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| Although the
medicinal properties of Ginkgo biloba L. have been known in
China since the most ancient times, a systematic pharmacological and
clinical study of this plant only began in Europe in the last decades(1). Often defined as a “living fossil”, the Ginkgo biloba tree is the only survivor of a genus originated 150 millions years ago. It derives its name from a wrong transcription of the Japanese Yin-Kwo, meaning “silver fruit”. In an extensive review by DeFeudis(2) in 1991, the activity of Gingo biloba is describred as “polyvalent”, as its pharmacological action is due to the combined activity of several actives. The major therapeutic indications for the standardized Ginkgo biloba leaves extract concern cerebral insufficiency and peripheral vascular disorders(1). The term “cerebral insufficiency” indicates a collection of symptoms concerning the cerebral functions, such as impairment of short term memory, confusion, change in social behavior, lack of initiative, affective and somatic troubles. These symptoms may be associated with impaired cerebral circulation and ageing. Considered as early signs of senile dementia both of degenerative type and vascular origin, the symptoms are treated with Ginkgo biloba extract (GBE) which is considered a drug of choice in the growing area of senile dementia. | |
| A natural cognition enhancer | |
The cognition enhancing properties of the plant are attributed to the flavonoids fraction which are responsible for:
≥ 24% of ginkgoflavonglucosides ≥ 6% of ginkgolides and bilobalide ≤ 5 ppm of ginkgoic acids To further improve its bioavailability, GBE has been complexed with soy phospholipids (1:3 w/w), thus obtaining Ginkgoselect® Phytosome®. Pharmacokinetic data on human volunteers support the bioavailability improvement in Ginkgoselect® Phytosome®, while its activity is supported by clinical trials(3,4) with pharmacokinetic(5,6) and pharmacological data(1,8). | |
| Clinical studies | |
| Ginkgo biloba
extract is reputed to be potent in circulatory and other disorders.
Because of the interest in its use, a number of clinical trials have
been carried out evaluating cognitive functions, such as memory
disturbances and dementia, and classical disorders of the circulation
such as intermittent claudication. Within vascular disorders, the Raynaud’s disease is a common and painful condition characterized by episodic digital ischemia produced by emotion and cold. Clinically it manifests as blanching caused by artery vasospasm, cyanosis as the remaining blood becomes deoxygenated, and rubor by the reactive hypercirculation following the ischemia(10). The treatment of the Raynaud’s disease by vasodilator drugs is notoriously difficult because of the high incidence of side effects; it is a common disease and is estimated to afflict 10-20% of young women(9). The efficacy of Ginkgoselect® Phytosome® in the treatment of the Raynaud’s disease was verified in a double-blind, placebo-controlled trial(3). It was proven effective in improving vascular disorders and in counteracting the symptmoms of digital ischemia. This initial study is of interest as it shows a highly statistically significant reduction of the number of attacks of Raynaud’s disease per day due to the improvement of peripheral circulation. A similar mechanism of action may be associated with the congnition enhancing activity of Ginkgoselect® Phytosome®. | |
| Improvement of the vascular disorders associated to the Raynaud’s disease(3) | |
| Ginkgoselect®
Phytosome® was
administered at a dosage of 360 mg/day (120 mg three times per day) to
22 subjects affected by the Raynaud’s disease in a double-blind,
placebo-controlled trial. Patients were required to record the frequency and duration of any vasospastic attack, also completing a scoring scale of the overall perception of the severity of the episodes. Patients were reviewed after two, four and ten weeks of treatment. This pilot study showed the efficacy of Ginkgoselect® Phytosome® in promoting a clear and highly statistically significant reduction in the frequency (56%) and severity of Raynaud’s attacks per day. | 
|
| improvement of the vascular disorders associated to the Raynaud’s phenomenon(4) | |
| Twelve patients with Raynaud’s phenomenon received 180 mg of Ginkgoselect® Phytosome® daily for 6 days. After a 5 days washout period, they received 120 mg of GBE. Upon microscopic examination of nailbed, the Phytosome® preparation made visible capillary loops just under the skin that were not visible before, thus indicating an appreciable improvement of blood flow in capillary loops. | |
| Pharmacokinetics | |
| The pharmacokinetic profile of Ginkgoselect® Phytosome® has been defined in experimental animals and in human volunteers. Its bioavailability has been compared to GBE. | |
| Increase in plasma levels of total ginkgolides (A and B) and bilobalide in healthy volunteers(5) | |
| Fifteen healthy volunteers were
randomly divided into two groups and administered respectively 160 mg of
free formulation of GBE (corresponding to 9.6 mg of terpene lactone) and
160 mg of Ginkgoselect®
Phytosome®
(corresponding to the same amount of terpene lactone). The subjects
switched formulations after a week of wash out. Blood samples were
collected at 30, 60, 120, 180, 240, 300 and 400 min after ingestion.
