to aging in humans.
What's in It?
Ginkgo's pharmalogical activity is due to its high content of terpenes, flavonoids, pro-dither, quercetin, and Ginkgo Heterosides (flaviglycerides). A Ginkgo Biloba extract has demonstrated remarkable pharmalogical action on different parts of the circulatory and nervous system (arteries, capillaries, veins, and heart). Its effects include enhancement of energy, increase of cellular glucose intake, and lubricating of platelet aggregation.
Ginkgo Biloba also promotes radical scavenging activity, increased blood flow to the brain, and improved transmission of nerve signals. In clinical patients both chronic cerebral arterial insufficiency and/or peripheral arterial insufficiency responded favorable to Ginkgo Biloba extract.
Furthermore, since Ginkgo Biloba extract improves some same aspects of neural transmission, it may be effective in certain cases of senility, including early stages of Alzheimer disease.
Cerebral Vascular Insufficiency: In a large open trial including 112 geriatric patients with chronic cerebral insufficiency. Ginkgo Biloba extract, at 120 mg. per day, displayed a statistically significant regression of the major cerebral vascular insufficiency symptoms. These symptoms included short term memory loss, vertigo, headache, ringing in ears, lack of vigilance, and depression.
Symptoms of decreased cerebral blood flow are extremely common in the senior population, due to the atherosclerotic cardiovascular disease. The significant regression of these symptoms offered by Ginkgo Biloba suggests that vascular insufficiency may be the causative factor, accounting for age related cerebral disorders.
It appears that the improved vertebral blood flow from Ginkgo Biloba provides an increase in oxygen and glucose supplied to the brain. This offers relief from the presumed side effects of aging and may offer significant protection against development of these symptoms.
Improved Mental Performance
Ginkgo Biloba extract has been shown in clinical studies to increase the rate at which information is transmitted at the nerve cell level. Hindmarch and Sudhan's double blind study, the time of reaction even in healthy young women performing a memory test was significantly improved after administration of Ginkgo Biloba extract.
In another double blind clinic study, Ginkgo Biloba extract was shown to produce restoration of vigilance to approximately normal levels together with improved mental performance correlate with improvements in EEG tracings.
The patients with a more unfavorable initial situation (as measured in resting EEG activity) displayed the greatest improvement. The conclusion of the study was:
The results show that chronic Ginkgo Biloba extract usage has a positive effect in geriatric subjects with deterioration of mental performance and vigilance. This effect is reflected at the behavioral level. Ginkgo Biloba extract may be of great benefit to many cases of senility, including Alzheimer.
Free Radical Inhibition
In recent studies, Ginkgo Biloba has demonstrated an ability to neutralize free radicals. Free radicals are directly implicated in the aging process as in many other debilitating conditions. Since oxygen scavengers are among the best substances used to prevent the formation of free radicals. The flavonoids of Ginkgo inducing guecetin, are extremely potent oxygen scavengers.
Possessing a particular affinity for the central nervous system as well as the adrenal, and thyroid glands, concentrated Ginkgo Biloba is ideally suited for use in protecting heart blood vessels and brain against the destructive influence of free radicals.
Research has shown that Ginkgo Biloba extract significantly prevents the onset and severity of visual impairment, probably because of its effect on free radicals.
In other research involving the visual apparatus, Ginkgo has likewise demonstrated anti-radical properties. For example, one team of researchers found that Ginkgo Biloba extract significantly improved long distance usual visual activity in patients suffering from senile macular degeneration (a troublesome opacity of the pupils that occurs in elderly people).
Platelet Aggregation Inhibition
In 1980, it was discovered that Ginkgo Biloba extract effectively reduced the tendency of blood components to stick together, therefore, it reduced the tendency for dangerous clots or thrombi to form in veins and arteries.
The ability to inhibit blood clotting implied, of course, that Ginkgo Biloba extract was probably an effective agent in the prevention of coronary thrombosis and in recovery from strokes and heart attacks, etc. The effects last for no more than a prolonged thinning of the blood could produce a dangerous tendency for excessive bleeding.
Problems of the inner ear stem from some underlying vascular defect. In one study, Ginkgo Biloba was given to persons suffering from hearing loss due to old age (presbyacusia), patients with persistent ringing in the ears, and patients with vertigo.
Improved hearing was experienced by 40% of the presbyacusia patients, those who did not respond were assumed to have irreversible lesions of the sensory structures of the inner ear. Most of those patients with ringing in the ears experienced significant improvement within ten (10) to twenty (20) days. The action of Ginkgo Biloba on cerebral circulation resulted in swift and complete disappearance of vertigo.