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Monday, July 11, 2016

Most Common Diseases of 50plus: Disease of CNS -: Alzheimer's Disease(AD) Research and studies - The effects of Herbal Medicine

Kyle J. Norton(Scholar and Master of Nutrients, all right reserved)
Health article writer and researcher; Over 10.000 articles and research papers have been written and published on line, including world wide health, ezine articles, article base, healthblogs, selfgrowth, best before it's news, the karate GB daily, etc.,.
Named TOP 50 MEDICAL ESSAYS FOR ARTISTS & AUTHORS TO READ by Disilgold.com Named 50 of the best health Tweeters Canada - Huffington Post
Nominated for shorty award over last 4 years
Some articles have been used as references in medical research, such as international journal Pharma and Bio science, ISSN 0975-6299.


Alzheimer's disease is a brain disorder correlated with major reductions of neurons to the respective target areas and named after German physician Alois Alzheimer. Alzheimer's destroys brain cells, causing cognitive modalities severe enough to affect language communication, memory, lifelong hobbies or social life. Alzheimer's gets worse over time, and it is fatal.
According to statistic, over 25 million people in the world today are affected by dementia and most are suffering from Alzheimer's disease. It may be results of cigarette smoking, midlife high blood pressure and obesity, diabetes, and cerebrovascular lesions) and the possible beneficial roles of psychosocial factors (eg, high education, active social engagement, physical exercise, and mentally stimulating activity)(1) Strong evidences emerged in epidemiological studies suggested that certain herbs(2) may have potential in reduced risk and treatments of Alzheimer's disease but geographic source of the plant material, climatation, and time of harvest may effect their effectiveness. It is understandable that commercially available herbal medicinal products with the same herbal ingredients vary in their content and concentration of chemical constituents when compared between manufacturers.

                         The effects of Herbal Medicine

1. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Extracts of the leaves of the maidenhair tree, Ginkgo biloba, in identified trails on 26 June 2002 through a search of the CDCIG Specialized Register which contains records from all main medical databases, showed a positive effect of Ginkgo biloba in improvement of cognition and function(3). Study from Hospital St. Naum, Sofia, in enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, showed no significance effect in either EGb 761(R)(Ginkgo biloba extract) and donepezil, but the result of the combination of 2 both substances are efficacy in treatment in patients with AD and neuropsychiatric features(4). But in the study of the same extract, Maria-Hilf Hospital Krefeld, Krefeld indicated that EGb 761® improved cognitive functioning, neuropsychiatric symptoms and functional abilities in both types of dementia namely Alzheimer's disease and vascular dementia(5)(6).

2. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root).
In an open-label study, conducted by Seoul National University Hospital, Ginseng improved ADAS and MMSE scores declined and may be considered as clinically effective in the cognitive performance of AD patients(7). Other study also showed the effect of KRG on cognitive functions which was sustained for 2 yr follow-up and may be an indication of a feasible efficacy of long-term follow-up for Alzheimer's disease(9). Korean red ginseng (KRG) in high doses, significant improved on the ADAS and CDR after 12 weeks(8). Unfortunately, Study by the Korea Institute of Oriental Medicine, on Mini-Mental Status and the Alzheimer's Disease Assessment Scale (ADAS)-cognitive, showed inconclusive in the result of the efficacy of Ginseng(10).

3. Gotu Kola
Gotu Kola also known as centella, is a annual plant of the genus, belonging to the family Mackinlayaceae, native to India, Sri Lanka, northern Australia, Indonesia, Iran, Malaysia, Melanesia, Papua New Guinea. The herb has been used in traditional medicine to treat nervous disorders, epilepsy, senility, premature aging, etc.
Centella asiatica (CA), commonly named gotu kola water extract of CA (GKW), in the Tg2576 mouse, a murine model of AD with high β-amyloid burden, showed to attenuated β-amyloid-associated behavioral abnormalities and protected SH-SY5Y cells and MC65 human neuroblastoma cells from toxicity(11) through the impact of the amyloid cascade altering amyloid beta pathology(12) and colchicine-induced memory impairment and oxidative damage(13).