Terpene lactone detection was performed by means of liquid cromatography/atmospheric
pressure chemical ionization mass spectrometry (LC/APCI-ITMS). Ginkgolides A, B and bilobalide were absorbed to a higher extent (about three-fold) after administration of Ginkgoselect® Phytosome®. As an example, the here reported chart, reports plasma concentrations of ginkgolide A which, according to AUC, shows a 3.5 folds higher absorption of the Ginkgoselect® Phytosome®. | 
|
| Improvement of DHBA urinary excretion in healthy volunteers(6) | |
| Ginkgoselect® Phytosome® (120 mg/day as GBE) or GBE were administered for 5 days to 6 healthy volunteers in a cross-over study. Urine samples were collected and analyzed twice daily and metabolite 3,4-dihydrobenzoic acid (DHBA) was determined by HPLC. Volunteers were asked to refrain from consuming flavonoids-rich foods for the duration of the study. | 
|
| Pharmacology | |
| The pharmacological profile of Ginkgoselect® Phytosome® has been defined by extensive in vitro and in vivo experimental studies. It is reported that the flavonoidic components of the extract are responsible for the antioxidant activity(7-8), whereas the terpene lactones, being strong PAF-antagonists, are inhibitors of induced bronchoconstriction(10), thus suggesting possible anti-asthma applications. | |
| Antioxidant activity(7) | |
| GBE and Ginkgoselect®
Phytosome®
demonstrated their effective antioxidant capacity by increasing total
plasma and brain antioxidant capacity in rats, according to the
experimental protocol described below. Ginkgoselect®
Phytosome®,
though, induced a higher antioxidant protection compared to GBE. GBE and Ginkgoselect® Phytosome® have been administered to a group of 5 rats respectively (plus a control group) at 300 mg/kg/day (and 300 mg/kg/day as GBE for the complexed form). The total plasma antioxidant capacity and the brain antioxidant capacity have been measured by FRAP method. Ginkgoselect® Phytosome® total plasma antioxidant capacity in rats resulted 27.9% higher compared to GBE. | 
|
|
In an other study(8), Ginkgoselect®
Phytosome®
was administered to Wistar rats at 50 mg/kg and 100 mg/kg for 7 and 14 days.
Chemical hypoxia was induced by administration of sodium nitrite (75 mg/kg) 1 h after the last administration of treatment.
Thirty minutes after sodium nitrite administration, the animals were killed and the cerebral cortex, cerebellum, hippocampus and striatum were isolated and homogenized.
