Howes, M. J. and E. Perry. The role of phytochemicals in the treatment and prevention of dementia. Drugs Aging 28, 6: 439-468.

Abstract:  Dementia pathologies such as Alzheimer's disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients. Other phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.

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Keheyan, G., L. A. Dunn and W. L. Hall. 2011. Acute Effects of Ginkgo Biloba Extract on Vascular Function and Blood Pressure. Plant Foods Hum Nutr. [Epub ahead of print].

Abstract: We investigated whether a single dose of standardized Ginkgo biloba extract (GBE) can improve vascular function. A randomised controlled crossover trial was conducted on 14 young healthy men, who received GBE or placebo. The digital volume pulse was monitored to measure reflection index (DVP-RI) and stiffness index (DVP-SI) and peripheral augmentation index (pAIx) was assessed using radial pulse wave analysis at baseline and 2, 4 and 6 h after treatment. DVP-SI was slightly higher 2 h following GBE compared to placebo (P < 0.05); other outcome variables were unaffected by treatment.

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Szczurko, O., N. Shear, A. Taddio and H. Boon. 2011. Ginkgo biloba for the treatment of vitilgo vulgaris: an open label pilot clinical trial. BMC Complement Altern Med. 15, 11: 21.

ABSTRACT:

BACKGROUND: Vitiligo is a common hypopigmentation disorder with significant psychological impact if occurring before adulthood. A pilot clinical trial to determine the feasibility of an RCT was conducted and is reported here.

METHODS: 12 participants 12 to 35 years old were recruited to a prospective open-label pilot trial and treated with 60 mg of standardized G. biloba two times per day for 12 weeks. The criteria for feasibility included successful recruitment, 75% or greater retention, effectiveness and lack of serious adverse reactions. Effectiveness was assessed using the Vitiligo Area Scoring Index (VASI) and the Vitiligo European Task Force (VETF), which are validated outcome measures evaluating the area and intensity of depigmentation of vitiligo lesions. Other outcomes included photographs and adverse reactions. Safety was assessed by serum coagulation factors (platelets, PTT, INR) at baseline and week 12.

RESULTS: After 2 months of recruitment, the eligible upper age limit was raised from 18 to 35 years of age in order to facilitate recruitment of the required sample size. Eleven participants completed the trial with 85% or greater adherence to the protocol. The total VASI score improved by 0.5 (P = 0.021) from 5.0 to 4.5, range of scale 0 (no depigmentation) to 100 (completely depigmented). The progression of vitiligo stopped in all participants; the total VASI indicated an average repigmentation of vitiligo lesions of 15%. VETF total vitiligo lesion area decreased 0.4% (P = 0.102) from 5.9 to 5.6 from baseline to week 12. VETF staging score improved by 0.7 (P = 0.101) from 6.6 to 5.8, and the VETF spreading score improved by 3.9 (P < 0.001)) from 2.7 to -1.2. There were no statistically significant changes in platelet count, PTT, or INR.

CONCLUSIONS: The criteria for feasibility were met after increasing the maximum age limit of the successful recruitment criterion; participant retention, safety and effectiveness criteria were also met. Ingestion of 60 mg of Ginkgo biloba BID was associated with a significant improvement in total VASI vitiligo measures and VETF spread, and a trend towards improvement on VETF measures of vitiligo lesion area and staging. Larger, randomized double-blind clinical studies are warranted and appear feasible.

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Gorby, H. E., A. M. Brownawell and M. C. Falk. 2010. Do specific dietary constituents and supplements affect mental energy? Review of the evidence. Nutr Rev. 68, 12: 697-718.

Abstract: The numbers of marketing claims and food, beverage, and drug products claiming to increase mental energy have risen rapidly, thus increasing the need for scientific specificity in marketing and food label claims. Mental energy is a three-dimensional construct consisting of mood (transient feelings about the presence of fatigue or energy), motivation (determination and enthusiasm), and cognition (sustained attention and vigilance). The present review focuses on four dietary constituents/supplements (Ginkgo biloba, ginseng, glucose, and omega-3 polyunsaturated fatty acids) to illustrate the current state of the literature on dietary constituents and mental energy. The strongest evidence suggests effects of Ginkgo biloba on certain aspects of mood and on attention in healthy subjects, as well as associations between omega-3 polyunsaturated fatty acids and reduced risk of age-related cognitive decline. Limitations of the current data and challenges for future research are discussed.