4. Lemon Balm
Lemon Balm is is a perennial plant in the genus Melissa, belonging to the family Lamiaceae, native to southern Europe and the Mediterranean region. The herb has been used in traditional medicine to treat nervous complaints, lower abdominal disorders and as anti-inflammatory, antivirus, antibacterial agent.
Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy(14). In a study of 20 healthy, young participants received single doses of 600, 1000, and 1600 mg of encapsulated dried leaf at 7-day intervals, indicated that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood(15). Other study of a standardized M. officinalis extract (300 mg, 600 mg), indicated a significantly increased self-ratings of calmness and reduced self-ratings of alertness and negated the negative mood effects of the DISS(16)(17).

5. Rosemary
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing. Rosnary has been used in traditional medicine as an antiseptic, antioxidant, and antispasmodic agent to treat circulatory problem, eczema, rheumatism, muscle pain, etc.
Carnosic acid (CA), a chemical compound found in rosemary and sage, reduces Aβ production, at least partially, by activating TACE in human astroglial cells(18) and the University of Tlemcen, also indicated that CA may be potential against Acetylcholinesterase (AChE) which gradual and irreversible declines in cognitive functions in AD patients(19). In an aromatherapy consisted of the use of rosemaryand lemon essential oils in the morning, and lavender and orange in the evening, showed that the combination may have some potential for improving cognitive function, especially in AD patients(20).

6. Chinese Cat's claw
Chinese Cat's claw also known as Gou Teng, Uncaria rhynchophylla, a genus of Uncaria, belonging to the family Rubiaceae, native to China. The herb is said to consist neuroprotective, anticonvulsive, sedative and antipsychotic effect.
Mice given a subcutaneous injection of D-gal (50 mg/kg) and orally administered Uncaria rhynchophylla (EUR) (100, 200, or 400 mg/kg) daily for 8 weeks,significantly increased exploratory behavior (assessed by an open-field test) and improved spatial learning and memory function (assessed by the Morris water maze test) as well as increasing the levels of acetylcholine and glutathione and decreasing the activity of acetylcholinesterase and the level of malondialdehyde in the brains through enhancement of the antioxidant status of brain tissue(21. Center for Asian Traditional Medicine Research, Tohoku University also indicated thatUncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils(22), a significant step in the pathogenesis of Alzheimer's disease.

7. Polygala tenuifolia
Polygala tenuifolia also known as Yuan Zhi is a genus Polygala, belonging to family Polygalaceae, native to China. The herb has been used in TCM to insomnia, forgetfulness, emotional and disorientation with abundance of phlegm, seizures, anxiety, listlessness, boils, abscesses, sores,etc.
Extract of dried root of Polygala tenuifolia Willdenow was found to provide some protective effects against neuronal death and cognitive impairments in Alzheimer's disease (AD), in the study by the Seoul National University(23). Tenuigenin, a crude extract of Polygala tenuifolia Willd. significantly decreased Abeta secretion from COS-7 cells without altering the ratio of Abeta1-40 and Abeta-42 (in differentiation of change in Abeta metabolism) probably through inhibition of the deposit of beta-site APP cleaving enzyme(causing increased levels of amyloid beta (Abeta) peptide, an early and critical feature of Alzheimer's disease)(24) or inhibited the secretion of A beta in SH-SY5Y APP 695 cells (amyloid precursor protein (APP)) via BACE1 inhibition(reduced risk of the build up of beta-amyloid and slow or stop Alzheimers disease)(25). Ninjin-yoei-to (NYT; Ren-shen-yang-rong-tang in Chinese formula, among 14 kinds of component herbs in NYT, the roots of Polygala tenuifolia extracts increased nerve growth factor NGF levels from the astrocytes(star shaped glial cells with function of support to neurons and clean up debris within the brain)(26).

8. Salvia officinalis (Sage)
Sage is a ornamental plant of the genus Salvia, belonging to family Lamiaceae, native to the Central and South America, Central, Eastern Asia and Mediterranean. The herb has been used in traditional medicine as carminative, antiperspirant, antispasmodic, astringent, antiseptic, and antibiotic agent and to calm the central nervous system, treat spasms in smooth and skeletal muscles, relieve digestive problems, regulate menstruation, etc.
According to the Northumbria University, extracts Salvia officinalis exerted its anti-oxidant, estrogenic, anti-inflammatory properties, to inhibited butyryl- and acetyl-cholinesterase (to prevent impeded neurotransmission)(27). Rosmarinic acid from Sage, in mild to moderate Alzheimer's disease (AD), enhanced the neuroprotective effect of sage against Abeta-induced toxicity, through inhibition of reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation(cell apoptosis), and tau protein hyperphosphorylation(neurofibrillary degeneration)(28)