The supernatants were used for the estimation of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione
reductase. Ginkgoselect®
Phytosome®
treatment was found to increase superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities in all the brain regions compared with those treated only with sodium nitrite. Finally, in an other animal model in rats(9), Ginkgoselect® Phytosome® exhibited both antiamnestic and antidepressant activities in a scopolamine-induced amnesia and behavioural despair test. The authors concluded that these observations suggest that Ginkgoselect® Phytosome® possess moderate antiamnestic/nootropic activity. | |
| Antibronchospastic activity(11) | |
| Ginkgoselect®
Phytosome®,
administered at 300 mg/kg/die (as GBE) for 5 days in guinea pigs, was
proven to prevent bronchoconstriction induced by three different
agonists (histamine, PAF and acetylcholine). The bronchospastic inhibition was measured at the maximum peak, expressed as variation versus the basal values (cmH2O as intra-tracheal pressure). The results obtained indicate that Ginkgoselect® Phytosome® can not only counteract direct bronchoconstriction, but also it may reduce the TXA2 mediated bronchoconstriction of histamine and PAF, thus suggesting a possible indication in allergen induced bronchospasm. GBE and Ginkgoselect® Phytosome® also proved their efficacy in protecting rat isolated hearts against ischemia/reperfusion damages. The recovery of the heart activity expressed as left ventricular developed pressure was 76% in Ginkgoselect® Phytosome® and 52% in GBE treated animals(7). | 
|
| Cardioprotective activity(12) | |
| The protective effects of Ginkgoselect®
Phytosome® in isoproterenol (ISO)-induced cardiotoxicity and the antioxidant activity involved in this protection were investigated in
rats. Ginkgoselect®
Phytosome® elicited a significant cardioprotective activity by lowering the levels of serum marker enzymes and lipid peroxidation and elevated the levels of
glutathione, superoxide dismutase, catalase, glutathione peroxidase and
glutathione reductase. The present findings may suggest that the cardioprotective effects of Ginkgoselect®
Phytosome® in ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation of membrane. Finally in a 7 arm animal study with Ginkgoselect® Phytosome® alone and combined with Ocimum sanctum leaf extract(13), in the same model described before, these results have been further confirmed for Ginkgoselect® Phytosome® while the combination product did not show batter activity then Ginkgoselect® Phytosome® alone. |
|
| Toxicology | |
|
In a 30-day sub-chronic toxicity study in rats, Ginkgoselect®
Phytosome® orally
administered at the daily dose of 3.5 g/kg proved to be well tolerated.
No mortality or toxic effects that could be attributed to the treatment
were observed(14). | |
| |
| Conclusive remarks | |
| Ginkgoselect®
Phytosome® was
proven able to be effective in the treatment of disorders of cerebral
function and peripheral vascular insufficiency. The complexation of GBE
in the phospholipid complex (Ginkgoselect®
Phytosome®)
resulted successful in improving the bioavailability of the actives,
thus improving the efficacy of the ingredient. Terpene lactones as ginkgolides and bilobalide and flavonoids are responsible for the biological action of Ginkgoselect® Phytosome®. | |
| References | |
| 1.
Van Beek T.A., Bombardelli E., Morazzoni P., Peterlongo F., Fitoterapia LXIX (3) 193-244 (1998). 2. DeFeudis F.V., “Ginkgo biloba extract: pharmacological activities and clinical applications”, Elsevier (1991). 3. Muir A.H., Robb R., McLaren M., Daly F., Belch J., Vascular Medicine 7, 265-267 (2002). 4. Arpaia G., Curri S.B., Bombardelli E., “Evaluation of the effects of the Ginkgo biloba Phytosome® on skin microcirculation in normal and pathological conditions”, Unpublished (1991). 5. Mauri P., Simonetti P., Gardana C., Minoggio M., Morazzoni P., Bombardelli E., Pietta P., Rapid Commun. Mass Spectrom. 15, 929-934 (2001). 6. Indena - data on file. 7. Carini M, Aldini G, Rossoni G, Morazzoni P, Facino RM., Complexation of Ginkgo biloba extract with phosphatidylcholine improves cardioprotective activity and increases the plasma antioxidant capacity in the rat, Planta Medica 67, 326-330 (2001). 8. Naik SR, Pilgaonkar VW, Panda VS., Evaluation of antioxidant activity of Ginkgo biloba phytosomes in rat brain, Phytother Res. 2006 Nov;20(11):1013-6. 9. Naik SR, Pilgaonkar VW, Panda VS., Neuropharmacological evaluation of Ginkgo biloba phytosomes in rodents, Phytother Res. 2006 Oct;20(10):901-5. 10. Kidd P., “Phytosome report, Part 3”, Dec 13, 2004. 11. Indena - data on file. 12. Panda VS, Naik SR., Cardioprotective activity of Ginkgo biloba Phytosomes in isoproterenol-induced myocardial necrosis in rats: a biochemical and histoarchitectural evaluation, Exp Toxicol Pathol. 2008 Aug;60(4-5):397-404. Epub 2008 Jun 2. 13. Panda VS, N SR., Evaluation of cardioprotective activity of Ginkgo biloba and Ocimum sanctum in rodents, Altern Med Rev. 2009 Jun;14(2):161-71. 14. Indena - data on file. 15. Indena - data on file. | |
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