According to the World Health Organization, the number of individuals living with dementia worldwide is currently estimated at 47.5 million and is projected to increase to 75.6 million by 2030. The number of cases of dementia is estimated to more than triple by 2050. Although dementia primarily affects older people, it is not considered a normal part of the aging process.1 Dementia is an overall term that involves damage to nerve cells in the brain and describes a wide range of symptoms associated with a deterioration in cognitive function, affecting memory and thinking skills severe enough to reduce an individual's ability to perform everyday activities.2 The most frequent pathologies underlying dementia in the elderly are Alzheimer disease pathology and cerebrovascular disease. Although Alzheimer disease and vascular disease exist as separate disorders, a combination of the 2 pathologies is often found in neuropathology studies.3,4 In recent years, considerable progress has been made using cholinesterase inhibitors, as well as standardized ginkgo leaf extract in the symptomatic treatment of dementia, which are recommended by current guidelines.5 Although synthetic drugs are employed to promote the attenuation of the symptoms of diseases, they often precipitate undesirable side effects. The clinical efficacy and tolerability of a proprietary leaf extract of Ginkgo biloba (EGb 761) in the treatment of dementia has been positively assessed through a series of randomized, placebo-controlled, double-blind clinical studies and evaluated through meta-analyses, offering a therapeutic alternative for addressing symptoms associated with dementia.6-10
Ginkgo biloba EGb 761 leaf extract is widely prescribed to improve cognitive function in cases of age-related dementia.
PHYTOMEDICINE OVERVIEW
Ginkgo biloba
Ginkgo biloba L. (Fam: Ginkgoaceae), or maidenhair tree, is considered a "living fossil" because it is the oldest known living tree species and the only surviving member of its botanical family, Ginkgoaceae. The Ginkgo species shares features with other genera of gymnosperms that date back to the Permian period for more than 248 million years ago. Ginkgo flourished in great numbers during the Jurassic period through the Cretaceous period approximately 213 million to 65 million years ago. During this era of the first flower bearing plants, fossil records reveal several different Ginkgo species that were commonly spread throughout Asia, Europe, and America. Although, paleobotanists originally believed that Gingko ended in complete extinction during the Ice age, along with its incredible kingdom of prehistoric plants and animals, historic records reveal that in 1691, Englebert Kaempfer, a German physician and botanist discovered Ginkgo biloba in China. Legend ascribes the survival of the "living fossil" to its remarkable adaptability, its resistance to disease, and to the ancient Chinese monks, who cultivated and preserved the trees as sacred plantings that landscaped their Temple grounds.
Ginkgo biloba is a notable deciduous tree, with great longevity, living as long as 1000 years, and growing to a height of 100 ft or more. It is easy to identify by its flabellate (fan-shaped) leaves with long petiole and their openly branched, dichotomous (forking) pattern of leaf venation. In 1771, the Swedish botanist, Carolus Linnaeus, the founder of the system of binomial nomenclature, designated the species name "biloba" to denote the bisection of the wedge-shaped lamina of leaf into 2 divergent lobes. Botanically, Ginkgo is classified as a dioecious plant, indicating that the male and female reproductive structures are located on separate trees, the fruit of which is produced by the female plant and is noted for its distinctive odoriferous quality that becomes increasingly disagreeable as it reaches maturity.
Venerated as a sacred plant in both China and Japan, the genus name Ginkgo is derived from the Japanese word gingkyo, a corruption of the Chinese yin-hsing, translated as, "silver apricot." The name vividly describes the fleshy, spherical-shaped fruits that are borne by the female trees. Ginkgo leaves and seeds have been used in traditional Chinese medicine for more than 5000 years.
Traditional and modern applications
Traditionally, the Chinese used the seed of Ginkgo biloba (yin xing yi) for lung-related disorders, particularly asthma, coughs, and other bronchial conditions.11-13 The medicinal uses of the seeds were first recorded during the Yuan dynasty (1280-1368 AD) in Li Tung-wan's Si Wu Ben Cao (Edible Herbal). Ginkgo leaves were later included in remedies to strengthen the heart and lungs and first mentioned in a textbook by Liu Wen-Tai in 1505 AD. In Western phytomedicine, Dr Willmar Schwabe, a German physician and pharmacist introduced the first leaf extracts into medical practice in 1965.14 Since that time, the eminence of Ginkgo biloba and its medicinal properties has spread throughout the world for its ability to improve circulation, particularly to the brain and extremities.