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Esposito, M. and M. Carotenuto. 2010. Ginkgolide B complex efficacy for brief prophylaxis of migraine in school-aged children: an open-label study. Neurol Sci. 32, 1: 79-81.

Abstract: Primary headaches (migraines and tension-types headaches) are very common in school-aged children. Ginkgolide B, a herbal constituent extract from Ginkgo biloba tree leaves, was considered as a promising pharmacological aid for the treatment of migraine in adult patients because of its modulation of the glutamatergic transmission in the CNS and on antiplatelet activating factor (PAF). The aim of study is to verify the effectiveness and safety of association of Ginkgolide B/Coenzyme Q10/Riboflavin/Magnesium complex for brief prophylaxis in a population of school-aged children with migraine. In our sample after 3 months of treatment with association of Ginkgolide B/CoenzymeQ10/Riboflavin/Magnesium complex, the mean frequency per month of migraine was significantly decreased (9.71 ± 4.33 vs. 4.53 ± 3.96 attacks; p < 0.001). Our findings suggest that in childhood headache management, the use of alternative treatments must be considered not to evoke a placebo effect, but as soft therapy without adverse reactions.

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Campos, H. C., M. D. da Rocha, F. P. Viegas, P. C. Nicastro, P. C. Fossaluzza, C. A. Fraga, E. J. Barreiro and Viegas C Jr. 2010. The Role of Natural Products in the Discovery of New Drug Candidates for the Treatment of Neurodegenative Disorders II: Alzheimer's Disease. CNS Neurol Disord Drug Targets. 10, 2: 251-270.

Abstract: The present review is part II in a series (part I focuses on Parkinson's Disease) that addresses the value of natural product chemistry in the discovery of medicines for the treatment of neurodegenerative disorders. Data reviewed document that a host of products from plant species and derivatives have neuroprotectant effects in vitro and in vivo. In addition, besides neuroprotection, natural products also demonstrate biological effects that target biochemical pathways underlying associated symptoms of neurdegnerative disorders that include cognitive impairments, energy/fatigue, mood, and anxiety. This part of the review series focuses specifically upon Alzheimer's Disease (AD). AD is postulated to result from extracellular formation of amyloid plaques and intracellular deposits of neurofibrilary tangles in the hippocampus, cerebral cortex and other areas of the brain essential for cognitive function. Plaques are formed mostly from the deposition -amyloid (A ), a peptide derived from the amyloid precursor protein (APP). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorilated tau protein, a microtubule-associated protein. In addition, environmental factors can engender the production of cytokines that are closely related to the installation of an inflammatory process that contributes to neuronal death and the development and the progression of AD. In this review we focus on the recent main contribuitions of natural products chemistry to the discovery of new chemical entities usefull to the control and prevention of AD installation and progression. More than sixteen plant species, including Ginseng, Celastrus paniculatus, Centella asiatica, Curcuma longa, Ginkgo biloba, Huperzia serrata, Lycoris radiate, Galanthus nivalis, Magnolia officinalis, Polygala tenuifolia, Salvia lavandulaefolia, Salvia miltiorrhiza, Coptis chinensis, Crocus sativus, Evodia rutaecarpa, Sanguisorba officinalis, Veratrum grandiflorum and Picrorhiza kurvoa, are discussed as potential sources of active extracts. In addition, more than sixty secondary metabolites are under evaluation for their efficacy on controlling symptoms and to impede the development and progression of AD.

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Fransen, H. P., S. M. Pelgrom, B. Stewart-Knox, D. de Kaste and H. Verhagen. 2010. Assessment of health claims, content, and safety of herbal supplements containing Ginkgo biloba. Food Nutr Res. 54.

Abstract:

BACKGROUND: European Regulation 1924/2006 states that all health claims made on foods need to be substantiated scientifically.

OBJECTIVE: To apply the PASSCLAIM criteria for the scientific substantiation of health claims on foods to herbal supplements containing Ginkgo biloba. Evaluation of three selected claimed health effects for G. biloba (improvement of blood circulation, improvement of symptoms of old age, and improvement of memory) was achieved through review of publicly available scientific data. A total of 35 human intervention studies were evaluated. Commercially available products claimed to contain mainly G. biloba (N=29) were randomly sampled in the Netherlands and analyzed for their content on ginkgo extract. Also, a toxicological risk assessment was performed.