9. Papaver somniferum (Opium poppy)
Papaver somniferum is a genus of Papaver, belonging to the family Papaveraceae, native to the Mediterranean Basin, Southeastern Europe, and Western Asia. The herb has been used in folk medicine for treating asthma, stomach illnesses, and bad eyesight.
Opium poppy exerted it neuroprotective effect through interaction of alkaloid opioids of herb with endogenous opiate receptors in the brain, according to Medical Research Council, Newcastle General Hospital(29). Some alkaloids isolated from plants, or are derived from templates of compounds from plant sources have been in clinical use for treatment of cognitive disorders(30).

10. saffron (Crocus sativus)
Saffron is a spice derived from the flower of Crocus sativus which is a genus Crocus, belonging to the family Iridaceae, native to Southeast Asia.
Saffron extract, showed moderated AChE inhibitory activity, verified by in silico docking studies(31) and some promising effects in clinical studies with dementia patients(32). In a double-blind, placebo-controlled Tehran University of Medical Science study, suggested a positive mild to moderate Alzheimer's disease effect through inhibition of the aggregation and deposition of amyloid β in the human brain(33). Crocin isolated from Saffron, in Alzheimer's disease induced by intracerebroventricular (icv) streptozocin (STZ) in male rats, significantly attenuated learning and memory impairment(34).

11. Bacopa monnieri
Bacopa monnieri is a genus Bacopa, belonging to family Plantaginaceae, native to the wetlands of southern India and Australia. The herb has been used in Indian traditional medicine as a neurological tonic and cognitive enhancer.
In intracerebroventricular administration of colchicine induced cognitive impairment in rats, Bacopa monnieri decreased in activity of antioxidant enzyme, reversed memory impairment and altered activity of membrane bound enzymes(35). Other study of Bacopa monnieri extract indicated an improvement of the escape latency time (p<.01) in Morris water maze test with reduction of neurons and cholinergic neuron densities were also mitigated(36). Researchers at the suggested that Bacopa monnieri may be effective in improving memory performance and exerted protective effects against AD by increasing expression or activity of Na⁺, K⁺-ATPase.Na⁺-K⁺-ATPase which plays an important role in AD, and may be a potent neuroprotective modulator against AD(37).

12. Alpinia galanga
Alpinia galanga is the genus Alpinia, belonging to the family Zingiberaceae, native to Indonesia and South Asia. The herb has been used in folk medicine in treating arthritis and rheumatoid arthritis, relieving discomfort caused due to inflammation of the abdomen and ulcers, etc.
On oxidative stress induced Alzheimer's type amnesia in mice, Alphinia galanga attenuated the elevated levels of acetylcholinesterase and monoamine oxidase enzymes in amnesia induced mic(38) and acted as Acetylcholinesterase (AChE) inhibitors which are widely used for the treatment of Alzheimer's disease (AD)(39). The Lalitha College of Pharmacy study suggested that Alpinia galanga fractions increases habituation memory and decreased escape latency in Alzheimer's type of amnesia in mice induced by Aβ((25-35), through increment in Na(+)/K(+)-ATPase and antioxidant activity depicts brain membrane integrity improvement and free radical scavenging property(40).

13. Calabar bean
Calabar bean is the seed of climbing perennial plant, a genus Physostigma, belonging to the family Fabaceae, native to the tropical Africa. The herb has been used in folk medicine in contract the pupil, manage ocular pressure in glaucoma, etc.
Physostigmine, a major alkaloids from Physostigma venenosum exhibited its neuroprotective affect in Alzheimers' disease through inhibition of acetyl- and butyrylcholinesterase (BChE) activities(41) and alleviated of AD pathology and associated symptoms, for cognitive and for behavioural and psychological symptoms of dementia (BPSD)(42). The University of Massachusetts study showed that Calabar bean in dose-response relationships, enhances memory, and improves drug discovery activities(42).