Today, Ginkgo biloba leaf extract is widely prescribed to improve cognitive function in cases of age-related mental decline, including memory loss and the early stages of Alzheimer disease. Although there are diverse types of Ginkgo biloba in the worldwide marketplace for therapeutic purposes, there is a preponderance of both preclinical and clinical data that have been generated by the use of the proprietary Ginkgo biloba extract 761 (EGb 761). This standardized extract is one of the most esteemed phytomedicines known for its therapeutic applications and the most researched for its toxicological and pharmacological properties and clinical efficacy. Ginkgo biloba (EGb 761) standardized leaf extract has been used extensively in the treatment of Alzheimer disease, dementia, neurosensory impairment, and peripheral vascular disturbances.15 In the United States, ginkgo is used as a complementary and integrative health therapy for Alzheimer disease and vascular dementia.16
Phytochemistry and phytopharmacology
Ginkgo biloba (EGb 761)
The standardized extract of Ginkgo biloba (EGb 761) is a proprietary compound of biologically active constituents obtained from the ginkgo leaves and contains 24% flavonol glycosides (primarily quercetin and kaempferol, and isorhamnetin), 6% terpene trilactones of which 2.9% is bilobalide and 3.1% ginkgolides, and other components including proanthocyanidins.17,18
Ginkgo biloba (EGb 761) is a well-defined standardized extract derived from leaves that are collected while green in coloration and then dried and analyzed morphologically and microbiologically and chemically for heavy metals content and other pollutants. The complex extraction methodology begins with a water/acetone menstruum, followed by the removal of lipophilic organic compounds that render adverse effects and finally the concentration of bioactive constituents. The biological actions of the flavonoids and terpenes, which are the main components present in EGb 761, are, therefore, present in higher concentrations than found naturally in ginkgo leaves.
Ginkgo biloba (EGb 761) has demonstrated clinical efficacy in the symptomatic treatment of dementia by affecting a variety of pathogenic mechanisms involved in both Alzheimer disease and vascular dementia.16 These mechanisms include restoration of mitochondrial function, resulting in the improvement of neuronal energy supply,19 enhancing hippocampal neurogenesis and neuroplasticity,20 decreasing blood viscosity, and improving microperfusion.21
Meta-analysis summary of Ginkgo biloba (EGb 761)
In a recent study, the efficacy and tolerability of Ginkgo biloba extract EGb 761 in dementia was assessed using a systematic review and meta-analysis of randomized placebo-controlled trials.22
This meta-analysis included large, randomized placebo-controlled, double-blind clinical trials using the proprietary standardized Ginkgo biloba extract EGb 761 in patients meeting the inclusion criteria of being diagnosed with dementia (Alzheimer disease and/or vascular dementia pathology) in accordance with internationally accepted guidelines, and treated for a duration of 20 weeks or more, with an assessment of efficacy that included at least 2 of the 3 traditionally specified domains, such as cognition, activities of daily living, and clinical global rating. Patients with other mental deficiencies or those who incorporated EGb 761 in combination with cholinesterase-inhibiting drugs were excluded.
The study located 15 randomized, placebo-controlled, clinical trials of EGb 761; of these, 7 trials met selection criteria and were included in the meta-analysis. In these trials, there was a representation of a total of 2625 outpatients; 1396 patients were administered 120 mg or 240 mg/of the standardized EGb 761 extract and 1229 patients were given a placebo for the duration of 22 to 26 weeks.
All included trials (n = 7) evaluated cognition using the SKT Short Cognitive Performance Test (Snydrome-Kurztest) and 2 using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog). Five of the trials reported significant beneficial effects on cognition in patients taking EGb 761 in comparison with those in the placebo group (P = .03). The effects of EGb 761 on cognition were dose-dependent. Those patient taking 240 mg of EGb 761 showed a significantly better overall effect on cognition than those in the placebo group. Standardized mean differences for change in cognition (-0.52; 95% confidence interval: -0.98, -0.05; P = .03), activities of daily living (-0.44; 95% confidence interval: -0.68, -0.19; P < .001), and global rating (-0.52; 95% confidence interval: -0.92, -0.12; P = .01) significantly favored EGb 761 compared with placebo. Treatment-associated risks in terms of relative risks of adverse events did not differ noticeably between the 2 treatment groups. In conclusion, the meta-analysis confirmed the efficacy and tolerability of Ginkgo biloba (EGb 761) standardized extracts in patients with dementia.
AUTHOR COMMENT
The chemical composition of a phytomedicine extract, in particular, the quantities and relative proportions of pharmacodynamically active constituents, is determined by the quality of the raw materials, the extract solvents, and the extraction methodology. Given this, in order to yield reasonable and interpretable results when studying the clinical effects of phytomedicines, it is imperative for researchers to maintain the integrity of the research design by utilizing the same standardized phytomedicine extract.
REFERENCES