RESULTS: The three selected health claims investigated could not be substantiated. This was mainly because of a lack of data from studies in healthy volunteers. In most studies results performed with a 24% standardized G. biloba extract were described. However, our chemical analysis showed that 25 of the 29 sampled products did not contain the required minimum 24% standardized extract. Moreover, in most preparations the content of substances typical for G. biloba did not conform to what was declared on the label. Since toxicity data for G. biloba are very limited, a safety limit could not be established.

CONCLUSIONS: Evidence is lacking for three health claims of herbal products with G. biloba. Neither safety nor efficacy can be guaranteed at the recommended daily dose. The multidisciplinary approach described in this paper provides good insight into issues that are relevant for the evaluation of health claims for herbal food supplements.

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Haines, D. D., B. Varga, I. Bak, B. Juhasz, F. F. Mahmoud, H. Kalantari, R. Gesztelyi, I. Lekli, A. Czompa and  A. Tosaki. 2010. Summative interaction between astaxanthin, Ginkgo biloba extract (EGb761) and vitamin C in Suppression of respiratory inflammation: a comparison with ibuprofen Phytother Res. 25, 1: 128-136.

Abstract:  In this study, combinations of Ginkgo biloba leaf extract (EGb761) plus the carotenoid antioxidant astaxanthin (ASX) and vitamin C were evaluated for a summative dose effect in the inhibition of asthma-associated inflammation in asthmatic guinea-pigs. Ovalbumin-sensitized Hartley guinea-pigs challenged with ovalbumin aerosol to induce asthma, were administered EGb761, ASX, vitamin C or ibuprofen. Following killing, bronchoalveolar lavage (BAL) fluid was evaluated for inflammatory cell infiltrates and lung tissue cyclic nucleotide content. Each parameter measured was significantly altered to a greater degree by drug combinations, than by each component acting independently. An optimal combination was identified that included astaxanthin (10 mg/kg), vitamin C (200 mg/kg) and EGb761 (10 mg/kg), resulting in counts of eosinophils and neutrophils each 1.6-fold lower; macrophages 1.8-fold lower, cAMP 1.4-fold higher; and cGMP 2.04-fold higher than levels in untreated, asthmatic animals (p < 0.05). In conclusion, EGb761, ASX and vitamin C are shown here to interact summatively to suppress inflammation with efficacy equal to or better than ibuprofen, a widely used non-steroidal antiinflammatory drug (NSAID). Such combinations of non-toxic phytochemicals constitute powerful tools for the prevention of onset of acute and chronic inflammatory disease if consumed regularly by healthy individuals; and may also augment the effectiveness of therapy for those with established illness.

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Canis, M., B. Olzowy, C. Welz, M. Suckfüll and K. Stelter. 2010. Simvastatin and Ginkgo biloba in the treatment of subacute tinnitus: a retrospective study of 94 patients. Am J Otolaryngol. 32, 1: 19-23.

Abstract:

OBJECTIVES: Studies suggest that hypercholesterolemia promotes the development of inner ear disorders such as tinnitus. However, the underlying pathomechanisms are still not clearly defined.

METHODS: A retrospective study was performed to assess whether a reduction of serum cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may result in a relief of subacute tinnitus. Remission rates of 58 patients were investigated after 4 months of treatment with simvastatin (40 mg). Results were compared to treatment with Ginkgo biloba (120 mg; n = 36) as control group. Differences between tinnitus score at the day of first treatment and after 4 months were used as main outcome measure.

RESULTS: After treatment with simvastatin or G biloba, tinnitus score decreased from 41.3 ± 10.4 to 37.4 ± 17.3 and from 44.7 ± 11.2 to 41.2 ± 8.7, respectively. However, independently of the treatment regimen, differences of tinnitus scores were considered not significant.

CONCLUSIONS: After administration of simvastatin over 4 months, this retrospective study has shown no significant efficacy in treatment of subacute tinnitus. For a more conclusive answer, further prospective, double-blind, and placebo-controlled studies with a larger number of patients are needed.

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Mashayekh, A., D. L. Pham, D. M. Yousem, M. Dizon, P. B. Barker and D. D. M. Lin. 2010. Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study. Neuroradiology. [Epub ahead of print]

Abstract