14. The Compositions
14.1. Yi-Gan San
Yi-Gan San also known as Yokukansanin Japan, is a Bupleurum Formula consisting Chai Hu, Fu Ling, Chuan Xiong, Gan Cao, Dang Gui, Gou Teng and Cang Zhu. The composition has been used in traditional Chinese medicine for treatment of calm impatience, difficulty falling asleep or staying asleep.
Yi-Gan San exhibited a clinically significant decrease in terms of hallucinations, agitation, anxiety, irritability or abnormal behavior(44)(45) and improved behavioral and psychological symptoms of dementia (BPSD) and activities of daily living (ADL)(46). In olfactory bulbectomized (OBX) mice, The composition reversed spatial working memory and non-spatial working memory impairments, through reversed OBX-induced down-regulation of choline acetyltransferase and muscarinic muscarinic M1 receptor expression without affecting muscarinic M₃ receptor expression or AChE activity(47). But the Kanto Central Hospital study reported a case of 81 years of age patient with symptoms of metabolic alkalosis with hypokalemia, due to intake of Yokukansan for 6 months(48).

14.2. Ba Wei Di Huang Wan (BDW)
Ba Wei Di Huang Wan (BDW) is also known as Rehmannia Eight Formula, cosisting, Chinese herbs Fu Zi, Rou Gui, Shu Di Huang, Shan Yao, Shan Zhu Yu, Mu Dan Bi, Fu Ling and Ze Xie. The formula has been used in traditional Chniese medicine in tonifying Kidney and enhancing kidney Qi.
In the search combined the terms Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy, the composition found to be effective in treating cognitive impairment of AD(49). The Tohoku University suggested that Ba Wei Di Huang Wan (BDW) improved Cognitive function and activities of daily living (ADLs)(50).

Taking altogether, without going into reviews. the list of herbs above may be effective in alleviating symptoms and treating Alzheimer's disease through inhibition of of acetyl- and butyrylcholinesterase (BChE) activities. Some researchers suggested that the use of herbal medicines in the treatment of AD should be comparable to the pharmacological treatment currently in use, including the identification of the active ingredients in order to improve the validation of the clinical trial with large-scale, multicenter studies(51). 
 References
(1) Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. by Qiu C, Kivipelto M, von Strauss E.(PubMed)
(2) The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review by Leopoldo Luiz dos Santos-Neto,1 Maria Alice de Vilhena Toledo,2 Patrícia Medeiros-Souza,3 and Gustavo Almeida de Souza(PubMed)
(3) Ginkgo biloba for cognitive impairment and dementia by Birks J, Grimley EV, Van Dongen M.(PubMed)
(4) Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: a randomised, double-blind, exploratory trial by Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R; GINDON Study Group(PubMed)
(5) Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trial by Ihl R, Tribanek M, Bachinskaya N; GOTADAY Study Group(PubMed)
(6) Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trialby Napryeyenko O,Borzenko I; GINDEM-NP Study Group(PubMed)
(7) Panax ginseng enhances cognitive performance in Alzheimer disease by Lee ST, Chu K, Sim JY, Heo JH, Kim M(PubMed)
(8) An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease by Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.(PubMed)
(9) Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with korean red ginseng by Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M(PubMed)
(10) Ginseng for cognitive function in Alzheimer's disease: a systematic review by Lee MS, Yang EJ, Kim JI, Ernst E(PubMed)
(11) Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model ofAlzheimer's Disease: Investigation of a Possible Mechanism of Action by Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J, Gold BG, Quinn JF(PubMed)
(12) Neuroprotective Effects of Centella asiatica against Intracerebroventricular Colchicine-Induced Cognitive Impairment and Oxidative Stress by Kumar A, Dogra S, Prakash A(PubMed)
(13) Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer's disease animal model by Dhanasekaran M, Holcomb LA, Hitt AR, Tharakan B, Porter JW, Young KA, Manyam BV(PubMed)
(14) Effect of aromatherapy on patients with Alzheimer's disease by Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K(PubMed)
(15) Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties by Kennedy DO, Wake G, Savelev S, Tildesley NT, Perry EK, Wesnes KA, Scholey AB.(PubMed)
(16) Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm) by Kennedy DO, Little W, Scholey AB(PubMed)
(17) Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm) by Kennedy DO, Scholey AB, Tildesley NT, Perry EK, Wesnes KA.(PubMed)
(18) Carnosic acid suppresses the production of amyloid-β 1-42 and 1-43 by inducing an α-secretase TACE/ADAM17 in U373MG human astrocytoma cells by Yoshida H1, Meng P2, Matsumiya T2, Tanji K3, Hayakari R2, Xing F2, Wang L2, Tsuruga K4, Tanaka H5, Mimura J6, Kosaka K7, Itoh K6, Takahashi I8, Imaizumi T(PubMed)2.
(19) Molecular Interaction of Acetylcholinesterase with Carnosic Acid Derivatives: A Neuroinformatics Study by Merad M, Soufi W, Ghalem S, Boukli F, Baig MH, Ahmad K, Kamal MA.(PubMed)
(20) Effect of aromatherapy on patients with Alzheimer's disease by Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K(PubMed)
(21) Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice.
Xian YF, Lin ZX, Zhao M, Mao QQ, Ip SP, Che CT(PubMed)
(22) Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins by Fujiwara H, Iwasaki K, Furukawa K, Seki T, He M, Maruyama M, Tomita N, Kudo Y, Higuchi M, Saido TC, Maeda S, Takashima A, Hara M, Ohizumi Y, Arai H(PubMed)
(23) Novel cognitive improving and neuroprotective activities of Polygala tenuifolia Willdenow extract, BT-11 by Park CH, Choi SH, Koo JW, Seo JH, Kim HS, Jeong SJ, Suh YH.(PubMed)

(24) Tenuifolin, an extract derived from tenuigenin, inhibits amyloid-beta secretion in vitro by Lv J, Jia H, Jiang Y, Ruan Y, Liu Z, Yue W, Beyreuther K, Tu P, Zhang D(PubMed)
(25) Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid beta-protein in cultured cells by Jia H, Jiang Y, Ruan Y, Zhang Y, Ma X, Zhang J, Beyreuther K, Tu P, Zhang D(PubMed)
(26) Induction of NGF synthesis in astrocytes by onjisaponins of Polygala tenuifolia, constituents of kampo (Japanese herbal) medicine, Ninjin-yoei-to by Yabe T, Tuchida H, Kiyohara H, Takeda T, Yamada H.(PubMed)
(27) The psychopharmacology of European herbs with cognition-enhancing properties by Kennedy DO, Scholey AB(PubMed)
(28) The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity by Iuvone T, De Filippis D, Esposito G, D'Amico A, Izzo AA(PubMed)
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(35) Neuroprotective effects of Bacopa monnieri in experimental model of dementia by Saini N, Singh D, Sandhir R.(PubMed)
(36) Cognitive enhancement and neuroprotective effects of Bacopa monnieri inAlzheimer's disease model by Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K.(PubMed)
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(38) Neurotransmitter metabolic enzymes and antioxidant status on Alzheimer's disease induced mice treated with Alpinia galanga (L.) Willd by Hanish Singh JC, Alagarsamy V, Sathesh Kumar S, Narsimha Reddy Y.(PubMed)
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(40) Neuroprotective effect of Alpinia galanga (L.) fractions on Aβ(25-35) induced amnesia in mice by Hanish Singh JC, Alagarsamy V, Diwan PV, Sathesh Kumar S, Nisha JC, Narsimha Reddy Y.(PubMed)
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(46) A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients by Iwasaki K, Satoh-Nakagawa T, Maruyama M, Monma Y, Nemoto M, Tomita N, Tanji H, Fujiwara H, Seki T, Fujii M, Arai H, Sasaki H.(PubMed)
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(48) [A case of severe hypokalemia caused by a Chinese herbal remedy (Yokukansan) in an 81-year-old woman with dementia].[Article in Japanese]by Nishiyama N, Takeshita M, Tanaka K, Miyao M, Mizuno Y.(PubMed)
(49) The use of herbal medicine in Alzheimer's disease-a systematic review by Dos Santos-Neto LL, de Vilhena Toledo MA, Medeiros-Souza P, de Souza GA.(PubMed)
(50) A randomized, double-blind, placebo-controlled clinical trial of the Chinese herbal medicine "ba wei di huang wan" in the treatment of dementia by Iwasaki K, Kobayashi S, Chimura Y, Taguchi M, Inoue K, Cho S, Akiba T, Arai H, Cyong JC, Sasaki H.(PubMed)
(51) The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review by Leopoldo Luiz dos Santos-Neto,1 Maria Alice de Vilhena Toledo,2 Patrícia Medeiros-Souza,3 and Gustavo Almeida de Souza(PubMed)3


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